Azobenzene derivatives, methods for their preparation and their use in therapeutic treatments in combination with ionizing radiation - Patents.com

Abstract

The present invention relates to new ionizing radiation activatable derivatives, their preparation and their therapeutic use.

Description

[Technical field]

[0001] The present invention relates to the therapeutic treatment of medical conditions, such as cancer, using compounds activatable by ionizing radiation. [Background technology]

[0002] Redox and photosensitive systems have been developed for over a century and are used to induce complex actions such as specific bond cleavage or conformational switching, which result in the release of active molecules that can be used to control protein activity and gene expression, etc. Unfortunately, the clinical application of these sensitive systems remains limited to topical or ophthalmic procedures due to the current lack of techniques capable of activating these systems at depths greater than several hundred micrometers below the body surface, except for the use of invasive electrodes or optical fibers. In fact, all photosensitive molecules developed so far are only sensitive to UV, visible, or near-infrared radiation, and their penetration into tissues is inherently limited.

[0003] Ionizing radiation-induced activation of compounds has been proposed in WO 2011 / 158189, however the efficacy is very limited and requires doses that are too high for clinical application. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] WO 2011 / 158189 [Non-patent literature]

[0005] [Non-Patent Document 1] S.M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 66:1-19 (1977) [Non-Patent Document 2] RC Larock, "Comprehensive Organic Transformations", VCH Publishers, 1989 [Non-Patent Document 3] TW Green and PGM Wuts, Protective Groups in Organic Chemistry, John Wiley and Sons, 1991 [Non-Patent Document 4] JFW McOmie, Protective Groups in Organic Chemistry, Plenum Press, 1973. Summary of the Invention [Problem to be solved by the invention]

[0006] It is therefore desirable to have available new compounds that can be activated by irradiation without depth limitations in target biological tissues. Ionizing radiation can be used to effectively reach deep tissues, where the high energy of the radiation is locally converted to specifically activate redox / photosensitive therapeutic systems. [Means for solving the problem]

[0007] According to the present invention, a molecular energy transducer (a metal chelate) is combined with a photosensitive switch (an azobenzene moiety) to give a photosensitive system that can be activated by moderate doses of highly penetrating light compatible with clinical applications.

[0008] Therefore, according to a first object, the present invention provides a method for producing ... liquid crystal display comprising the steps of: In the form of cis and / or trans isomers and mixtures thereof, Formula (I)

[0009] [ka]

[0010] Compounds of or a pharma- ceutically acceptable salt thereof. [In the formula, M is Ce(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb( III), Mg(II), Ca(II), Mn(II), Fe(II), Fe(III), Cu(II), Zn(II), Ga(III), Y(III), Zr(III), Tc(IV), Tc(VI), Tc (VII), Ru(II), Ru(III), Ru(IV), Pd(II), Ag(I), In(III), Hf(IV), Re(VI), W(II), W(III), W(IV), W(V), W(VI), O represents a metal atom selected from s(III), Os(IV), Ir(III), Ir(IV), Pt(II), Au(I), Au(III), Tl(III), Zr(IV), Nb(III), Bi(III), n is 1, 2, 3, 4, 5, 6, or 7; V and V' may be the same or different and are a hydrogen atom, or a linear or branched C1-C10 alkyl or alkoxy chain, or a C1-C10 alkyl chain bonded to each other and containing one or more heteroatoms selected from N, O, or S, and optionally substituted with halogen atoms, and one or more substituents independently selected from nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid, or carboxylate groups to form a ring; R1, R1', R2, and R2' may be the same or different and are a hydrogen atom or a linear or branched C1-C10 alkyl or alkoxy chain optionally substituted with one or more substituents independently selected from halogen atoms, nitrile groups, nitro groups, thio groups, amino groups, amido groups, aryl groups, heteroaryl groups, hydroxyl groups, carboxylic acid groups, or carboxylate groups; R3 and R3' may be the same or different and are hydrogen atoms or linear or branched C1-C10 alkyl or alkoxy chains, optionally substituted with one or more substituents independently selected from halogen atoms and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid, or carboxylate groups; or R3 and R3' are bonded together to form a 5-14 membered heterocycle or heteroaryl; m and m' may be the same or different and are equal to 1 or 2; X, X', X", X''', Y, Y', Y", and Y''', may be the same or different and are independently selected from H; a halogen atom; an alkoxy, alkyl, or cycloalkyl group optionally interrupted or substituted with one or more heteroatoms, or COOH, CONH2, COSH, OH, NH2, or SH groups; a 5-12 membered aryl or heteroaryl group optionally substituted with one or more COOH, CONH2, or COSH groups; a COOH group or an NH2 group; Z represents an alkyl group, optionally interrupted or substituted with one or more heteroatoms, or COOH, CONH2, COSH, OH, NH2, SH groups; a 5-12 membered aryl or heteroaryl group, optionally substituted with one or more COOH, CONH2, COSH groups; or a COOH or NH2 group, W and W' may be the same or different and independently represent a CH group; or an aryl or cycloalkyl group; an oxygen or nitrogen atom (secondary or tertiary); an amide bond; an ester bond; or a thioether bond; U and U' may be the same or different and represent a CH or NH group, it being understood that the double bond U=U' is in cis or trans form, T represents a CH group; a -C(=O)NH group; an alkoxy group, alkyl group, or cycloalkyl group, optionally interrupted or substituted with one or more heteroatoms, or COOH, CON, COSH, OH, NH, SH groups; a 5-12 membered aryl group or heteroaryl group containing one or more heteroatoms and / or optionally substituted with one or more groups selected from COOalkyl, CONHalkyl, COSHalkyl; R represents H or a linear or branched C1-C18 alkyl or alkoxy chain, optionally substituted with one or more substituents independently selected from halogen atoms, nitrile groups, nitro groups, thio groups, amino groups, amido groups, aryl groups, heteroaryl groups, hydroxyl groups, carboxylic acid groups, or carboxylate groups; p and q are integers between 0 and 6, specifically between 1 and 6; It is understood that to ensure neutrality of the molecule, the n cationic charges of M may be optionally neutralized by 0 to n carboxylate groups (-COOH) substituted on R1, R1', R2, R2', R3, R3', V, V', and / or by 0 to n counter ions present in solution, if necessary.

[0011] The compounds according to the invention, when activated by ionizing radiation, can induce the permeability and death of cancer cells. After the introduction of the inactive (cis) form, irradiation with ionizing radiation to the target site is applied. This radiation induces the conversion of the molecule to its active form (trans), resulting in the permeability and death of the cells due to the change in the lipophilic balance of the molecule. The light beam used to activate the molecule penetrates into biological tissues without depth limitations, making the activation technique perfectly suitable for clinical applications and different from conventional photosensitive tools (penetration of less than 1 cm of biological tissues), whose activation is limited to UV to near-infrared irradiation.

[0012] The compounds according to the invention are radiosensitive, in that their action is induced by ionizing radiation, and therefore are promising tools for the control and modulation of therapeutic action in real time.

[0013] Metal atoms with sizes between Z=20 and Z=83, specifically the following metals: Fe, Cu, Zn, Ga, Y, Zr, Tc, Ru, Pd, Ag, In, Eu, Gd, Tb, Dy, Ho, Yb, Hf, W, Os, Ir, Pt, Au, Bi.

[0014] In the above general formula (I), the following embodiments - V and V' are linked to each other by a C1-C9 alkyl chain containing two nitrogen atoms and optionally substituted with two carboxylate groups; and / or - V and V' combine to form a chain

[0015] [ka]

[0016] and / or - Z represents a -CH(COOH)- group, and / or - m=m'=1, and / or - R2=R3=R2'=R3'=H, and / or R1=R1′=(CH2)COOH, and / or - p=q=2, and / or - Y=Y'=Y"=Y'''=H, - W=W'=O, - U=U'=NH are contemplated separately or in any combination thereof.

[0017] According to one embodiment, the compound of formula (I) has the general formula (IA)

[0018] [ka]

[0019] or a pharma- ceutically acceptable salt thereof. [In the formula, M, n, R1, R2, R3, V, m, R1', R2', R3', V', m', p are defined as in formula (I); X is selected from a hydrogen atom and a halogen atom; R is a linear or branched C1-C12 alkyl group; The N=N double bond may be in cis or trans configuration; It is understood that the n cationic charges of M may be neutralized by 0 to n carboxylate groups (-COOH) substituted on R1, R1', R2, R2', R3, R3', V, V', and / or by 0 to n counter ions present in solution, if necessary, to ensure neutrality of the molecule.

[0020] According to one embodiment, the compound of formula (I) has the general formula (IB)

[0021] [ka]

[0022] or a pharma- ceutically acceptable salt thereof. [In the formula, M, n, p, X, and R are defined as above.

[0023] According to one embodiment, the compound of formula (I) has the general formula (IC)

[0024] [ka]

[0025] or a pharma- ceutically acceptable salt thereof. [In the formula, M, n, and X are defined as above.

