Pyridophane macrocyclic ligands and fe(III) complexes thereof

Abstract

The invention relates to the compounds of formula (I) as well as ions, stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts thereof, or mixtures of the same; the compounds of formula (I) are ligands that are able to chelate Fe(III) ions, thereby generating Fe(III) complexes, which are particularly suitable in diagnostic imaging, for example as contrast agents for magnetic resonance imaging (MRI), due to their high relaxivity, thermodynamic stability, kinetic inertness and redox stability.

Description

[0001] PYRIDOPHANE MACROCYCLIC LIGANDS AND FE(III) COMPLEXES THEREOF

[0002] Technical field

[0003] The invention relates to novel compounds able to complex Fe(III), and to the complexes with Fe(III) thereof. These complexes are particularly suitable as contrast agents for magnetic resonance imaging (MRI).

[0004] Background of the invention

[0005] Magnetic resonance imaging (MRI) contrast agents currently used in clinical practice are small and hydrophilic paramagnetic Gd(III) complexes, or chelates, that accelerate the relaxation rates (n and r?) of proximate tissue water protons in regions of agent accumulation. For clinical applications, Gd(III) complexes are generally considered the best contrast agents from the standpoint of benefit-risk balance. However, despite the fact that these clinically used Gd(III) complexes are generally very safe and very well tolerated by patients, there has been recently some concerns related to contraindications in patients with severely compromised kidney function (nephrogenic systemic fibrosis, or NSF), to the retention of small amounts of Gd(III) in the tissues of patients exposed to multiple MRI scans (although without any evidence that this is associated with clinical harm), and possibly to the environment (due to difficulties in the removal of gadolinium-based contrast agents, or GBCAs, in wastewater treatment plants). Therefore, alternative contrast agents based on chemical species different than Gd(III) have been sought.

[0006] Among these alternatives, complexes chelating endogenous paramagnetic metals, such as iron, are possible candidates. Indeed, iron complexes, and in particular Fe(III) complexes, have been studied for their use in MRI. Fe(II) complexes are generally less suitable for providing MRI contrast, as they are characterized by lower relaxivity compared to Fe(III) complexes.

[0007] For a clinical use in MRI, the ideal Fe(III) complex possesses high relaxivity to obtain high contrast in vivo, high thermodynamic stability and kinetic inertness to minimalize and possibly to avoid the hydrolyzation, transmetallation and transchelation reactions with the challenging endogenous metal ions and ligands, and stability to reduction to avoid triggering the Fenton reaction, that is the reduction of Fe(III) to Fe(II) (Baranyai et al. Chem. Sci. 2021, 12, 11138)) triggered in vivo e.g. by anti-oxidants such as ascorbic acid. This reduction would indeed lower the relaxivity of the administered iron complex (due to the generation of the Fe(II)-complex) and might generate in vivo OH- radicals, which are toxic.

[0008] US 5,334,371 discloses macrocyclic ligands possibly complexing a great number of ions. Such complexes are aimed at several diagnostic uses, such as NMR diagnosis, nuclear medicine, and X-ray. US 5,334,371 further discloses the iron(III)-complex of 3,6,9- tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1] -pentadeca- 1(15), 11,13-triene, with a low Ti relaxivity (0.49 mM1s1at 40 °C and 20 MHz in water).

[0009] Currently, there is a lack of Fe(III)-complexes for use in magnetic resonance imaging that exhibit a high relaxivity, kinetic inertness, thermodynamic stability and stability to reduction.

[0010] It has now been found that the ligands of the invention, when complexed to Fe(III) ions, thus forming the complexes of the invention, have surprisingly and advantageous properties. In particular, said ligands have been found to possess a balanced profile of high relaxivity, kinetic inertness, thermodynamic stability and stability to reduction. Accordingly, the complexes of the invention can be advantageously used as contrast agents for MRI.

[0011] Summary of the invention

[0012] The invention relates to a compound of formula (I), or an ion, a stereoisomer, a tautomer, a hydrate, a solvate, or a salt thereof, or a mixture of same, as set out in the claims. The compound of formula (I) is a ligand that, when complexed to Fe(III) ions, forms a Fe(III) complex (also object of the invention, as set out in the claims) that possess a balanced profile of high relaxivity, kinetic inertness, thermodynamic stability and stability to reduction.

[0013] The invention further relates to the methods of preparation of the compound and of the complex of the invention, as well as their use as MRI contrast agents and in diagnostic (MRI) imaging, as set out in the claims.

[0014] Moreover, it has been found that the compound of formula (I) is able to chelate Fe(III) with high affinity and stability, whereby according to a further aspect, the invention relates to its use as a medicament, particularly for use in the treatment or prevention of disorders caused by the excess and / or accumulation of iron ions within a body.

[0015] Detailed description of the invention

[0016] According to a first aspect, the invention relates to a compound of Formula (I): Formula (I) wherein : n is an integer selected from 0, 1, 2, 3, and 4; m and o are integers independently selected from 1, 2, 3 and 4;

[0017] Y1and Y2are independently selected from the group consisting of hydrogen and a Ci-C4-alkyl;

[0018] R1and R2are independently selected from the group consisting of hydrogen and Ci-C4-alkyl; L1and L2are independently selected from the group consisting of Ci-C4-alkylaminyl, Ci-C4-alkylamidyl, and Ci-C4-alkylether;

[0019] Z1and Z2are independently selected from the group consisting of hydrogen and a Ci-Ce-alkyl, said Ci-Ce-alkyl being optionally substituted by one or more groups selected from the group consisting of hydroxyl (-OH), carboxyl (-COOH), and phosphonate (-PO3H2);

[0020] RA, RB, Rc, RD, and REare independently selected for each occurrence from the group consisting of hydrogen and Ci-C4-alkyl;

[0021] L is selected from the group consisting of hydrogen, a direct bond, a ether (— O— ), a thioether (— S— ), an amido (— CONH— ), an amino (— NH— ), and a C1-C20- alkylene; said Ci-C2o-alkylene being optionally substituted by one or more functional groups selected from the group consisting of: carbonyl (—CO—), carboxyl (— COOH), amido (—CONH—), amino (— NH— ), ether (—0—), thioether (— S— ), (hetero)aryl, (hetero)cyclo-alkyl, and hydroxyl (—OH); with L preferably bonding the position 4 of the pyridine ring; p is an integer selected from 0, 1, 2, 3, and 4; provided that when L is hydrogen, p is 0; and when L is a direct bond, p is an integer selected from 1, 2, and 3;

[0022] A is independently selected for each occurrence from the group consisting of a biological moiety and a macrocycle of formula (IA) : Formula (IA) wherein : the bond interrupted by the squiggly line (~) indicates the point of attachment to L; said bond interrupted by the squiggly line (~) bonding preferably the position 4 of the pyridine ring of the macrocycle of formula (IA); m' , n' , and o' independently have the same meaning provided above for m, n, and o, respectively;

[0023] Y3and Y4independently have the same meaning provided above for Y1and Y2;

[0024] R3and R4independently have the same meaning provided above for R1and R2; L3and L4independently have the same meaning provided above for L1and L2;

[0025] Z3and Z4independently have the same meaning provided above for Z1and Z2; and

[0026] RA', RB', Rc', RD', and RE' independently have the same meaning provided above for RA, RB, Rc, RD, and RE. or an ion, or a stereoisomer, or a tautomer, or a hydrate, or a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of the same.

[0027] In the present description, the term "alkyl" refers to any linear or branched, saturated or unsaturated (preferably saturated) hydrocarbon chain. The term "Cx-Cy-alkyl", wherein x and y denote two integers, refers to an alkyl as above defined with a number of carbon atoms comprised between x and y. For example, "Ci-Ce-alkyl" comprises within its meaning a linear or branched, saturated or unsaturated (preferably saturated) chain comprising from 1 to 6 carbon atoms such as: methyl, ethyl, propyl, iso-propyl, butyl, / so-butyl, tert-butyl, and the like, as well as n-pentyl and isomers thereof, and n-hexyl and isomers thereof. Similarly, the term "Ci-C4-alkyl" refers to a linear or branched, saturated or unsaturated (preferably saturated) chain comprising from 1 to 3 carbon atoms such as: methyl, ethyl, propyl, isopropyl, butyl, / so-butyl, tert-butyl, and the like; the term "Ci-Cs-alkyl" refers to a linear or branched, saturated or unsaturated (preferably saturated) chain comprising from 1 to 3 carbon atoms such as, for instance, methyl, ethyl, propyl and / so-propyl; the term "C1-C2- alkyl" refers to a linear or branched, saturated or unsaturated (preferably saturated) chain comprising from 1 to 2 carbon atoms such as methyl and ethyl; the term "Ci-alkyl" refers to a methyl (-CH3) group.

[0028] In the present description, the term "alkylene" when referring to the substituent L, refers to any bivalent linear or branched, saturated or unsaturated hydrocarbon chain bonding both (i) the pyridine ring of the compound of formula (I) and (ii) the substituent A as herein defined. The term "Cx-Cy-alkylene", wherein x and y denote two integers, refers to an alkylene as above defined with a number of carbon atoms comprised between x and y.

[0029] In the present description, the term "alkylaminyl" refers to an alkyl as above defined wherein one of the hydrogen atoms is substituted by an amine group, said alkylaminyl being attached to both (i) the phenolic moiety of the compound of the invention and (ii) the Z1, Z2, Z3, or Z4group (as the case may be). The term "Cx-Cy-alkylaminyl", wherein x and y denote two integers, refers to an alkylaminyl as above defined with a number of carbon atoms comprised between x and y.

[0030] In the present description, the term "alkylamidyl" refers to an alkyl as above defined wherein one the carbon atoms is a carbonyl group (C=O) directly bonded to a nitrogen atom, said alkylamidyl being attached to both (i) the phenolic moiety of the compound of the invention and (ii) the Z1, Z2, Z3, or Z4group (as the case may be). The term "Cx-Cy- alkylamidyl", wherein x and y denote two integers, refers to an alkylamidyl as above defined with a number of carbons comprised between x and y.

[0031] In the present description, the term "alkylether" refers to an alkyl as above defined wherein one of the hydrogen atoms is substituted by an ether group (-O-), said alkylether being attached to both (i) the phenolic moiety of the compound of the invention and (ii) the Z1, Z2, Z3, or Z4group (as the case may be). The term "Cx-Cy-alkylether", wherein x and y denote two integers, refers to an alkylether as above defined with a number of carbons comprised between x and y.

[0032] In the present description, the term "(hetero)aryl" refers to an aromatic ring possibly containing one or more heteroatoms, such as oxygen, nitrogen and / or sulphur atom(s). Preferred (hetero)aryl include phenyl, pyridinyl, and triazolyl.

[0033] In the present description, the term "(hetero)cyclo-alkyl" refers to a saturated ( / .e. cycloaliphatic) carbocyclic ring, possibly containing one or more heteroatoms, such as oxygen, nitrogen and / or sulphur atom(s). Preferred (hetero)cyclo-alkyl include a C5-C7 carbocyclic ring, e.g. cyclohexyl ring, and a 5-6 membered saturated ring comprising at least one heteroatom in the cyclic chain, e.g. as pyrrolidine, piperazine, morpholine and piperidine.

[0034] In the present description, the term "L-Z" when referring to substituent groups generally refers to any or all of the L1-Z1, L2-Z2, and L3-Z3and L4-Z4(if present), substituent groups.

[0035] In the present description, the term "protecting group" designates a protective group adapted for preserving the function of the group and / or atom to which it is bonded. Specifically, protective groups can be used to preserve e.g. amino, hydroxyl, carboxyl, and / or amido functions. Appropriate carboxyl protective groups may thus include, for example, benzyl, alkyl e.g. tert-butyl or benzyl esters, or other substituents commonly used for the protection of such functions, which are all well known to those skilled in the art (e.g. from T. W. Greene and P. G. M. Wuts; "Protective Groups in Organic Synthesis", Wiley, N.Y. 1999, third edition).

[0036] The compounds of the above formula (I) may have one or more asymmetric carbon atom, otherwise referred to as a chiral carbon atom, and may thus give rise to diastereomers, optical isomers and enantiomers. The invention further includes all such possible diastereomers, optical isomers and enantiomers, as well as their racemic mixtures and their substantially pure resolved enantiomers. All possible geometric isomers are included as well. The individual stereoisomer of a compound of formula (I), e.g. a particular diastereomer, may be isolated by any conventional means, such as for example chromatography, possibly chiral chromatography.

[0037] In the present description, the term "pharmaceutically acceptable salt" refers to derivatives of the compounds of the invention wherein the parent compound is suitably modified by converting any of the free acid or basic groups, if present, into the corresponding addition salt with any base or acid conventionally intended as being pharmaceutically acceptable, for example as disclosed in S. M. Berge, et al., J. Pharm. Sci. 1977, 66, 1-19. In the present description, the term "biological moiety", in particular when referring to the substituent A, refers to any pharmaceutically suitable molecule that can be conventionally coupled to a drug in order to confer to the drug specific properties, such as targeting properties for targeting specific biomarkers, receptors, tissues, proteins, and / or organs. Illustrative and preferred biological moieties are the ones binding human serum proteins, such as human serum albumin; this allows providing to the compound of the invention blood-pool specificity, thereby providing an MRI blood-pool contrast agent. For instance, a preferred biological moiety is a derivative of a bile acid as disclosed in WO 00 / 38738, such as derivative of a bile acid.

[0038] According to an embodiment, Y1and Y2, as well as Y3and Y4if present, are independently selected from the group consisting of hydrogen and a Ci-Cs-alkyl, preferably of hydrogen and a Ci-C2-alkyl, and more preferably of hydrogen and a Ci-alkyl (that is, methyl). Preferably, Y1and Y2, as well as Y3and Y4if present, are simultaneously the same group, most preferably hydrogen.

[0039] According to an embodiment, R1and R2, as well as R3and R4if present, are independently selected from the group consisting of hydrogen and Ci-Cs-alkyl, preferably of hydrogen and Ci-C2-alkyl, more preferably of hydrogen and Ci-alkyl, and even more preferably Ci-alkyl (that is, methyl (-CH3)). According to a preferred embodiment, R1, R2, as well as R3and R4if present, are simultaneously the same group most preferably methyl.

[0040] According to an embodiment, L1and L2, as well as L3and L4if present, are independently selected from the group consisting of Ci-Cs-alkylaminyl, Ci-Cs-alkylamidyl, and C1-C3- alkylether; preferably of Ci-C2-alkylaminyl, Ci-C2-alkylamidyl, and Ci-C2-alkylether; and more preferably of Ci-alkylaminyl, Ci-alkylamidyl, and Ci-alkylether; according to this latter more preferred embodiment, L1and L2, as well as L3and L4if present, are independently selected from *-CH2-NH--, *-C(O)-NH--, *-NHC(O)--, and *-CH2-O--, preferably from *-CH2- NH-‘, *-C(O)-NH--, and *-CH2-O--, and more preferably from *-CH2-NH--, and *-C(O)-NH--, with the asterisk (*) representing the phenolic moiety and the middle dot (■) representing the Z1, Z2, Z3, or Z4group (if present) (as the case might be). According to a preferred embodiment, L1and L2, as well as L3and L4if present, are simultaneously the same group.

