1,3,5-triaza-7-phosphaadamantane (PTA) and derivatives thereof for use in photodynamic therapy (PDT) and photoactivated chemotherapy (PACT)

Abstract

The present invention is related with the use of 1,3,5-triaza-7-phosphaadamantane (PTA) and derivatives thereof of formula (I) as active antiproliferative agents for photodynamic therapy (PDT) and Photoactivated Chemotherapy (PACT). The invention is further related with new compounds of formula (I').

Description

[0001] 1,3,5-TRIAZA-7-PHOSPHAADAMANTANE (PTA) AND DERIVATIVES THEREOF FOR USE IN PHOTODYNAMIC THERAPY (PDT) AND PHOTOACTIVATED CHEMOTHERAPY (PACT)

[0002] TECHNICAL FIELD

[0003] The present invention refers to the chemical field of anticancer drugs, more particularly to antiproliferative agents for photodynamic therapy (PDT) and Photoactivated Chemotherapy (PACT) of cancer.

[0004] BACKGROUND

[0005] Chemotherapy is one of the most used treatments against cancer, being based on the use of drugs which eradicate replicating cells. Ideally, the death of the replicating cells is faster than the death of patient’s normal cells. However, current clinical chemotherapeutics display a large number of drawbacks related to lack of selectivity.

[0006] In this sense, one of the most known examples is the complex [PtCh(HN3)2], also known as cisplatin, that was the first drug used for curative purposes against cancer and remains one of the most effective for many diagnosed cases. Cisplatin has a wide range of action being useful in the treatment of many tumors, such as lung cancer, stomach cancer, testicular cancer, ovarian cancer or bladder cancer among others, and is still used in a percentage that ranges between 50-70% of all cancer patients. However, this complex displays a large number of drawbacks related to lack of selectivity. In fact, due to its mechanism of action, highly replicating normal cells also suffer its toxic effects, damaging kidneys and provoking nausea or vomiting. These side effects are also commonly accompanied by hair loss, which usually produces severe emotional effects in patients. Additionally, platinum is very expensive, as it is scarce and largely demanded in many other applications such as catalysis.

[0007] In view of these drawbacks, alternative therapies have been developed in order to improve the quality of life of patients suffering cancer. One of these therapies is photoactivation, a non-invasive procedure that displays fewer side effects than conventional therapies, and consists of the administration of substances followed by irradiation of the affected by cancer area at a certain wavelength. Under irradiation, the administered substance in contact with cells exhibits cytotoxic activity. This procedure limits the cytotoxic effect of the compounds to the irradiated area, reducing their effect on the healthy tissues. Visible light (400-700 nm) is usually used to activate antiproliferative agents, but near-infrared light is more convenient as it penetrates deeper into tissues. This technique is known as photodynamic therapy (PDT) and is based on the combination of three components: a substance acting as a photosensitizer (PS), oxygen and light. Irradiation of the photosensitizing agent causes photochemical reactions that produce singlet oxygen and other reactive oxygen species (ROS), leading to the death of cancer cells. It acts even with greater selectivity if the PS accumulates in malignant tissue at a higher concentration than in healthy cells [Chem. Rev. 2023, 123, 10135-10155], The ideal properties of a photosensitizing agent include adequate solubility, high chemical stability, and high photoreactivity [J. Inorg. Biochem. 2020, 208, 111080], This technique is largely dependent on the concentration of oxygen to be effective, particularly in solid tumours, wherein oxygen concentration is low. Another technique is Photoactivated Chemotherapy (PACT) [Chem. Commun. 2012, 48(77), 9649], which involves the administration of kinetically inactive complexes that, upon irradiation, release a ligand and exert their action in the desired area and in contrast to PDT, is independent of the oxygen levels in the cell. [J. Inorg. Biochem. 2019, 196, 110684], An adequate hydro-lipophilic balance that allows the compound to migrate easily through ideally every physiological environment is also necessary [Coord. Chem. Rev. 2022, 469, 214656],

[0008] Despite the advantages displayed by Photodynamic Therapy (PDT) and Photoactivated Chemotherapy (PACT) in comparison with traditional chemotherapy, the photoactivable agents used therein usually contain metals. The presence of metals in these therapeutic agents supposes a high economical cost, and sometimes it is harder to achieve an adequate chemical stability, an adequate hydro-lipophilic balance as well as a hydrosolubilty and liposolubilty.

[0009] Therefore, it is highly desirable to have further agents inactive in the absence of light but active against cell proliferation when contacted with said cells and under light, without requiring the participation of a metal.

[0010] BRIEF DESCRIPTION OF THE INVENTION

[0011] This invention proposes a new use of derivatives of formula (I) which are non-toxic in the dark but become active, when contacted with cells under visible and infrared radiation, in photodynamic therapy (PDT) and / or photoactive chemotherapy (PACT) in the treatment of cancer. This strategy enhances the selectivity of the treatment, since the activation of the drug occurs only in the irradiated area, avoiding side effect on the healthy tissues. Additionally, the compounds proposed in this invention are metal-free, easy and cheap to synthesize and exhibit a high solubility in water, which facilitates their administration.

[0012] Therefore, a first aspect of the invention relates to a compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer

[0013] Formula (I) wherein

[0014] R1and R2are independently selected from:

[0015] • H;

[0016] • C1-C18 linear or branched alkyl, optionally substituted with a group selected from

[0017] ■ =0,

[0018] ■ a -COOR5group or -COR5group, wherein R5represents H or Ci- 012 alkyl;

[0019] ■ a sulfonate group and

[0020] ■ a phosphate group;

[0021] • allyl optionally substituted in C2 with C1-C18 linear or branched alkyl; and

[0022] • monosaccharide optionally substituted with acyl or amino group.

[0023] R3, R3’, R3” R4, R4’ and R4” are independently selected from H or C1-C4 linear or branched alkyl;

[0024] Y is independently selected from O, S, Se and C1-C4 alkyl;

[0025] X is independently selected from CF SOs' or halogen; a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; d represents 0, 1 or 2; and the dashed line represents a simple bond or a double bond.

[0026] A second aspect of the invention is related with a compound of formula (I’)

[0027] Formula (I’) wherein a represents 1 , then

[0028] R1and R2are independently selected from:

[0029] • H;

[0030] • C1-C18 linear or branched alkyl substituted with a group selected from

[0031] ■ =0,

[0032] ■ sulfonate and

[0033] ■ phosphate groups;

[0034] • C7-C11 linear or branched unsubstituted alkyl;

[0035] • C7-C18 linear or branched alkyl substituted with a COOR5group or - COR5group , wherein R5represents H or C1-C12 alkyl;

[0036] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0037] • monosaccharide optionally substituted with acyl or amino group.

[0038] R3, R3’, R3”, R4, R4’ and R4” are independently selected from H or C1-C4 lineal or branched alkyl;

[0039] Y is independently selected from O, S, Se and C1-C4 alkyl;

[0040] X is independently selected from CF SO ' or halogen; the sum of m+n represents 1 or 2; z represents 0 or 1 ; and d represents 1 or 2; or wherein a represents 0, then

[0041] R1and R2are independently selected from

[0042] • C2-C18 linear or branched alkyl, optionally substituted with a group selected from

[0043] ■ a COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl;

[0044] ■ a sulfonate group; and

[0045] ■ a phosphate group;

[0046] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0047] • monosaccharide optionally substituted with acyl or amino group.

[0048] R3, R3’, R3” R4, R4’, R4” are independently selected from H or C1-C4 lineal or branched alkyl;

[0049] Y is independently selected from O, S and Se; the sum of m+n represents 2; z represents 0 or 1 ; d represents 0; and the dashed line represents a simple bond or a double bond.

[0050] A third aspect of the invention relates to a method for the preparation of a compound of formula (I’) as defined in the previous aspect.

[0051] DETAILED DESCRIPTION OF THE INVENTION

[0052] A first aspect of the invention is related to a compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer.

[0053] Formula (I) wherein

[0054] R1and R2are independently selected from:

[0055] • H;

[0056] • C1-C18 linear or branched alkyl, optionally substituted with a group selected from

[0057] ■ =0,

[0058] ■ a -COOR5group or -COR5group, wherein R5represents H or Ci- 012 alkyl;

[0059] ■ a sulfonate group and

[0060] ■ a phosphate group;

[0061] • allyl optionally substituted in C2 with C1-C18 linear or branched alkyl; and

[0062] • monosaccharide optionally substituted with acyl or amino group.

[0063] R3, R3’, R3” R4, R4’ and R4” are independently selected from H or C1-C4 linear or branched alkyl;

[0064] Y is independently selected from O, S, Se and C1-C4 alkyl;

[0065] X is independently selected from CF SOs' or halogen; a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; d represents 0, 1 or 2; and the dashed line represents a simple bond or a double bond.

