Compounds for use in diseases associated with iron ion excess and / or accumulation

Abstract

The present invention relates to compounds capable of forming complexes with Fe(III) ions, to their use for treating diseases associated with an excess and / or accumulation of iron ions in the body, such as iron overload or iron poisoning, and to methods for treating or preventing diseases caused by an excess and / or accumulation of iron ions in the body.

Description

Technical Field

[0001] This invention relates to compounds capable of coordinating with Fe(III) and to their use in treating diseases such as iron overload associated with excess and / or accumulation of iron ions in the body. Background Technology

[0002] Iron ions are essential metal ions for most organisms, especially mammals. However, excessive and / or accumulated iron ions in the body can lead to mild to severe toxicity. In fact, iron poisoning and iron overload are terms used to treat diseases that may require the administration of medications, namely iron chelators.

[0003] Iron chelators are drugs that form complexes with iron ions in the body after administration. These iron complexes are then excreted from the body, leading to the elimination of accumulated iron ions.

[0004] For most organisms, such as humans, the most stable iron ion in body fluids is Fe(III) (i.e., Fe). 3+ Iron chelators should primarily form complexes with Fe(III) ions and related ferric compounds, such as Fe(OH)3. Therefore, for their clinical use, iron chelators should primarily form complexes with Fe(III) ions, characterized by high conditional stability to avoid the Fenton reaction, i.e., the in vivo reduction of Fe(III) to Fe(II) ions (mediated by antioxidants such as ascorbic acid), which can lead to the formation of toxic free radicals (e.g., OH·). Furthermore, the Fe(III) complexes formed by the applied iron chelator should advantageously possess high thermodynamic stability to minimize and potentially avoid interaction with competing endogenous metal ions (e.g., Cu). 2+ Zn 2+ and Ca 2+ The reactions involve hydrolysis, metal transfer, and transchelation of ligands (such as transferrin). These reactions do indeed lead to the release of Fe(III) ions from the Fe(III)-complexes formed in vivo, thus preventing their excretion along with the iron chelating agent. Finally, another important property of the Fe(III) complexes formed with the iron chelating agent is their high kinetic inertness, which ensures the efficient excretion of accumulated iron ions and reduces the risk of their release.

[0005] The most common commercially available iron chelators are deferoxamine (DFO, which is the only one typically administered subcutaneously or intravenously), deferoxone (DFP), and deferasirox (DFX), both of which are typically administered orally.

[0006]

[0007] These commercially available iron chelators have some drawbacks. For example, DFO has a very short plasma half-life, thus requiring multiple administrations to achieve effective treatment. Furthermore, Fe(DFX)2 and Fe(DFP)3 complexes exhibit relatively low conditional stability under physiological conditions, meaning that DFX and DFP are less effective against Fe... 3+ The affinity of the ions is relatively low. Therefore, multiple oral administrations of DFP and DFX are required to effectively remove accumulated iron ions, which may cause side effects. Furthermore, the Fe(III) complexes formed by DFO, DFP, and DFX are characterized by low kinetic inertness; therefore, dissociation of Fe(DFO), Fe(DFP)3, and Fe(DFX)2 may occur under physiological conditions, thereby reducing the efficiency of removing accumulated iron ions.

[0008] In view of the above, there is a need for iron chelating agents that avoid the drawbacks of existing technologies.

[0009] It has now been discovered that the compounds disclosed herein can form complexes with Fe(III) ions with surprisingly favorable properties, such as high thermodynamic and conditional stability, kinetic inertness, and a balance of resistance to reduction. Such compounds can therefore be advantageously used as iron chelating agents for the treatment or prevention of diseases associated with abnormal iron levels (i.e., above predetermined levels), such as diseases caused by iron excess and / or accumulation that typically occur in the body, like iron poisoning and / or iron overload. Invention Overview

[0011] This invention relates to compounds of formula (I) as described in claims, or their ions, stereoisomers, tautomers, hydrates, solvates, or complexes formed with metal ions other than iron ions, or salts thereof, or mixtures thereof, particularly for use as pharmaceuticals. Compounds of formula (I) are ligands that can act as iron chelating agents, thereby enabling their use in treating diseases associated with excess and / or accumulation of iron ions in the body, such as iron overload. In practice, compounds of formula (I) can form complexes with Fe(III) ions that possess a balance of kinetic inertness, thermodynamic stability, conditional stability, and reduction stability, as demonstrated, for example, in Examples 9 to 12. Therefore, a therapeutically effective amount of a compound of formula (I) can be administered to a subject in need to form a complex with accumulated iron ions in the body possessing the aforementioned balance of properties; once formed, this complex is subsequently eliminated, thereby effectively reducing excess and / or accumulated iron ions.