[0041] The nitrogen atoms of the alkylaminyl and of the alkylamidyl groups L1and L2, as well as L3and L4if present, preferably bear at least one hydrogen; in other words, the amines of the alkylaminyl groups and / or the amides of the alkylamidyl groups L1and L2, as well as L3and L4if present, are preferably primary or secondary; more preferably secondary.

[0042] According to a preferred embodiment, Z1and Z2, as well as Z3and Z4if present, are directly bonded to the nitrogen of the alkylaminyl or of the alkylamidyl group, to the carbonylic (C=O) portion of the alkylamidyl group, or to the oxygen of the alkylether group of (respectively) L1, L2, L3, and L4.

[0043] According to a preferred embodiment, Z1and Z2, as well as Z3and Z4if present, are independently selected from the group consisting of hydrogen, Ci-Ce-alkyl substituted by two or more hydroxyl (-OH) groups, and Ci-Cs-alkyl substituted by at least one group selected from the group consisting of carboxyl (-COOH), and phosphonate (-PO3H2). According to a more preferred embodiment, Z1and Z2, as well as Z3and Z4if present, are independently selected from the group consisting of hydrogen, Ce-alkyl substituted by two or more, such as two to five (preferably five), hydroxyl (-OH) groups, Ci-Cs-alkyl substituted by at least one, such as two, hydroxyl (-OH) groups, and Ci-alkyl substituted by carboxyl (-COOH) or phosphonate (-PO3H2).

[0044] According to an embodiment, RA, RB, Rc, RD, and RE, as well as RA', RB', Rc', RD', and RE' (if present), are independently selected for each occurrence from the group consisting of hydrogen and Ci-Cs-alkyl; preferably of hydrogen and Ci-C2-alkyl; more preferably of hydrogen and Ci-alkyl (that is, methyl). According to an embodiment, RAand RE, as well as RA' and RE' (if present), are Ci-Cs-alkyl (preferably Ci-alkyl), and RB, Rc, and RD, as well as RB', Rc', RD' (if present), are hydrogen . According to an embodiment, RA, RB, Rc, RD, and RE, as well as RA', RB', Rc', RD', and RE' (if present), are hydrogen.

[0045] According to an embodiment, p is 0 and L is hydrogen, whereby the compound of the invention has the following formula (II) : wherein n, m, o, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as above defined for formula (I) or for any embodiment thereof. According to this embodiment, the compound of the invention is a monomer, that is it complexes exclusively one iron(III) ion.

[0046] According to an embodiment, p is an integer selected from 1, 2, 3, and 4, and A is the macrocycle of formula (IA). According to this embodiment, the compound of the invention is a multimer, such as a dimer, trimer, tetramer, or pentamer (based on the number of p); in this case, the compound of the invention can complex a number of iron(III) ions that is as high as the number of p + 1. According to this embodiment, L is preferably selected from the group consisting of a Ci-C2o-alkylene substituted by a (hetero)aryl or a (hetero)cyclo- alkyl; more preferably, the Ci-C2o-alkylene is a Ci-C4-alkylene, the (hetero)aryl is phenyl, and the (hetero)cyclo-alkyl is cyclohexyl.

[0047] According to an embodiment, L is a direct bond, p is an integer selected from 1, 2, and 3, whereby the compound of the invention has the following formula (III) : Formula (III) wherein A, n, m, o, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as above defined for formula (I) or for any embodiment thereof; according to a preferred embodiment of the compound of formula (III), p is 1 and A bonds the position 4 of the pyridine ring.

[0048] According to an embodiment, p is an integer selected from 1, 2, 3, and 4, and A is a biological moiety; preferably, p is 1 and the biological moiety is a derivative of a bile acid; more preferably, the derivative of a bile acid is selected from the group consisting of residues of cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, lithocholic acids, and derivatives thereof; said derivative also comprising the conjugate of the acid group at the 24 position with taurine and glycine, and / or keto group(s) instead of hydroxyl group(s).

[0049] According to this embodiment wherein A is a derivative of a bile acid, L is preferably selected from the group consisting of a direct bond, a ether (—0—), a thioether (— S— ), an amido (— CONH— ), an amino (— NH— ), and a Ci-C2o-alkylene optionally substituted by one or more functional groups selected from the group consisting of: carbonyl (—CO—), carboxyl (— COOH), amido (—CONH—), amino (— NH— ), ether (—0—), thioether (— S— ), (hetero)aryl, (hetero)cyclo-alkyl, and hydroxyl (—OH); more preferably, L is selected from the group consisting of a direct bond, a ether (—0—), a thioether (— S— ), an amido (—CONH—), an amino (— NH— ), and a Ci-Ce-alkylene optionally substituted by one or more functional groups selected from the group consisting of: carbonyl (—CO—), carboxyl (—COOH), amido (— CONH— ), amino (— NH— ), ether (—0—), thioether (— S— ), (hetero)aryl, (hetero)cyclo-alkyl, and hydroxyl (—OH).

[0050] According to an embodiment, p is an integer selected from 2, 3, and 4, and a first A substituent is in at least one occurrence a biological moiety, and a second A substituent is in at least another occurrence a macrocycle of formula (IA); preferably, the biological moiety is a derivative of a bile acid, such as the derivative of a bile acid selected from the group consisting of residues of cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, lithocholic acids, and derivatives thereof; said derivative also comprising the conjugate of the acid group at the 24 position with taurine and glycine, and / or keto group(s) instead of hydroxyl group(s). According to this embodiment, the compound of the invention is a multimer (namely a dimer, a trimer, or a tetramer) comprising a biological moiety.

[0051] According to a preferred embodiment, n, m, and o are integers selected from 1 and 2.

[0052] According to a further preferred embodiment, n, m, and o are 1, whereby the compound of the invention has the following formula (IV) Formula (IV) wherein p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as above defined for formula (I) or for any embodiment thereof; according to a preferred embodiment of the compound of formula (IV), L, RA, RB, Rc, RD, and REare hydrogen, and p is 0.

[0053] According to another preferred embodiment, m and o are 1, and n is 2, whereby the compound of the invention has the following formula (V) Formula (V) wherein p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as above defined for formula (I) or for any embodiment thereof, and RC1is independently selected from and has the same meaning provided above for Rc(according to any embodiment thereof); according to a preferred embodiment of the compound of formula (V), L, RA, RB, Rc, RC1, RD, and REare hydrogen, and p is 0.

[0054] According to a further embodiment, either m or o is 2, and n as well as the other remaining between m and o are 1, whereby the compound of the invention has one of the formulae (VIA), or (VIB) wherein, for formulae (VIA) and (VIB), p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as above defined for formula (I) or for any embodiment thereof, and RA1and RE1are independently selected from and have the same meaning provided above for, respectively, RAand RE(according to any embodiment thereof); according to a preferred embodiment of the compound of formula (VIA) or (VIB), L, RA, RA1, RB, Rc, RD, RE, and RE1are hydrogen, and p is 0.

[0055] According to another embodiment, m and o are 2, and n is 1, whereby the compound of the invention has a triazacyclododecane macrocyclic cage and has the following formula (VII) Formula (VII) wherein p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RA1, RB, Rc, RD, RE, and RE1are as above defined for formula (I) or for any embodiment thereof; according to a preferred embodiment of the compound of formula (VII), L, RA, RA1, RB, Rc, RD, RE, and RE1are hydrogen, and p is 0.

[0056] According to a further embodiment, either m or o is 1, and n as well as the other remaining between m and o are 2, whereby the compound of the invention has one of the wherein, for formulae (VIA) and (VIB), p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RA1, RB, Rc, RC1, RD, RE, and RE1are as above defined for formula (I) or for any embodiment thereof; according to a preferred embodiment of the compound of formula (VIIIA) or (VIIIB), L, RA, RA1, RB, Rc, RC1, RD, RE, and RE1are hydrogen, and p is 0. According to another embodiment, m, n, and o are 2, whereby the compound of the invention has a triazacyclododecane macrocyclic cage and has the following formula (IX) Formula (IX) wherein p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RA1, RB, Rc, RC1, RD, RE, and RE1are as above defined for formula (I) or for any embodiment thereof; according to a preferred embodiment of the compound of formula (IX), L, RA, RA1, RB, Rc, RC1, RD, RE, and RE1are hydrogen, and p is 0.

[0057] According to a preferred embodiment, the compound of the invention is selected from the group consisting of:

[0058]

[0059]

[0060]

[0061]

[0062]

[0063]

[0064]

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073] The chemical names provided for the Compounds of the invention listed above were generated through the software ACD / Chem Sketch 2021.2.2 (ACD / Labs 2023.1.0 (File Version C45H41, Build 134223, 03 Jul 2023)). These chemical names might slightly differ from standard IUPAC nomenclature. For the sake of clarity, in case of discrepancy between the chemical structures and the corresponding chemical names, the compound of the invention is identified univocally by its chemical structure.

[0074] According to a further aspect, the invention relates to a complex of a compound of formula (I) as above defined in any of its embodiments, hence encompassing compounds of formulae (II) to (IX) as above defined, with Fe3+, or a physiologically acceptable salt thereof. As demonstrated in the Experimental section, the complex of the invention possesses a balanced profile of high relaxivity, kinetic inertness, thermodynamic stability and stability to reduction, making it very suitable for its use in the diagnosis field, in particular as a contrast agent for magnetic resonance imaging (MRI).

[0075] According to another aspect, the invention relates to a complex as defined above or a physiologically acceptable salt thereof for use in a method of diagnosis preferably in vivo; more preferably, the complex or a physiologically acceptable salt thereof is for use in a method of diagnosis e.g. in vivo of a pathology by magnetic resonance imaging (MRI). According to a further aspect, the invention relates to the use of the complex as defined above or of a physiologically acceptable salt thereof for diagnostic methods e.g. in vivo, preferably for diagnosis e.g. in vivo of a pathology by magnetic resonance imaging (MRI). According to another aspect, the invention relates to the use of the complex of the invention as defined above, or of a salt thereof, as a contrast agent, preferably for MRI.

[0076] According to an additional aspect, the invention relates to the use of the complex as defined above or of a physiologically acceptable salt thereof for the manufacture of a medicament, e.g. of a diagnostic agent, such as of a contrast agent for magnetic resonance imaging (MRI), for in vivo applications, such as for the in vivo diagnosis of a disease.

[0077] According to a further aspect, the invention relates to a method of imaging of a body tissue in a patient comprising the steps of administering to the patient an effective amount of a complex as defined above or of a physiologically acceptable salt thereof in a pharmaceutically acceptable carrier, and subjecting the patient to magnetic resonance imaging (MRI).

[0078] According to another aspect, the invention relates to a pharmaceutical composition comprising a complex as defined above or a physiologically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0079] Further to its use as MRI agent when complexed to Fe3+, it has been found that the compound of the invention can act as an iron-sequestering agent for therapeutic use, namely it can be useful for the therapy of disorders associated with excess and / or accumulation of iron ions within the body, e.g. iron overload. This is thanks to the properties of the compound of the invention, showed e.g. in Example 10 B). Thus, according to a further aspect, the invention relates to the compound of formula (I) as above defined in any of its embodiment, hence encompassing compounds of formulae (I) to (IX) as above defined, or an ion, a stereoisomer, a tautomer, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable complex thereof with a metal ion, provided that such metal ion is not iron ion, in particular is not Fe3+and / or Fe2+ion, or a mixture of the same, for use as a medicament; particularly for use in the treatment or prevention of disorders caused by the excess and / or accumulation of iron ions within a body, preferably a human body, such as iron intoxication and / or iron overload. According to a further aspect, the invention relates to a method for the treatment or prevention of disorders caused by the excess and / or accumulation of iron ions within the body, preferably the human body, such as iron intoxication and / or iron overload, in a subject in need of such treatment, which comprises administering to said subject a therapeutically effective amount of a compound of formula (I) according to any of its embodiments; preferably, the compound is in a pharmaceutically acceptable form and part of a pharmaceutical composition. According to another aspect, the invention relates to the use of a compound of formula (I) according to any of its embodiments for the manufacture of a medicament, preferably a medicament for the treatment or prevention of disorders caused by the excess and / or accumulation of iron ions within the body, preferably the human body, such as iron intoxication and / or iron overload. According to another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I) according to any of its embodiments, or an ion, or a stereoisomer, or a tautomer, or a hydrate, or a solvate, or a pharmaceutically acceptable complex, or a pharmaceutically acceptable salt thereof, or a mixture of the same, and at least one pharmaceutically acceptable excipient, provided that the pharmaceutically acceptable complex is not an iron complex, in particular is not a Fe3+and / or Fe2+complex. According to these aspects, the pharmaceutically acceptable complex is preferably a complex with a pharmaceutically acceptable alkali metal ion or alkaline earth metal ion, such as Ca2+ion or with a Mg2+ion.

[0080] In the present description, the term "iron intoxication" refers to any disorder commonly known that is caused by the excessive intake of iron ions within a short period, thus resulting in acute toxicity. Symptoms of iron intoxication can range from mild to severe, even possibly leading to permanent organ damage and death. Iron intoxication can also be commonly known as iron poisoning.

[0081] In the present description, the term "iron overload" refers to a commonly known disorder that is caused by an excessive accumulation of iron ions within the body, typically in organs like the liver, heart, pancreas, and joints. As used herein, iron overload comprises both primary iron overload, often referred to as primary hemochromatosis (e.g. hemochromatosis type 1 and non-HFE hereditary hemochromatosis), and secondary iron overload (that is iron overload caused e.g. by excess intake of iron with diet, or by multiple frequent blood transfusions, such as transfusions to treat anaemias like Diamond-Blackfan anaemia, thalassaemia, and sickle cell anaemia). Iron overload can also be known as hemochromatosis.

[0082] According to an aspect, the invention relates to a process for manufacturing a compound of the invention as above defined in any of its embodiment, hence encompassing compounds of formulae (I) to (IX) as above defined. This process can be generally carried out by coupling a suitable macrocycle, e.g. the macrocycle of formula (XI) set out below, possibly suitably protected with one or more protecting groups on one or more nitrogen atoms, with suitable moieties to obtain the compound of the invention, or to obtain an intermediate thereof that can be then converted (e.g. by further coupling and / or reduction reactions) to the compound of the invention. In case the substituent A of the compound of the invention is a biological moiety and / or a macrocycle of formula (IA), a further step of coupling the macrocycle with one or more of the substituent A is carried out either before or after (preferably before) the coupling of the macrocycle with the suitable moieties to obtain the compound of the invention, or to obtain an intermediate thereof.