[0066] Alternatively, this aspect may also be defined as a method of treating cancer in a human subject in need thereof, comprising administering to said subject an effective amount of compound of formula (I) as described above in photodynamic therapy and / orphotoactivated chemotherapy.

[0067] Photodynamic therapy (PDT) uses a drug, which is activated with light (photosensitizer). PDT requires a photosensitizer, a light source and tissue oxygen and is considered a multi-stage process, since first a photosensitizer is administered in the absence of light, systemically or topically. When this photosensitizer is contacted with the cells of the desired tissue, the photosensitizer is activated by exposure to light for a specific period of time. Irradiation of the photosensitizer agent causes photochemical reactions that produce singlet oxygen and other reactive oxygen species (ROS), leading to the death of cancer cells.

[0068] Photoactivated chemotherapy (PACT) also employs drugs which are biologically inactive until exposed to light. After contacted with cells and irradiation of a certain wavelength of light, a cytotoxic response is triggered. In contrast to PDT, which relies on oxygen to generate cytotoxic molecules, PACT can be effective in oxygen-poor (hypoxic) tumor environments, making it potentially useful for treating a wider range of cancers.

[0069] This aspect may also be defined as the use of a compound of formula (I) characterized in that it is for the preparation of a medicament for the treatment of cancer in photodynamic therapy and / or photoactivated chemotherapy.

[0070] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood to one of ordinary skill in the art to which this disclosure belongs. As used herein, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise.

[0071] In the context of the present invention, the following terms have the meaning that is described in detail below.

[0072] In the context of the present invention the term “contacted with cells” refers to the compound of formula (I) being in physical contact with the cells, or to the compound of formula (I) being inside of the cells.

[0073] The derivatives of the present invention can be contacted with cells in the body of a living being or in organs or tissues derived from said living being. Alternatively, the derivatives of the present invention can be contacted with cells outside the body of a living being, meaning that the derivatives of the present invention are outside the body of a living being and in the same medium than the cells. In a particular embodiment, the derivatives of the present invention can be contacted with cultured cells.

[0074] The term “medium” or “culture medium” is recognized in the art and refers generally to any substance or preparation used for the cultivation of living cells. The term “medium” or “culture medium” as used in reference to a cell culture, includes the components of the environment surrounding the cells. Media may be solid, liquid, gaseous or a mixture of phases and materials. The term “alkyl” refers to a lineal or branched hydrocarbon chain radical or group consisting of carbon and hydrogen atoms, containing no unsaturation, having a number of carbon atoms as specified in each case, for example, between 1 and 18 (“C1-C18 alkyl”), between 1 and 12 (“C1-C12 alkyl”), etc., which is bound to the rest of the molecule through a single bond. Illustrative non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, and the like.

[0075] The term oxo refers to a moiety of the formula =0.

[0076] The term “sulfonate” refers to moieties of the formula -O-SO2-R, wherein R is C1-C4 alkyl. Illustrative non-limiting examples of sulfonates include, methanesulfonate (mesylate), trifluoromethanesulfonate (triflate), and the like.

[0077] The term “phosphate” refers to a moiety of the formula -OP(=O)(R)(R) where each R is independently selected from OH or O' or OZ, where Z is a counterion (e.g., Na+, etc.).

[0078] The term “allyl” refers to a moiety of formula -CH2-CH=CH2 or a -CH2-C(R)=CH2, i.e. , allyl substituted in C2 with R where R is C1-C18 alkyl.

[0079] The term “monosaccharide” refers to a sugar moiety having a five-membered carbon backbone (pentose) or a six-membered carbon backbone (i.e., a hexose). Illustrative non-limiting examples of monosaccharide include pyranose, furanose, xylose, arabinose, ribose, glucose, galactose, mannose, fructose, and the like.

[0080] The term “acyl” refers to a moiety of the formula -COR- where R is C1-C4 alkyl.

[0081] The term “amino” refers to a moiety of the formula -NRR where each R is independently selected from hydrogen, C1-C4 alkyl and C1-C4 acyl. The term “halogen” refers to fluorine (F), chlorine (Cl), bromine (Br), or iodine (I).

[0082] The aforementioned groups can be unsubstituted or can be substituted at one or more available positions with the suitable groups disclosed in each case.

[0083] The compounds described in the present description can be obtained as free compounds, as salts or as solvates (for example, hydrates, alcoholates, etc.), all forms being included within the scope of the present invention.

[0084] Likewise, when a particular compound, or group of compounds, is excluded from the claims, any salts, solvates thereof are also to be considered as excluded, unless stated otherwise.

[0085] The term “salt” refers to a compound which is composed by two counterions, wherein one counterion is positively charged and the other counterion is negatively charged.

[0086] The term "solvate" refers to a complex formed by combining a compound of Formula I or any other formula disclosed herein with a solvent, or an amount incorporated into a crystal structure. Solvation methods are generally known in the state of the art.

[0087] When the compounds of the invention have chiral centers, they can exist in different stereoisomeric forms, such as enantiomeric or diastereomeric forms. As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space and include enantiomers and diastereomers.

[0088] Thus, any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms and one or more diastereomeric forms. All the stereoisomers including enantiomers and diastereoisomers of the compounds referred to herein, and mixtures thereof (including racemic mixtures, enantiomerically enriched mixtures and diastereomerically enriched mixtures), are considered within the scope of the present invention. Also, the invention further contemplates any E / Z possible isomers.

[0089] In the compound of Formula (I) as defined above, the methylene bridging groups connecting each of the nitrogen atoms with the other two, or the methylene bridging groups connecting each of the nitrogen atoms with the phosphorus atom can be substituted. Thus, R3, R3’, R3” R4, R4’ and R4” are independently selected from H or C1-C4 linear or branched alkyl. In a particular embodiment, R3, R3’ and R3” are H. In another particular embodiment, one, two, or three of R3, R3’, R3” are independently selected from C1-C4 linear or branched alkyl, preferably selected from methyl, ethyl, propyl, isopropyl, butyl or tert-butyl; C1-C3 linear or branched alkyl, preferably selected from methyl, ethyl or propyl, more preferably ethyl or methyl group. In a particular embodiment, R4, R4’ and R4” are H. In a further particular embodiment, one, two or three of R4, R4’ and R4” is independently selected from C1-C4 linear or branched alkyl, preferably selected from methyl, ethyl, propyl, isopropyl, butyl or tert-butyl; C1-C3 linear or branched alkyl, preferably selected from methyl, ethyl or propyl, more preferably ethyl or methyl group. In a more preferred embodiment, R3, R3’, R3” R4, R4’ and R4” are H.

[0090] In the compound of Formula (I), one of the methylene bridging groups connecting each of the nitrogen atoms with the other two nitrogen atoms (CHR3) can be optionally absent. In one embodiment of the invention all these methylene bridging groups are present, therefore a represents 1. In another embodiment a represents 0, meaning that the group denoted as CHR3is absent.

[0091] The phosphorus atom is directly linked to a CHR4group, a CHR4’ group and a CHR4” group, and it can be further bonded to an additional atom. In a preferred embodiment z represents 0. In another preferred embodiment z represents 1. When z represents 1 , the phosphorus atom is bonded to a heteroatom belonging to group 16 of the periodic table or to a C1-C4 alkyl. Therefore, when z represents 1 , Y is selected from the group consisting of O, S Se and C1-C4 alkyl. In a preferred embodiment, z is 1 and Y is O. In another preferred embodiment, z is 1 and Y is S. In another preferred embodiment, z is 1 and Y is Se. In another preferred embodiment, z is 1 and Y is C1-C4 alkyl, preferably is C1-C2 alkyl, more preferably CH3.

[0092] Two of the nitrogen atoms of the PTA structure are optionally substituted. In other words, the sum of m and n may be 0, 1 or 2. In a particular embodiment, the sum of m + n is 0. In another particular embodiment, the sum of m + n is 1. In another particular embodiment, the sum of m + n is 2.

[0093] In an embodiment, m represents 0 and n represents 0, meaning that none of the nitrogen atoms of the PTA structure is substituted, i.e., R1and R2are absent. In other embodiments, at least one of the nitrogen atoms of the PTA structure is substituted. Therefore, in one embodiment, n represents 1 and m represents 0, meaning that R1is present and R2is absent. In another embodiment, n represents 0 and m represents 1 meaning that R2is present and R1is absent. In another embodiment, n represents 1 and m represents 1 , meaning that both R1and R2are present.

[0094] When present, R1and R2are independently selected from:

[0095] • H;

[0096] C1-C18 linear or branched alkyl, optionally substituted with a group selected from

[0097] ■ =0,

[0098] ■ a -COOR5group or -COR5group, wherein R5represents H or Ci- 012 alkyl;

[0099] ■ a sulfonate group and

[0100] ■ a phosphate group;

[0101] • allyl optionally substituted in C2 with C1-C18 linear or branched alkyl; and

[0102] • monosaccharide optionally substituted with acyl or amino group.