[0012] The present invention also relates to methods for treating or preventing diseases caused by excess and / or accumulation of iron ions in the body, and the use of the compound of formula (I) in the preparation of a medicament.

[0013] Various embodiments are described in the dependent claims. Invention Details

[0015] According to a first aspect, the present invention relates to compounds of formula (I):

[0016] Formula (I)

[0017] Where n, m, and o are integers independently selected from 1 and 2;

[0018] Y 1 and Y 2 Independently selected from hydrogen and C1-C4-alkyl;

[0019] R 1 and R 2 Independently selected from hydrogen and C1-C4-alkyl;

[0020] L 1 and L 2 Independently selected from C1-C4-alkylamino, C1-C4-alkylamide and C1-C4-alkyl ether; preferably selected from C1-C4-alkylamino and C1-C4-alkylamide;

[0021] Z 1 and Z 2 The group is independently selected from hydrogen and C1-C6-alkyl, preferably C1-C4-alkyl, wherein the C1-C6-alkyl (preferably C1-C4-alkyl) is optionally substituted by one or more groups selected from hydroxyl (-OH), carboxyl (-COOH) and phosphonate (-PO3H2);

[0022] R is selected from hydrogen, C1-C4 alkyl groups optionally substituted with aryl groups (e.g., substituted or unsubstituted aryl groups), and the part of formula (IA):

[0023] Formula (IA)

[0024] Among them: asterisk ( ) represents the connection point between a portion of formula (IA) and a nitrogen atom with an R group;

[0025] Y 3 Having the above for Y 1 and Y 2 The same meaning provided;

[0026] R 3 Having the above for R 1 and R 2 The same meaning provided;

[0027] L 3 Having the above for L 1 and L 2 The same meaning provided; and

[0028] Z 3 Having the above for Z 1 and Z 2 The same meaning provided;

[0029] Or its ions, or stereoisomers, or tautomers, or hydrates, or solvates, or pharmaceutically acceptable complexes formed with metal ions (provided that the metal ion is not an iron ion, especially not Fe). 3+ and / or Fe 2+ Iron ions), or pharmaceutically acceptable salts thereof, or mixtures thereof, used as a medicine; preferably, used to treat or prevent diseases caused by excess and / or accumulation of iron ions in the body, preferably in the human body, such as iron poisoning and / or iron overload; according to one embodiment, the compound used as a medicine or for the preferred use disclosed herein is in a pharmaceutically acceptable form and is part of a pharmaceutical composition.

[0030] According to a second aspect, the present invention relates to a method for treating or preventing diseases caused by excess and / or accumulation of iron ions in the body, preferably in the human body, such as iron poisoning and / or iron overload, in a subject requiring such treatment, said method comprising administering to said subject a therapeutically effective amount of a compound of formula (I) described herein according to any embodiment thereof; according to one embodiment, said compound is in a pharmaceutically acceptable form and is part of a pharmaceutical composition.

[0031] According to a third aspect, the present invention relates to the use of compounds of formula (I) according to any embodiment thereof for the manufacture of a medicament, preferably for the treatment or prevention of diseases caused by excess and / or accumulation of iron ions in the body, preferably in the human body, such as iron poisoning and / or iron overload.