[0083] In an embodiment, the compound of the invention can be prepared according to the following general synthesis steps: a) providing a phenol substituted at least in its orto positions (i) with a Ci-Cs-alkyl- bonded to a suitable leaving group, such as mesylate (MsO) or halo, thus providing e.g. a halo-Ci-Cs-alkyl, such as chloro-Ci-Cs-alkyl or bromo-Ci-Cs-alkyl; and (ii) with a L-Z group or a suitable substituent group that can be later converted to the L-Z groups, e.g. a substituent group selected from the group consisting of C1-C4- alkyl-aldehyde, Ci-C4-alkyl-ester, and Ci-C4-alkyl-carboxyl; for example, the phenol can be the compound of formula (X): wherein Y1and R1have the same meaning provided for formula (I) or any embodiment thereof;

[0084] X is a leaving group, such as mesylate (MsO) or halogen, preferably Cl or Br, and

[0085] L5is a group selected from the group consisting of Ci-C4-alkyl-aldehyde, Ci-C4-alkyl-ester, and Ci-C4-alkyl-carboxyl; b) providing a macrocycle, for example the macrocycle of formula (XI): wherein m, n, o, RA, RB, Rc, RD, and REare as above defined for formula (I) or for any embodiment thereof; and

[0086] L' is selected from the group consisting of hydrogen, hydroxyl, thiol, amido, amino, a leaving group (such as mesylate or halogen), and a Ci- C2o-alkylene; said Ci-C2o-alkylene being optionally substituted by one or more functional groups selected from the group consisting of: leaving group (such as mesylate or halogen), carbonyl (—CO—), amido (— CONH— ), amino (— NH— ), ether (—0—), thioether (— S— ), (hetero)aryl, (hetero)cyclo-alkyl, hydroxyl (—OH), ester (— COO— R°, wherein R° is a leaving group lower alkyl group, preferably a Ci-C2-alkyl group), thiol (— SH), and carboxyl (— COOH); L' bonding preferably the position 4 of the pyridine ring; the macrocycle being optionally suitably protected with one or more protecting groups, such as on one or more of the nitrogen atoms thereof; bl) if the substituent A of the compound of the invention is a biological moiety and / or a macrocycle of formula (IA), optionally reacting the macrocycle provided in step b) with one or more biological moiety and / or a further macrocycle, such as a macrocycle of formula (IA'): wherein m', n', o', RA', RB', Rc', RD', and RE' have the same meaning provided above;

[0087] L" is selected from the group consisting of a hydroxyl, a thiol, an amido, an amino, a leaving group (such as mesylate or halogen), and a Ci-C2o-alkylene; said C1-C20- alkylene being optionally substituted by one or more functional groups selected from the group consisting of: leaving group (such as mesylate or halogen), carbonyl (—CO—), amido (— CONH— ), amino (— NH— or — NH2), ether (— O— ), thioether (— S— ), (hetero)aryl, (hetero)cyclo-alkyl, hydroxyl (—OH), ester (— COO— R°, wherein R° is a leaving group or lower alkyl group, preferably a C1-C2- alkyl group), thiol (— SH), and carboxyl (—COOH); preferably, L' bonding the position 4 of the pyridine ring; the macrocycle of formula (IA') being optionally suitably protected with one or more protecting groups, such as on one or more of the nitrogen atoms thereof; c) reacting the phenol provided in step a), e.g. the compound of formula (X), with the macrocycle provided in step b), e.g. the compound of formula (XI), or with the product obtained by step bl), to obtain the compound of the invention, or to obtain an intermediate of the compound of the invention, such as an intermediate bearing substituent groups that can be converted to the L-Z groups in the later steps. Such suitable substituent groups are e.g. two L5moieties, which can advantageously be converted in the subsequent step(s) to the groups L1-Z1, and L2-Z2. Such intermediate is for example the compound of formula (XII) Formula (XII) wherein L', R1, R2, Y1, Y2, m, n, o, RA, RB, Rc, RD, and REhave the same meaning provided above, and

[0088] L5is a group selected from the group consisting of Ci-C4-alkyl-aldehyde, Ci-C4-alkyl-ester, and Ci-C4-alkyl-carboxyl; cl) if the substituent A of the compound of the invention is a biological moiety and / or a macrocycle of formula (IA), and if step bl) has not been carried out, reacting the compound obtained in step c) with one or more biological moieties and / or further macrocycles, to obtain the compound of the invention, or to obtain an intermediate of the compound of the invention; d) converting the intermediate of step c) or cl) to the compound of the invention, e.g. converting the L5moieties to the groups L1- / 1, L2-Z2, whereby the compound of the invention is obtained, e.g. by reacting the intermediate obtained in step c) or cl), such as the compound of formula (XII), with one or more suitable substrates, and optionally by reducing the so-obtained compound.

[0089] According to the invention, the term "Ci-C4-alkyl-aldehyde" refers to an alkyl group as above defined comprising from 1 to 4 carbons, one of which is an aldehyde group. Accordingly, the group Ci-C4-alkyl-aldehyde comprises up to four carbons.

[0090] According to the invention, the term "Ci-C4-alkyl-ester" refers to an alkyl group as above defined comprising from 1 to 4 carbons, one of which is a carboxylate bound to an alkyl group ( / .e. one of which is -C(O)O-R°, wherein R° is a lower alkyl group, preferably a Ci-C2-alkyl group, or a leaving group, such as mesylate or halogen). Accordingly, the group Ci-C4-alkyl- ester comprises up to four carbons (not counting the alkyl group R° bound to the oxygen).

[0091] According to the invention, the term "Ci-C4-alkyl-carboxyl" refers to an alkyl group as above defined comprising from 1 to 4 carbons, one of which is a carboxyl (-COOH) group. Accordingly, the group Ci-C4-alkyl-carboxyl comprises up to four carbons.

[0092] Step a) involves providing a phenol that is advantageously substituted in one of its orto positions with a leaving group-Ci-Cs-alkyl, preferably a halomethyl group such as chloromethyl, bromomethyl, or a MsO-methyl group. This group allows to couple the phenol to the nitrogen atoms of the macrocycle in step c). The phenol further comprises, in its orto position, a group that can be advantageously converted in the subsequent steps in the moiety L-Z, such as a group selected from the group consisting of Ci-C4-alkyl-aldehyde, Ci-C4-alkyl- ester, and Ci-C4-alkyl-carboxyl. Alternatively, in addition to the leaving group-Ci-Cs-alkyl, such as the halo-Ci-Cs-alkyl, the phenol may further comprise in its orto positions the L-Z group, e.g. L^Z1group, whereby the compound of the invention is directly obtained when the phenol is coupled to the macrocycle provided in step b). Advantageously, the phenol of step a), e.g. the compound of formula (X), can be obtained by reacting the correspondent non- methylene-halogenated compound with paraformaldehyde in concentrated hydrohalic acids, preferably in hydrochloric or hydrobromic acid, at a temperature comprised in the range of 30 to 70 °C, preferably of 40 to 60 °C, more preferably at 50 °C, e.g. as set out in WO 2024 / 023314.

[0093] Step b) involves providing a suitable macrocycle, for example the one of formula (XI), optionally suitably protected with one or more protecting groups on one or more of the nitrogen atoms thereof. Such macrocycle will be coupled in step bl) with one or more biological moieties and / or further macrocycles (if the substituent A of the compound of the invention is such), or in c) with the phenol of step a), in order to provide an intermediate of the compound of the invention (later to be converted to the compound of the invention), or to directly provide the compound of the invention. The macrocycle of step b) is commercially available or can be obtained according to conventional methods starting from commercially available products, for example as set out in US 5,334,371 or by analogy of the same.

[0094] According to an embodiment, the macrocycle provided in step b), e.g. the macrocycle of formula (XI), is selected from the group consisting of the following macrocycles: wherein L' has the same meaning provided above.

[0095] Step bl) can be carried out if the substituent A of the compound of the invention is a biological moiety and / or a macrocycle of formula (IA), that is if the compound of the invention is a multimer (such as a dimer, a trimer, a tetramer, or a pentamer), and / or if the compound of the invention comprises a biological moiety for providing e.g. targeting properties thereto. Step bl) is optional even if the substituent A of the compound of the invention is a biological moiety and / or a macrocycle of formula (IA), in that step cl) can be carried out instead of step bl). Preferably, step bl) is carried out instead of step cl); thus, it is preferred to obtain a multimer and / or a compound comprising the biological moiety before, and not after, the reaction between the macrocycle and the phenol, that is before step c).

[0096] The macrocycle and the further macrocycle(s) reacted in step bl) can be suitably protected, for example on one or more of the nitrogen atoms within the macrocyclic ring, so that it is the linker portion (e.g. L') of the macrocycle that reacts with the linker portion (e.g. L") of the further macrocycle(s) and / or with biological moieties, to provide a protected multimer and / or a protected compound comprising the biological moiety; then, the so- obtained product can be de-protected and reacted according to step c).

[0097] Step c) provides for reacting the phenols of step a), e.g. of formula (X), with the macrocycle of step b), e.g. of formula (XI), or with the product of step bl), to directly obtain the compound of the invention, or to obtain an intermediate of the compound of the invention, said intermediate being indeed reacted in step d) to possibly obtain the final product.

[0098] Step c) can be carried out in an organic solvent, such as dichloromethane, toluene, acetonitrile, or mixtures thereof. Salts, such as potassium salts, for example KI, KOH, and K2CO3, can be comprised within such organic solvent.

[0099] Step c) can be advantageously carried out without heating the reaction mixture. In particular, to reduce the risk of undesired polyalkylation reactions, step c) can be carried out at temperatures equal or lower than room temperature, that is, lower than 25 °C), for example for a temperature comprised in the range of 0 °C to 25 °C.

[0100] Step cl) is carried out in case the substituent A of the compound of the invention is a biological moiety and / or a macrocycle of formula (IA), that is if the compound of the invention is a multimer (such as a dimer, a trimer, a tetramer, or a pentamer) and / or comprises a biological moiety, and in case step bl) has not been carried out.

[0101] Step d) is optional, and it may be optionally carried out when step c) or cl) provides an intermediate of the compound of the invention. Step d) involves converting the groups of the intermediate, e.g. group L5, to the L-Z groups. This can be done e.g. by reacting the L5groups with one or more suitable substrates, e.g. as set out below or in WO 2024 / 023314. By way of example, if L1is a Ci-C4-alkylaminyl and Z1is a Ci-Ce alkyl substituted by one or more hydroxyl groups, L5can be a Ci-C4-alkyl-aldehyde, and the suitable substrate can be a Ci-Ce-alkyl-amine substituted by two or more hydroxyl groups, such as serinol or glucamine, whereby the coupling of the two provides an imide that is later reduced to obtain the intended I -Z1moiety (such as disclosed e.g. in Examples 1, 3 and 4 below). Alternatively, when L1is a Ci-C4-alkylaminyl and Z1is a Ci-Ce alkyl substituted by a phosphonate group, L5can be a C1-C4 alkyl-aldehyde, and the suitable substrate can be an amino-alkyl-phosphonate ester, e.g. diethyl-2-aminomethylphosphonate. As a further illustrative example, when L1is a Ci-C4-alkylamidyl and Z1hydrogen, L5can be a C1-C4 alkyl-ester, and the suitable substrate could be e.g. ammonia.

[0102] As another illustrative example, when L1is a Ci-C4-alkylether and Z1is a Ci-Ce-alkyl substituted by one or more hydroxyl groups, L5can be a Ci-C4-alkyl-aldehyde, which can be reduced to obtain an hydroxyl group that can be in turn converted to an alkoxide; such alkoxide can undergo the Williamson synthesis of ethers, whereby it is reacted with a suitable substrate such as e.g. an alkyl-hydroxyl-halide with its hydroxyl groups suitably protected, for example 2-chloro-l,3-propanediol or 2-bromo-l,3-propanediol with their hydroxyl groups suitably protected.

[0103] The compound of the invention might also be prepared by providing in step a) a phenol as defined above and bearing I. a. in its orto position the L-Z group. In this case, the compound of the invention can be directly obtained by reacting in step c) such orto-subtituted phenol with the macrocycle provided in step b) or bl).

[0104] According to a further aspect, the invention relates to a method to obtain a Fe(III) complex of a compound of the invention by complexing the compound of the invention with Fe(III) ions, e.g. after step c), step cl), or step d); said complexation can be carried out for example according to the following : e) reacting the compound of the invention, for example as obtained in step c), step cl), or step d), with a Fe(III) salt, preferably with FeCh, Fe(NOs)3, Fe(OH)3, and FeO(OH), to obtain the Fe(III) complex of the compound of the invention.

[0105] Step e) can be carried out in a non-aqueous polar solvent, such as a lower alcohol, e.g. methanol, ethanol, n-propanol, i-propanol, and mixtures thereof. Step e) can also be carried out in an aqueous solvent.

[0106] Non-limiting examples of the preparation of preferred compounds of the invention and intermediates for their preparation are reported in the following section, aimed to illustrate the invention in greater detail without limiting its scope.

[0107] Experimental Section

[0108] Material and methods

[0109] Reactants and / or solvents employed in the following examples that are not specifically synthesized in the following Examples are known and readily available. If they are not commercially available per se, they may be prepared according to known methods in literature.

[0110] 1H and13C NMR spectra were recorded on a Bruker Avance III spectrometer (Bruker, Milano, Italy) operating at 11.74 T and 298 K, corresponding to a protonic resonance frequency of 499.8 MHz.XH and13C NMR chemical shifts are reported relative to TMS and are referenced using the residual proton solvent resonances. Samples were prepared in 5 mm NMR tubes by dissolving the compounds in appropriate deuterated solvents. Analytical and semi-preparative HPLC-MS runs were carried out on a Waters modular system equipped with Waters 1525 binary pump, Waters 2487 UV / Vis and Waters SQD 3100 (ESCI ionization mode) detectors (Waters Corporation, Milford, MA, USA). UPLC-MS analyses were performed using a UPLC Acquity H-Class coupled with QDa and TUV detectors (Waters Corporation, Milford, MA, USA). The ESI-MS were recorded on a Waters SQD 3100 (Waters Corporation, Milford, MA, USA).

[0111] Example 1 - Synthesis of Compound 1 ) l,4,8-Triaza-2,6-pyridinophane (also known as 3,7,13- triazabicyclo[7.3.1]trideca-l(13),9,ll-triene) was prepared as set out in Scheme 1 :

[0112] Scheme 1

[0113] 2 g of 1,3-diaminopropane were reacted with 10.3 g p-toluenesulfonyl chloride in 22 mL pyridine, stirring for 4 hours at 40 °C. The desired compound was precipitated in cold water and then crystallized in ethanol at RT, obtaining after drying 4.87 g of a white solid (yield: 47%). The recovered product (3.74 g) was then salified with 2 eq. of NaOH in water / acetonitrile, and recovered by freeze-drying (4.22 g). A solution of bis- chloromethyl pyridine (2.4 g) in DMF (50 mL) was dropped in 6 hours into a solution of the salified product (4.22 g) in DMF (1 L) at 100 °C, and the resulting solution was stirred at 110 °C overnight. Solvent was then removed under reduced pressure up to ca. 100 mL and the desired compound was recovered after 2 precipitations (the first one from water, and the second one from acetonitrile), obtaining 1.36 g of a white solid. 1.36 g of the recovered product was treated for 2 h in cone. H2SO4 (5 mL) at 100 °C, then precipitated with diethyl ether (300 mL). The crude solid was dissolved in water and 50% NaOH was added up to pH 13.2. The free base was extracted in dichloromethane (12 X). The organic phase was concentrated, the residue was dissolved in methanol and filtered to remove salts (twice). A yellow solid was recovered (492 mg).

[0114] Starting from l,4,8-Triaza-2,6-pyridinophane obtained as above, the synthesis of Compound 1 was carried out, according to the following Scheme 2:

[0115]

[0116] Scheme 2.

[0117] B) l,4,8-Triaza-2,6-pyridinophane (85 mg, 0.48 mmol) and K2CO3 (66 mg, 0.48 mmol) were dissolved in 3 ml of a 1: 1 mixture of DCM and ACN and a solution of 3- bromomethyl-2-hydroxy-5-methylbenzaldehyde (166 mg, 0.96 mmol, prepared according to WO 2024 / 023314) in 2 ml DCM was slowly dropped in 1 h. The reaction mixture was then stirred at room temperature overnight. The solution was filtered, and the solvent removed under reduced pressure to obtain 187 mg of a yellow solid (yield: 82%).