[0103] In a particular embodiment, R1and R2are independently selected from:

[0104] • H;

[0105] • C1-C18 linear or branched alkyl, optionally substituted with a group selected from

[0106] ■ =0,

[0107] ■ a -COOR5group or -COR5group, wherein R5represents H or C1-C12 alkyl;

[0108] ■ a sulfonate group and

[0109] ■ a phosphate group.

[0110] In one embodiment R1and / or R2are H. In a more particular embodiment, m and n are each 1 , and R1and R2are H.

[0111] In another embodiment, R1and R2are independently selected from C1-C18 alkyl, C1-C16 alkyl, C1-C12 alkyl, Ci-Cs alkyl, Ci-Ce alkyl, C1-C4 alkyl or C1-C3, alkyl substituted with a group selected from =0; a sulfonate group; a phosphate group; a COOR5group and a - COR5group, wherein R5represents H or C1-C12 alkyl, Ci-Cs alkyl, Ci-Ce alkyl, C1-C4 alkyl, or C1-C3 alkyl, preferably ethyl or methyl. In another embodiment, R1and R2are independently selected from C2-C18 alkyl, Ce-Cis alkyl, Cs-Ci8 alkyl, C12-C18 alkyl, C14-C18 alkyl, substituted with a group selected from =0; a sulfonate group; a phosphate group; a COOR5group and a -COR5group, wherein R5represents H or C1-C12 alkyl, C1-C10 alkyl, Ci-Cs alkyl, Ci-Ce alkyl, C1-C4 alkyl, or C1-C3 alkyl, preferably ethyl or methyl.

[0112] In a particular embodiment, R1and R2are independently selected from:

[0113] • H;

[0114] • Ci-Cs linear or branched alkyl, preferably C1-C4 linear or branched alkyl, optionally substituted with a group selected from

[0115] ■ =0,

[0116] ■ a -COOR5group or -COR5group, wherein R5represents H or Ci- 04 alkyl.

[0117] In a preferred embodiment, R1and R2are independently selected from H or Ci-Cs linear or branched alkyl, C1-C4 linear or branched alkyl, C1-C3 linear or branched alkyl, preferably substituted with =0. In a more preferred embodiment R1and R2are C1-C3 alkyl substituted with a =0 group, preferably ethyl substituted with a =0 group.

[0118] In another embodiment, R1and R2are independently selected from unsubstituted C1-C18 alkyl, C1-C16 alkyl, C1-C12 alkyl, Ci-Cs alkyl, Ci-Ce alkyl, C1-C4 alkyl or Ci-Cs alkyl.

[0119] In another embodiment, R1and R2are independently selected from unsubstituted C2-C18 alkyl, Ce-Cis alkyl, Cs-Cis alkyl, C12-C18 alkyl, C14-C18 alkyl.

[0120] In a preferred embodiment, R1and / or R2are selected from the group consisting of hexyl, pentyl, butyl, propyl, ethyl and methyl, preferably R1and / or R2are selected from propyl, ethyl and methyl, even more preferably R1and / or R2are methyl.

[0121] In another embodiment, R1and / or R2are selected from allyl optionally substituted in C2 with C1-C18 linear or branched alkyl. In a preferred embodiment, R1and R2are independently selected from unsubstituted allyl. In another preferred embodiment, R1and R2are independently selected from allyl substituted in C2 with C1-C18 linear or branched alkyl, preferably with C1-C12 linear or branched alkyl, more preferably with Ci- Ce linear or branched alkyl, even more preferably with C1-C3 linear or branched alkyl. In a preferred embodiment, R1and / or R2are allyl substituted in C2 with an ethyl group or a with a methyl group.

[0122] In another embodiment, R1and R2are independently selected from a monosaccharide optionally substituted with acyl or amino group. Non limiting examples of monosaccharides are pyranose, furanose, xylose, arabinose, ribose, glucose, fructose, mannose, galactose, rhamnose, fucose, glyceraldehyde, dihydroxyacetone, erythrulose, erythrose, threose, ribulose, xylulose, lyxose. In a preferred embodiment, R1and / or R2are a monosaccharide selected from the group consisting of glucose, glucosamine, N- acetyl-glucosamine galactosamine, tetraacetyl-glucose, tetraacetyl-mannose, tetraacetyl-galactose, 3-amino-3-deoxyribose and triacetyl-ribose. In another preferred embodiment, R1and / or R2are unsubstituted monosaccharide. In a more preferred embodiment, the monosaccharide is selected from pyranose and furanose.

[0123] In an embodiment, a represents 0. In another embodiment a represents 1.

[0124] In some embodiments, a represents 1 , the sum of n + m is 0 and d is 0. In another embodiment, a represents 1 , the sum of n + m is 1 (i.e., m =1 , and n = 0 or m =0, and n = 1) and d is 1. In another embodiment, a represents 1 , the sum of n + m is 2 and d is 2. In another embodiment, a represents 0, the sum of n + m is 2 and d is 0.

[0125] In a more particular embodiment, a represents 1 , m is 0 such that R2is absent, n is 1 , where R1is as defined in any of the above particular and preferred embodiments, and d is 1 . Within this particular embodiment z may be 0 or 1 . When z is 1 , Y is selected from O, S or Se, preferably O.

[0126] In another more particular embodiment, a represents 1 , m is 1 where R2is as defined in any of the above particular and preferred embodiments, n is 1 , such that R1is absent, and d is 1 . Within this particular embodiment z may be 0 or 1. When z is 1 , Y is selected from O, S, Se or C1-C4 alkyl, preferably O or CH3.

[0127] In a further particular embodiment, a represents 1 , m is 1 and n is 1 , where R1and R2are as defined above as defined in any of the above particular and preferred embodiments, and d is 2. Within this particular embodiment z may be 0 or 1 . When z is 1 , Y is selected from O, S, Se or C1-C4 alkyl, preferably O or CH3.

[0128] In an even further more particular embodiment, a represents 0, m is 1 and n is 1 , where R1and R2are as defined above as defined in any of the above particular and preferred embodiments, and d is 0. Within this particular embodiment z may be 0 or 1. When z is 1 , Y is is selected from O, S or Se, preferably O.

[0129] When d represents 1 or 2, X is independently selected from CFsSCh' or halogen. In a particular embodiment, X is selected from CF3SO3, chloro or bromo. In a preferred embodiment, X is CFsSCh'.

[0130] In an embodiment, the compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer is a compound of formula (I) wherein:

[0131] R1and R2are independently selected from:

[0132] • H;

[0133] • C1-C18 linear or branched alkyl, optionally substituted with a group selected from

[0134] ■ =0,

[0135] ■ a -COOR5group or -COR5group, wherein R5represents H or Ci- 012 alkyl;

[0136] ■ a sulfonate group and

[0137] ■ a phosphate group;

[0138] • allyl optionally substituted in C2 with C1-C18 linear or branched alkyl; and

[0139] • monosaccharide optionally substituted with acyl or amino group.

[0140] R3, R3’, R3” R4, R4’ and R4” are independently selected from H or C1-C4 linear or branched alkyl;

[0141] Y is independently selected from O, S and Se;

[0142] X is independently selected from CFsSOs' or halogen; a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; and d represents 0, 1 or 2.

[0143] In a particular embodiment of the compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer is a compound of formula (I) wherein: R1and R2are independently selected from:

[0144] • C1-C4 linear or branched alkyl, optionally substituted with =0

[0145] R3, R3’, R3” R4, R4’ and R4” are H

[0146] Y is independently selected from O, S, Se and C1-C2 alkyl;

[0147] X is independently selected from CF3SO3or halogen- a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; and d represents 0, 1 or 2.

[0148] In a particular embodiment of the compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer is a compound of formula (I) wherein:

[0149] R1and R2are independently selected from:

[0150] • CH3

[0151] • C2 alkyl substituted with =0

[0152] R3, R3’, R3” R4, R4’ and R4” are H;

[0153] Y is independently selected from O, S, Se and CH3;

[0154] X is CF3SO3- a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; and d represents 0, 1 or 2. In a preferred embodiment, the compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer is selected from the group consisting of:

[0155] In a more preferred embodiment, the compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer is selected from the group consisting of: OTf

[0156] In a most preferred embodiment, the compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer is selected from the group consisting of:

[0157] As previously mentioned, the PTA derivatives of the present invention are non-toxic in the dark but active under visible and infrared radiation when contacted with cells. To exert this antiproliferative activity, compounds according to any of the embodiments of the invention may be contacted with cells and irradiated with visible or infrared light. One skilled in the art would know that visible light has wavelengths comprised between 300 and 700 nm, whereas infrared is generally understood to include wavelengths from above 700 nm to 1 mm. Therefore, in an embodiment, a compound of formula (I) according to the present invention is contacted with cells and irradiated with light at a wavelength comprised between 300 and 700 nm, preferably between 300 and 650 nm, between 300 and 500 nm, more preferably between 400 and 500 nm. In a most preferred embodiment, the compound of formula (I) is contacted with cells and irradiated with light at a wavelength between 430 and 470 nm, even more preferably between 450 and 470 nm.