[0032] In this specification, the term "alkyl" refers to any straight-chain or branched hydrocarbon chain. In particular, "C1-C4-alkyl" includes, within its meaning, a straight-chain or branched chain containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc. Similarly, the term "C1-C3-alkyl" refers to a straight-chain or branched chain containing 1 to 3 carbon atoms, such as methyl, ethyl, propyl, and diisopropyl; the term "C1-C2-alkyl" refers to a straight-chain or branched chain containing 1 to 2 carbon atoms, such as methyl and ethyl; the term "C1-alkyl" refers to a methyl (-CH3) group; and the term "C1-C6-alkyl" refers to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, etc., as well as n-pentyl and its isomers (such as isopentane, neopentane, etc.), and n-hexyl and its isomers (such as 2-methylpentane, 3-methylpentane, 2,3-dimethylbutane, etc.).

[0033] In this specification, the term "alkylamino" refers to an alkyl group as defined above, in which one of its hydrogen atoms is replaced by an amino group, said alkylamino being attached to (i) the phenolic moiety and (ii) the Z group of the compound as defined above. 1 Z 2 or Z 3 Group (depending on the situation). Term "C" x -C y "-alkylamino", where x and y represent two integers, refers to an alkylamino group as defined above with carbon numbers from x to y.

[0034] In this specification, the term "alkylamide" refers to an alkyl group as defined above, in which one carbon atom is directly bonded to a carbonyl group (C=O) of a nitrogen atom, said alkylamide being connected to (i) the phenolic moiety and (ii) the Z group of the compound as defined above. 1 Z 2 or Z 3 Group (depending on the situation). Term "C" x -C y "-alkylamide", where x and y represent two integers, referring to the alkylamide as defined above with carbon numbers from x to y.

[0035] In this specification, the term "alkyl ether" refers to an alkyl group as defined above, in which one of its hydrogen atoms is replaced by an ether group (-O-), said alkyl ether being attached to (i) the phenolic moiety and (ii) the Z group of the compound as defined above. 1 Z 2 or Z 3 Group (depending on the situation). Term "C" x -C y "-alkyl ether", where x and y represent two integers, referring to the alkyl ether defined above with carbon numbers from x to y.

[0036] In this specification, the term "aryl" refers to an aromatic hydrocarbon, and preferably to a benzene ring. Unless otherwise specifically provided, the aryl group according to the invention may be unsubstituted or substituted with one or more substituents selected simultaneously or independently from hydroxyl (-OH), halogens, and C1-C4-alkyl groups optionally substituted with one or more hydroxyl (-OH); preferably, the term "aryl" refers to an unsubstituted aromatic hydrocarbon, such as an unsubstituted phenyl group.

[0037] In this specification, when referring to substituents, the term "LZ" generally refers to any or all L... 1 -Z 1 L 2 -Z 2 and L 3 -Z 3 (If present) substituents.

[0038] In this specification, when references are made to triazacyclononane (or [9]-membered ring), triazacyclodecane (or

[10] -membered ring), triazacycloundecane (or

[11] -membered ring), or triazacyclododecane (or

[12] -membered ring), the term "macrocycle" or "macrocycle cage" refers to a macrocycle having the following structure:

[0039]

[0040] Triazacyclononane (TACN) Triazacyclodecane (TACD)

[0041]

[0042] Triazacycloundecane (TACUD) Triazacyclododecane (TADD)

[0043] In this specification, the term "protecting group" refers to a protective group suitable for maintaining the function of the group and / or atom to which it is bonded. Specifically, a protecting group may be used to maintain the function of an amino, hydroxyl, or carboxyl group. Thus, suitable carboxyl protecting groups may include, for example, benzyl, alkyl such as tert-butyl or benzyl ester, or other substituents commonly used to protect these functional groups, all of which are well known to those skilled in the art (e.g., from TW Greene and PGM Wuts; "Protective Groups in Organic Synthesis", Wiley, NY 1999, 3rd edition).

[0044] The compound of formula (I) above may have one or more asymmetric carbon atoms, also known as chiral carbon atoms, and thus may produce diastereomers, optical isomers, and enantiomers. The invention also includes all these possible diastereomers, optical isomers, and enantiomers, as well as racemic mixtures thereof, and their substantially pure resolved enantiomers. All possible geometric isomers are also included. Individual stereoisomers of the compound of formula (I), such as specific diastereomers, can be separated by any conventional means, such as chromatography, possibly chiral chromatography.