[0118] ESI-MS (m / z): found 474.2 (M + H+) (calc for C28H31N3O4: 473.23).

[0119] HPLC-MS (Waters XBridge Phenyl 3.5 pm (4.6x150 mm)): (A): H2O + 0.1% TFA, (B): MeOH; flow= 1 mL / min; 0-15 min = from 30% to 100% B; 15-19 min = 100% B. Rt: 10.22 min.

[0120] C) The product prepared in step B (187 mg, 0.394 mmol), was dissolved in 5 ml dry MeOH and a solution in 2 ml dry MeOH of 2-amino-propane diol (serinol, 72 mg, 0.789 mmol) was slowly dropped in. The reaction mixture was stirred for 2h at room temperature. The solution was cooled in an ice bath and NaBH4 (60 mg, 1.576 mmol) was added and left for other 2h. The excess of NaBH4 was quenched with water, then evaporated under vacuum, redissolved in EtOH and filtered off. The final product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5pm (19x100mm);

[0121] (A): H2O + 0.1% TFA, (B): MeOH; flow = 17 mL / min; 0-1 min = 10% B; 1-5 min = from 10% to 29% B; 5-6 min = 100% B; 6-8 min = 100% B. Rt: 5.4 min). 96 mg of a white solid were obtained (yield: 39%).

[0122] ESI-MS (m / z): found 624.4 (M + H+) (calc for C34H49N5O6: 623.37).

[0123] HPLC-MS (Waters XBridge Phenyl 3.5 pm (4.6x100 mm)): (A): H2O + 0.1% TFA,

[0124] (B): MeOH; flow = 1 mL / min; 0-15 min = from 10% to 100% B; 15-19 min = 100% B. Rt: 12.14 min

[0125] XH-NMR (500 MHz, MeOD): 2.04 (bquint, -CH2-CH2-N-, 2H), 2.34 (s, -CH3, 6H), 3.31 (bt, -CH2-CH2-N-, 4H), 3.33 (bquint, -NH-CH-(CH2OH)2, 2H), 3.88 (d, -NH-CH- (*CH2OH)2, 8H), 4.43 (s, BZ-CH2-NH-, 4H), 4.67 (s, -N-CHz-Bz, 4H), 4.81 (s, Py-CFh- N-, 4H), 7.40 (s, -CH-CCH3-CH-, 2H), 7.46 (d, Py, 2H), 7.54 (s, -CH-CCH3-CH-, 2H), 7.96 (t, Py, 1H).

[0126] 13C-NMR{1H} (125 MHz, MeOD): 19.0 (-CH3), 24.8 (-CH2-CH2-N-), 44.8 (Bz-CH2- NH-), 50.4 (-CH2-CH2-N-), 54.7 (-N-CH2-Bz), 57.6 (-NH-CH-(CH2OH)2), 58.3 (Py-CH2- N-), 60.2 (-NH-CH-(CH2OH)2), 118.7 (-COH-C-CH-CH2Ser), 120.9 (-CH2-C-CH-CH-), 121.2 (-CH2-C-COH-), 131.5 (-CH-CCH3-CH), 134.5 (-C-CH-CCH3-), 135.3 (-CCH3-CH- ), 139.2 (-CH-CH-CH-), 149.2 (-COH-), 152.9 (Cq Py).

[0127] Example 2 - Synthesis of Compound 4

[0128] Starting from the l,4,8-Triaza-2,6-pyridinophane obtained as in Example 1 A), the synthesis of Compound 4 was carried out according to the following Scheme 3:

[0129] Scheme 3 Details of the synthesis of the present Example are provided in the following paragraphs. l,4,8-Triaza-2,6-pyridinophane prepared according to Example 1, step A) (85 mg, 0.18 mmol) was dispersed in 10 mL of a 7M NH3 solution (in MeOH); the mixture was cooled in an ice bath, then NaBHsCN (112 mg, 10 eq) was added. The suspension was stirred under N2 pressure at room temperature for 5 days. The reaction was quenched with 0.5 mL of H2O, and stirred for further 15 min. The solvent was removed under nitrogen pressure, then the solid was dissolved in 30 mL of DCM and washed with Na2COs IM (3x15 mL). The organic phase was dried with Na2SC>4, filtered and dried under reduced pressure, obtaining 20 mg of crude product that was purified by semi-preparative HPLC- MS. 3 mg of a white solid were obtained (yield: 3.5%).

[0130] ESI-MS (m / z): found 476.4 (M + H+) (calc for C34H49N5O6: 476.65).

[0131] HPLC-MS (Waters Atlantis 5 pm (4.6x100 mm)): (A) : H2O + 0.1% TFA, (B): ACN + 0.1% TFA flow = 1 mL / min; 0-12 min = from 10% to 30% B; 12-20 min = from 30% to 70% B; 20-22 min = from 70% to 100% B. Rt: 13.90 min

[0132] HPLC-MS semipreparative (Waters Atlantis Prep OBD 5pm (19x100mm)); (A): H2O + 0.1% TFA, (B): ACN + 0.1% TFA; flow = 20 mL / min; 0-7 min = from 50% to 30% B; 7-11 min = from 30% to 70% B; 11-12 min = from 70% to 100% B. Rt: 7.55 min).

[0133] XH-NMR (500 MHz, D2O) : 1.81 (b, -CH2-CH2-N-, 2H), 2.24 (s, -CH3, 6H), 3.04 (b, -CH2- CH2-N-, 4H), 3,75 (b, -CH2-CH2-N-, 4H), 4.25 (dd, Py-CH2-NH-, 4H), 4.57 (s, -N-CH2- Bz, 4H), 4.69 (s, Bz-CH2-NH3+, 4H), 7.20 (s, -CH-CCH3-CH-, 2H), 7.23 (d, Py, 2H), 7.38 (s, -CH-CCH3-CH-, 2H), 7.90 (t, Py, 1H).

[0134] Example 3 - Synthesis of Compound 12 ) l,4,9-Triaza-2,6-pyridinophane (also known as 3,8,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene) was prepared as set out in Scheme 4:

[0135] Scheme 4

[0136] 2 g of 1,4-diaminobutane were reacted with 8.66 g of p-toluenesulfonyl chloride in 22 mL of pyridine, stirring 4 hours at 40 °C. The desired compound was precipitated in cold water (50 mL) and then crystallized in ethanol at RT, obtaining after drying 5.14 g of a white solid (yield: 57%). The recovered product (4.91 g) was then salified with 2 eq. of NaOH in water / acetonitrile, and recovered by freeze-drying (5.38 g). A solution of bis-chloromethyl pyridine (2.15 g) in DMF (50 mL) was dropped in 3 hours into a solution of the salified product (5.38 g) in DMF (1.5 L) at 100 °C, and the resulting solution was stirred at 110 °C overnight.

[0137] Solvent was then removed under reduced pressure up to ca. 100 mL and the desired compound was recovered after 2 precipitations (the first one from water, and the second one from acetonitrile), obtaining 2.55 g of a white solid. 2.55 g of the recovered product was treated for 2 h in cone. H2SO4 (6 mL) at 100 °C, then precipitated with diethyl ether (300 mL). The crude solid was dissolved in water and 50% NaOH was added up to pH 13.2. The free base was extracted in dichloromethane (12 X). The organic phase was concentrated, the residue was dissolved in methanol and filtered to remove salts (twice). A yellow solid was recovered (1.08 g).

[0138] Starting from the l,4,9-triaza-2,6-pyridinophane obtained according to step A), the synthesis of Compound 12 was carried out according to the following Scheme 5:

[0139] Scheme 5.

[0140] Details of the synthesis of the present Example are provided in the following paragraphs. B) l,4,9-Triaza-2,6-pyridinophane obtained as above (106 mg, 0.554 mmol) and K2CO3 (76 mg, 0.554 mmol) were dissolved in 4 ml of a 1: 1 mixture of DCM and ACN. A solution of 3-bromomethyl-2-hydroxy-5-methylbenzaldehyde (254 mg, 1.108 mmol, prepared according to WO 2024 / 023314) in 2 ml DCM was slowly dropped in lh at room temperature. The reaction mixture was then stirred at room temperature overnight. The solution was filtered, and the residue solvent removed under reduced pressure to obtain 216 mg of a yellow solid (yield: 80%).

[0141] ESI-MS (m / z): found 488.2 (M + H+) (calc for C29H33N3O4: 487.59).

[0142] HPLC-MS: same method as Example 1 : Rt: 11.45 min

[0143] C) The product prepared in the step B (216 mg, 0.443 mmol) was dissolved in 5 ml dry MeOH and a solution of 2-amino-propane diol (serinol, 81 mg, 0.887 mmol) in 2 ml dry MeOH was slowly dropped in. The reaction mixture was stirred for 2h at room temperature. The solution was cooled in an ice bath and NaBH4 (67 mg, 1.774 mmol) was added and stirred for other 2h. The excess of NaBH4 was quenched with water, after evaporated under vacuum and redissolved in EtOH and filtered off. The product was purified by semi-preparative HPLC-MS (same method and column of Example 1; Rt: 5.0 min). 73 mg of a white solid were obtained (yield: 26%).

[0144] ESI-MS (m / z): found 638.4 (M + H+) (calc for C35H51N5O6: 637.81).

[0145] HPLC-MS: same method and column of Example 1. Rt: 11.17 min

[0146] XH-NMR (500 MHz, MeOD): 1.64 (bquint, -CH2-CH2-N-, 4H), 2.25 (s, -CH3, 6H), 2.48 (bt, -CH2-CH2-N-, 4H), 2.75 (bquint, -NH-CH-(CH2OH)2, 2H), 3.81 (d, -NH-CH- (*CH2OH)2, 8H), 3.82 (s, BZ-CH2-NH-, 4H), 3.86 (s, -N-CH2-BZ, 4H), 3.90 (s, Py-CHz- N-, 4H), 6.86 (s, -CH-CCH3-CH-, 2H), 6.98 (s, -CH-CCH3-CH-, 2H), 7.12 (d, Py, 2H), 7.73 (t, Py, 1H).

[0147] 13C-NMR{1H} (125 MHz, MeOD): 19.5 (-CH3), 22.0 (-CH2-CH2-N-), 46.5 (Bz-CH2- NH-), 50.4 (-CH2-CH2-N-), 56.9 (-N-CH2-Bz), 57.2 (Py-CH2-N-), 58.5 (-NH-CH- (CH2OH)2), 59.5 (-NH-CH-(CH2OH)2), 121.8 (-CH2-C-CH-CH-), 122.0 (-COH-C-CH- CH2Ser), 125.2 (-CH2-C-COH-), 127.7 (-CH-CCH3-CH), 128.4 (-C-CH-CCH3-), 129.6 (- CCH3-CH-), 137.6 (-CH-CH-CH-), 153.9 (-COH-), 156.0 (Cq Py).

[0148] Example 4 - Synthesis of Compound 67

[0149] Starting from the l,4,8-triaza-2,6-pyridinophane obtained according to Example 1 A), the synthesis of Compound 67 was carried out according to the following Scheme 6:

[0150] Scheme 6

[0151] Details of the synthesis of the present Example are provided in the following paragraphs. l,4,8-triaza-2,6-pyridinophane prepared according to Example 1, step A) (108 mg, 0.228 mmol) was dissolved in 5 mL of anhydrous THF, then D-glucamine (2 eq, 83 mg) was added; the mixture was stirred under nitrogen at 50°C for 3 days, then at reflux for 6 days. The mixture was cooled to 0°C, added with NaBE (5 eq, 43 mg), and stirred for 1.5 h under nitrogen atmosphere. The reaction was quenched with 0.5 mL H2O and stirred for further 1.5 h. The solvent was removed under reduced pressure and the solid was suspended in 10 mL of methanol; then, HCI 4 M was added to the suspension until pH 1 was measured. The solvent was evaporated again under reduced pressure, obtaining 250 mg of crude product that was purified by semi-preparative HPLC-MS. 75 mg of a white solid were obtained (yield: 41%).

[0152] ESI-MS (m / z): found 805.0 (M + H+), 403.1 (M+2H+) (calc, for C40H61N5O12: 803.95).

[0153] HPLC-MS (Waters Atlantis 5 pm (4.6x100 mm)): same method of Example 2) Rt: 6.55 min

[0154] HPLC-MS semipreparative (Waters Atlantis Prep OBD 5pm (19x100mm)); (A): H2O + 0.1% TFA, (B): ACN + 0.1% TFA; flow = 20 mL / min; 0-7 min = from 5% to 20% B; 7-11 min = from 20% to 70% B; 11-12 min = from 70% to 100% B. Rt: 5.32 min).

[0155] 1H-NMR (500 MHz, D2O) : 1.88 (m, -CH2-CH2-N-, 2H), 2.20 (s, -CH3, 6H), 2.98 (b, -CH2-CH2-N-, 4H), 3.12 (m, NHCH2CHOH, 4H), 3.5-3.7 (m, -CH-OH-CH2-OH, 10H), 4.03 (b, NHCH2CHOH, 2H), 4.24 (m, Py-CHz-NH-, 4H), 4.58 (s, -N-CHz-Ph, 4H), 4.77 (s, Ph- CHz-NH, 4H), 7.26 (s, -CH-CCH3-CH-, 2H), 7.31 (m, Py, 2H), 7.36 (s, -CH-CCH3-CH-, 2H), 7.84 (t, Py, 1H).

[0156] 13C-NMR{1H} (125 MHz, D2O): 19.4 (-CH3), 24.7 (-CH2-CH2-N-), 46.8 (Py-CH2-N- ), 49.0 (NHCH2CHOH) 54.7 (-N-CHz-Ph), 58.1 (Ph-CH2-NH), 59.0 (-CH2-CH2-N-), 62.7 (-CH2OH), 68.1, 70.6, 70.7, 70.9 (C-OH), 120.9 (-CH2-C-CH-CH-), 121.2 (-CH2-C-COH- ), 131.5 (-CH-CCH3-CH), 134.5 (-C-CH-CCH3-), 135.3 (-CCH3-CH-), 139.2 (-CH-CH-CH- ), 149.2 (-COH-), 152.9 (Cq Py).

[0157] The product obtained as in Example 1, step B) (65 mg, 0.137 mmol) was dissolved in 9 mL of 1-butanol, then 1 mL of a saturated aqueous glycine solution was added; the resulting suspension was stirred at room temperature for 66 h, then at 80°C for 4.5 h. The suspension was filtered, and the solvent was removed under reduced pressure. Then, the solid was redissolved in 3 mL of anhydrous methanol; the solution was cooled to 0°C and NaBH4 (7 eq, 36 mg) was added to the solution, that was stirred at RT for 18h. The reaction was quenched with 0.5 mL of H2O and the solvent was removed under reduced pressure, obtaining 124 mg of crude product.

[0158] ESI-MS (m / z): found 592.2 (M + H+), (calc for C32H41N5O6: 591.7).

[0159] HPLC-MS (Waters XTerra 5 pm (4.6x100 mm)): (A): H2O + 0.1% TFA, (B): ACN, flow = 1 mL / min; 0-15 min = from 1% to 100% B. Rt: 3.93 min

[0160] HPLC-MS semipreparative (Waters Atlantis Prep OBD 5pm (19x100mm)); (A): H2O + 0.1% TFA, (B): ACN + 0.1% TFA; flow = 20 mL / min; 0-7 min = from 10% to 30% B; 7-11 min = from 30% to 70% B; 11-12 min = from 70% to 100% B. Rt: 3.72 min).