[0158] In another embodiment, the compound of formula (I) according to the present invention is contacted with cells and irradiated with light at a wavelength above 300 nm, preferably above 400 nm.

[0159] In another embodiment, the compound of formula (I) is contacted with cells and irradiated with light at a wavelength below 700 nm, preferably below 600 nm, 500 nm, even more preferably below 480 nm.

[0160] In another embodiment, the compound of formula (I) is contacted with cells and irradiated with light at a wavelength in the infrared region, preferably between 700 and 900 nm.

[0161] In an embodiment, the compound of formula (I) of the invention is contacted with cells and irradiated with light as in any of the embodiments described above during a time comprised between 0.5 and 5 hours, preferably between 0.5 and 4 hours, between 0.5 and 3 hours, between 0.5 and 2 hours, even more preferably between 0.5 and 1.5 hours.

[0162] In another embodiment, the compound of formula (I) of the invention is contacted with cells and irradiated with light as in any of the embodiments described above during at least 10 minutes, at least 20 minutes, at least 30 minutes, at least 40 minutes, at least 50 minutes, at least 60 minutes, at least 70 minutes, at least 80 minutes, at least 90 minutes and at least 100 minutes. In a preferred embodiment, the compound of formula (I) is contacted with cells and irradiated during at least 40 minutes.

[0163] In another embodiment, the compound of formula (I) is contacted with cells and irradiated with light as in any of the embodiments described above during less than 5 hours, less than 4 hours, less than 3 hours, less than 2 hours.

[0164] In an embodiment, the compound of formula (I) is contacted with cells and irradiated with light at a wavelength between 430 and 470 nm, during a time comprised between 0.5 and 2 hours. In an embodiment, the compound of formula (I) is contacted with cells and irradiated with light as in any of the embodiments described above, with an irradiance of between 5 and 150 mW / cm2.

[0165] The compounds of formula (I) of the present invention are useful as active antiproliferative agents for photodynamic therapy (PDT) and Photoactivated Chemotherapy (PACT) in the treatment of cancer. In a particular embodiment, the compound of formula (I) is for use in the treatment of a cancer selected from lung cancer, cervical cancer, prostate cancer, colorectal cancer and melanoma, preferably in a human subject. Synthesis procedures of compounds of formula (I) are well known in the state of the art Examples of these synthesis procedures can be found in examples 1 to 12 in the experimental section below.

[0166] A second aspect of the invention is related with a compound of formula (I’):

[0167] Formula (I’) wherein a represents 1 , then

[0168] R1and R2are independently selected from:

[0169] • H;

[0170] • C1-C18 linear or branched alkyl substituted with a group selected from

[0171] ■ =0,

[0172] ■ sulfonate and

[0173] ■ phosphate groups;

[0174] • C7-C11 linear or branched unsubstituted alkyl;

[0175] • C7-C18 linear or branched alkyl substituted with a COOR5group or - COR5group , wherein R5represents H or C1-C12 alkyl;

[0176] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0177] • monosaccharide optionally substituted with acyl or amino group. R3, R3’, R3”, R4, R4’ and R4” are independently selected from H or C1-C4 lineal or branched alkyl;

[0178] Y is independently selected from O, S, Se and C1-C4 alkyl;

[0179] X is independently selected from CFsSCh' or halogen; the sum of m+n represents 1 or 2; z represents 0 or 1 ; and d represents 1 or 2; or wherein a represents 0, then

[0180] R1and R2are independently selected from

[0181] • C2-C18 linear or branched alkyl, optionally substituted with a group selected from

[0182] ■ a COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl;

[0183] ■ a sulfonate group; and

[0184] ■ a phosphate group;

[0185] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0186] • monosaccharide optionally substituted with acyl or amino group.

[0187] R3, R3’, R3” R4, R4’, R4” are independently selected from H or C1-C4 lineal or branched alkyl;

[0188] Y is independently selected from O, S and Se; the sum of m+n represents 2; z represents 0 or 1 ; d represents 0, and the dashed line represents a simple bound or a double bound.

[0189] In the compound of formula (I’), R3, R3’, R3” R4, R4’ and R4” are independently selected from H or C1-C4 linear or branched alkyl. In a particular embodiment, R3, R3’ and R3” are H. In another particular embodiment, one, two, or three of R3, R3’, R3” are independently selected from C1-C4 linear or branched alkyl, preferably selected from methyl, ethyl, propyl, isopropyl, butyl or tert-butyl; C1-C3 linear or branched alkyl, preferably selected from methyl, ethyl or propyl, more preferably ethyl or methyl group. In a particular embodiment, R4, R4’ and R4” are H. In a further particular embodiment, one, two or three of R4, R4’ and R4” is independently selected from C1-C4 linear or branched alkyl, preferably selected from methyl, ethyl, propyl, isopropyl, butyl or tert-butyl; C1-C3 linear or branched alkyl, preferably selected from methyl, ethyl or propyl, more preferably ethyl or methyl group. In a more preferred embodiment, R3, R3’, R3” R4, R4’ and R4” are H.

[0190] In the compound of formula (I’), when z represents 1 , the phosphorus atom is bonded to a heteroatom belonging to group 16 of the periodic table or to a C1-C4 alkyl group. Therefore, in an embodiment z represents 1 and Y is selected from the group consisting of O, S Se and C1-C4 alkyl, preferably O and CH3, even more preferably O. In another embodiment, z is 0.

[0191] In a particular embodiment, a represents 1. When a represents 1 , it means that the group denoted as CHR3, as defined above, is present.

[0192] In a particular embodiment, when a is 1 , the sum of m + n is 1. In another particular embodiment, when a is 1 , the sum of m + n is 2. In a more particular embodiment, when the sum of m+n is 1 , d is 1. In another more particular embodiment, when the sum of m+n is 2, d is 2.

[0193] In a particular embodiment, X is independently selected from CFsSCh' or halogen. In a more particular embodiment, X is CF3SO3 or halogen selected from chloro or bromo. Preferably, X is CFsSCh'.

[0194] In another more particular embodiment, n represents 1 and m represents 0, meaning that R1is present and R2is absent. In another embodiment, n represents 0 and m represents 1 meaning that R2is present and R1is absent. In another embodiment, n represents 1 and m represents 1 , meaning that both R1and R2are present.

[0195] In the compound of formula (I’), when a represents 1 , R1and R2are independently selected from:

[0196] • H;

[0197] • C1-C18 linear or branched alkyl substituted with a group selected from

[0198] ■ =0,

[0199] ■ sulfonate and

[0200] ■ phosphate;

[0201] • C7-C11 linear or branched unsubstituted alkyl;

[0202] • C7-C18 linear or branched alkyl substituted with a COOR5group or - COR5group , wherein R5represents H or C1-C12 alkyl;

[0203] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and monosaccharide optionally substituted with acyl or amino group.

[0204] In a more particular embodiment, a represents 1 , then:

[0205] R1and R2are independently selected from:

[0206] • H;

[0207] • C1-C18 linear or branched alkyl substituted with a group selected from =0, sulfonate or phosphate;

[0208] • C7-C11 linear or branched unsubstituted alkyl;

[0209] • C7-C18 linear or branched alkyl substituted with a COOR5group or - COR5group , wherein R5represents H or C1-C12 alkyl;

[0210] In another particular embodiment, a represents 1 , then:

[0211] R1and R2are independently selected from:

[0212] • H;

[0213] • C1-C18 linear or branched alkyl substituted with a group selected from =0,

[0214] • C7-C11 linear or branched unsubstituted alkyl;

[0215] • C7-C18 linear or branched alkyl substituted with a COOR5group or - COR5group , wherein R5represents H or C1-C12 alkyl;

[0216] In a particular embodiment R1and / or R2are H.

[0217] In another particular embodiment, R1and / or R2are selected from C1-C18 alkyl, C1-C12 alkyl, C1-C10 alkyl, Ci-Cs alkyl, Ci-Ce alkyl, C1-C4 alkyl or C1-C3 alkyl substituted with a group selected from =0, a sulfonate group or a phosphate group, preferably substituted with =0. In a preferred embodiment, R1and / or R2are selected from C1-C3 substituted with =0, sulfonate or phosphate, more preferably with =0.

[0218] In another particular embodiment, R1and / or R2are selected from C2-C18 alkyl, C4-C18 alkyl, Ce-Ci8 alkyl, Cs-Cis alkyl, C10-C18 alkyl, C12-C18 alkyl substituted with a group selected from =0, a sulfonate group or a phosphate group, preferably substituted with =0.