[0045] As used herein, the term “pharmaceutically acceptable salt” refers to a derivative of a compound as defined above, wherein the parent compound is suitably modified by converting any free acid or basic group (if present) into a corresponding addition salt with any base or acid generally considered pharmaceutically acceptable, such as SM Berge. et al As published in J. Pharm.Sci. 1977, 66, 1-19.

[0046] As used herein, the term "pharmaceutically acceptable complex" refers to a complex of a compound as defined above with an ion generally considered pharmaceutically acceptable. By an additional condition, the pharmaceutically acceptable complex is not an iron complex, that is, a complex of a compound as defined above with an ion that is not an iron ion, particularly not Fe. 3+ and / or Fe 2+ The pharmaceutically acceptable complex is a complex formed with an alkali metal ion or alkaline earth metal ion that is generally considered pharmaceutically acceptable, such as a complex formed with a calcium ion or a magnesium ion, thereby providing a calcium complex or a magnesium complex, such as a Ca(II)-complex or a Mg(II)-complex. The pharmaceutically acceptable complex may be advantageous because, when administered, it can be better tolerated than the compound itself (i.e., uncoordinated). Therefore, another aspect of the invention is a complex formed by a compound of formula (I) as defined herein (and thus including compounds of formulas (II) to (V) as defined herein) according to any embodiment thereof with a pharmaceutically acceptable ion or a physiologically acceptable salt of said complex, provided that said ion is not an iron ion, such as Fe. 3+ and / or Fe 2+ Preferably, the complex is a pharmaceutically acceptable alkali metal ion or alkaline earth metal ion such as Ca2+. 2+ ions or Mg 2+ Ion-formed complexes.

[0047] In this specification, the term "iron poisoning" refers to any illness commonly known to result from acute toxicity caused by the excessive intake of iron ions over a short period of time. Symptoms of iron poisoning can range from mild to severe, and may even lead to permanent organ damage and death. Iron intoxication is also commonly referred to as iron poisoning.

[0048] In this specification, the term "iron overload" refers to a condition commonly known as the excessive accumulation of iron ions in the body, typically in organs such as the liver, heart, pancreas, and joints. As used herein, iron overload includes primary iron overload, commonly referred to as primary hemochromatosis (e.g., type 1 hemochromatosis and non-HFE hereditary hemochromatosis), and secondary iron overload (i.e., iron overload caused, for example, by excessive intake of iron in the diet, or by frequent blood transfusions, such as those used to treat anemias such as Diamond-Blackfan anemia, thalassemia, and sickle cell anemia). Iron overload may also be referred to as hemochromatosis.

[0049] According to one implementation plan, Y 1 and Y 2 and Y 3(If present), independently selected from hydrogen and C1-C3-alkyl, preferably hydrogen and C1-C2-alkyl, and more preferably hydrogen and C1-alkyl (i.e., methyl). Preferably, Y 1 and Y 2 and Y 3 (If present), and being the same group, hydrogen is the preferred choice.

[0050] According to one implementation plan, R 1 R 2 , and R 3 (If present), independently selected from hydrogen and C1-C3-alkyl, preferably hydrogen and C1-C2-alkyl, more preferably hydrogen and C1-alkyl, and even more preferably C1-alkyl (i.e., methyl (-CH3)). According to a preferred embodiment, R 1 R 2 , and R 3 (If present), and are the same group.

[0051] According to one implementation plan, L 1 L 2 , and L 3 (If present), independently selected from C1-C3-alkylamino, C1-C3-alkylamide, and C1-C3-alkyl ether; preferably C1-C2-alkylamino, C1-C2-alkylamide, and C1-C2-alkyl ether; and more preferably C1-alkylamino, C1-alkylamide, and C1-alkyl ether; according to this latter more preferred embodiment, L 1 L 2 , and L 3 (If it exists), select independently -CH2-NH-·, -C(O)-NH-·, -NHC(O)-·and -CH2-O-·, preferably selected from -CH2-NH-·, -C(O)-NH-· and -CH2-O-·, and more preferably selected from -CH2-NH-·and -C(O)-NH-·, where the asterisk ( () represents the phenolic moiety and the midpoint (·) represents Z. 1 Z 2 or Z 3 Group (if present) (depending on the situation). According to the preferred embodiment, L 1 L 2 , and L 3 (If present), and are the same group.