[0026] According to one embodiment, in formula (I), (IA) or (IB), - X is selected from H and F; and / or - R represents a linear C4-C8 alkyl group; - p=2, M is a metal selected from Cu, Ga, Y, In, Eu, Gd, Yb, Bi, - n=2 or 3.

[0027] In the above and below: "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups have 1 to about 12 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain.

[0028] "Alkoxy" means an alkyl-O- group, where the alkyl group is as previously described. Typical alkoxy groups include methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, and heptoxy.

[0029] "Cycloalkyl" means a non-aromatic monocyclic or multicyclic ring system of about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred ring sizes of the ring systems contain about 5 to about 6 ring atoms. Exemplary monocyclic cycloalkyls include cyclopentyl, cyclohexyl, and cycloheptyl.

[0030] "Carboxy" refers to a HO(O)C-group (carboxylic acid).

[0031] "Aryl" means an aromatic monocyclic or multicyclic ring system having about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. Typical examples of aryl groups include phenyl and naphthyl.

[0032] "Heteroaryl" means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 carbon atoms, preferably about 5 to about 10 carbon atoms, where one or more of the carbon atoms in the ring system is a heteroatom other than carbon, such as nitrogen, oxygen, or sulfur. Preferred ring sizes of the ring system include about 5 to about 6 ring atoms. Exemplary heteroaryl groups include pyrazinyl, thienyl, isothiazolyl, oxazolyl, pyrazolyl, furazanyl, pyrrolyl, 1,2,4-thiadiazolyl, pyridazinyl, quinoxalinyl, phthalazinyl, imidazo[1,2-a]pyridine, imidazo[2,1-b]thiazolyl, benzofurazanyl, azaindolyl, benzimidazolyl, benzothienyl, thienopyridyl, thienopyrimidinyl, pyrrolopyridyl, These include imidazopyridyl, benzazaindole, 1,2,4-triazinyl, benzothiazolyl, furanyl, imidazolyl, indolyl, indolizinyl, isoxazolyl, isoquinolinyl, isothiazolyl, oxadiazolyl, pyrazinyl, pyridazinyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, 1,3,4-thiadiazolyl, thiazolyl, thienyl, and triazolyl.

[0033] "Halogen" means fluorine, chlorine, bromine or iodine. Preferred are fluorine, chlorine or bromine, especially fluorine.

[0034] The present invention also relates to the therapeutic use of the compounds according to the invention.

[0035] According to another object, the present invention relates to a pharmaceutical composition comprising a compound of formula (I) predominantly in the cis form and at least one pharma- ceutically acceptable excipient.

[0036] According to another object, the present invention relates to compounds of formula (I), in the cis and / or trans form, for use in the treatment of cancer.

[0037] Compounds of formula (I) below can be activated by exposure to ionizing radiation, whereby the cis double bond switches to the cytotoxic trans form.

[0038] Said use therefore comprises the steps of administering a compound of formula (I) which is predominantly in the cis form, and applying radiation to the target site so as to form the trans compound in situ.

[0039] The use also includes monitoring the treatment by in vivo MRI, PET, X-ray, or SPECT imaging.

[0040] According to one embodiment, said use comprises administering to a patient in need thereof an effective amount of a compound of formula (I) in the cis form.

[0041] According to one embodiment, the administration of said compounds of formula (I) may generally be performed parenterally.

[0042] The ionizing radiation generally considered corresponds to the radiation used in radiotherapy treatments. Such effects, induced by external stimuli, allow temporal and spatial control and can be adjusted according to real-time requirements to achieve optimal therapeutic effects. Such effects include ionizing radiation such as photons (X-rays and gamma rays with energies ranging from 1 keV to 25 MeV), electrons, and hadrons (such as protons or carbon with energies ranging from 60 to 300 MeV), specifically X-rays (1 to 200 keV), gamma rays (662 keV), and electron beams (4500 keV).

[0043] This radiation makes it possible to achieve the desired activation at low doses of between 2 and 20 Gy, in particular between 2 and 10 Gy, more particularly between 2 and 5 Gy.

[0044] When the action of the compound of the present invention works through cell permeability, therapeutic approach is not limited to specific cell surface characteristics, so in some cases, all cancers can be treated by the compound of the present invention.Cancer includes lung cancer, pancreatic cancer, liver cancer, spleen cancer, small cell lung cancer, prostate cancer, rhabdomyosarcoma, gastric cancer, gastrointestinal cancer, colorectal cancer, kidney cancer, breast cancer, ovarian cancer, testicular cancer, thyroid cancer, head and neck cancer, skin cancer, soft tissue sarcoma, bladder cancer, bone cancer, myeloma, plasmacytoma, germ cell cancer, uterine cancer, leukemia, lymphoma, neuroblastoma, osteosarcoma, retinoblastoma, central nervous system cancer, Wilms' tumor, especially pancreatic cancer or leukemia.

[0045] In one embodiment, the use also allows the presence of the compound and its molecular switching to be detected in vivo by MRI due to the presence of a metal atom in the molecular structure of the compound of the invention.

[0046] MRI detection of the compounds of the invention allows for non-invasive localization and monitoring of the therapeutic action of said compounds, thus facilitating the development and monitoring of therapeutic protocols and thus enabling theranostic approaches.

[0047] According to one embodiment, the compounds of the present invention may be administered in combination with one or more anti-cancer agents, for example chemotherapy or immunotherapy, such as immune checkpoint inhibitors, such as anti-CTLA4, anti-PD-L1, and anti-PD1.

[0048] "Effective amount" means an amount of a compound / composition according to the invention that is effective in producing a desired therapeutic effect.

[0049] "Formulations suitable for parenteral administration" means formulations that are in a form suitable for parenteral administration to a patient. The formulations are sterile, may contain suspending agents, viscosity agents, and antioxidants (after ensuring that potential radioprotective effects of these doses under radiation do not interfere with the desired effect), emulsions, suspensions, aqueous and non-aqueous injection solutions, buffers, bacteriostats, and solutes that render the formulation isotonic and have a pH properly adjusted to the blood of the desired recipient.

[0050] The formulation is preferably administered by injection, including intramuscular, intravenous, intraperitoneal, and subcutaneous. For injection, the compound useful according to the present invention can be formulated in a liquid solution, preferably in a physiologically compatible buffer such as Hank's solution or Ringer's solution. In addition, the compound can be formulated in solid form and redissolved or suspended immediately before use. Lyophilized forms are also included.

[0051] The selection of the vehicle and the content of active substance in the vehicle is generally determined by the solubility and chemical properties of the active compound, the particular mode of administration, and regulations followed in pharmaceutical practice.

[0052] The formulation may be prepared in individual pharmaceutical forms by any method well known in the pharmaceutical field.These methods include the step of combining the active ingredient with the carrier that constitutes one or more accessory ingredients.Generally, the formulation is prepared by uniformly and directly combining the active ingredient with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product.

[0053] The actual dosage level of the active ingredient in the compositions of the present invention may be varied to obtain an effective amount of the active ingredient to achieve the desired therapeutic response for the particular composition and mode of administration. The selected dosage level will therefore depend on the desired therapeutic effect, the mode of administration, the desired duration of treatment, and other factors.

[0054] A dosage unit composition may contain the amount of the composition that may be used to make up a daily dose. However, it will be understood that the specific dosage level for any particular patient will depend on a variety of factors, including body weight, general health, sex, diet, timing and method of administration, absorption rate, excretion rate, combination with other drugs, and the severity of the disease being treated.

[0055] The amount of each component to be administered will be determined by the treating physician, taking into account the etiology and severity of the disease, the health status and age of the patient, the potency of each component and other factors.

[0056] The formulations may be presented in single or multi-dose containers, for example, ampoules and vials sealed with elastomeric stoppers and may be stored in lyophilized form requiring only the addition of the sterile liquid carrier, for example, water for injections, prior to use. Extemporaneous solutions in injection solutions and suspensions may be prepared from sterile powders, granules, and tablets of the kind described above.

[0057] "Liquid dosage form" refers to the dosage of active compound administered to a patient in liquid form, such as emulsions, solutions, suspensions, syrups, and pharma- ceutically acceptable elixirs. In addition to the active compound, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (after confirming that potential radioprotective effects of these doses under irradiation do not interfere with the desired effect), specifically cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and sorbitan fatty acid esters, or mixtures of these substances.

[0058] A "patient" includes both humans and other mammals.

[0059] "Pharmaceutical composition" refers to a composition containing a compound of formula I and, depending on the nature of the mode of administration and dosage form, at least one component selected from the group consisting of pharma- ceutically acceptable carriers, diluents, adjuvants, excipients, or vehicles, such as preservatives, fillers, wetting agents, emulsifiers, suspending agents, antibacterial agents, antifungal agents, lubricants, and dispersing agents. Examples of suspending agents include ethoxylated isostearyl alcohol, polyoxyethylene sorbitol esters and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, and tragacanth, or mixtures of these substances. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, and sorbic acid. It may also be desirable to include isotonic agents, such as sugars and sodium chloride. Examples of suitable carriers, diluents, solvents, or vehicles include water, ethanol, polyol, suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate.