[0219] In another embodiment, R1and / or R2are selected from C7-C11 linear or branched unsubstituted alkyl, C7-C10 unsubstituted alkyl, a C7-C9 unsubstituted alkyl or a C7-C8 unsubstituted alkyl. In a further embodiment, R1and / or R2are selected from Cs-Cn unsubstituted alkyl, C9-C11 unsubstituted alkyl or C10-C11 unsubstituted alkyl. In another embodiment, R1and / or R2are selected from C7-C18 linear or branched alkyl, C7-C16 alkyl, C7-C14 alkyl, C7-C12 alkyl, C7-C10 alkyl substituted with a COOR5group or - COR5group, wherein R5represents H or C1-C12 alkyl, Ci-Cs alkyl, Ci-Ce alkyl, C1-C4 alkyl or C1-C3 alkyl.

[0220] In another embodiment, R1and / or R2are independently selected from Cs-Cis linear or branched alkyl, C12-C18 alkyl, C16-C18 alkyl substituted with a COOR5group or -COR5group, wherein R5represents H or C1-C12 alkyl, C1-C10 alkyl, Ci-Cs alkyl, Ci-Ce alkyl, C1- C4 alkyl or C1-C3 alkyl.

[0221] In another embodiment, R1and R2are independently selected from allyl optionally substituted in C2 with C1-C18 linear or branched alkyl. In a preferred embodiment, R1and / or R2are unsubstituted allyl. In another preferred embodiment, R1and / or R2are allyl substituted in C2 with C1-C12 linear or branched alkyl, preferably with Ci-Cs linear or branched alkyl, more preferably with Ci-Ce linear or branched alkyl, even more preferably with C1-C3 linear or branched alkyl, most preferably with an ethyl group or a with a methyl group.

[0222] In another embodiment, R1and R2are independently selected from a monosaccharide optionally substituted with acyl or amino group. In a preferred embodiment, R1and / or R2are a monosaccharide selected from glucose, glucosamine, N-acetyl-glucosamine galactosamine, tetraacetyl-glucose, tetraacetyl-mannose, tetraacetyl-galactose, 3- amino-3-deoxyribose and triacetyl-ribose. In another preferred embodiment, R1and / or R2are an unsubstituted monosaccharide. In a more preferred embodiment, the monosaccharide is selected from pyranose and furanose.

[0223] In a particular embodiment, when a is 1 for the compound of formula (I’) as defined above z is 0. In another particular embodiment, when a is 1 , z is 1 and Y is O.

[0224] In a further embodiment of the compound of formula (I’) as defined above, a represents 0. When a represents 0, it means that the group denoted as CHR3is absent.

[0225] In a particular embodiment, a is 0 and the sum of m+n is 2. Therefore, m and n represent 1 such that two nitrogen atoms of the PTA structure are substituted, meaning that both R1and R2are present, then

[0226] R1and R2are independently selected from

[0227] C2-C18 linear or branched alkyl, preferably C4-C18 alkyl, more preferably

[0228] C6-C12 alkyl optionally substituted with a group selected from ■ a COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl;

[0229] ■ a sulfonate group; and

[0230] ■ a phosphate group;

[0231] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0232] • monosaccharide optionally substituted with acyl or amino group.

[0233] In a particular embodiment a is 0, then R1and R2are independently selected from

[0234] • C2-C18 linear or branched alkyl, optionally substituted with a group selected from

[0235] ■ a -COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl;

[0236] ■ a sulfonate group; and

[0237] ■ a phosphate group;

[0238] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0239] • monosaccharide optionally substituted with acyl or amino group.

[0240] In another embodiment, R1and / or R2are selected from C2-C18 linear or branched alkyl, C2-C12 alkyl, , C2-C8 alkyl, C2-C6 alkyl, C2-C4 alkyl, optionally substituted with a group selected from a -COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl, C1- Cs alkyl, Ci-Ce alkyl, C1-C4 alkyl, or C1-C3 alkyl, preferably ethyl or methyl.

[0241] In another embodiment, R1and / or R2are selected from C4-C18 linear or branched alkyl, Ce-Ci8 alkyl, C10-C18 alkyl or C12-C18 alkyl, alkyl, optionally substituted with a group selected from a COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl, C1- C10 alkyl, Ci-Cs alkyl, Ci-Ce alkyl, C1-C4 alkyl, or C1-C3 alkyl, preferably ethyl or methyl.

[0242] In another embodiment, R1and R2are independently selected from allyl optionally substituted in C2 with C1-C18 linear or branched alkyl. In a preferred embodiment, R1and R2are independently selected from unsubstituted allyl. In another preferred embodiment, R1and R2are independently selected from allyl substituted in C2 with C1-C18 linear or branched alkyl, preferably with C1-C12 linear or branched alkyl, more preferably with Ci- Ce linear or branched alkyl, even more preferably with C1-C3 linear or branched alkyl, most preferably with an ethyl group or a with a methyl group.

[0243] In another embodiment, R1and R2are independently selected from a monosaccharide optionally substituted with acyl or amino group. In a preferred embodiment, R1and / or R2are a monosaccharide selected from glucose, glucosamine, N-acetyl-glucosamine galactosamine, tetraacetyl-glucose, tetraacetyl-mannose, tetraacetyl-galactose, 3- amino-3-deoxyribose and triacetyl-ribose. In another preferred embodiment R1and / or R2 are an unsubstituted monosaccharide. In a more preferred embodiment, the monosaccharide is selected from pyranose and furanose.

[0244] In a particular embodiment, when a is 0 for the compound of formula (I’) as defined above z is 0. In another particular embodiment, when a is 0 z is 1 and Y is O.

[0245] In a further aspect, the present invention relates to a method for preparing a compound of formula (I’) according to any embodiment of the invention, comprising the steps of: a) providing a solution containing 1 ,3,5-triaza-7-phosphaadamantane (PTA) or a precursor thereof, wherein the precursor is a mixture of P(CH2OH)3, formaldehyde and hexamethylenetetramine; b) optionally adding a C1-C4 linear or branched alkyl derivative to the solution of step (a) to obtain a compound of formula (II): wherein at least one of R3, R3’, R3” R4, R4’ and R4” is C1-C4 linear or branched alkyl; c) adding a R’-X derivative or an acid, to the solution of step (a) or step (b) to obtain a compound of formula (I’) wherein z is 0; d) optionally reacting the P atom of the compound of step (c) with an oxidizing agent to obtain a compound of formula (I’) wherein z is 1.

[0246] In an embodiment, the solution of step (a) comprises PTA or a PTA precursor in a solvent, preferably selected from toluene, acetone, dichloromethane, chloroform and acetonitrile or a mixture thereof.

[0247] In an embodiment, the alkyl derivative of step (b) is a C1-C4 alkyl aldehyde, a C1-C4 alkyllithium, a C1-C4 haloalkyl derivative or a combination thereof. In a particular embodiment, the alkyl derivative of step (b) is a C1-C4 alkyl aldehyde. In another particular embodiment, the alkyl derivative of step (b) is a C1-C4 alkyllithium, a C1-C4 haloalkyl derivative or a mixture thereof.

[0248] In a particular embodiment, in step (b) a C1-C4 alkyl aldehyde is added to the solution of step (a) comprising a mixture of P(CH2OH)3, formaldehyde and hexamethylenetetramine as a PTA precursor to yield a compound of formula (II) as defined above, wherein one or more of R3, R3’, R3” is C1-C4 alkyl, and R4, R4’, R4” are H.

[0249] In a more particular embodiment, upon addition of the C1-C4 alkyl aldehyde to the solution of step (a) in step (b) the resulting mixture is stirred at a temperature between 0 °C and reflux, preferably for a period between 0.5 and 12 hours.

[0250] Preferably, 1 to 10 equivalents of Ci-C4-alkyl aldehyde to PTA precursor are added.

[0251] In another particular embodiment, in step (b) a C1-C4 alkyllithium and / or a C1-C4 haloalkyl derivative such as a C1-C4 bromoalkyl derivative is added to the solution of step (a) comprising PTA to yield a compound of formula (II) as defined above, wherein R3, R3’, R3” is H, and one or more of R4, R4’, R4” is C1-C4 alkyl.

[0252] In a more particular embodiment, upon addition of a C1-C4 alkyllithium and / or a C1-C4 haloalkyl derivative to the solution of step (a) in step (b), the resulting mixture is stirred at a temperature between 0 °C and reflux. Preferably, the mixture is stirred for a period between 0.5 and 12 hours.

[0253] In a further particular embodiment, in step (b) a C1-C4 alkyl aldehyde is firstly added to the solution of step (a) comprising a mixture of P(CH2OH)3, formaldehyde and hexamethylenetetramine as PTA precursor, followed by addition of a C1-C4 alkyllithium and / or a C1-C4 haloalkyl to yield a compound of formula (II) as defined above, wherein one or more of R3, R3’, R3” is H, and one or more of R4, R4’, R4” is C1-C4 alkyl.