[0052] Alkylamino L 1 L 2 , and L 3 (if present) and alkyl acylamino L 1 L 2 , and L 3 The nitrogen atom (if present) preferably carries at least one hydrogen atom; in other words, the alkylamino group L 1 L 2 , and L 3 (If present) amines and / or alkyl acylamino groups L 1 L 2 , and L 3 The amide (if present) is preferably a primary or secondary group; more preferably a secondary group.

[0053] According to the preferred implementation scheme, Z 1 Z 2 , and Z 3 (If present), (each) directly bond to L 1 L 2 and L 3 The nitrogen of the alkylamino group or the alkylacylamino group, the carbonyl (C=O) portion of the alkylacylamino group, or the oxygen of the alkyl ether group.

[0054] According to the preferred implementation scheme, Z 1 Z 2 , and Z 3 (If present), independently selected from hydrogen, C4-C6-alkyl groups substituted with two or more hydroxyl groups (-OH), and C1-C3-alkyl groups substituted with at least one group selected from hydroxyl (-OH), carboxyl (-COOH), and phosphonate (-PO3H2). According to a more preferred embodiment, Z 1 Z 2 , and Z 3 (If present), independently selected from hydrogen, C6-alkyl substituted with two or more, for example two to five (preferably five) hydroxyl (-OH) groups, C1-C3-alkyl substituted with at least one, for example two hydroxyl (-OH) groups, and C1-alkyl substituted with carboxyl (-COOH) or phosphonate (-PO3H2).

[0055] According to one embodiment, when R is a C1-C4 alkyl group optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), R is preferably a C1-C3-alkyl group or a C1-C3-alkyl group substituted with an aryl group (e.g., substituted or unsubstituted aryl group), preferably a phenyl-substituted C1-C3-alkyl group, more preferably a C1-C2-alkyl group or a C1-C2-alkyl group substituted with an aryl group (e.g., substituted or unsubstituted aryl group), preferably a phenyl-substituted C1-alkyl group (thereby providing benzyl-CH2-C6H5).

[0056] According to a preferred embodiment, R is selected from hydrogen, C1-alkyl, aryl (e.g., substituted or unsubstituted aryl), preferably phenyl-substituted C1-alkyl (thereby providing benzyl-CH2-C6H5), and the part of formula (IA), wherein Y 3 R 3 L 3 and Z 3 Y, respectively having the above-described properties for compounds of formula (I) and any of its embodiments. 1 R 1 L 1 and Z 1 The same meaning provided.

[0057] According to one embodiment, n, m, and o in formula (I) are 1, thus the compound defined above has a triazacyclononane macrocyclic cage and has the following formula (II).

[0058] Equation (II)

[0059] Where R, R 1 , R 2 Y 1 Y 2 , L 1 , L 2 Z 1 and Z 2 As defined above for equation (I) or any of its implementations.

[0060] According to another embodiment, in formula (I), only one of n, m, and o is 2, while the other two are 1, thus the compound defined above has a triazacyclodecane macrocyclic cage and has one of formulas (IIIA), (IIIB), or (IIIC).

[0061] Formula (IIIA)

[0062] Formula (IIIB)

[0063] Formula (IIIC)

[0064] For equations (IIIA), (IIIB), and (IIIC), R 1 , R 2 , R 3 Y 1 Y 2 Y 3 , L 1 , L 2 , L 3 Z 1 Z 2 and Z 3 As defined above for formula (I) or any embodiment thereof, and R' is a C1-C4-alkyl group substituted with hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), preferably a C1-C3-alkyl group substituted with hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), more preferably a C1-C2-alkyl group substituted with hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), and even more preferably a C1-alkyl group substituted with hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group).

[0065] According to another embodiment, in formula (I), only one of n, m, and o is 1, while the other two are 2, thus the compound defined above has a triazacycloundecane macrocycle and has one of formulas (IVA), (IVB), or (IVC).