[0161] XH-NMR (500 MHz, D2O) : 1.87 (m, -CHz-CH2-N-, 2H), 2.23 (s, -CH3, 6H), 3.00 (b, -CH2-CH2-N, 2H), 3.55 (b, -CH2-CH2-N-, 2H), 3.82 (m, -CHz-COOH, 4H), 4.29 (m, Py- CHz-N-, 4H), 4.59 (s, -N-CHz-Ph, 4H), 4.77 (s, Ph-CHz-NH, 4H), 7.28 (s, -CH-CCH3-CH- , 2H), 7.33 (m, Py, 2H), 7.37 (s, -CH-CCH3-CH-, 2H), 7.86 (t, Py, 1H).13C-NMR{1H} (125 MHz, D20) : 19.4 (-CH3), 24.9 (-CH2-CH2-N-), 46.4 (Py-CH2-N- ), 46.7 (NHCH2COOH), 54.9 (-N-CH2-PI1), 58.2 (Ph-CH2-NH), 59.1 (-CH2-CH2-N-), 119.0 (-CH2-C-CH-CH-), 120.4 (-CH2-C-COH-), 121.4 (-CH2-C-CH-), 132.7 (-CH-CCH3-CH), 134.9 (-C-CH-CCH3-), 135.3 (-CCH3-CH-), 139.9 (-CH-CH-CH-), 148.5 (-COH-), 152.0 (Cq Py), 169.2 (-COOH).

[0162] Example 6 - Fe(III) complexation

[0163] The Fe(III)-complexes of Compounds 1, 4, 12, 67, and 86 were prepared as follows.

[0164] For Compound 1 and Compound 12 : a solution of the compound of the invention in water was brought to pH = 3, and the solvent was evaporated under reduced pressure. The compound of the invention was redissolved in EtOH and an equimolar amount of FeCH was added. The complexation reaction was left stirring overnight at room temperature. Water was added to adjust the pH to 8, whereby the Fe(III)-complex precipitated. The complex was isolated by filtration.

[0165] For Compound 4, Compound 67, and Compound 86: an equimolar amount of the compound of the invention was added to an aqueous stock solution of Fe(NOs)3 (54.7 mM) in HNO3. The pH was corrected to 2.5 and the complexation reaction was carried out overnight by stirring at room temperature. At the end of the reaction, the solution was neutralized with diluted NaOH, and small amounts of the Fe(III)-complex so-precipitated were isolated by filtration.

[0166] Example 7 - Relaxometric analysis

[0167] The relaxivity values of some the complexes of the invention were evaluated by measuring them at 298 K in the 2-11 pH range at the magnetic fields that are relevant in clinical practice, namely at 1.5 T and at 3.0 T, as follows. The magnetic-field dependence of the longitudinal relaxation rate Ti of solvent protons (XH-NMRD profiles) were measured in aqueous solution by using a variable field relaxometer equipped with an HTS-110 3T Metrology Cryogen-free Superconducting Magnet (Mede, Italy), operating in the overall range of proton Larmor frequencies of 20-120 MHz (0.47-3.00 T). The measurements were performed using the standard inversion recovery sequence (20 experiments, 2 scans) with a typical 90° pulse width of 3.5 ps and the reproducibility of the data was within ± 0.5%. The temperature was controlled with a Stelar VTC-91 heater airflow. Additional points in the 0.01 - 10 MHz frequency range were collected on a Fast-Field Cycling (FFC) Stelar SmarTracer Relaxometer. Ti values at 500 MHz were collected with a Bruker NMR spectrometer operating at 11.7 T. All the experiments are repeated three times with a reproducibility of the data within ± 0.5%. The concentration of Fe3+in the different solutions was determined by using bulk magnetic susceptibility (BMS) shift measurements performed at 11.7 T (D. F. Evans, J. Chem. Soc., 1959, 2003) and confirmed by ICP-MS analysis after mineralization of the samples with HNO3 65% at 408 K. The relaxivity n values of the Fe(III)-complexes of Compound 1 (concentration 0.60 mM), of Compound 4 (concentration 0.15 mM), of Compound 12 (concentration 0.50 mM), of Compound 67 (concentration 0.52 mM), and of Compound 86 (concentration 0.48 mM) at 1.5 and 3.0 T field strength, pH = 7.4 and 310 K in 0.15 M NaCI, in 0.15 M NaCI and 25 mM NaHCOs, and in Seronorm™ (lyophilized human serum) were determined as above described and are shown in Table 1.

[0168] Table 1

[0169] As a comparison, it can be observed that the relaxivity of the compound of the invention is higher than the relaxivity of the iron(III) complex disclosed in US 5,334,371, i.e. of the iron (III) -complex of 3,6,9-tris(carboxymethyl)-3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca- l(15),ll,13-triene, which is 0.49 mM1s1(at 40 °C and 20 MHz in water); in most instances, the relaxivity of the complexes of the invention is even at least 2.5 times higher, such as even at least 3.0 times higher, with respect to the iron(III) complex disclosed in US 5,334,371.

[0170] Thus, in view of the data of Table 1, it can be seen that the complexes of the invention show high and suitable relaxivity n values for MRI imaging, in particular at physiological conditions, as they possess a relaxivity of 0.50 mM1s1or higher at physiological conditions and using magnetic fields that are relevant for clinical practice (1.5 T and at 3.0 T).

[0171] Moreover, it can be observed from Table 1 that the complexes of the invention, when not comprising biological moieties for specifically doing so, do not substantially interact with proteins of the human serum, such as e.g. human serum albumin, because the relaxivity values in Seronorm™ (lyophilized human serum) are similar to the values obtained in the two other conditions, i.e. NaCI 0.15 M and NaCI 0.15 M (HCO3_25 mM). For this reason, in vivo, the complexes of the invention could have a faster clearance and a homogeneous distribution into the organs and textiles, and thus could have a broader spectrum of MRI applications, compared to complexes interacting with proteins of the human serum. Example 8 - Thermodynamic stability analysis

[0172] To assess the thermodynamic stability of the Fe(III) complexes of the invention, as well as of references and comparative ones, the protonation constants of the respective ligands first, and then of the Fe(III) complexes, were determined byXH-NMR spectroscopy and by UV-Vis spectrophotometry. Finally, based on the protonation constants, the thermodynamic stability constant of the Fe(III) complexes of the invention were determined by observing the competition reaction between the Fe(III) complexes and the N,N'-bis(2-hydroxybenzyl) ethylenediamine-N,N'-diacetic acid (HBED) ligand and ethylenediaminetetraacetate (EDTA), which are thus reference (Ref.) compounds, using UV-Vis spectrophotometry. HBED is the ligand with the formula below that forms a complex with Fe(III) having low relaxivity (rl of 0.49 mM-1,s1at 60 MHz, 40°C in PBS buffer as mentioned in Bales et al., Contrast Media &

[0173] Molecular Imaging, Volume 2019, Article ID 8356931); EDTA is the ligand with the formula below forming a complex with Fe(III) that, in physiological conditions, forms a dimer having low solubility and low relaxivity (as mentioned in Baranyai Z. et al., Chem. Sci., 2021, 12,

[0174] HBED (ref.) EDTA (ref.)

[0175] A) Determination of the protonation constants of the ligands

[0176] Solid Fe(NOs)3 was dissolved in 0.1 M HNO3 solution. The concentration of Fe(NOs)3 solution was determined by using standardized Na?H2EDTA in excess. The excess of the Na?H2EDTA was measured with a standardized ZnC solution and xylenol orange as indicator. The H+concentration of the Fe(NOs)3 solution was determined by pH potentiometric titration in the presence of Na2H2EDTA excess. The concentration of the ligands H3NOTA (see formula below - used as reference, to determine the stability of Fe(HBED) complex), H4HBED (reference), and EDTA (reference) was determined by pH-potentiometric titrations in the presence and absence of a 40-fold excess of Ca2+. The pH-potentiometric titrations were made with standardized 0.2 M NaOH (concentration of the ligands was generally 0.002 M). For the pH measurements and titrations, Metrohm 888 Titrando titration workstation Metrohm-6.0234.110 combined electrode was used. The concentration of Compound 1 and of Compound 12 was determined by using standardized Fe(NOs)3 with UV-Vis spectrophotometry at 490 nm and pH = 3.5 on the absorption band of the resulting Fe(III) complexes. For the UV-Vis spectrophotometric measurements, PerkinElmer Lambda 365 UV-Vis spectrophotometer was used.

[0177] The protonation constants (KiH= [HiLigand] / ([Hi-iLigand] x [H+])) of NOTA (reference) and of HBED (reference) obtained by the pH potentiometric method above were later used for determining the protonation constants and the thermodynamic stabilities of the corresponding Fe(III) complexes.

[0178] The protonation constants of Compound 1 and of Compound 12 have been determined byXH-NMR spectroscopy with Bruker Avance III (9.4 T) spectrometer, equipped with Bruker Variable Temperature Unit (BVT), Bruker Cooling Unit (BCU) and a BB inverse z gradient probe (5 mm) by recording the chemical shift variations of the non-labile protons as a function of pH at 25°C in 0.15 M NaNOs solution. Since the protonation / deprotonation is fast on the NMR time scale, the chemical shifts of the observed signals represent a weighted average of the shifts of the different species with different protonation states and expressed by the following equation (J. L. Sudmeier, C.

[0179] N. Reilley, Anal. Chem. 1964, 36, 1698 -1706.):

[0180] §H(obs) = Ci §HHILwherein §H(obs) is is the observed chemical shift of a given signal, ci and 8HH'Lare the concentration and the chemical shift of the involved species, respectively. The observed chemical shift values (§H(obs)) have been fitted to the equation above (the concentration of the different protonated ligand has been expressed by the protonation constants iH). B) Determination of the protonation constants of the Fe(III) complexes

[0181] The stepwise protonation constants (KMHiugand=[MHiLigand] I ([MH; iLigand] x [H+])) of the Fe(III) complexes of Compound 1, of Compound 12, of NOTA (reference), and of HBED (reference) were determined by pH-potentiometric and / or by spectrophotometric studies.

[0182] In particular, the protonation constants of the Fe(NOTA) and Fe(HBED) complexes were determined using pH-potentiometry by titrating the pre-prepared complexes from pH = 1.7 to pH = 12.0 with 0.2 M NaOH ([FeL] = 0.002 M). For the pH measurements and titrations, Metrohm 888 Titrando titration workstation Metrohm-6.0234.110 combined electrode was used. Equilibrium measurements were carried out at a constant ionic strength (0.15 M NaNOs or NaCIC ) in 6 ml samples at 25 °C. The solutions were stirred, and N2 was bubbled through them. The titrations were made in the pH range of 1.7- 12.0. KH-phthalate (pH=4.005) and borax (pH=9.177) buffers were used to calibrate the pH meter. For the calculation of [H+] from the measured pH values, the method disclosed in Irving et al. Anal. Chim. Acta, 1967, 38, 475-488 was used as follows: a

[0183] O.01M HNO3 or HCIO4 solution was titrated with a standardized NaOH solution at 0.15 M NaNOs ionic strength. The differences (A) between the measured (pHread) and calculated pH (-log[H+]) values were used to obtain the equilibrium H+concentration from the pH values measured in the titration experiments (>4 = 0.02 for 0.15 M NaNOs, 0.01 for 0.15 M NaCICk). For the equilibrium calculations, the stoichiometric water ionic product pKw) was also needed to calculate [OH ] values under basic conditions. The VNaoH - pHread data pairs of the HNO3 - NaOH titration obtained in the pH range 10.5 - 12.0 were used to calculate the p / wvalue (p / <w= 13.76).

[0184] The protonation constants of Fe(Compound 1) and Fe(Compound 12) complexes were determined by UV spectrophotometry analysis (with the instrument PerkinElmer Lambda 365 UV-Vis spectrophotometer) in the wavelength range of 210 - 700 nm ([Fe(Compound l)] = [Fe(Compound 12)]= 100 pM, 0.15 M NaCICk, 25 °C) according to the method disclosed in Example 8A above. The absorbance of the Fe(III) complexes is a combination of the absorption of each protonated species and expressed by the following equation (Beck, M. T. et al., Chemistry of Complex Equilibria, Akademia Kiado Budapest and Nostrand Reinhold Company Ltd. London, 1990):

[0185] A = Zci & I wherein A is the absorbance at a given wavelength, ci, EI and I are the concentration, the molar absorptivity of the species and the path length of the cell, respectively. The absorbance values (A) have been fitted to the equation above (the concentration of the different protonated ligand has been expressed by the protonation constants iH).

[0186] The protonation constants of the Fe(III) complexes of Compound 1, of Compound 12, of NOTA (reference) and of HBED (reference) were later used for determining the thermodynamic stability of the same Fe(III) complexes.

[0187] C) Determination of the thermodynamic stability and cumulative stability constant of the Fe(III) complexes

[0188] The thermodynamic stability constants (KMLigand = ([MLigand] I ([M] x [Ligand])) and cumulative stability constants (PMHiugand=([MHiLigand] I ([M] x [Ligand] x [H]'))) of the Fe(III) complexes were determined as follows.

[0189] The stability constant of the Fe(NOTA) complex was determined by spectrophotometry studies of the Fe3+- NOTA system at the absorption band of Fe111complexes at [H+] = 0.01 - 3.0 M in the wavelength range of 350 - 800 nm. The concentrations of Fe3+and NOTA were 0.002 M. The H+concentration in the samples was adjusted with the addition of calculated amounts of a 6 M solution of HNO3 (I=[Na+] + [H+] = 0.15, [H+]<0.15 M). The samples were kept at 25°C for two weeks. The absorbance values of the samples were determined at 11 wavelengths (370, 380, 390, 395, 400, 405, 410, 415, 420, 425 and 430 nm). For the calculations of the thermodynamic stability constant of the Fe(NOTA), the molar absorptivities of Fe3+and Fe(NOTA) were determined by recording the spectra of l.OxlO-3, 1.5xl0-3, 2.0xl0-3and 2.5xl0-3M solutions of Fe3+and Fe(NOTA) solutions. The absorption spectra of the Fe(NOTA) solutions were recorded in the pH range of 1.7 - 7.5. All spectrophotometric measurements were performed at 25°C in 0.15 M NaNOs solution. The pH was adjusted by stepwise addition of concentrated NaOH or HNO3 solutions.

[0190] The stability constants of the Fe(HBED) complex was determined by following the competition reaction between HBED and NOTA ligands for Fe3+-ion with spectrophotometry at the absorption band of Fe(HBED) complex in the wavelength range of 400-700 nm. For Fe3+-HBED - NOTA systems, six samples were prepared with [Fe3+] = 0.1 mM, [HBED] = 0.2 mM and [NOTA] = 0.0, 2.0, 4.0, 6.0, 8.0 and 10.0 mM in 0.15 M NaNOs solution. The pH values of the samples were adjusted to 5.0 by stepwise addition of the concentrated NaOH and HNO3 solutions. The samples were kept for four weeks at 25 °C in order to attain equilibrium. The time needed to reach the equilibria was determined by spectrophotometry. The absorbance values of the samples were determined at the absorption band of the Fe(HBED) complex ([Fe(HBED)]- species predominates at pH = 5.0). For the calculations of the thermodynamic stability constants of the Fe(HBED) complexes, the molar absorptivities of [Fe(HBED)]- species were determined by recording the spectra of 0.5, 0.1 and 0.2 mM solutions of [Fe(HBED)]- at pH = 5 in the presence of 0.15 M NaNOs. The spectrophotometric measurements were made with the use of PerkinElmer Lambda 365 UV-Vis spectrophotometer, using 1.0 cm cells. The thermodynamic stability constants were calculated with the PSEQUAD program (L. Zekany et al., Computational Method for Determination of Formation Constants, Ed. Legett D J, Plenum, New York, 1985, p. 291.)