[0254] Particular and preferred embodiments for R3, R3’, R3’’ R4, R4’, R4” are those as described above for the compound of formula (I’).

[0255] In a particular embodiment, the acid of step (c) is an inorganic acid, preferably selected from hydrochloric acid, sulfuric acid, phosphoric acid; or an organic acid, preferably selected from triflic acid, acetic acid, lactic acid, citric acid.

[0256] In a particular embodiment, the R’-X derivative of step (c) is a compound comprising a X moiety, which is a leaving group selected from tosylate, triflate, halide and -OCOR”, wherein R is C1-C12 alkyl, and a R’ moiety selected from the group consisting of C1-C18 linear or branched alkyl, optionally substituted with a group selected from =0, a sulfonate group, a phosphate group, a -COOR5group or -COR5group wherein R5represents H or C1-C12 alkyl; allyl optionally substituted in C2 with C1-C18 linear or branched alkyl; and monosaccharide optionally substituted with acyl or amino group.

[0257] The R’ moiety of the R’-X derivative of step (c) reacts with a N atom of the PTA structure, yielding a compound of formula (I’) wherein z is 0 and wherein R1and / or R2are a substituent as defined above for the compound of formula (I’). Thus, particular and preferred embodiments for the R’ moiety of the R’-X derivative correspond to those described above for R1and R2in the compound of formula (I’).

[0258] In a more particular embodiment, upon addition of the R-X’ derivative to the solution of step (a) in step (b), the resulting mixture is stirred at a temperature between 0 °C and reflux, preferably between room temperature and reflux. More preferably, the mixture is refluxed under stirring for a period between 0.5 and 12 hours.

[0259] Preferably, 0.5 to 10 equivalents of R-X’ derivative to compound of formula (I’) are added.

[0260] In further embodiments, the P atom of the compound of step (c) is reacted with an oxidizing agent to yield a compound of formula (I’) wherein z is 1. As used herein, an oxidizing agent is a compound capable of reacting it with the P atom of the PTA structure and oxidizing to P(V). In a particular embodiment, the oxidizing agent is selected from hydrogen peroxide, oxygen, m-chloroperoxybenzoic acid, sulfur and potassium selenocyanate. In a preferred embodiment, the oxidizing agent is hydrogen peroxide dissolved in ethanol. In a particular embodiment, step (d) is performed under stirring at room temperature, preferably for a period of 10 min to 1 h.

[0261] Examples of synthesis of derivatives of formula (I’) can be found in examples 13-16 of the experimental section.

[0262] Further particular embodiments

[0263] Embodiment 1. Compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancer

[0264] Formula (I) wherein

[0265] R1and R2are independently selected from:

[0266] • H;

[0267] • C1-C18 linear or branched alkyl, optionally substituted with a group selected from

[0268] ■ =0,

[0269] ■ a -COOR5group or -COR5group, wherein R5represents H or Ci- 012 alkyl;

[0270] ■ a sulfonate group and

[0271] ■ a phosphate group;

[0272] • allyl optionally substituted in C2 with C1-C18 linear or branched alkyl; and

[0273] • monosaccharide optionally substituted with acyl or amino group.

[0274] R3, R3’, R3” R4, R4’ and R4” are independently selected from H or C1-C4 linear or branched alkyl;

[0275] Y is independently selected from O, S and Se;

[0276] X is independently selected from CF SOs' or halogen; a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; and d represents 0, 1 or 2.

[0277] Embodiment 2. Compound for use according to embodiment 1 , wherein R3, R3’, R3”, R4, R4’ and R4” are H. Embodiment 3. Compound for use according to embodiments 1 or 2, wherein z is 0.

[0278] Embodiment 4. Compound for use according to embodiments 1 or 2, wherein z is 1 and Y is O.

[0279] Embodiment 5. Compound for use according to any one of embodiments 1 to 4, wherein a is 1.

[0280] Embodiment 6. Compound for use according to embodiment 5, wherein the sum of m and n is 1 and d is 1.

[0281] Embodiment 7. Compound for use according to embodiment 5, wherein the sum of m and n is 2 and d is 2.

[0282] Embodiment 8. Compound for use according to any one of embodiments 1 to 4, wherein a is 0.

[0283] Embodiment 9. Compound for use according to any one of the previous embodiments, wherein R1and R2are independently selected from:

[0284] • H;

[0285] • C1-C18 linear or branched alkyl, optionally substituted with a group selected from

[0286] ■ =0,

[0287] ■ a -COOR5group or -COR5group, wherein R5represents H or C1-C12 alkyl;

[0288] ■ a sulfonate group and

[0289] ■ a phosphate group.

[0290] Embodiment 10. Compound for use according to any of the previous embodiments, wherein R1and R2are independently selected from: H or Ci-Cs linear or branched alkyl, optionally substituted with =0.

[0291] Embodiment 11. Compound for use according to any of the previous embodiments in photodynamic therapy and / or photoactivated chemotherapy of cancer, wherein X is CF3SO3'.

[0292] Embodiment 12. Compound for use according to any of the previous embodiments, selected from the group consisting of:

[0293]

[0294] Embodiment 13. Compound of formula (I’) Formula (I’) wherein a represents 1 , then

[0295] R1and R2are independently selected from:

[0296] • H;

[0297] • C1-C18 linear or branched alkyl substituted with a group selected from

[0298] ■ =0,

[0299] ■ sulfonate and

[0300] ■ phosphate groups;

[0301] • C7-C11 linear or branched unsubstituted alkyl; • C7-C18 linear or branched alkyl substituted with a COOR5group or -

[0302] COR5group , wherein R5represents H or C1-C12 alkyl; • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0303] • monosaccharide optionally substituted with acyl or amino group.

[0304] R3, R3’, R3”, R4, R4’ and R4” are independently selected from H or C1-C4 lineal or branched alkyl;

[0305] Y is independently selected from O, S and Se;

[0306] X is independently selected from CF SO ' or halogen; the sum of m+n represents 1 or 2; z represents 0 or 1 ; and d represents 0, 1 or 2; or wherein a represents 0, then

[0307] R1and R2are independently selected from

[0308] • H;

[0309] • C2-C18 linear or branched alkyl, optionally substituted with a group selected from

[0310] ■ =0,

[0311] ■ a COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl;

[0312] ■ a sulfonate group; and

[0313] ■ a phosphate group;

[0314] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0315] • monosaccharide optionally substituted with acyl or amino group.

[0316] R3, R3’, R3” R4, R4’, R4” are independently selected from H or C1-C4 lineal or branched alkyl; the sum of m+n represents 2; z represents 0 or 1 ; and d represents 0.

[0317] Embodiment 14. Compound of formula (I’) according to embodiment 13 wherein a represents 0 and R1and R2are independently selected from: • H;

[0318] • C2-C18 linear or branched alkyl, optionally substituted with a group selected from ,

[0319] ■ a COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl;

[0320] ■ a sulfonate group; and

[0321] ■ a phosphate group;

[0322] • allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and

[0323] • monosaccharide optionally substituted with acyl or amino group.

[0324] Embodiment 15. A method for preparing a compound of formula (I’) according to any of embodiments 13 or 14, comprising the steps of: a) providing a solution containing 1 ,3,5-triaza-7-phosphaadamantane (PTA) or a precursor thereof, b) optionally adding a C1-C4 linear or branched alkyl derivative to the solution of step (a) to obtain a compound of formula (II): wherein at least one of R3, R3’, R3” R4, R4’ and R4” is C1-C4 linear or branched alkyl; c) adding a R’-X derivative or a an acid to the solution of step (a) or step (b) to obtain a compound of formula (I’) wherein z is 0; d) optionally reacting the P atom of the compound of step (c) with an oxidizing agent to obtain a compound of formula (I’) wherein z is 1 .

[0325] The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

[0326] EXAMPLES Synthesis examples

[0327] Synthesis of compounds of formula (I)

[0328] Example 1: Synthesis of compound J1 J1 was synthesized as described in J. Heterocycl. Chem. 1974, 77(3), 407-408. In brief, hydrogen peroxide (0.5 g, 30%, 0.0044 mol) diluted in 20 mL of ethanol was slowly added over 10 min to a solution of PTA (0.5 g, 0.0032 mol) in methanol (20 mL) and the mixture was stirred for 20 minutes. After evaporation at room temperature, the solid was recrystallized from ethanol. Example 2: Synthesis of compound J2

[0329] OTf

[0330] J2 was synthesized following the procedure described in Inorg. Chem. 2006, 45 (3), 1289-1298. In brief, CH3OSO2CF3 (0.36 mL, 3.2 mmol) was added via a syringe to a vigorously stirred solution of PTA (500 mg, 3.2 mmol) in 50 mL of CHCI3 at room temperature. The reaction mixture was refluxed for 30 minutes and cooled to room temperature. The precipitate was separated by filtration, washed with CHCI3 (3 * 10 mL) and air-dried.