[0066] Formula (IVA)

[0067] Formula (IVB)

[0068] Formula (IVC)

[0069] Among them, for equations (IVA), (IVB), and (IVC), R 1 , R 2 , R 3 Y 1 Y 2 Y 3 , L 1 , L 2 , L 3 Z 1 Z 2 and Z 3As defined above for formula (I) or any embodiment thereof, and R' is a C1-C4-alkyl group substituted with hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), preferably a C1-C3-alkyl group substituted with hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), more preferably a C1-C2-alkyl group substituted with hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), and even more preferably a C1-alkyl group substituted with hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group).

[0070] According to the fourth embodiment, n, m, and o in formula (I) are 2, thus the compound defined above has a triazacyclododecane macrocycle and has the following formula (V).

[0071] Formula (V)

[0072] Where R, R 1 , R 2 Y 1 Y 2 , L 1 , L 2 Z 1 and Z 2 As defined above for equation (I) or any of its implementations.

[0073] According to the preferred embodiment, the compounds defined above are selected from:

[0074]

[0075] Compound 1 (3,3',3''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tri[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0076]

[0077] Compound 2 (2,2',2''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol)),

[0078]

[0079] Compound 3 (3,3'-[1,4,7-triazacyclononane-1,4-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0080]

[0081] Compound 4 (2,2'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0082]

[0083] Compound 5 (3,3',3''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0084]

[0085] Compound 6 (3,3'-[1,4,7-triazacyclononane-1,4-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0086]

[0087] Compound 7 (2,2',2''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0088]

[0089] Compound 8 (2,2'-[1,4,7-triazacyclononane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0090]

[0091] Compound 9 ({1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}tri(phosphonic acid)),

[0092]

[0093] Compound 10 ({1,4,7-triazacyclononane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid)),

[0094]

[0095] Compound 11 ({1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}tri(phosphonic acid)),

[0096]

[0097] Compound 12 ({1,4,7-triazacyclononane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0098]

[0099] Compound 13 (3,3',3''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tri[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0100]

[0101] Compound 14 (1,1',1''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethylene-1,2-diol)),

[0102]

[0103] Compound 15 (3,3'-[1,4,7-triazacyclononane-1,4-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0104]

[0105] Compound 16 (1,1'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0106]

[0107] Compound 17 ( N , N ', N ''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide)),

[0108]

[0109] Compound 18 ( N , N '-{1,4,7-triazacyclononane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropamide)),

[0110]

[0111] Compound 19 ( N , N ', N ''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0112]

[0113] Compound 20 ( N , N '-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0114]

[0115] Compound 21 ({1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}tri(phosphonic acid)),

[0116]

[0117] Compound 22 ({1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0118]

[0119] Compound 23 (3,3',3''-[1,4,7-triazacyclodecane-1,4,7-triyltri(methylene)]tri[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0120]

[0121] Compound 24 (2,2',2''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol)),

[0122]

[0123] Compound 25 (3,3'-[1,4,7-triazacyclodecane-1,7-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0124]

[0125] Compound 26 (3,3'-[1,4,7-triazacyclodecane-1,4-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0126]

[0127] Compound 27 (2,2'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0128]

[0129] Compound 28 (2,2'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0130]

[0131] Compound 29 (3,3',3''-[1,4,7-triazacyclodecane-1,4,7-triyltri(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0132]

[0133] Compound 30 (3,3'-[1,4,7-triazacyclodecane-1,7-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0134]

[0135] Compound 31 (3,3'-[1,4,7-triazacyclodecane-1,4-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0136]

[0137] Compound 32 (2,2',2''-[1,4,7-triazacyclodecane-1,4,7-triyltri(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0138]

[0139] Compound 33 (2,2'-[1,4,7-triazacyclodecane-1,7-dimethylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0140]

[0141] Compound 34 (2,2'-[1,4,7-triazacyclodecane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0142]

[0143] Compound 35 ({1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazinedimethylmethylene]}tri(phosphonic acid)),

[0144]

[0145] Compound 36 ({1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazinedimethylmethylene]}bis(phosphonic acid),

[0146]

[0147] Compound 37 ({1,4,7-triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazinedimethylmethylene]}bis(phosphonic acid)),

[0148]

[0149] Compound 38 ({1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}tris(phosphonic acid)),

[0150]

[0151] Compound 39 ({1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0152]