[0060] "Pharmaceutically acceptable" means, within the scope of sound medical judgment, suitable for use in contact with the cells of humans and lower animals without undue toxicity, irritation, or allergic response, etc., and commensurate with a reasonable risk / benefit ratio.

[0061] The term "pharmaceutically acceptable salts" refers to relatively non-toxic inorganic and organic acid addition and base addition salts of the compounds of the present invention. These salts can be prepared in situ during the final isolation and purification of the compounds. Specifically, acid addition salts can be prepared by separately reacting the purified compounds in their purified form with an organic or inorganic acid and isolating the resulting salt. Examples of acid addition salts include, for example, salts described by S. M. Berge et al., "Pharmaceutical Salts," J. Pharm. Sci, 66:1-19 (1977). Acid addition salts can also be prepared by separately reacting the purified compounds in their acid form with an organic or inorganic base and isolating the resulting salt. Suitable inorganic base addition salts are prepared from metal bases including sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, and zinc hydroxide. Suitable base amino addition salts are prepared from amines having sufficient alkalinity to form stable salts, and preferably include those amines frequently used in medicinal chemistry due to their low toxicity and acceptability for medical applications.

[0062] It is to be understood that the present invention covers all appropriate combinations of particular and preferred groupings referred to herein.

[0063] According to another object, the present invention also provides a process for preparing a compound of formula (I), comprising in the form of cis and / or trans isomers and mixtures thereof, Compound of formula (II)

[0064] [ka]

[0065] [In the formula, R1, R2, R3, V, m, R1', R2', R3', V', m', Z, T, q, p, W, W', X, X', X", X''', Y, Y', Y", Y''', R, U, U' are as defined above. with a precursor of metal M; - possible UV irradiation of the resulting product to obtain mainly the cis isomer. The present invention relates to a method comprising the steps of:

[0066] Complexation with the metal agent M can be carried out in a solvent such as water at a temperature between room temperature and the reflux temperature of the reaction mixture, for example between 40 and 100° C. Typically the pH of the solution is maintained between 5 and 7.

[0067] According to one embodiment, the compound of formula (II) has the formula (IIA)

[0068] [ka]

[0069] have [wherein R1, R2, R3, V, m, R1', R2', R3', V', m', p, X, and R are defined as in formula (I)].

[0070] According to one embodiment, the compound of formula (II) has the formula (IIB)

[0071] [ka]

[0072] have [wherein p, X, R are defined as in formula (I)].

[0073] According to one embodiment, the compound of formula (II) has the formula (IIC)

[0074] [ka]

[0075] have wherein X is defined as in formula (I).

[0076] According to one embodiment, the compound of formula (II) is a compound of formula (III) and a compound of formula (IV)

[0077] [ka]

[0078] [In the formula, R1, R2, R3, V, m, R1', R2', R3', V', m', Z, T, q, p, W, W', X, X', X", X''', Y, Y', Y", Y''', R, U, U' are as defined above; E is a linear or branched C1-C10 alkyl or alkoxy chain, a cycloalkyl group or an aryl group, optionally containing one or more heteroatoms selected from N, O, or S, and optionally fused to or substituted with one or more substituents independently selected from halogen atoms, and anhydride, carboxy, nitrile, nitro, thio, amino, amide, aryl, heteroaryl, hydroxyl, ester, carboxylic acid, or carboxylate groups, with the proviso that E contains a nucleophilic substituent such as a hydroxyl, thiol, or primary or secondary amine functionality to effect coupling to molecule (III); G is a linear or branched C1-C10 alkyl or alkoxy chain, a cycloalkyl group, or an aryl group, optionally containing one or more heteroatoms selected from N, O, or S, and optionally substituted with one or more substituents independently selected from halogen atoms, anhydride groups, carboxy groups, nitrile groups, nitro groups, thio groups, amino groups (primary or secondary), amide groups, aryl groups, heteroaryl groups, hydroxyl groups, carboxylic acid groups, or carboxylate groups, it being understood that G contains an electrophilic substituent, such as an activated carboxylic acid or anhydride functional group, for coupling to molecule (IV). This is obtained by coupling with

[0079] The coupling reaction may be carried out in the presence of a base, in particular an organic base such as triethylamine, etc. The reaction may be carried out under anhydrous conditions.

[0080] According to one embodiment, the compound of formula (III) has the formula (IIIA)

[0081] [ka]

[0082] have [In the formula, R1, R2, R3, V, m, R1', R2', R3', V', and m' are as defined above.]

[0083] According to one embodiment, the compound of formula (III) has the formula (IIIB)

[0084] [ka]

[0085] has. According to one embodiment, the compound of formula (IV) has the formula (IVA)

[0086] [ka]

[0087] have [wherein p, X and R are as defined in formula (I)].

[0088] According to one embodiment, the compound of formula (IV) has the formula (IVB)

[0089] [ka]

[0090] have [wherein p, W, W', X, X', X", X''', Y, Y', Y", Y''', R, U and U' are as defined above].

[0091] According to one embodiment, the compound of formula (IV) has the formula (IVC)

[0092] [ka]

[0093] have wherein X is as defined in formula (I).

[0094] Compounds of formula (III) are generally commercially available. Specifically, the compound of formula (IIIB) is the compound DOTAGA.

[0095] Compounds of formula (IV) may be prepared by application and / or adaptation of the synthetic methods illustrated hereinafter in the examples.

[0096] In general, the starting products and intermediates of the compounds useful in the present invention can be prepared by the application and / or adaptation of known methods used heretofore or described in the literature, for example those described by RC Larock in "Comprehensive Organic Transformations", VCH Publishers, 1989.

[0097] In the reactions, reactive functional groups, such as hydroxy, amino, imino, thio, and carboxy groups, may need to be protected to avoid their undesired participation in the reaction if their presence in the final product is desired. Conventional protecting groups can be used in accordance with standard practice, see, for example, TW Green and PGM Wuts, "Protective Groups in Organic Chemistry", John Wiley and Sons, Inc., 1991; JFW McOmie, "Protective Groups in Organic Chemistry", Plenum Press, Inc., 1973.

[0098] Unless otherwise stated, there are no particular limitations on the nature of the solvent used, provided that it has no adverse effect on the reaction or the reagents involved. Examples of suitable solvents include hydrocarbons, which may be aromatic, aliphatic, or cycloaliphatic hydrocarbons, such as hexane, cyclohexane, benzene, toluene, and xylene; amides, particularly fatty acid amides, such as dimethylformamide, and ethers, such as diethyl ether, and tetrahydrofuran.

[0099] The reaction may take place over a wide range of temperatures, typically between about 0° C. and 150° C., preferably between about room temperature and about 100° C. The time required for the reaction may vary widely, depending on many factors, including the reaction temperature and the nature of the reagents.

[0100] Thus, the compound prepared can be recovered from the reaction mixture by conventional means.For example, the compound can be recovered by distilling the solvent from the reaction mixture, or, if necessary, by distilling the solvent from the solution mixture and then pouring the residue into water, followed by extraction with a water-immiscible organic solvent and distilling the solvent from the extract.In addition, if desired, the product can be further purified by various techniques, such as recrystallization, reprecipitation, or various chromatographic methods, including column chromatography or preparative thin-layer chromatography.

[0101] Acid addition salts can be formed with compounds useful in the present invention in which a basic functional group such as an amino group, an alkylamino group, or a dialkylamino group is present. Pharmaceutically acceptable, i.e. non-toxic, acid addition salts are preferred. The salt selected is optimally selected to be compatible with common pharmaceutical vehicles and suitable for parenteral administration. Acid addition salts of compounds useful in the present invention can be prepared by reaction of the free base with a suitable acid by applying or adapting known methods. For example, acid addition salts of compounds useful in the present invention can be prepared either by dissolving the free base in water, or aqueous alcoholic solution, or a suitable solvent containing the appropriate acid, and isolating the salt by evaporating the solution, or by reacting the free base with the acid in an organic solvent, in which case the salt can be directly separated or obtained by concentration of the solution. Acid addition salts of compounds useful in the present invention can be regenerated from the salt by applying or adapting known methods. For example, the parent compound useful in the present invention can be regenerated from its acid addition salt by treatment with an alkali, for example aqueous sodium bicarbonate or aqueous ammonia.

[0102] Compounds that are useful according to the invention can be regenerated from their base addition salts by the application or adaptation of known methods. For example, parent compounds that are useful according to the invention can be regenerated from their base addition salts by treatment with an acid, for example hydrochloric acid.

[0103] Base addition salts may be formed when the compounds useful according to the invention contain a carboxyl group. Bases that may be used to prepare base addition salts preferably include those which, when combined with the free acid, produce pharma- ceutically acceptable salts, i.e., salts whose cations are not toxic to patients at pharmaceutical doses of the salt, such that the beneficial inhibitory effects inherent in the free base are not offset by side effects attributable to the cation. Pharmaceutically acceptable salts, including those derived from alkaline earth metal salts, that are within the scope of the present invention include those derived from the following bases: sodium hydride, sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, lithium hydroxide, magnesium hydroxide, zinc hydroxide, ammonia, ethylenediamine, N-methyl-glucamine, lysine arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)-aminomethane, tetramethylammonium hydroxide, and the like.