[0331] Example 3: Synthesis of compound J3

[0332] J3 was obtained by treating a methanol solution of J2 with H2O2in ethanol at room temperature for 20 minutes.

[0333] Example 4: Synthesis of compound J4

[0334] The compound J4 was synthesized as described in Inorg. Chem. 2007, 46 (15), 6120- 6128. In particular, CH3OSO2CF3 (0.36 mL, 3.2 mmol) was added via a syringe to a vigorously stirred solution of PTA (500 mg, 3.2 mmol) in 60 mL of acetone at 40 °C. After 20 min, an additional 0.36 mL of CH3OSO2CF3 was added, and then the solution was refluxed for 2 h, after which the solvent was evaporated to ~90%. The addition of CHCI3 (15 mL) and the cooling of the mixture at 0 °C produced an abundant white precipitate, which was stirred for 30 min, filtered, washed with cold ether / acetone (5 / 5 mL), and vacuum-dried.

[0335] Example 5: Synthesis of compound J5

[0336] J5 was obtained by treating a methanol solution of J4 with H2O2in ethanol at room temperature for 40 minutes. Example 6: Synthesis of compound J6

[0337] J6 was synthesized as described in J. Heterocycl. Chem. 1977, 14 (2), 337-339. In particular, acetic anhydride (3.1 g, 0.03 mol) was added to a solution of PTA (1.57 g., 0.01 mmol) in 20 mL of water over 15 minutes at 0-5°C while stirring. After aging for 20 minutes the solution was evaporated under vacuum. The crude material was recrystallized from acetone.

[0338] Example 7 Synthesis of compound J7 J7 was synthesized as follows: CH3OSO2CF3 (0.299 mL, 2.64 mmol) was added via a syringe to a vigorously stirred solution of PTA=S (500 mg, 2.64 mmol) in 50 mL of dry acetone at 45 °C. After dissolved, the solution was refluxed for 2 h, and the 90% of the volume of the solvent was removed by evaporation. The solution was cooled to 0 °C and the addition of 50 mL of chloroform produced an abundant white precipitate, which was stirred for 30 min, filtered, washed with cold ether / acetone (2.5 / 1 mL), and vacuum-dried.

[0339] Example 8: Synthesis of compound J8 J8 was synthesized as follows: CH3OSO2CF3 (0.096 mL, 0.847 mmol) was added via a syringe to a vigorously stirred solution of PTA=Se (200 mg, 0.847 mmol) in 20 mL of dry acetone at 45 °C. After dissolved, the solution was refluxed for 2.5 h, and the solvent was evaporated to 90%. The solution was cooled to -20 °C and filtered. The addition of 20 mL of chloroform produced an abundant white precipitate, which was stirred for 30 min, filtered and then washed with cold ether / acetone (2.5 / 1 mL). Finally the precipitate was vacuum-dried.

[0340] Example 9: Synthesis of compound J9

[0341] J9 was synthesized as follows: A solution of Ag OSChCFs) (0.215 g, 0.836 mmol) in 5 mL of ethanol was slowly added to a vigorously stirred solution of P-mPTA (0.25 g, 0.836 mmol) in 15 mL of ethanol. A yellowish precipitate quickly formed, and the solution was stirred for 30 minutes covered from light. The suspension was filtered through Celite and the 90% of the volume of the solvent was removed by evaporation, resulting in the formation of a white crystalline precipitate. The addition 40 mL of Et20 produced an abundant white precipitate, which was filtered, washed with Et20 (3x3 mL) and vacuum- dried.

[0342] Example 10: Synthesis of compound J10

[0343] J10 was synthesized as follows: A solution of Me OSChCFs) (0.044 mL, 0.389 mmol) was added via a syringe to a vigorously stirred solution of P-mPTA(OSO2CF3) (J9) (125 mg, 0.847 mmol) in 25 mL of dry acetone. The solution was stirred for 15 minutes at room temperature and the 95% of the volume of the solvent was removed by evaporation, resulting in the formation of a white micro-crystalline precipitate. After cooling to -20 °C, the solution was filtered and washed with cold ether / acetone (2:1).

[0344] Example 11: Synthesis of compound J11

[0345] J11 was synthesized as follows: KOH (27.2 mg, 0.412 mmol) and N,N- dmPTA(OSO2CF3)2 (J4) (200 mg, 0.412 mmol) were dissolved in 20 mL of MeOH. After the mixture was refluxed for 1 h, the resulting colourless solution was evaporated to 2 mL, and then 5 mL of Et20 was added. The resulting white precipitate was filtered and washed with Et20 (2x2 mL). The filtered solution and the filtered Et20 were combined and evaporated to obtain a white powder.

[0346] Example 12: Synthesis of compound J12

[0347] J12 was synthesized as follows: To a stirred suspension of / V, / V-dmPTA=O(OSO2CF3)2 (J5) (0.3 g, 0.598 mmol) in 30 mL of acetone, 2 mL of water was slowly added. After 2 h at room temperature, the precipitate completely dissolved. The addition of 200 mL of Et20 led to the formation of an oily solid. After cooling to -20°C and decantation, the oily solid obtained was sonicated three times with mixture ether / acetone (1 :1) and Et20, resulting in the formation of a white powder.

[0348] Synthesis of compounds of formula (I’)

[0349] Example 13: Synthesis of compound of formula (I) wherein R1or R2is allyl. 1 ,3,5-triaza-7-phosphaadamantane (PTA) is dissolved in CH2CI2, and is reacted with 1.1 equivalents of allyl-tosylate in acetone. The reaction mixture is refluxed for 1 hour. The solution therein obtained is filtered and cooled at room temperature. After this cooling, the solution is concentrated, until the volume reaches a quarter of the initial volume leading to the formation of a white precipitate. The precipitate obtained is filtered, washed with CH2Ch and dried.

[0350] Example 14: Synthesis of compound of formula (I) wherein R1orR2is a monosaccharide:

[0351] 8a. R1and / or R2is furanose

[0352] 1 ,3,5-triaza-7-phosphaadamantane (PTA) is reacted with 3-5 equivalents of furanosyl tosylate in refluxing toluene. After 2 hours, a colorless solution is obtained. The solution is filtered, cooled temperature and the solvent is removed. After the removal of the solvent, a powder is obtained which is recrystallized from acetone, filtered and dried.

[0353] 8b. R1and / or R2is piranose

[0354] 1 ,3,5-triaza-7-phosphaadamantane (PTA) is reacted with 3-5 equivalents of piranosyl tosylate in refluxing toluene. After 2 hours, a colorless solution is obtained. The solution is filtered, cooled at room temperature and the solvent is removed. After the complete removal of the solvent, a powder is obtained which is recrystallized from acetone, filtered and dried.

[0355] Example 15: Synthesis of compound of formula (I) wherein R3, R3’orR3”is a C1-C4 alkyl.

[0356] To a solution of P(CH2OH)3 (1 equivalent) in water, toluene or dichlorometane, 1-10 equivalents of the selected C1-C4 alkyl aldehyde, 0-2 equivalents of formaldehyde and 0.8 equivalents of hexamethylenetetramine are added. After 12 hours of stirring, solvent is completely removed, and the resulting solid is dissolved in CH2CI2 and filtered. The filtrated liqueur is dried and the solid obtained is recrystallized from ethanol or from a mixture of acetone / ethanol (1 :1). The microcrystalline powder obtained is filtered, washed with diethyl ether and dried.

[0357] Example 16: Synthesis of compound of formula (I) wherein R4, R4’and R4”are a C1-C4 alkyl.

[0358] Under inert atmosphere, 1 equivalent of PTA is dissolved in toluene and reacted with 3 butyllithium (3 equivalents). The reaction mixture is stirred at room temperature for 12 hours, and 3 equivalents of C1-C4 alkyl-Br in tetrahydrofuran are added. The mixture is fluxed for 5 hours. After cooling to room temperature, the reaction mixture is filtered, obtaining a precipitate, which is dried under reduced pressure leading to a solid which is recrystallized from ethanol.