[0191] The thermodynamic stability constant of the Fe(Compound 1) and of the Fe(Compound 12) complexes was determined by following the competition reaction for Fe3+-ion between Compound 1 and HBED ligands, and between Compound 12 and EDTA ligands, with UV-Vis spectrophotometry on the absorption band of Fe(Compound 1), Fe(HBED) and Fe(Compound 12) complexes in the wavelength range of 400-700 nm.

[0192] For Fe3+- Compound 1 - HBED systems, six samples were prepared with [Fe3+] = [Compound l] = 0.1 mM, [HBED] = 0.0, 0.05, 0.1, 0.15, 0.2 and 0.25 mM in 0.15 M NaNOs solution. The pH values of the samples were adjusted to 3.6 by stepwise addition of the concentrated NaOH and HNO3 solutions. The samples were kept for four weeks at 25 °C in order to attain equilibrium. The time needed to reach the equilibria was determined by spectrophotometry. The absorbance values of the samples were determined at the absorption band of the Fe(Compound 1) and Fe(HBED) complexes ([Fe(H2Cpd. l)] and [Fe(HBED)]- species predominate at pH = 3.6). For the calculations of the thermodynamic stability constant of the Fe(Cpd. l) complex, the molar absorptivities of [Fe(H2Cpd. l)] and [Fe(HBED)]- species were determined by recording the spectra of 0.05, 0.1 and 0.2 mM solutions of [Fe(H2Cpd. l)] and [Fe(HBED)]- species at pH 3.6 in the presence of 0.15 M NaNOs.

[0193] For Fe3+- Compound 12 - EDTA systems, seven samples were prepared with [Fe3+] = 0.05 mM, [Compound 12] = 0.95 mM, [EDTA] = 0.0, 0.04, 0.05, 0.07, 0.09, 0.18 and 0.53 mM in 0.15 M NaNOs solution. The pH values of the samples were adjusted to 6.7 by stepwise addition of the concentrated NaOH and HNO3 solutions. The samples were kept for four weeks at 25 °C in order to attain equilibrium. The time needed to reach the equilibria was determined by spectrophotometry. The absorbance values of the samples were determined at the absorption band of the Fe(Cpd. l2) and Fe(EDTA) complexes ([Fe(H2Cpd. l2)H 1] and [Fe(EDTA)]- species dominate at pH = 6.7). For the calculations of the thermodynamic stability constant of the Fe(Cpd. l2) complex, the molar absorptivities of [Fe(H2Cpd. l2)H 1] and [Fe(EDTA)]- species were determined by recording the spectra of 0.05, 0.1 and 0.2 mM solutions of [Fe(H2Cpd. l2)H 1] and [Fe(EDTA)]’ species at pH 6.7 in the presence of 0.15 M NaNOs. The spectrophotometric measurements were made with the use of PerkinElmer Lambda 365 UV-Vis spectrophotometer and 1.0 cm cells. The thermodynamic stability constants were calculated with the PSEQUAD program (L. Zekany et al., Computational Method for Determination of Formation Constants, Ed. Legett D J, Plenum, New York, 1985, p. 291). D) Protonation constants and thermodynamic stabilities of Fe(III) complexes

[0194] The thermodynamic (KMLigand) and cumulative (PMHiugand) stability and the stepwise protonation constants (KMHiugand) of Fe(III)-complexes of Compound 1 and Compound 12, as well as of reference complexes Fe(III)-EDTA and Fe(III)-HBED, and of comparative complex Fe(III)-NOTA, determined according to the experiments above, are summarized in Table 2 below.

[0195] Table 2aSpectrophotometry (0.15 M NaNO3, 25°C),bReference compound, used to determine the thermodynamic stability of Fe(III)-complex of Cpd. l,cadapted from ref. : Baranyai, Z. et al., Chem. Sci. 2021, 12, 11138- 11145.,dReference compound, used to determine the thermodynamic stability of Fe(III)-complex of Cpd.12

[0196] In order to compare the thermodynamic stabilities of the Fe(Cpd. l), Fe(Cpd. l2), Fe(HBED) (reference), Fe(NOTA) (reference) and Fe(EDTA) (reference) complexes, the pFe values (pFe = -log[Fe3+]free, [Fe3+]tot = 1 pM, [L]tot = 10 pM, pH = 7.4) characterizing the conditional stability of the Fe(III)-complexes have been calculated at pH = 7.4 in the presence of 1 pM Fe3+and 10 pM ligand. Based on the pFe values, as it can be observed from the data of Table 2, Fe(III) complexes of Compound 1 and Compound 12, and of NOTA have similar conditional stability.

[0197] The conditional stability (pFe) of Fe(Cpd. l) and of Fe(Cpd. l2) showed in Table 2 is high and thus suitable for an MRI used in that, as further confirmed in Example 10 below, it is comparable or even higher than the pFe of the Fe(III) complex formed with Human serum transferrin (sTf) (log / FeTf=21.44, log / Fe2Tf=20.34, pFe= 22.4, [Fe3+] = 1 pM, [Trf] = 10 pM, pH = 7.4) (W. R. Harris et al., Inorg. Chem., 1994, 33, 4991). Thus, the in vivo stability of the Fe(III) complex of the invention is confirmed.

[0198] Example 9 - Kinetic inertness analysis

[0199] To obtain data relating to the kinetic inertness of Fe(Compound 1), and of Fe(Compound 12), the transchelation reaction systems of Fe(III) complexes (schematized below) were investigated by UV-VIS-spectrophotometry in the presence of a large excess of CDTA (reference) and HBED (reference) as an exchanging ligand in order to guarantee the pseudo- first order kinetic conditions.

[0200] Fe(Cpd. l) system : [Fe(Cpd. l)] = 0.1 mM, [HBED] = 1.0 and 2.0 mM, 0.15 M NaNO3, 25°C Fe(Cpd. l2) system : [Fe(Cpd. l2)] = 0.1 mM, [CDTA] = 2.0, 4.0, 6.0 and 8.0 mM, 0.15 M NaNO3, 25°C.

[0201] Pseudo-first order kinetic reaction :

[0202] FeL + X Fe(X) + L with L=Compound 1 or Compound 2, X=HBED or CDTA.

[0203] A) Determination of kinetic inertness of Fe(III) complexes

[0204] The transchelation reactions of Fe(Compound 1) and Fe(Compound 12) were studied by spectrophotometry, following the dissociation of the Fe(III) complexes and the formation of the resulting Fe(HBED) or Fe(CDTA) complex at 490 nm with PerkinElmer Lambda 365 UV-Vis spectrophotometer. The concentration of the Fe(Cpd. l) and Fe(Cpd. l2) complex was 0.1 mM, while the concentration of the HBED and CDTA was 10 - 80 times higher, in order to guarantee pseudo-first-order conditions. The temperature was maintained at 25 °C and the ionic strength of the solutions was kept constant, 0.15 M for NaNO3. The exchange rates were studied in the pH range about 5.5 - 11.5. For keeping the pH values constant, MES (pH range 5.5 - 6.5) HEPES (pH range 7.4 - 8.5), piperazine (pH range 8.5 - 10.5) and Na?HPO4 (pH range 11.0 - 12.5) buffers (0.01 M) were used. The pseudo-first-order rate constants ( d) were calculated by fitting of the absorbance - time data pairs to the following Equation 1 : Equation 1 where A, A and A are the absorbance values at time t, the start of the reaction and at equilibrium, respectively. Calculation were performed with the Micromath Scientist computer program (version 2.0, Salt Lake City, UT, USA).

[0205] B) Kinetic inertness of Fe(III) complexes

[0206] The kinetic inertness results (in terms of dissociation rate constants, kd, and of half-life, ti / 2) at 25°C and at pH = 7.4 of Fe(III)-complexes of Compound 1 and of Compound 12 are reported in Table 3 below:

[0207] Table 3

[0208] The dissociation half-life (ti / 2=ln(2) / d) of the Fe(III) complexes with Cpd.l and Cpd.12 are about 74 and 2.2 hours, confirming the high inertness of the Fe(III) complexes of the invention near to physiological condition (pH = 7.4, 25 °C).

[0209] Example 10 - Transferrin challenge reactions

[0210] Transferrins are Fe3+-binding transport proteins present in the body fluids. Human serum transferrin (sTf) is known to bind Fe3+with high affinity (log / FeTf=21.44, log / Fe2Tf=20.34, pFe= 22.4, [Fe3+] = 1 mM, [Trf] = 10 mM, pH = 7.4) (W. R. Harris et al., Inorg. Chem., 1994, 33, 4991). Since serum transferrin is normally only 30% saturated with Fe3+, it retains a relatively high capacity for binding Fe3+possibly released by other Fe(III)- complexes, and even to promote the release of Fe3+from other Fe(III)-complexes.

[0211] A) Transchelation reaction between Fe(III) complexes and Transferrin

[0212] To investigate the possible role of transferrin in the dissociation of the Fe(III)-complexes of the invention, and thereby to further investigate the stability of the Fe(III)-complexes of the invention, the reaction of 23.5% Fe3+saturated human serum transferrin (Sigma) with Fe(III) complexes of Compound 1 and of Compound 12 was studied by following the possible formation of the Fe3+saturated human serum transferrin and the possible dissociation of Fe(Cpd.l) and Fe(Cpd.l2). Fe3+saturation of the human serum transferrin was determined as disclosed in Z. Baranyai et al., Eur. J. Inorg. Chem. 2013, 147-162; as the Fe3+binding of sTf requires the concomitant binding of a synergistic anion, which in vivo is bicarbonate (G. W. Bates et al., J. Biol. Chem., 1975, 250, 2177 - 2181), all measurements were performed in the presence of 25 mM NaHCO3at pH = 7.4 and 25 °C. Since the molar absorptivites of the Fe(III)-complexes and Fe3+-human serum transferrin species are different, the possible metal-exchange reactions of Fe(Cpd.l) and Fe(Cpd.l2) complexes with 23.5% Fe3+-saturated human serum transferrin were determined by following the eventual dissociation of Fe(Cpd.l) and Fe(Cpd.l2) complexes and the formation of the Fe3+-saturated human serum transferrin by spectrophotometry with PerkinElmer Lambda 365 UV-Vis spectrophotometer in the presence of equimolar human transferrin in the wavelength range 400 - 700 nm. The concentration of the Fe(Cpd.l) and Fe(Cpd.l2) complexes and 23.5% Fe3+saturated human serum transferrin was 0.1 mM. The temperature was maintained at 25 °C and the ionic strength of the solutions was kept constant (0.15 M of NaCI). The pH of the sample was adjusted by stepwise addition of the concentrate NaOH and HCI solution.

[0213] It was observed that the absorption spectra of the Fe(Cpd.l) - human serum transferrin reacting system within 1000 min reaction times remained practically unchanged (the decrease of the absorbance value is about 5% at 460 nm), meaning that the Fe(Cpd.l) has a high kinetic inertness and / or higher conditional stability compared to the Fe(III)-complex of sTf.

[0214] Absorption spectra of the Fe(Cpd.l2) - human serum transferrin reacting system reveal the decrease the absorbance values by about 10% at 460 nm. By considering the conditional stability of the Fe(Cpd.l2), Fe(sTf) and Fe?(sTf) complexes (see Example 8, Part D) and the experimental condition ([Fe(Cpd.l2)] = 0.1 mM, [sTf] = 0.1 mM, saturation of sTf is 23.5%, pH = 7.4), the 10% decrease of the absorbance value can be explained by the partial (ca. 40%) formation of Fe(sTf) and Fe?(sTf) complexes. Considering the in vivo concentration of human serum transferrin ([sTf]=4.0 JJM), the transmetallation between the Fe(Cpd.l2) and human serum transferrin can be assumed to be non-relevant at physiological condition.

[0215] In view of the results mentioned above, it has thus been demonstrated that the complexes of the invention do not substantially dissociate, or dissociate very slightly, even in the presence of 23.5% Fe3+-saturated sTf (namely, close to physiological condition, the latter being pH = 7.5, 25°C, 25 mM NaHCOs, 0.15 M NaCI). This further demonstrate the high stability of the compounds of the invention when complexed with Fe(III).

[0216] B) Transchelation reaction between Fe?(sTf) complex and Compound 1, and Fe?(sTf) complex and Compound 12

[0217] To investigate the therapeutic efficiency of Compound 1 and Compound 12 as iron- sequestering agent, the kinetics of iron removal from human diferric-transferrin (Fe?sTf) by the free ligands of Compound 1 and Compound 12, with the subsequent formation of Fe(Cpd.l) and Fe(Cpd.l2), were followed. Free ligands Compound 1 and Compound 12 were each added into a solution of Fe?sTf near physiological condition (pH = 7.4, 25°C, 25 mM NaHCOs, 0.15 M NaCI), thus providing the two following reaction systems: Fe?sTf - Cpd. l ([Fe2sTf] = [Cpd.l] = 0.1 mM), and Fe?sTf - Cpd.12 ([Fe2sTf] = [Cpd.l2] = 0.1 mM). The rate of the metal-exchange reactions between Fe2sTf and the free ligands Compound 1 and Compound 12 were determined by monitoring the formation of Fe(Cpd.l) and Fe(Cpd.l2) by spectrophotometry with PerkinElmer Lambda 365 UV-Vis spectrophotometer at 460 nm on the absorption band of the resulting Fe(Cpd.l) and Fe(Cpd.l2) in the presence of equimolar Fe2sTf and free ligands Compound 1 and Compound 12. The temperature was maintained at 25 °C and the ionic strength of the solutions was kept constant (0.15 M of NaCI). Reactions were monitored in the presence of 25 mM NaHCOs. The pH of the sample was adjusted by stepwise addition of the concentrate NaOH and HCI solution. Absorption spectra of the Fe2sTf - Cpd.l and Fe2sTf - Cpd.12 reacting systems show that the absorbance values in the wavelength range 400 - 700 nm increase by 14% as a function of time, meaning that the Fe(III)-complexes of the invention are formed. Accordingly, the competition reactions of Fe2sTf vs. Cpd.l or Cpd.12 favor the latter two, due to the higher or at least comparable conditional stability constant of, respectively, Fe(Cpd.l) and Fe(Cpd.l2) complexes, compared to the Fe(III)-complex of sTf. Considering the conditional stability of the Fe(Cpd.l), Fe(Cpd.l2), Fe(sTf) and Fe2(sTf) complexes (see Example 9) and the experimental condition ([Fe(Cpd.l)] = 0.1 mM, [Fe(Cpd.l2)] = 0.1 mM, [sTf] = 0.1 mM, saturation of sTf is 23.5%, pH = 7.4), the 14% increase of the absorbance values in Fe2sTf - Cpd.l and Fe2sTf - Cpd.12 reacting systems can be associated to the complete formation of the Fe(Cpd.l) and Fe(Cpd.l2) complexes, which can be explained by the complete removal of one of the Fe(III) ion from diferric-transferrin (Fe2sTf) complex. Moreover, the formation of the Fe(Cpd.l) and Fe(Cpd.l2) is completed in a very short period of time (ca. 60 min) at physiological condition (pH = 7.4, 25 mM NaHCOs, 0.15 M NaCI, 25 °C).