[0104] The compounds useful according to the invention can be readily prepared or formed during the process of the invention as solvates (e.g., hydrates). Hydrates of the compounds useful according to the invention can be readily prepared by recrystallization using organic solvents, such as dioxane, tetrahydrofuran, or methanol, from aqueous / organic solvent mixtures. [Brief description of the drawings]

[0105] [Figure 1]Absorbance spectra of cis-GdAzo (a) and cis-GdFAzo (d) under gamma irradiation in PBS are shown. PPS1: photoequilibria containing mainly cis isomers. b, e: Histograms (n=3) representing the molecular activation of cis-GdAzo and cis-Azo (Gd-free control molecules) (b) or of cis-GdFAzo and cis-FAzo control molecules without Gd (e) under gamma irradiation in PBS, as determined by HPLC and calculated by the difference in the proportion of trans isomers in the medium. c: Molecular activation of cis-GdAzo and cis-GdFAzo under X-ray, gamma, and linac linear electron accelerator. f: Histograms (n=3) representing the molecular activation of cis-MAzo (M is the metal indicated on the X-axis) under gamma irradiation in PBS, as determined by HPLC and calculated by the difference in the proportion of trans isomers in the medium. Gy: Gray (JL-1). XR: X-ray irradiation. GR: gamma irradiation. E: linac linear electron accelerator irradiation. NI: no irradiation. Standard deviations are plotted in the graph. ***P<0.001 (2-way ANOVA with Bonferroni post-hoc test). [Diagram 2]a: Microscopic images of cancer cells (Panc-1, human pancreatic cancer) in the presence of propidium iodide and the inactive compound cis-GdAzo (1, 2) at a concentration of 500 μM, or the active compound trans-GdAzo (3, 4), before (1, 3) or 30 min (2, 4) introduction of the compounds. Overlay of white light and fluorescent images (propidium iodide in the nucleus appears red, indicating membrane permeabilization). b: Microscopic images of cancer cells (Panc-1) in the presence of propidium iodide and the inactive compound cis-GdAzo at a concentration of 250 μM (1, 2) or 500 μM (3, 4), under gamma radiation irradiation (2 Gy), before (1, 3) or 30 min (2, 4) irradiation of the medium. c: Histograms comparing the impact of gamma irradiation (2 Gy) on cell permeabilization (Panc-1) in the presence of propidium iodide and cis-GdAzo (n=3). d, e: Histograms comparing the impact of gamma irradiation (2 Gy) on the mortality of Gem-resistant cancer cells (CCRF-CEM ARAC-8C, human acute lymphoblastic leukemia) after 4 days of treatment in the presence of cis-GdAzo (d) or in the presence of cis-GdAzo and Gem (0.1 μM) (e) for 1 hour. f: Histograms comparing the impact of gamma irradiation (2 Gy) on the mortality of Gem-resistant cancer cells (CCRF-CEM ARAC-8C) in the presence of Dotarem® or Dotarem® and Gem (0.1 μM). Gy: Gray (JL-1). GR: gamma irradiation. NI: no irradiation. The standard error of the mean is plotted in graph c, and the standard deviation is plotted in graphs d–f. *P<0.05, **P<0.01, ***P<0.001 (2-way ANOVA with Bonferroni post-hoc test). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS EXAMPLES

[0106] I. Chromatographic Analysis Method A HPLC (high performance liquid chromatography) analysis was performed with a 1565 binary HPLC pump (Waters), a PAD2998 reader (Waters) using an Agilent EclipseXDB-C18 reversed-phase column (length: 250 mm, diameter: 4.6 mm, stationary phase: 5 μm) with a 0.05% water-TFA / 0.05% acetonitrile-TFA gradient system; 0' (98 / 2), 5' (98 / 2), 25' (0 / 100), 27' (0 / 100), 29' (98 / 2), 35' (98 / 2) at a flow rate of 1 mL min. -1 (30 μL injection). Data were processed in Empower.

[0107] Method B LCMS (liquid chromatography mass spectrometry) analysis was performed using an Alliance 2695 system (Waters) with an XBridge C18 reversed-phase column (length: 150 mm, diameter: 2.1 mm, stationary phase: 3.5 μm) and a 0.1% water-FA / acetonitrile gradient system; 0' (95 / 5), 20' (0 / 100) at a flow rate of 0.25 mL / min. -1 (10 μL injection). The mass analyzer was a TOF LCT Premier (Waters). The capillary voltage was 2.8 kV. The cone voltage was 35 V. The source temperature was 120° C. and the desolvation temperature was 280° C. Data were processed with MassLynx.

[0108] Method C HPLC analysis was performed on a 2525 binary HPLC pump (Waters) connected to a 515 HPLC pump (Waters), a PAD2996 reader (Waters) using an XBridge C18 reversed-phase column (length: 100 mm, diameter: 3.0 mm, stationary phase: 3.5 μm) with a 0.05% water-TFA / acetonitrile isocratic system at a flow rate of 0.75 mL.min. -1 (10 μL injection). The detection wavelength corresponded to the isobestic point of the studied compound in the mobile phase used. Data were processed with MassLynx.

[0109] II.Overview overview All reagents were purchased from Sigma-Aldrich or Alfa Aesar at the highest purity available and used without further purification. DOTAGA anhydride was purchased from CheMatech and used without further purification. Silica gel (Aldrich 717185 Si 60, 40-63 μm) used for flash chromatography was purchased from VWR. RP-18 reversed-phase flash chromatography was performed on a CombiFlash® instrument (Biotage). Thin-layer chromatography was performed using aluminum foil coated with 60F254 silica gel (detection by 254 nm UV lamp or ninhydrin). 1 H, 13 C, and 19 F NMR spectra were obtained on a Bruker 300 MHz or 400 MHz spectrometer at ambient temperature. Chemical shifts δ are given in ppm using the solvent as reference. Coupling constants J are measured in Hz. Coupling profiles are described by the abbreviations d (doublet), t (triplet) and m (multiplet). High-resolution mass spectrometry (HRMS) experiments were carried out in a 3 / 7 H2O / methanol mixture using a time-of-flight mass analyzer with a TOF-LCT Premier mass spectrometer (Waters) by electrospray ionization in positive mode unless otherwise indicated. Chromatographic analytical methods (HPLC and LCMS) are described in the dedicated paragraphs. The purity of the synthetic intermediates was confirmed by the following methods: 1 The purity of the final product was determined by reverse phase HPLC and found to be >95%.

[0110] The following compounds

[0111] [ka]

[0112] [Wherein, X=H or F, Wherein M=Cu, Ga, Y, In, Eu, Gd, Yb, or Bi; In the formula, n=2 or 3] The synthesis scheme below

[0113] [ka]

[0114] It was synthesized according to

[0115] Synthesis of 4-hydroxy-4'-butoxyazobenzene (1) 4-Butoxyaniline (2.00 mL, 12.0 mmol) and sodium nitrite (0.854 g, 12.0 mmol, 1.0 equiv.) were dissolved in a 1:1 EtOH / H2O mixture (24 mL) and the medium was cooled to 0 °C. Ice (12 g) was introduced into the medium, then cc HCl (2.6 mL) was carefully added. An aqueous solution (6.3 mL) of phenol (1.14 g, 12.0 mmol, 1.0 equiv.) and NaOH (0.960 g, 24.0 mmol, 2.0 equiv.) previously prepared was cooled to 0 °C and carefully introduced into the medium at 0 °C. The medium was stirred for 20 min at 0 °C and then for 70 min at ambient temperature (AT). After adjusting the pH to 1 (cc HCl), the medium was left at AT for 30 min and then filtered. The precipitate was washed with water (4×50 mL), dissolved in DCM, and the organic phase was dried over MgSO4 and concentrated. 4-Hydroxy-4′-butoxyazobenzene 1 (2.76 g, 10.2 mmol, 85%) was isolated as a black amorphous powder. 1 H NMR(400 MHz; CDCl3) δ (ppm): 7.87 (d; J = 8.9 Hz; 2H); 7.82 (d; J = 8.8 Hz; 2H); 6.98 (d; J = 8.9 Hz; 2H); 6.91 (d; J = 8.8 Hz; 2H); 4.03 (t; J = 6.5 Hz; 2H); 1.85 - 1.75 (m; 2H); 1.58 - 1.45 (m; 2H); 0.99 (t; J = 7.4 Hz; 3H) 13C NMR(75 MHz; CDCl3) δ (ppm): 161.51; 158.38; 146.89; 146.63; 124.81; 124.56; 116.07; 114.92; 68.22; 31.35; 19.33; 13.96. HRMS (m / z): C 16 H 19 Calculated value for N2O2: 271.1447 ([M+H] + ). Actual value: 271.1440. R f = 0.36 (SiO2; DCM; UV).