[0359] Activity examples

[0360] Example 17: Photocytotoxicity assays

[0361] The anticancer activity of invention compounds J1 to J6 was tested against human lung (A549), cervical (HeLa), and prostate (PC3) cancer cells, obtained from the American Type Culture Collection. All cell lines were cultured in Dulbecco’s Modified Eagle’s Medium supplemented with 10% fetal bovine serum, 1 % glutamine and 1 % penicillinstreptomycin (Corning) at 37°C in a humidified atmosphere of 5% CO2. For the assays, cells were seeded into 96-well cell culture plates at a density of 2500 cells per well and allowed to attach for 24 h. Next, cells were treated with the complexes diluted from 1 to 100 pM in cell culture medium. Cells were incubated for 4 h to allow the internalization of the compounds and then maintained in the dark or irradiated for 1 h with a blue light (460 nm, 24.1 J cm-2). In A549 cells, Cisplatin (1 mg / ml; Accord Healthcare) was used as a positive control. After 72 h of treatment, solutions were removed, and cells were washed with phosphate-buffered saline (PBS). Next, 100 pL of culture medium together with 10 pLof 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) (Sigma- Aldrich) (final concentration 0.5 mg / ml) was added to each well and plates were incubated for 2 h at 37 °C. After discarding the medium, DMSO was added to each well to dissolve the purple formazan crystals. The absorbance of each well was determined on a Multiscan Plate Reader (Synergy 4, Biotek, Winooski, USA) at a wavelength of 570 nm. For each treatment, four replicates were measured. The concentration that reduces the cell viability by 50% (IC50) was established for each compound using the Gen5 software (BioTek). Three independent experiments were carried out for each compound.

[0362] Table 1. Data of photocytotoxicity assays forA549 lung cancer cell line.

[0363] PI* = Phototoxic Index: IC50, Dark / ICsO, Light

[0364] Table 2. Data of photocytotoxicity assays for HeLa cervix cancer cell line.

[0365] PI* = Phototoxic Index: IC50, Dark / ICsO, Light Table 3. Data of photocytotoxicity assays for MRC-5 normal lung cells

[0366] PI* = Phototoxic Index: IC50, Dark / ICsO, Light

[0367] Example 17: Comparative photocytotoxicity assays

[0368] For comparative purposes, the photocytotoxicity activity of compounds according to the invention (J1-J12) was compared with that shown by similar derivatives (1-4) having ruthenium in its structures [Journal of Inorganic Biochemistry 246, 2003, 112291], The structures of metallic complexes 1-4 are depicted below:

[0369]

[0370] Table 4. Data of photocytotoxicity assays for A549 lung cancer cell line of metal complexes (1-4) and compounds J1-J12. PI* = Phototoxic Index: IC50, Dark / ICsO, Light. ’Comparative complexes 1-4 were previously irradiated for 2.5 h with continuous visible light.

[0371] Table 5. Data of photocytotoxicity assays for HeLa cervix cancer cell line of metal complexes (1-4) and compounds J 1 -J 11. previously irradiated for 2.5 h with continuous visible light.

[0372] The data shown in tables 4 and 5 show that, not only the compounds of the presence invention display photocytotoxic activity without the presence of a metal, but that this photocytotoxic activity is even increased in most of the cases.

[0373] It is also noted that irradiation in the photocitotoxicity examples performed with derivatives J1-J12 took place during 1 hour, whereas irradiation in the photocitotoxicity examples performed with metallic complexes 1-4 took place during 2.5 hours. Interestingly the latter metallic examples showed worse antiproliferative activities.

Claims

CLAIMS1 . Compound of formula (I) for use in photodynamic therapy and / or photoactivated chemotherapy of cancerFormula (I) whereinR1and R2are independently selected from:• H;• C1-C18 linear or branched alkyl, optionally substituted with a group selected from■ =0,■ a -COOR5group or -COR5group, wherein R5represents H or Ci- 012 alkyl;■ a sulfonate group and■ a phosphate group;• allyl optionally substituted in C2 with C1-C18 linear or branched alkyl; and• monosaccharide optionally substituted with acyl or amino group.R3, R3’, R3” R4, R4’ and R4” are independently selected from H or C1-C4 linear or branched alkyl;Y is independently selected from O, S , Se and C1-C4 alkyl;X is independently selected from CF SOs' or halogen; a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ;d represents 0, 1 or 2; and the dashed line represents a simple bond or a double bond.

2. Compound for use according to claim 1 , whereinR1and R2are independently selected from:• H;• C1-C18 linear or branched alkyl, optionally substituted with a group selected from■ =0,■ a -COOR5group or -COR5group, wherein R5represents H or Ci- 012 alkyl;■ a sulfonate group and■ a phosphate group;• allyl optionally substituted in C2 with C1-C18 linear or branched alkyl; and• monosaccharide optionally substituted with acyl or amino group.R3, R3’, R3” R4, R4’ and R4” are independently selected from H or C1-C4 linear or branched alkyl;Y is independently selected from O, S and Se;X is independently selected from CF SOs' or halogen; a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; and d represents 0, 1 or 2.

3. Compound for use according to claim 1 or 2, wherein R3, R3’, R3”, R4, R4’ and R4” are H.

4. Compound for use according to any of claims 1 to 3, wherein z is 0.

5. Compound for use according to any of claims 1 to 3, wherein z is 1 and Y is O.

6. Compound for use according to any one of claims 1 to 5, wherein a is 1 .

7. Compound for use according to claim 6, wherein the sum of m and n is 1 and d is 1.

8. Compound for use according to claim 6, wherein the sum of m and n is 2 and d is 2.

9. Compound for use according to any one of claims 1 to 5, wherein a is 0.

10. Compound for use according to any one of the previous claims, wherein R1and R2are independently selected from:• H;• C1-C18 linear or branched alkyl, optionally substituted with a group selected from■ =0,■ a -COOR5group or -COR5group, wherein R5represents H or C1-C12 alkyl;■ a sulfonate group and■ a phosphate group.

11. Compound for use according to any of the previous claims, wherein R1and R2are independently selected from: H or Ci-Cs linear or branched alkyl, optionally substituted with =0.

12. Compound for use according to any of the previous claims in photodynamic therapy and / or photoactivated chemotherapy of cancer, wherein X is CFsSCh'.

13. Compound for use according to claim 1 , whereinR1and R2are independently selected from:• C1-C4 linear or branched alkyl, optionally substituted with =0R3, R3’, R3” R4, R4’ and R4” are HY is independently selected from O, S, Se and C1-C2 alkyl;X is independently selected from CFsSCh'or halogen;a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; andd represents 0, 1 or 2.

14. Compound for use according to claim 13, whereinR1and R2are independently selected from:• CH3• C2 alkyl substituted with =0R3, R3’, R3” R4, R4’ and R4” are H;Y is independently selected from O, S, Se and CH3;X is CF3SO3- a represents 0 or 1 ; m represents 0 or 1 ; n represents 0 or 1 ; z represents 0 or 1 ; and d represents 0, 1 or 2.

15. Compound for use according to any of claims 1 to 3 or 13 to 14, selected from the group consisting of:

16. Compound for use according to any of claims 1 to 3 or 13 to 14, selected from the group consisting of:

17. Compound for use according to any of claims 1 to 3 or 13 to 14, selected from the group consisting of:

18. Compound of formula (I’)Formula (I’) wherein a represents 1 , thenR1and R2are independently selected from:• H;• C1-C18 linear or branched alkyl substituted with a group selected from■ =0,■ sulfonate and■ phosphate groups;• C7-C11 linear or branched unsubstituted alkyl;• C7-C18 linear or branched alkyl substituted with a COOR5group or - COR5group , wherein R5represents H or C1-C12 alkyl;• allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and• monosaccharide optionally substituted with acyl or amino group.R3, R3’, R3”, R4, R4’ and R4” are independently selected from H or C1-C4 lineal or branched alkyl;Y is independently selected from O, S, Se and C1-C4 alkyl;X is independently selected from CF SO ' or halogen; the sum of m+n represents 1 or 2; z represents 0 or 1 ; and d represents, 1 or 2; or wherein a represents 0, thenR1and R2are independently selected from• C2-C18 linear or branched alkyl, optionally substituted with a group selected from■ a COOR5group or -COR5, wherein R5represents H or C1-C12 alkyl;■ a sulfonate group; and■ a phosphate group;• allyl optionally substituted in C2 with: C1-C18 linear or branched alkyl; and• monosaccharide optionally substituted with acyl or amino group.R3, R3’, R3” R4, R4’, R4” are independently selected from H or C1-C4 lineal or branched alkyl;Y is independently selected from O, S and Se; the sum of m+n represents 2; z represents 0 or 1 ; and d represents 0; and the dashed line represents a simple bond or a double bond.

19. A method for preparing a compound of formula (I’) according to f claim 18, comprising the steps of: a) providing a solution containing 1 ,3,5-triaza-7-phosphaadamantane (PTA) or a precursor , wherein the precursor is a mixture of P(CH2OH) , formaldehyde and hexamethylenetetramine; b) optionally adding a C1-C4 linear or branched alkyl derivative to the solution of step (a) to obtain a compound of formula (II):wherein at least one of R3, R3’, R3” R4, R4’ and R4” is C1-C4 linear or branched alkyl; c) adding a R’-X derivative or a an acid to the solution of step (a) or step (b) to obtain a compound of formula (I’) wherein z is 0; d) optionally reacting the P atom of the compound of step (c) with an oxidizing agent to obtain a compound of formula (I’) wherein z is 1 .

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