[0218] This example 10 D) demonstrates that the compound of formula (I) can be effectively used to treat or prevent disorders caused by the excess and / or accumulation of iron ions, such as iron intoxication and / or iron overload, in that it is able to form a complex with iron ions, particularly Fe3+ions, even when such iron ions have already been complexed by endogen proteins, such as human serum transferrin. Accordingly, once administered, the compound of formula (I) can form a complex with excess and / or accumulated iron ions, particularly Fe3+ions, and then be excreted as an iron complex, thereby effectively lowering the excess and / or accumulated iron ions.

[0219] Example 11 - Redox stability analysis

[0220] To characterize the redox stabilities of the Fe(III) complexes, the reaction of ascorbic acid with Fe(III)-Compound 1, Fe(III)-Compound 12, and Fe(III)(NOTA) (comparative) were studied by following the reduction of the Fe(III)-complexes by spectrophotometry in the presence of the large ascorbic acid excess ([Fe(III)(NOTA)] = 2.0 mM, [Fe(Cpd.l)] = [Fe(Cpd.l2)] = 0.2 mM, [ascorbic acid] = 20 mM, pH = 7.4, [HEPES] =0.01 M, 0.15 M NaNOs, 25°C) as follows.

[0221] A) Determination of redox stability of Fe(III) complexes

[0222] The redox stability of the Fe(NOTA) (comp.), Fe(Cpd.l) and Fe(Cpd.l2) was characterized by assessing the rates of their reduction with ascorbic acid, observing the reduction reactions by spectrophotometry, following the formation of the Fe(II)-Ligand complexes at 375 nm for Fe(NOTA) (comp.), and at 490 nm for Fe(Cpd.l) and Fe(Cpd.l2) with PerkinElmer Lambda 365 UV-Vis spectrophotometer. The concentration of the Fe(NOTA) (comp.) was 2.0 mM, and of Fe(Cpd.l) and Fe(Cpd.l2) was 0.2 mM, while the ascorbic acid was used in high excess ([ascorbic acid] = 20 mM) in order to guarantee the pseudo-first-order condition. For Fe(III)(NOTA) (comp.) experiments, a four-fold excess of free NOTA ligand was added to the Fe(III)(NOTA) complexes to ensure the reduction of the Fe(III)(NOTA) complex to the Fe(II)(NOTA) complex without the release of Fe2+ion. The temperature was maintained at 25 °C and the ionic strength of the solutions was kept constant, 0.15 M for NaNOs. The reduction rates were studied at pH = 7.4. For keeping the pH values constant, HEPES buffer was used ([HEPES] = 0.01 M). In the sample preparation, air was bubbled through all solutions in order to maintain oxygen free condition. The pseudo-first-order rate constants (Obs= d) were calculated by fitting the absorbance - time data pairs to Equation 1 supra) with the Micromath Scientist computer program (version 2.0, Salt Lake City, UT, USA).

[0223] B) Redox stability data of Fe(III) complexes

[0224] The absorption spectra of the experiments show that, for Fe(III)(NOTA) (comp.), the absorbance values decrease as a function of time due to the reduction of Fe(III)(NOTA) (comp.) by ascorbic acid, and indeed the reduction half-life (ti / 2=ln2 / Obs) characterizing the ascorbic acid mediated reduction of Fe(III)(NOTA) (comp.) was found to be ti / 2=2.7 min (with the excess of ascorbic acid mentioned in section A) above). By taking into account in vivo concentration of the ascorbic acid ([ascorbic acid] =43 pM, P. M. May et al., J. Chem. Soc. Dalton Trans., 1977, 588 - 595) and considering that the reduction rate of the Fe(III)-complex is directly proportional to the concentration of the ascorbic acid (Baranyai, Z. et al., M. Chem. Sci. 2021, 12, 11138-11145), the ascorbic acid mediated reduction of Fe(III)(NOTA) (comp.) was found to be ti / 2=19.5 h at physiological condition ([ascorbic acid]=43 pM, pH = 7.4, 0.01 M HEPES, 0.15 M NaNOs 25 °C).

[0225] It was further observed that the absorbance values of Fe(III)-Compound 1 - ascorbic acid reacting system slowly decreases as a function of time, by ca. 20% decrease of the absorbance values within 1 day. By taking into account in vivo concentration of the ascorbic acid ([ascorbic acid]=43 pM) and considering that the reduction rate of the Fe(III)-complex is directly proportional to the concentration of the ascorbic acid, the ascorbic acid mediated reduction of Fe(III)-Compound 1 was found to be ti / 2=2.6x 103h at physiological condition ([ascorbic acid]=43 pM, pH = 7.4, 0.01 M HEPES, 0.15 M NaNOs 25 °C). This ti / 2 value can be an indication of the safe and effective in vivo applications of the iron complex of the invention.

[0226] Furthermore, it was observed that the absorption spectra of the Fe(III)-Compound 12 - ascorbic acid reacting system within 1 day reaction time remains practically unchanged, even in the presence of 200 fold ascorbic acid excess. This can be explained by the high selectivity of the Compound 12 for Fe(III)-ion over Fe(II)-ion (ApFe> 16); in other words, when complexed with the compound of the invention, iron prefers to remain in its +3 oxidation state, without being reduced to +2, even in the presence of large ascorbic acid (reducing agent) excess.

Claims

CLAIMS1. A compound of Formula (I) :Formula (I) wherein : n is an integer selected from 0, 1, 2, 3, and 4; m and o are integers independently selected from 1, 2, 3 and 4;Y1and Y2are independently selected from the group consisting of hydrogen and a Ci-C4-alkyl;R1and R2are independently selected from the group consisting of hydrogen and Ci-C4-alkyl;L1and L2are independently selected from the group consisting of C1-C4- alkylaminyl, Ci-C4-alkylamidyl, and Ci-C4-alkylether;Z1and Z2are independently selected from the group consisting of hydrogen and a Ci-Ce-alkyl, said Ci-Ce-alkyl being optionally substituted by one or more groups selected from the group consisting of hydroxyl (-OH), carboxyl (-COOH), and phosphonate (-PO3H2);RA, RB, Rc, RD, and REare independently selected for each occurrence from the group consisting of hydrogen and Ci-C4-alkyl;L is selected from the group consisting of hydrogen, a direct bond, a ether (—0—), a thioether (— S— ), an amido (— CONH— ), an amino (— NH— ), and a Ci-C2o-alkylene; said Ci-C2o-alkylene being optionally substituted by one or more functional groups selected from the group consisting of: carbonyl (—CO—), carboxyl (— COOH), amido (—CONH—), amino (— NH— ), ether (— 0—), thioether (— S— ), (hetero)aryl, (hetero)cyclo-alkyl, and hydroxyl (— OH); p is an integer selected from 0, 1, 2, 3, and 4; provided that when L is hydrogen, p is 0; and when L is a direct bond, p is an integer selected from 1, 2, and 3;A is independently selected for each occurrence from the group consisting of a biological moiety and a macrocycle of formula (IA):wherein : the bond interrupted by the squiggly line (~) indicates the point of attachment to L; and said bond interrupted by the squiggly line (~) bonds preferably the position 4 of the pyridine ring of the macrocycle of formula (IA); m' , n' , and o' independently have the same meaning provided above for m, n, and o;Y3and Y4independently have the same meaning provided above for Y1and Y2;R3and R4independently have the same meaning provided above for R1and R2;L3and L4independently have the same meaning provided above for L1and L2;Z3and Z4independently have the same meaning provided above for Z1and Z2; andRA', RB', Rc', RD', and RE' independently have the same meaning provided above for RA, RB, Rc, RD, and RE, or an ion, or a stereoisomer, or a tautomer, or a hydrate, or a solvate, or a pharmaceutically acceptable salt thereof, or a mixture of the same.

2. The compound according to claim 1, wherein Y1and Y2, as well as Y3and Y4if present, are independently selected from the group consisting of hydrogen and a Ci-Cs-alkyl.

3. The compound according to claim 2, wherein Y1and Y2, as well as Y3and Y4if present, are independently selected from the group consisting of hydrogen and a Ci-C2-alkyl.

4. The compound according to claim 3, wherein Y1and Y2, as well as Y3and Y4if present, are independently selected from the group consisting of hydrogen and a Ci-alkyl.

5. The compound according to claim 4, wherein Y1and Y2, as well as Y3and Y4if present, are hydrogen.

6. The compound according to any one of claims 1 to 5, wherein R1and R2, as well as R3and R4if present, are independently selected from the group consisting of hydrogen and Ci-Cs-alkyl.

7. The compound according to claim 6, wherein R1and R2, as well as R3and R4if present, are independently selected from the group consisting of hydrogen and Ci-C2-alkyl.

8. The compound according to claim 7, wherein R1and R2, as well as R3and R4if present, are independently selected from the group consisting of hydrogen and Ci-alkyl.

9. The compound according to claim 8, wherein R1and R2, as well as R3and R4if present, are Ci-alkyl.

10. The compound according to any one of claims 1 to 9, wherein L1and L2, as well as L3and L4if present, are independently selected from the group consisting of Ci-Cs-alkylaminyl, Ci-Cs-alkylamidyl, and Ci-Cs-alkylether.

11. The compound according to claim 10, wherein L1and L2, as well as L3and L4if present, are independently selected from the group consisting of C1-C2- alkylaminyl, Ci-C2-alkylamidyl, and Ci-C2-alkylether.

12. The compound according to claim 11, wherein L1and L2, as well as L3and L4if present, are independently selected from the group consisting of Ci- alkylaminyl, Ci-alkylamidyl, and Ci-alkylether.

13. The compound according to claim 12, wherein L1and L2, as well as L3and L4if present, are independently selected from the group consisting of Ci- alkylaminyl, and Ci-alkylamidyl.

14. The compound according to any one of claims 1 to 13, wherein Z1and Z2, as well as Z3and Z4if present, are independently selected from the group consisting of hydrogen, and Ci-Ce-alkyl substituted by at least one group selected from the group consisting of hydroxyl (-OH), carboxyl (-COOH), and phosphonate (-PO3H2).

15. The compound according to claim 14, wherein Z1and Z2, as well as Z3and Z4if present, are independently selected from the group consisting of hydrogen, Ce-alkyl substituted by two or more hydroxyl (-OH) groups, Ci-Cs-alkyl substituted byat least one hydroxyl (-OH) group, and Ci-alkyl substituted by carboxyl (-COOH) or phosphonate (-PO3H2).

16. The compound according to claim 15, wherein Z1and Z2, as well as Z3and Z4if present, are independently selected from the group consisting of hydrogen, Ce-alkyl substituted by two to five hydroxyl (-OH) groups, and Ci-Cs-alkyl substituted by one or two hydroxyl (-OH) groups.

17. The compound according to any one of claims 1 to 16, wherein RA, RB, Rc, RD, and RE, as well as RA', RB', Rc', RD', and RE' (if present), are independently selected for each occurrence from the group consisting of hydrogen and Ci-Cs-alkyl.

18. The compound according to claim 17, wherein RA, RB, Rc, RD, and RE, as well as RA', RB', Rc', RD', and RE' (if present), are independently selected for each occurrence from the group consisting of hydrogen and Ci-C2-alkyl.

19. The compound according to claim 18, wherein RA, RB, Rc, RD, and RE, as well as RA', RB', Rc', RD', and RE' (if present), are independently selected for each occurrence from the group consisting of more preferably of hydrogen and Ci-alkyl.

20. The compound according to claim 19, wherein RA, RB, Rc, RD, and RE, as well as RA', RB', Rc', RD', and RE' (if present), are hydrogen.

21. The compound according to any one of claims 1 to 20, wherein p is 0 and L is hydrogen, whereby the compound of the invention has the following formula (II):Formula (II), wherein n, m, o, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as defined in any one of claims 1 to 20.

22. The compound according to any one of claims 1 to 20, wherein :- p is an integer selected from 1, 2, 3, and 4, and A is the macrocycle of formula (IA); preferably, L is selected from the group consisting of a Ci- C2o-alkylene substituted by a (hetero)aryl or a (hetero)cyclo-alkyl; more preferably, the Ci-C2o-alkylene is a Ci-C4-alkylene, the (hetero)aryl is phenyl, and the (hetero)cyclo-alkyl is cyclohexyl; or- p is an integer selected from 1, 2, 3, and 4, and A is a biological moiety; preferably, the biological moiety is a derivative of a bile acid; more preferably, the derivative of a bile acid is selected from the group consisting of residues of cholic, chenodeoxycholic, deoxycholic, ursodeoxycholic, lithocholic acids, and derivatives thereof; said derivative also comprising the conjugate of the acid group at the 24 position with taurine and glycine, and / or keto group(s) instead of hydroxyl group(s); or- p is an integer selected from 2, 3 and 4, and a first A substituent is in at least one occurrence a biological moiety, and a second A substituent is in at least another occurrence a macrocycle of formula (IA).

23. The compound according to any one of claims 1 to 22, wherein n, m, and o are 1, whereby the compound of the invention has the following formula (IV) :Formula (IV) wherein p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as defined in any one of claims 1 to 22.

24. The compound according to any one of claims 1 to 22, wherein m and o are 1, and n is 2, whereby the compound of the invention has the following formula (V):Formula (V) wherein p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as defined in any one of claims 1 to 22, and RC1is independently selected from and has the same meaning of Rcas defined in any one of claims 1 to 22.

25. The compound according to any one of claims 1 to 22, wherein :- m or o is 2, and n as well as the other remaining between m and o are 1, whereby the compound of the invention has one of the formulae (VIA), or(VIB):wherein, for formulae (VIA) and (VIB), p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as above defined in any one of claims 1 to 22, and RA1and RE1are independently selected from and have the samemeaning of, respectively, RAand RE, as defined in any one of claims 1 to 22; or- m and o are 2, and n is 1, whereby the compound of the invention has a triazacyclododecane macrocyclic cage and has the following formula (VII) :wherein p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as above defined in any one of claims 1 to 22, and are RA1and RE1are independently selected from and have the same meaning of, respectively, RAand RE, as defined in any one of claims 1 to 22; or either m or o is 1, and n as well as the other remaining between m and o are 2, whereby the compound of the invention has one of the formulae (VIIIA), or (VIIIB):Formula (VIIIA)Formula (VIIIB) wherein, for formulae (VIA) and (VIB), p, L, A, Y1, Y2, R1, R2, L1, L2, Z1, Z2, RA, RB, Rc, RD, and REare as above defined in any one of claims 1 to 22, and are RA1, RC1, and RE1are independently selected from and have the same meaning of, respectively, RA, Rc, and RE, as defined in any one of claims 1 to 22.