[0116] Synthesis of (N-(tert-butyloxycarbonyl)-ethoxyamine)-4'-butoxyazobenzene (2) 4-Hydroxy-4'-butoxyazobenzene 1 (2.00 g, 7.40 mmol) and K2CO3 (1.53 g, 11.1 mmol, 1.5 equiv.) were dissolved in acetone (25 mL). After stirring at AT under argon for 30 min, 2-(Boc-amino)ethyl bromide (4.98 g, 22.2 mmol, 3.0 equiv.) was introduced into the medium. After stirring at reflux for 18 h, the medium was filtered off while hot and the precipitate was washed with hot acetone (75 mL). The filtrate was left at AT for 30 min, then filtered and the precipitate 1 obtained was washed with cold acetone. The filtrate was left at 0 °C for 3 h, then filtered. The precipitate 2 obtained was washed with cold acetone and added to precipitate 1. The filtrate was concentrated and purified by flash chromatography on silica (DCM). 4-(N-(tert-butyloxycarbonyl)-ethoxyamine)-4′-butoxyazobenzene 2 (2.27 g, 5.49 mmol, 74%) was isolated as a yellow amorphous powder (57% by precipitation, 17% by flash chromatography). 1H NMR(400 MHz; CDCl3) δ (ppm): 7.86 (2d; J = 8.9 Hz; 4H); 6.99 (2d; J = 8.9 Hz; 4H); 4.10 (t; J = 5.0 Hz; 2H); 4.04 (t; J = 6.5 Hz; 2H); 3.57 (m; 2H); 1.87 - 1.74 (m; 2H); 1.64 - 1.40 (m; 11H); 1.00 (t; J = 7.4 Hz; 3H). 13 C NMR(100 MHz; CDCl3) δ (ppm): 161.46; 160.62; 156.03; 147.51; 147.07; 124.52; 124.48; 114.84; 114.82; 79.79; 68.18; 67.64; 40.27; 31.42; 28.55; 19.38; 13.98. HRMS (m / z): C 23 H 32 Calculated value for N3O4: 414.2393 ([M+H] + ). Actual value: 414.2396. R f = 0.90 (SiO2; DCM / MeOH 98:2; UV).

[0117] Synthesis of 4-aminoethoxy-4'-butoxyazobenzene (3) 4-(N-(tert-butyloxycarbonyl)-ethoxyamine)-4'-butoxyazobenzene 2 (1.26 g, 3.04 mmol) was dissolved in a 4:1 DCM / TFA mixture (63 mL) and the medium was stirred at AT for 1.5 h. After concentration, diethyl ether (250 mL) was introduced and the formed precipitate was concretized for 1 h, filtered and washed with diethyl ether (4 x 50 mL). 4-Aminoethoxy-4'-butoxyazobenzene 3 (1.25 g, 2.93 mmol, 96%, TFA salt) was isolated as a yellow amorphous powder. 1H NMR (400 MHz; MeOD) δ (ppm): 7.88 (d; J = 8.9 Hz; 2H); 7.85 (d; J = 8.9 Hz; 2H); 7.15 (d; J = 8.9 Hz; 2H); 7.04 (d; J = 8.9 Hz; 2H); 4.32 (t; J 1.86 - 1.73 (m; 2H); 1.60 - 1.46 (m; 2H); 1.00 (t; J = 7.4 Hz; 3H). 13 C NMR (75 MHz; MeOD) δ (ppm): 163.03; 161.34; 148.97; 148.10; 125.42; 125.30; 115.99; 115.80; 69.12; 65.59; 40.24; 32.43; 20.28; 14.16. HRMS (m / z): C 18 H 24 Calculated value for N3O2: 314.1869 ([M+H] + ). Actual value: 314.1864. HPLC (Method A); t R 17.92 minutes (cis)-20.35 minutes (trans). R f = 0.70 (SiO2; DCM / MeOH 95:5; UV or ninhydrin).

[0118] Synthesis of 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (Azo) 4-Aminoethoxy-4'-butoxyazobenzene 3 (259 mg, 0.606 mmol, TFA salt) was dissolved in anhydrous DMF (4.3 mL). After introduction of triethylamine (253 μL, 1.81 mmol, 3.0 equiv.), the medium was stirred under argon at AT for 5 min. DOTAGA anhydride (278 mg, 0.606 mmol, 1.0 equiv.) was then introduced and the medium was stirred under argon at 70 °C for 21 h. After concentration, diethyl ether (100 mL) was introduced and the formed precipitate was allowed to flocculate for 30 min before being filtered and washed with diethyl ether (2 × 50 mL). The crude product was purified by reversed-phase flash chromatography (RP-18, Biotage, gradient H2O 0.05% FA / CH3CN 0.05% FA 1:0 to 2:8). 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic acid-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene Azo (294 mg, 0.381 mmol, 63%) was isolated by lyophilization in the form of a yellow electrostatic powder. HRMS(m / z):C 37 H 54 N7O 11 Calculated for: 772.3881 ([M+H] + ). 772.3883 was found. LCMS (Method B);t R 12.357min(cis)-14.437min(trans).

[0119] Synthesis of 2,6-difluoro-4-hydroxy-2',6'-difluoro-4'-butoxyazobenzene (4) 2.6-Difluoro-4-butoxyaniline (2.20 g, 10.9 mmol) and sodium nitrite (0.755 g, 10.9 mmol, 1.0 equiv.) were dissolved in a 1:1 EtOH / H2O mixture (22 mL) and the medium was cooled to 0 °C. Ice (11 g) was introduced into the medium, then cc HCl (2.37 mL) was carefully added. An aqueous solution (5.7 mL) of 3,5-difluorophenol (1.42 g, 10.9 mmol, 1.0 equiv.) and NaOH (0.876 g, 21.9 mmol, 2.0 equiv.) previously prepared was cooled to 0 °C and carefully introduced into the medium at 0 °C. The medium was stirred for 20 min at 0 °C and then for 70 min at AT. After adjusting the pH to 1 (cc HCl), the medium was left at AT for 30 min and then filtered. The precipitate was washed with water (4×50 mL), dissolved in DCM, and the organic phase was dried over MgSO4 and concentrated. The residue (black viscous liquid) was concentrated under reduced pressure manifold (3.15 g) and used in the next step without further purification. 1 H NMR (400 MHz; DMSO) δ (ppm): 6.93 (d; JH-F = 11.4 Hz; 2H); 6.64 (d; JH-F = 11.4 Hz; 2H); 4.09 (t; J = 6.5 Hz; 2H); 1.77 - 1.66 (m; 2H); 1.49 - 1.38 (m; 2H); 0.94 (t; J = 7.4 Hz; 3H) 13 C NMR (101 MHz; DMSO) δ (ppm): 161.40 (t; J C-F = 14.8 Hz); 161.11 (t; J C-F = 14.8 Hz); 157.69 (dd; J C-F = 39.1; 7.7 Hz); 155.13 (dd; J C-F = 38.2; 7.8 Hz); 125.00 (t; J C-F = 10.2 Hz) 124.05 (t; J C-F = 10.3 Hz); 100.26 (dd; J C-F = 22.6; 2.0 Hz); 99.68 (dd; J C-F= 24.2; 2.1 Hz); 68.74 (s); 30.31 (s); 18.55 (s); 13.58 (s). 19 F NMR (376 MHz; DMSO; decoupled) δ (ppm): -118.99; -119.27. 19 F NMR (376 MHz; DMSO) δ (ppm):-118.99 (d; J F-H = 12.1 Hz); -119.27 (d; J F-H = 12.0 Hz). HRMS (m / z): C 16 H 15 Calculated value for F4N2O2: 343.1070 ([M+H] + ). Actual value: 343.1060. R f = 0.20 (SiO2; cyclohexane / ethyl acetate 9:1; UV).