26. The compound according to anyone of claims 1 to 25, wherein the compound is selected from the group consisting of: 2,2'-{3,7,13- triazabicyclo[7.3.1] trideca- 1(13), 9, l l-triene-3,7-diyl bis [methylene(2-hydroxy-5- methyl-3,l-phenylene)methyleneazanediyl]}di(propane-l,3-diol); 3,3'-[3,7,13- triaza bicyclo[7.3.1] trideca- 1(13), 9, l l-triene-3,7-diylbis(methylene)]bis[N-( 1,3- dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[3,7,13- triazabicyclo[7.3.1] trideca- 1(13), 9, l l-triene-3,7-diylbis(methylene)]bis(2-hydroxy- 5-methylbenzamide); 2,2'-[3,7,13-triazabicyclo[7.3.1]trideca-l(13),9,l l-triene-3,7- diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {3,7,13- triazabicyclo[7.3.1]trideca-l(13),9,l l-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); {3,7,13-triazabicyclo[7.3.1]trideca-l(13),9,ll-triene-3,7-diylbis[methylene(2- hydroxy-5-methy 1-3, l-phenylene)carbonylazanediyl methylene] }bis(phosphonic acid;) 3,3'-[3,7,13-triazabicyclo[7.3.1]trideca-l(13),9,l l-triene-3,7- diylbis(methylene)] bis [N-(l,2-dihydroxyethyl)-2-hydroxy-5-methyl benzamide]; 1,1'- {3,7,13-triazabicyclo[7.3.1]trideca-l(13),9,ll-triene-3,7-diylbis[methylene(2- hydroxy-5-methy 1-3, 1-phenylene) methyleneaza nediy I] }di(ethane-l,2-diol); N,N'- {3,7,13-triazabicyclo[7.3.1]trideca-l(13),9,ll-triene-3,7-diylbis[methylene(2- hydroxy-5-methyl-3, 1-phenylene)] }bis(2,3-dihydroxypropanam ide); N,N'-{3,7,13- triazabicyclo[7.3.1]trideca-l(13),9,l l-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3,1 -phenylene)] }bis[3-hydroxy-2-(hydroxymethyl)propanam ide]; {3,7,13- triazabicyclo[7.3.1] trideca- 1(13), 9,1 l-triene-3,7-diyl bis [methylene(2-hydroxy-5-methyl-3,l-phenylene)azanediyl(2-oxoethane-2,l-diyl)]}bis(phosphonic acid); 2,2'- {3, 8, 14-triazabicyclo[8.3.1] tetradeca- 1(14), 10, 12-triene-3,8-diyl bis [methylene(2- hydroxy-5-methy 1-3, 1-phenylene) methyleneaza nediy I] }di(propane-l, 3-d iol); (3,3'- [3,8,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8- diylbis(methylene)]bis[N-(l,3-dihydroxypropan-2-yl)-2-hydroxy-5- methylbenzamide]; 3,3' -[3, 8, 14-triazabicyclo[8.3.1] tetradeca- 1(14), 10, 12-triene- 3, 8-diylbis(methylene)]bis(2-hydroxy-5-methy I benzamide); (2,2'-[3,8,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis(methylene)]bis[6- (aminomethyl)-4-methylphenol]; {3,8,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12- triene-3,8-diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneazanediylmethylene]}bis(phosphonic acid) ; {3,8,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); 3,3'- [3,8,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8- diylbis(methylene)] bis [N-(l,2-dihydroxyethyl)-2-hydroxy-5-methyl benzamide]; 1,1'- {3,8,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis[methylene(2- hydroxy-5-methy 1-3, 1-phenylene) methyleneaza nediy I] }di(ethane-l,2-d iol); N,N'- {3,8,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis[methylene(2- hydroxy-5-methyl-3, 1-phenylene)] }bis(2,3-dihydroxypropanam ide); N,N'-{3,8,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis[methylene(2-hydroxy-5- methyl-3,1 -phenylene)] }bis[3-hydroxy-2-(hydroxymethyl)propanam ide]; {3,8,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)azanediyl(2-oxoethane-2,l-diyl)]}bis(phosphonic acid); 2,2'- {3,7,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2- hydroxy-5-methy 1-3, 1-phenylene) methyleneaza nediy I] }di(propane-l, 3-d iol); 3,3'- [3,7,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7- diylbis(methylene)]bis[N-(l,3-dihydroxypropan-2-yl)-2-hydroxy-5- methylbenzamide]; 3,3'-[3,7,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene- 3, 7-diylbis(methylene)]bis(2-hydroxy-5-methy I benzamide); 2,2'-[3,7,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis(methylene)]bis[6- (aminomethyl)-4-methylphenol]; {3,7,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12- triene-3,7-diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneazanediylmethylene]}bis(phosphonic acid) ; {3,7,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); 3,3'- [3,7,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis(methylene)] bis [N-(l,2-dihydroxyethyl)-2-hydroxy-5-methyl benzamide]; 1,1'- {3,7, 14-triazabicyclo[8.3.1] tetradeca- 1(14), 10, 12-triene-3,7-diyl bis [methylene(2- hydroxy-5-methy 1-3, 1-phenylene) methyleneaza nediy I] }di(ethane-l,2-d iol); N,N'- {3,7,14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2- hydroxy-5-methyl-3, 1-phenylene)] }bis(2,3-dihydroxypropanam ide); N,N'-{3,7,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3,1 -phenylene)] }bis[3-hydroxy-2-(hydroxymethyl)propanam ide]; {3,7,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)azanediyl(2-oxoethane-2,l-diyl)]}bis(phosphonic acid); 2,2'- {4,8,15-triazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene-4,8-diylbis[methylene(2- hydroxy-5-methy 1-3, 1-phenylene) methyleneaza nediy I] }di(propane-l, 3-d iol); 3,3'- [4,8,15-triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8- diylbis(methylene)]bis[N-(l,3-dihydroxypropan-2-yl)-2-hydroxy-5- methylbenzamide]; 3,3'-[4,8,15-triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene- 4, 8-diylbis(methylene)]bis(2-hydroxy-5-methy I benzamide); 2,2'-[4,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8-diylbis(methylene)]bis[6- (aminomethyl)-4-methylphenol]; {4,8,15-triazabicyclo[9.3.1]pentadeca- l(15),ll,13-triene-4,8-diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneazanediylmethylene]}bis(phosphonic acid) ; {4,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid) ; 3,3'- [4,8,15-triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8- diylbis(methylene)] bis [N-(l,2-dihydroxyethyl)-2-hydroxy-5-methyl benzamide]; 1,1'- {4, 8, 15-triazabicyclo[9.3.1] pentadeca- 1( 15), ll,13-triene-4,8-diylbis[methylene(2- hydroxy-5-methy 1-3, 1-phenylene) methyleneaza nediy I] }di(ethane-l,2-d iol); N,N'- {4,8,15-triazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene-4,8-diylbis[methylene(2- hydroxy-5-methyl-3, 1-phenylene)] }bis(2,3-dihydroxypropanam ide); N,N'-{4,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8-diylbis[methylene(2-hydroxy- 5-methy 1-3, 1-phenylene)] }bis[3-hydroxy-2-(hydroxy methyl) propana m ide]; {4,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)aza nediy l(2-oxoethane-2,l-diyl)]}bis(phosphonic acid); 2,2'-{3,8,15-triazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene-3,8- diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneazanediyl]}di(propane-l,3-diol); 3,3'-[3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis(methylene)]bis[N-(l,3- dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'- [3,8,15-triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis(methylene)]bis(2- hydroxy-5-methylbenzamide); 2,2'-[3,8,15-triazabicyclo[9.3.1]pentadeca- l(15),ll,13-triene-3,8-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol] ;{3,8,15-triazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene-3,8-diylbis[methylene(2- hydroxy-5-methy 1-3, 1-phenylene) methyleneaza nediylmethylene]}bis(phosphonic acid); {3,8,15-triazabicyclo[9.3.1]pentadeca-l(15),ll,13-triene-3,8- diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)carbonylazanediylmethylene]}bis(phosphonic acid) ; 3,3'- [3,8, 15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis(methylene)]bis[N-(l,2- dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneazanediyl]}di(ethane-l,2-diol); N,N'-{3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)]}bis(2,3-dihydroxypropanamide); N,N'-{3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis[methylene(2-hydroxy- 5-methy 1-3, 1-phenylene)] }bis[3-hydroxy-2-(hydroxy methyl) propana m ide]; {3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)azanediyl(2-oxoethane-2,l-diyl)]}bis(phosphonic acid);2,2'-{4,9,16-triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9- diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneazanediyl]}di(propane-l,3-diol); 3, 3'- [4, 9, 16- triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis(methylene)]bis[N-(l,3- dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'- [4, 9, 16- triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis(methylene)]bis(2- hydroxy-5-methylbenzamide); 2,2'-[4,9,16-triazabicyclo[10.3.1]hexadeca- l(16),12,14-triene-4,9-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol] ;{4,9,16-triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis[methylene(2- hydroxy- 5-methy 1-3, 1-phenylene) methyleneaza nediylmethylene]}bis(phosphonic acid); {4,9,16-triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9- diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)carbonylazanediylmethylene]}bis(phosphonic acid) ; 3,3'-[4,9,16- triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis(methylene)]bis[N-(l,2- dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{4,9,16- triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneazanediyl]}di(ethane-l,2-diol); N, N' -{4,9,16- triazabicyclo[ 10.3.1] hexadeca- 1(16), 12, 14-triene-4,9-diylbis[methylene(2-hydroxy-5-methyl-3,l-phenylene)]}bis(2,3-dihydroxypropanamide); N,N'-{4,9,16- triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis[methylene(2-hydroxy- 5-methy 1-3, l-phenylene)]}bis[3-hydroxy-2-(hydroxy methyl) propana m ide]; {4,9,16- triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)aza nediy l(2-oxoethane-2,l-diyl)]}bis(phosphonic acid);6,6'-{3,7,13-triazabicyclo[7.3.1]trideca-l(13),9,l l-triene-3,7-diylbis[methylene(2- hydroxy- 5-methy 1-3, 1-phenylene) methyleneaza nediy I] }di(hexane- 1,2, 3, 4,5-pentol); 2-hydroxy-3-{[7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6- pentahydroxyhexyl)ca rbamoyl]phenyl}methyl)-3,7,13-triazabicyclo[7.3.1]trideca- l(13),9,ll-trien-3-yl]methyl}-5-methyl-N-(2,3,4,5,6- penta hydroxy hexyl) benzamide; 6,6'-{3,8,14-triazabicyclo[8.3.1]tetradeca- l(14),10,12-triene-3,8-diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneazanediyl]}di (hexane- 1,2, 3, 4,5-pentol); 2-hydroxy-3-{[8-({2- hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-3.8.14-triazabicyclo[8.3.1]tetradeca-l(14),10,12-trien-3-yl]methyl}-5-methyl-N- (2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{3,7,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3, 1 -phenylene) methyleneaza nediy I] }di(hexane- 1,2, 3, 4,5-pentol); 2- hydroxy-3-{[3-({2-hydroxy-5-methyl-3-[(2,3,4,5,6- pentahydroxyhexyl)ca rbamoyl]phenyl}methyl)-3,7,14-triazabicyclo[8.3.1]tetradeca- l(14),10,12-trien-7-yl]methyl}-5-methyl-N-(2,3,4,5,6- penta hydroxy hexyl) benzamide; 6,6'-{4,8,15-triazabicyclo[9.3.1]pentadeca- l(15),ll,13-triene-4,8-diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneazanediyl]}di (hexane- 1,2, 3, 4,5-pentol); 2-hydroxy-3-{[8-({2- hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-4.8.15-triazabicyclo[9.3.1]pentadeca-l(15),l l,13-trien-4-yl]methyl}-5-methyl-N- (2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneazanediyl]}di (hexane- 1,2, 3, 4,5-pentol); 2- hydroxy-3-{[3-({2-hydroxy-5-methyl-3-[(2,3,4,5,6- pentahydroxyhexyl)ca rbamoyl]phenyl}methyl)-3,8,15-triazabicyclo[9.3.1]pentadeca- l(15),ll,13-trien-8-yl]methyl}-5-methyl-N-(2,3,4,5,6- penta hydroxy hexyl) benzamide; 6,6'-{4,9,16-triazabicyclo[10.3.1]hexadeca- l(16),12,14-triene-4,9-diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneazanediyl]}di (hexane- 1,2, 3, 4,5-pentol); 2-hydroxy-3-{[9-({2- hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-4, 9, 16-triazabicyclo[ 10.3.1] hexadeca- 1(16), 12, 14-trien-4-yl]methyl}-5-methyl-N- (2,3,4,5,6-pentahydroxyhexyl)benzamide; 2,2'-{3,7,13-triazabicyclo[7.3.1]trideca- l(13),9,ll-triene-3,7-diylbis[methylene(2-hydroxy-5-methyl-3,l- phenylene)methyleneoxy]}di(propane-l,3-diol); 2,2'-{3,8,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)methyleneoxy]}di(propane-l,3-diol); 2,2'-{3,7,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)methyleneoxy]}di(propane-l,3-diol); 2,2'-{4,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneoxy]}di(propane-l,3-diol); 2,2'-{3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneoxy]}di(propane-l,3-diol); 2,2'-{4,9,16- triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneoxy]}di(propane-l,3-diol); 2,2'-{3,7,13- triazabicyclo[7.3.1] trideca- 1(13), 9, l l-triene-3,7-diyl bis [methylene(2-hydroxy-5- methyl-3,l-phenylene)carbonylazanediyl]}diacetic acid; 2,2'-{3,7,13- triazabicyclo[7.3.1] trideca- 1(13), 9, l l-triene-3,7-diyl bis [methylene(2-hydroxy-5- methyl-3,l-phenylene)methyleneazanediyl]}diacetic acid; 2,2'-{3,8,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)methyleneazanediyl]}diacetic acid; 2,2'-{3,8,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,8-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)carbonylazanediyl]}diacetic acid; 2,2'-{3,7,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)methyleneazanediyl]}diacetic acid; 2,2'-{3,7,14- triazabicyclo[8.3.1]tetradeca-l(14),10,12-triene-3,7-diylbis[methylene(2-hydroxy-5- methyl-3,l-phenylene)carbonylazanediyl]}diacetic acid; 2,2'-{4,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneazanediyl]}diacetic acid; 2,2'-{4,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-4,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)carbonylazanediyl]}diacetic acid; 2,2'-{3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneazanediyl]}diacetic acid; 2,2'-{3,8,15- triazabicyclo[9.3.1]pentadeca-l(15),l l,13-triene-3,8-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)carbonylazanediyl]}diacetic acid; 2,2'-{4,9,16- triazabicyclof 10.3.1] hexadeca- 1(16), 12, 14-triene-4, 9-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)methyleneazanediyl]}diacetic acid; and 2,2'-{4,9,16-triazabicyclo[10.3.1]hexadeca-l(16),12,14-triene-4,9-diylbis[methylene(2-hydroxy- 5-methyl-3,l-phenylene)carbonylazanediyl]}diacetic acid.

27. The compound according to any one of claims 1 to 26 for use as a medicament 28. The compound according to claim 27, for use in the treatment or prevention of disorders caused by the excess and / or accumulation of iron ions within a body.

29. The compound according to claim 28, for use in the treatment or prevention of iron intoxication and / or iron overload.

30. A complex of a compound according to any one of claims 1 to 26 withFe3+, or a physiologically acceptable salt of said complex.

31. Use of the complex as defined in claim 30 as a contrast agent.

32. The use according to claim 31, wherein the contrast agent is for MRI.

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