[0120] Synthesis of 2,6-difluoro-4-(N-(tert-butyloxycarbonyl)-ethoxyamine)-2',6'-difluoro-4'-butoxyazobenzene (5) 2,6-Difluoro-4-hydroxy-2',6'-difluoro-4'-butoxyazobenzene 4 (2.18 g crude, assumed to be 6.37 mmol) and K2CO3 (1.32 g, 9.57 mmol, 1.5 equiv.) were dissolved in acetone (22 mL). After stirring at AT under argon for 30 min, 2-(Boc-amino)ethyl bromide (4.29 g, 19.1 mmol, 3.0 equiv.) was introduced into the medium. After stirring at reflux for 18 h, the medium was concentrated and purified by flash chromatography on silica (cyclohexane / ethyl acetate, gradient 1 / 0 to 7 / 3). 2,6-Difluoro-4-(N-(tert-butyloxycarbonyl)-ethoxyamine)-2',6'-difluoro-4'-butoxyazobenzene 5 (624 mg, 1.28 mmol, 17% over two steps) was isolated as a yellow amorphous powder. 1H NMR (400 MHz; DMSO) δ (ppm): 7.04 (s; 1H); 6.95 (d; JH-F = 11.8 Hz; 4H); 4.10 (m; 4H); 3.34 - 3.26 (m; 2H); 1.75 - 1.67 (m; 2H); 1.49-1.39 (m; 2H); 1.38 (s; 9H); 0.94 (t; J = 7.4 Hz; 3H). 13 C NMR (101 MHz; DMSO) δ (ppm): 161.53 (t; J c-F = 14.3 Hz); 161.16 (t; J c-F = 14.2 Hz); 157.59 (t; J c-F = 7.9 Hz); 155.64 (s); 155.03 (t; J c-F = 7.7 Hz); 125.09 (t; J c-F = 8.3 Hz); 124.90 (t; J c-F = 8.3 Hz); 99.90 (dd; J c-F = 11.3; 1.7 Hz); 99.67 (dd; J c-F = 11.3; 1.7 Hz); 77.86 (s); 68.80 (s); 67.87 (s); 38.71 (s); 30.29 (s); 28.17 (s); 18.53 (s); 13.57 (s) 19 F NMR (376 MHz; DMSO; デカップリング) δ (ppm): -118.79; -118.85. 19 F NMR (376 MHz; DMSO) δ (ppm): -118.79 (d; J F-H = 12.0 Hz); -118.85 (d; J F-H = 11.9 Hz). HRMS (m / z): C 23 H 28 Calculated value of F4N3O4; 486.2016 ([M+H] + ). Measured value 486.2015. R f= 0.30 (SiO2; cyclohexane / ethyl acetate 8:2; UV).

[0121] Synthesis of 2,6-difluoro-4-aminoethoxy-2',6'-difluoro-4'-butoxyazobenzene (6) 2,6-Difluoro-4-(N-(tert-butyloxycarbonyl)-ethoxyamine)-2,6-difluoro-4'-butoxyazobenzene 5 (879 mg, 1.81 mmol) was dissolved in a 4:1 DCM / TFA mixture (37 mL) and the medium was stirred at AT for 1.5 h. After concentration, diethyl ether (200 mL) was introduced and the formed precipitate 1 was allowed to flocculate for 1 h before being filtered and washed with diethyl ether (4 x 100 mL). The filtrate was concentrated and a viscous precipitate 2 was formed in n-hexane (200 mL), filtered and washed with n-hexane (3 x 200 mL). Precipitates 1 and 2 were dried under a vacuum manifold. 2,6-Difluoro-4-aminoethoxy-2',6'-difluoro-4'-butoxyazobenzene 6 (858 mg, 1.72 mmol, 95%, TFA salt) was isolated as a yellow amorphous powder (precipitate 1, 70%) and a yellow oil (precipitate 2, 25%). 1 H NMR (400 MHz; DMSO) δ (ppm): 7.98 (s; 3H); 7.00 (d; J H-F = 11.3 Hz; 2H); 6.96 (d; J H-F 4.11 (t; J = 6.5 Hz; 2H); 3.26 (t; J = 5.0 Hz; 2H); 1.80 - 1.63 (m; 2H); 1.53 - 1.33 (m; 2H); 0.94 (t; J = 7.4 Hz; 3H). 13 C NMR (101 MHz; DMSO) δ (ppm): 161.76 (t; J C-F = 14.4 Hz); 160.27 (t; J C-F = 14.0 Hz); 157.57 (dd; J C-F= 25.8; 7.6 Hz); 155.00 (dd; J C-F = 25.9; 7.4 Hz); 125.57 (s); 124.86 (s); 100.07 (dd; J C-F = 24.7; 2.7 Hz); 99.80 (dd; J C-F = 24.7; 2.5 Hz); 68.85 (s); 65.82 (s); 38.06 (s); 30.29 (s); 18.54 (s); 13.57 (s) 19 F NMR (376 MHz; DMSO; decoupled) δ (ppm): -73.46; -118.60; -118.74. 19 F NMR (376 MHz; DMSO) δ (ppm): -73.46 (s); -118.60 (d; J F-H = 11.9 Hz); -118.73 (d; J F-H = 11.8 Hz). HRMS (m / z): C 18 H 20 Calculated value for F4N3O2: 386.1492 ([M+H] + ). Actual value: 386.1491. R f = 0.33 (SiO2; DCM / MeOH 95:5; UV or ninhydrin).

[0122] Synthesis of 2,6-difluoro-4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-2',6'-difluoro-4'-butoxyazobenzene (FAzo) 2,6-Difluoro-4-aminoethoxy-2',6'-difluoro-4'-butoxyazobenzene 6 (267 mg, 0.535 mmol, TFA salt) was dissolved in anhydrous DMF (3.8 mL). After the introduction of triethylamine (223 μL, 1.60 mmol, 3.0 equiv.), the medium was stirred under argon at AT for 5 min. DOTAGA anhydride (245 mg, 0.533 mmol, 1.0 equiv.) was then introduced and the medium was stirred under argon at 70 °C for 21 h. After concentration, diethyl ether (100 mL) was introduced and the formed precipitate was allowed to flocculate for 30 min before being filtered and washed with diethyl ether (2 × 50 mL). The crude product was purified by reversed-phase flash chromatography (RP-18, Biotage, gradient HO 0.05% FA / CHCN 0.05% FA 1:0 to 2:8). 2,6-Difluoro-4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-tri-acetic acid-10-glutaryl)-ethoxyamine)-2,6-difluoro-4'-butoxyazobenzene FAzo (92.1 mg, 0.109 mmol, 20%) was isolated by lyophilization in the form of a yellow electrostatic powder. HRMS(m / z):C 37 H 50 F4N7O 11 Calculated for: 844.3504 ([M+H] + ) 844.3495 was found. LCMS (Method B);t R 14.107min(cis)-14.894min(trans).

[0123] General protocol for complexing Azo and FAzo Azo or FAzo and metal reagents were dissolved in HO (26 mM). After adjusting the pH to 5.5, the medium was stirred at 50 °C for 17 h while ensuring that the pH remained in the range of 5.5-6.0. The pH was then adjusted to 6.5 before concentrating the medium by lyophilization and purifying by reversed-phase flash chromatography (RP-18, Biotage, gradient HO / CHCN 1:0 to 0:1). The final product was isolated by lyophilization as an electrostatic powder.

[0124] [Table 1]

[0125] Copper 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (CuAzo) HRMS(m / z):C 37 H 51 N7NaO 11 Calculated for Cu; 855.2840 ([M+Na] + ) 855.2854 was found. LCMS (Method B);t R 13.550min(cis)-15.934min(trans).

[0126] Gallium 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (GaAzo) HRMS(m / z):C 37 H 51 N7O 11 Calculated for Ga; 838.2902 ([M+H] + ) 838.2906 was found. LCMS (Method B);t R 12.840min(cis)-15.072min(trans).

[0127] Yttrium 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (YAzo) HRMS(m / z):C 37 H 49 N7Na2O 11 Calculated for Y: 902.2344 ([M-H+2Na] + ) 902.2349 was detected. LCMS (Method B);t R 15.957min(cis)-19.660min(trans).

[0128] Indium 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (InAzo) HRMS(m / z):C 37 H 49 N7Na2O 11 Calculated for In; 928.2324 ([M-H+2Na] + ) 928.2319 was detected. LCMS (Method B);t R 15.451min(cis)-18.899min(trans).

[0129] Europium 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (EuAzo) HRMS (m / z) (negative mode): C 37 H 49 N7O 11 Calculated for Eu: 920.2702 ([MH] - ) 920.2694 was detected. LCMS (Method B);t R 13.419min (cis) - 16.718min (trans).

[0130] Gadolinium 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (GdAzo) HRMS(m / z):C 37 H 49 N7Na2O 11 Calculated for Gd: 971.2527 ([M-H+2Na] + ) 971.2529 was detected. LCMS (Method B);t R 15.956min(cis)-19.633min(trans).

[0131] Gadolinium 2,6-difluoro-4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-2',6'-difluoro-4'-butoxyazobenzene (GdFAzo) HRMS(m / z):C 37 H 45 F4N7Na2O 11 Calculated for Gd: 1043.2150 ([M-H+2Na] + ). 1043.2158 was found. LCMS (Method B);t R 18.900min(cis)-20.524min(trans).

[0132] Ytterbium 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (YbAzo) HRMS(m / z):C 37 H 49 N7Na2O 11 Calculated for Yb: 987.2674 ([M-H+2Na] + ) 987.2683 was detected. LCMS (Method B);t R 16.112min (cis) - 19.968min (trans).

[0133] Bismuth 4-(N-(1,4,7,10-tetraazacyclododecane-1,4,7-triacetate-10-glutaryl)-ethoxyamine)-4'-butoxyazobenzene (BiAzo) HRMS(m / z):C 37 H 49 N7Na2O 11 Calculated for Bi: 1022.3089 ([M-H+2Na] + ) 1022.3093 was found. LCMS (Method B);t R 14.235min (cis) - 19.055min (trans).

[0134] III. Ionizing Radiation and Cellular Experiments overview Phosphate-buffered saline (PBS), Dulbecco's modified Eagle's medium high glucose (DMEM), Roswell Park Memorial Institute medium (RPMI), penicillin, streptomycin, and trypan blue solution (0.4%) were purchased from Sigma Aldrich (France), fetal bovine serum (FBS) was purchased from Gibco (France), propidium iodide (PI) was purchased from Thermo Fisher Scientific (France), and gemcitabine hydrochloride (Gem) was purchased from Sequoia Research Products (UK).

[0135] cell line Human pancreatic cancer (PANC-1) cells and human acute lymphoblastic leukemia (CCRF-CEM) cells were purchased from ATCC (USA) and maintained as recommended by the supplier. Gem-resistant human acute lymphoblastic leukemia cells (CCRF-CEM ARAC 8C, not expressing the hENT-1 receptor) were kindly provided by Dr. Buddy Ullmann (Oregon Health Sciences University). Briefly, PANC-1 cells were maintained in DMEM buffer supplemented with 10% (v / v) heat-inactivated FBS. CCRF-CEM and CCRF-CEM ARAC-8C cells were maintained in RPMI buffer supplemented with 10% (v / v) heat-inactivated FBS. All cell culture media contained penicillin (50 U.mL -1 ) and streptomycin (0.05 mg.mL -1 ) supplemented. Cells were maintained in a humidified atmosphere of 5% CO2 at 37°C. Cells were used up to passage 18 and harvested at 70-80% confluence.

[0136] Sources of ionizing radiation UV irradiation. UV irradiation to induce isomerization of trans isomers to cis isomers was performed at 0.817 mW.cm at the irradiation position. -2The experiments were carried out in a CN-15.LC chamber (Vilber Lourmat) equipped with two 15 W tubes (365 nm) giving an irradiance of 100 nm (determined by a Cole-Parmer VLX-3W microprocessor-controlled radiometer, Vilber Lourmat, calibrated to 365 nm).

[0137] X-ray irradiation. X-ray irradiation was performed using an X-ray generator (Xrad 320 Dx) delivering photons with a mean energy of 80 keV (range 0-200 keV) at a dose rate of approximately 1 Gy / min (operating at 200 kV, 20 mA). Radiation dose is expressed in Gray.

[0138] Gamma irradiation. Gamma irradiation was performed using a Cesium-137 source (IBL637) delivering 662 keV photons at a dose rate of approximately 1 Gy / min. Radiation dose is expressed in grays (1 Gy = 1 J / L).

[0139] Electron beam irradiation. Electron beam irradiation was performed using a linear electron accelerator (Linac, Kinetron) emitting electrons with an energy of 4.5 MeV at a dose rate of approximately 4 Gy / min. Radiation dose is expressed in grays.

[0140] Quantification of ionizing radiation-induced isomerization by spectrophotometry and HPLC (Figure 1) Gd-containing compounds (GdAzo or GdFAzo) and control compounds (Azo or FAzo) (50 μM, 200 μL, PBS) were introduced into two 96-well microplates (10 wells for each compound). Both microplates were first irradiated under UV light (365 nm, 0.817 mW.cm -2, 5 min). One microplate (plate 1) was then kept in the dark and used as a non-irradiated control, while the second microplate (plate 2) was irradiated with incremental doses of ionizing radiation (2 Gy, 3 Gy, 5 Gy, and 10 Gy). After each irradiation, spectrophotometric and HPLC injection (method C) analyses were performed on the non-irradiated compounds (plate 1) and the irradiated compounds (plate 2). Using a time difference of 26 min between UV irradiation of plates 1 and 2, the analysis of the non-irradiated control compounds (plate 1) was performed simultaneously with the ionizing irradiated compounds (plate 2) after UV irradiation. The complete experiment was performed in 4.6 h. The absorbance spectra were plotted by the average value of triplicates. The relative amount of each isomer was obtained by HPLC (detection at the isosbestic wavelength under the elution conditions) and the molecular activation (%) was determined by the difference in the proportion of the trans isomer in the medium (three independent experiments).

[0141] Confocal microscopy without ionizing radiation (Figure 2a) Cells (PANC-1) were transferred to an imaging plate (ibiTreat 8-well microslides purchased from Ibidi, Germany) 24 hours before the start of the experiment and maintained in culture medium (33000 cells in 200 μL / well) in a humidified atmosphere at 37°C with 5% CO2. Just before the experiment, the cell medium was replaced with culture medium without FBS and phenol red (100 μL), and then IP (5 μL, final concentration 1 μM) was added to the medium. 15 minutes after adding IP, the first series of images was acquired. Then, cis-GdAzo or trans-GdAzo compounds (100 μL, final concentrations 0 μM, 250 μM, or 500 μM) were introduced into the cell medium. The imaging plate was then kept in the dark and images were acquired every 5 minutes for 1 hour. The compound cis-GdAzo was incubated in a 96-well microplate with the compound trans-GdAzo irradiated with UV light (365 nm, 0.817 mW.cm -2, 30 min) (105 μL, 500 μM, or 1 mM, cis-GdAzo>85%). Cells were observed with a Leica TCS SP8 gated-STED inverted microscope (Leica, Germany) using a Fluotar CS2 10× / 0.30sec HC PL objective. The instrument was equipped with a white light laser (excitation wavelength 538 nm). Red fluorescence emission was collected with a bandwidth of 560–650 nm, and transmission images were acquired with the same light line and PMT-trans detector. The pinhole was set to 1.0 Airy (73.19 μm diameter). 16-bit digital images were acquired with Leica SP8 LAS X software (version 2.0.1, Leica, Germany).

[0142] Confocal microscopy in the presence of ionizing radiation (Figure 2b-c) Cells (PANC-1) were transferred to imaging plates (Lab-Tek chamber slide system, glass, 8 wells, purchased from Thermo Fisher Scientific, France) 24 hours before the start of the experiment and maintained in culture medium (10,000 cells in 200 μL / well) in a humidified atmosphere at 37°C with 5% CO2. Just before the experiment, the cell medium was replaced with PBS (100 μL) and IP (5 μL, final concentration 1 μM) was added to the medium. 15 minutes after adding PI, cis-GdAzo (100 μL, final concentrations 0 μM, 250 μM, 500 μM, or 850 μM) was introduced into the cell medium. At this stage, a first series of images was acquired and then the imaging plate was irradiated (gamma radiation, 2 Gy). The imaging plate was then left in the dark at 37°C (plate is warmer) and images were acquired every 5 min for 30 min and then every 10 min for 90 min. A similar procedure was used for the no-irradiation control experiment, except that the imaging plate was not irradiated with gamma rays. Cis-GdAzo compounds were obtained by UV irradiation (365 nm, 0.817 mW.cm-2, 30 min) of trans-GdAzo compounds in 96-well microplates (105 μL, 500 μM, 1 mM, or 1.7 mM, cis-GdAzo >85%). Cells were observed with a Nikon inverted microscope (Nikon Instruments Inc., Tokyo, Japan) equipped with a Yokogawa CSU-X1 head using a ×10sec objective NA0.4. The instrument was equipped with a laser diode with an excitation wavelength of 561 nm. Red fluorescence emission was collected with a bandwidth of 598-672 nm, and transmission images were obtained using a white diode. The pinhole was set at 50 μm and the magnification lens at 1.2. Images were recorded with an e-Volve s-CMOS camera (Photometrics). Four images were recorded per well, with two wells used for each concentration of cis-GdAzo. Analysis of 16-bit digital images was performed using ImageJ software (version 1.50i with the Adjustable Watershed plug-in).The number of cells in images acquired before irradiation was determined manually, and the number of fluorescent cells in images acquired before and after irradiation was calculated automatically using a script coded in ImageJ. Cell permeabilization was determined by the difference in the percentage of fluorescent cells before and 30 min after gamma irradiation (three independent experiments).

[0143] Treatment effect under ionizing radiation (Figure 2d-2f) Immediately before the experiment, cells (CCRF-CEM ARAC-8C) were dispersed in PBS and transferred (40,000 cells in 80 μL / well) into 48-well microplates (TPP cell culture microplates purchased from Thermo Fisher Scientific, France). Gem (20 μL, final concentration 0.1 μM) or PBS (20 μL) and cis-GdAzo compounds (100 μL, final concentrations 0 μM, 250 μM, 500 μM, or 850 μM) were added just before the medium was gamma-irradiated (2 Gy). The medium was kept in the dark in a humid atmosphere at 37°C with 5% CO2 for 1 h. Then, culture medium (600 μL) was added to each well and the cells were washed by three centrifugation cycles (300G, 5 min, 800 μL of culture medium was used for each wash). Finally, the cells were dispersed in culture medium (600 μL) with or without Gem (final concentration 0 μM or 0.1 μM) and maintained in a humidified atmosphere at 37° C. with 5% CO2 for 4 days. The number of viable cells was determined by cell counting in the presence of 1:1 (v / v) trypan blue (triplicate). The experiments were repeated three times independently. Cell viability was expressed as the ratio of the number of viable cells after treatment to the number of viable cells without any treatment (no irradiation, absence of Gem and cis-GdAzo). A similar procedure was used for the control experiment without irradiation, except that the 48-well microplates were not irradiated with gamma rays. A similar procedure was used for the control experiment with Dotarem®, except that Dotarem® was used instead of cis-GdAzo (FIG. 2f). Cis-GdAzo compounds were obtained by UV irradiation (365 nm, 0.817 mW.cm-2, 30 min) of trans-GdAzo compounds in 96-well microplates (105 μL, 500 μM, 1 mM, or 1.7 mM, cis-GdAzo>85%).

[0144] These results are (i) The new concept of activation of therapeutic molecules by the use of ionizing radiation (X-rays, gamma rays, electrons) (Fig. 1a-f). This new activation concept has strong potential for clinical use, since these radiations have a very high penetration power in living tissues. All organic molecules described in the literature today require the use of UV-near IR radiation, which does not penetrate deep into living tissues (it penetrates up to several hundred micrometers in the best conditions). (ii) It is possible to activate MAzo compounds (M = Cu, Ga, Y, In, Eu, Gd, Yb, Bi) by ionizing radiation, with different efficiencies depending on the metal and the radiation source used (Fig. 1a-c, f). The GdFAzo compound can also be activated by ionizing radiation (Fig. 1c-e). This compound is characterized by a thermal relaxation that is slow enough to allow for in vivo studies. Although the activation of the compound GdFAzo is relatively low under the experimental conditions used in vitro (compared to the compound GdAzo, Fig. 1c), it is difficult to predict the efficiency of molecular activation that the compound will have in vivo. (iii) The type of metal used to allow activation of the organic units. It has been shown that the atomic number Z of the metal must be greater than 39 (the atomic number of yttrium) to allow consistent activation (>30% under 5 Gy). Indeed, six compounds containing metals the size of yttrium or larger showed such activation, while two compounds containing smaller metals (Cu, Z=29 and Ga, Z=31) showed poor activation (<10% under 5 Gy) (Figure 1f). (iv) Molecular activation can be performed with various types of ionizing radiation (X-rays, gamma rays, electrons) with different particles (photons and electrons) and different energies (1 keV to 4.5 MeV) (Figure 1c), therefore, the set of radiotherapy devices currently used in clinical practice should be effective in generating the described molecular activation. (v) The compound GdAzo is capable of inducing permeabilization of cancer cell membranes under low doses of ionizing radiation (6.9% (vs. 1.2% without irradiation), 8.2% (vs. 2.8% without irradiation), and 12.4% (vs. 7.5% without irradiation) at GdAzo concentrations of 250 μM, 500 μM, and 850 μM, respectively, with 2 Gy of gamma radiation) (Figures 2a, 2b, and 2c). (vi) The compound GdAzo is capable of inducing toxicity in a gemcitabine-resistant cancer cell line (human acute lymphoblastic leukemia) after treatment with 2 Gy of gamma radiation in the absence or presence of gemcitabine (Fig. 2d, Fig. 2e). In the absence of gemcitabine, cell viability at 4 days after treatment was reduced to 23% (compared to 79% without irradiation), 18% (compared to 42% without irradiation), and 3.0% (compared to 27% without irradiation) at GdAzo concentrations of 250 μM, 500 μM, and 850 μM, respectively. In the presence of gemcitabine, cell viability at 4 days after treatment was reduced to 15% (vs. 49% without irradiation), 9.1% (vs. 30% without irradiation), and 1.2% (vs. 16% without irradiation) at GdAzo concentrations of 250 μM, 500 μM, and 850 μM, respectively. This study indicates that the compound is active under ionizing radiation alone, and that the presence of surrounding active material only slightly enhances the therapeutic effect of the compound (FIG. 2d, e). (vii) The presence of an azobenzene or stilbene motif on the molecule is necessary to produce a therapeutic effect, since the commercially available control compound Dotarem® (gadolinium chelate alone) has no therapeutic effect under ionizing radiation (Figure 2f). Shows.

Claims

1. In the form of cis and / or trans isomers and mixtures thereof, General formula (IB) 【Chemistry 1】 [In the formula, M is Ce(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Y b(III), Mg(II), Ca(II), Mn(II), Fe(II), Fe(III), Zn(II), Ga(III), Y(III), Zr(III), Tc(IV), Tc(VI), Tc(VII ), Ru(II), Ru(III), Ru(IV), Pd(II), Ag(I), In(III), Hf(IV), Re(VI), W(II), W(III), W(IV), W(V), W(VI), Os( III), Os(IV), Ir(III), Ir(IV), Pt(II), Au(I), Au(III), Tl(III), Zr(IV), Nb(III), Bi(III), n is 1, 2, 3, 4, 5, 6, or 7; X is H; a halogen atom; optionally one or more COOH groups, CONH 2 group, COSH group, OH group, NH 2 an alkoxy group, an alkyl group, or a cycloalkyl group substituted with a group, an SH group; optionally one or more COOH groups, CONH 2 a 5- to 12-membered aryl or heteroaryl group substituted with a COSH group; a COOH group or a NH 2 are independently selected from the group R represents H or a linear or branched C1-C18 alkyl or alkoxy chain, optionally substituted with one or more substituents independently selected from halogen atoms and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid, or carboxylate groups; p is an integer between 0 and 6. Compound.

2. General formula (IC) 【Chemistry 2】 [In the formula, M, n, X are defined as in claim 1.

2. The compound of claim 1 having the formula:

3. A process for preparing a compound according to claim 1 or 2, comprising the steps of: in the form of cis and / or trans isomers and mixtures thereof, Compound of formula (IIB) 【Chemistry 3】 wherein p, X, and R are as defined in claim 1. with a precursor of said metal M; - possible UV irradiation of the resulting product to obtain mainly the cis isomer. A method comprising:

4. The compound of formula (IIB) is reacted with a compound of formula (IIIB) and a compound of formula (IVA): 【Chemistry 4】 [In the formula, p is as defined in claim 1. The method of claim 3, obtained by

5. 13. A pharmaceutical composition comprising a compound of formula (IB) according to claim 1, predominantly in the cis form, and at least one pharma- ceutically acceptable excipient.

6. 2. The compound of formula (IB) according to claim 1 for use in the treatment of cancer such as lung cancer, pancreatic cancer, liver cancer, spleen cancer, small cell lung cancer, prostate cancer, rhabdomyosarcoma, gastric cancer, gastrointestinal cancer, colorectal cancer, renal cancer, breast cancer, ovarian cancer, testicular cancer, thyroid cancer, head and neck cancer, skin cancer, soft tissue sarcoma, bladder cancer, bone cancer, myeloma, plasmacytoma, germ cell cancer, uterine cancer, leukemia, lymphoma, neuroblastoma, osteosarcoma, retinoblastoma, central nervous system cancer, Wilms' tumor, etc.

7. The compound of formula (IB) for use according to claim 6, comprising the administration of a predominantly cis form of compound (IB) and irradiation of the tumor with ionizing radiation, in particular those selected from X-rays, gamma rays, electron beams and hadron beams, such as protons or carbon ions.

8. 8. The compound of formula (IB) for use according to claim 6 or 7, further comprising monitoring said treatment by in vivo medical imaging such as MRI, PET, X-ray or SPECT.

9. 9. The compound of formula (IB) for use according to any one of claims 6 to 8, further comprising the step of administering one or more anti-cancer agents such as chemotherapy or immunotherapy, such as immune checkpoint inhibitors such as anti-CTLA4, anti-PD-L1, and anti-PD1.

10. In the form of cis and / or trans isomers and mixtures thereof, Formula (IB) 【Chemistry 5】 [In the formula, M is Ce(III), Pr(III), Nd(III), Sm(III), Eu(III), Gd(III), Tb(III), Dy(III), Ho(III), Er(III), Tm(III), Yb( III), Mg(II), Ca(II), Mn(II), Fe(II), Fe(III), Cu(II), Zn(II), Ga(III), Y(III), Zr(III), Tc(IV), Tc(VI), Tc (VII), Ru(II), Ru(III), Ru(IV), Pd(II), Ag(I), In(III), Hf(IV), Re(VI), W(II), W(III), W(IV), W(V), W(VI), O represents a metal atom selected from s(III), Os(IV), Ir(III), Ir(IV), Pt(II), Au(I), Au(III), Tl(III), Zr(IV), Nb(III), Bi(III), n is 1, 2, 3, 4, 5, 6, or 7; X is H; a halogen atom; optionally a COOH group, CONH 2 group, COSH group, OH group, NH 2 an alkoxy group, an alkyl group, or a cycloalkyl group substituted with a group, an SH group; optionally one or more COOH groups, CONH 2 a 5- to 12-membered aryl or heteroaryl group substituted with a COSH group; a COOH group or a NH 2 are independently selected from the group R represents H or a linear or branched C1-C18 alkyl or alkoxy chain, optionally substituted with one or more substituents independently selected from halogen atoms and nitrile, nitro, thio, amino, amido, aryl, heteroaryl, hydroxyl, carboxylic acid, or carboxylate groups; p is an integer between 0 and 6. A cancer treatment agent comprising a compound activatable by ionizing radiation.

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