[0153] Compound 40 ({1,4,7-triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0154]

[0155] Compound 41 (3,3',3''-[1,4,7-triazacyclodecane-1,4,7-triyltri(methylene)]tri[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0156]

[0157] Compound 42 (1,1',1''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethylene-1,2-diol)),

[0158]

[0159] Compound 43 (3,3'-[1,4,7-triazacyclodecane-1,7-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0160]

[0161] Compound 44 (3,3'-[1,4,7-triazacyclodecane-1,4-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0162]

[0163] Compound 45 (1,1'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0164]

[0165] Compound 46 (1,1'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0166]

[0167] Compound 47 ( N , N ', N ''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide)),

[0168]

[0169] Compound 48 ( N , N '-{1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0170]

[0171] Compound 49 ( N , N '-{1,4,7-triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0172]

[0173] Compound 50 ( N , N ', N ''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0174]

[0175] Compound 51 ( N , N '-{1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0176]

[0177] Compound 52 ( N , N '-{1,4,7-triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0178]

[0179] Compound 53 ({1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}tri(phosphonic acid)),

[0180]

[0181] Compound 54 ({1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0182]

[0183] Compound 55 ({1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0184]

[0185] Compound 56 (3,3',3''-[1,4,8-triazacycloundecane-1,4,8-triyltri(methylene)]tri[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0186]

[0187] Compound 57 (2,2',2''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol)),

[0188]

[0189] Compound 58 (3,3'-[1,4,8-triazacycloundecane-1,8-dimethylbis(methylene)]bis[N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0190]

[0191] Compound 59 (3,3'-[1,4,8-triazacycloundecane-1,4-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0192]

[0193] Compound 60 (2,2'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0194]

[0195] Compound 61 (2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0196]

[0197] Compound 62 (3,3',3''-[1,4,8-triazacycloundecane-1,4,8-triyltri(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0198]

[0199] Compound 63 (3,3'-[1,4,8-triazacycloundecane-1,8-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0200]

[0201] Compound 64 (3,3'-[1,4,8-triazacycloundecane-1,4-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0202]

[0203] Compound 65 (2,2',2''-[1,4,8-triazacycloundecane-1,4,8-triyltri(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0204]

[0205] Compound 66 (2,2'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0206]

[0207] Compound 67 (2,2'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0208]

[0209] Compound 68 ({1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}tri(phosphonic acid)),

[0210]

[0211] Compound 69 ({1,4,8-triazacycloundecane-1,8-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid)),

[0212]

[0213] Compound 70 ({1,4,8-triazacycloundecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid)),

[0214]

[0215] Compound 71 ({1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}tri(phosphonic acid)),

[0216]

[0217] Compound 72 ({1,4,8-triazacycloundecane-1,8-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0218]

[0219] Compound 73 ({1,4,8-triazacycloundecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0220]

[0221] Compound 74 (3,3',3''-[1,4,8-triazacycloundecane-1,4,8-triyltri(methylene)]tri[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0222]

[0223] Compound 75 (1,1',1''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethylene-1,2-diol)),

[0224]

[0225] Compound 76 (3,3'-[1,4,8-triazacycloundecane-1,8-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0226]

[0227] Compound 77 (3,3'-[1,4,8-triazacycloundecane-1,4-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0228]

[0229] Compound 78 (1,1'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0230]

[0231] Compound 79 (1,1'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0232]

[0233] Compound 80 ( N , N ', N ''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide)),

[0234]

[0235] Compound 81 ( N , N '-{1,4,8-triazacycloundecane-1,8-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0236]

[0237] Compound 82 ( N , N '-{1,4,8-triazacycloundecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0238]

[0239] Compound 83 ( N , N ', N ''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0240]

[0241] Compound 84 ( N , N '-{1,4,8-triazacycloundecane-1,8-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0242]

[0243] Compound 85 ( N , N '-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0244]

[0245] Compound 86 ({1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}tri(phosphonic acid)),

[0246]

[0247] Compound 87 ({1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0248]

[0249] Compound 88 ({1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0250]

[0251] Compound 89 (3,3',3''-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)]tri[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0252]

[0253] Compound 90 (2,2',2''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol)),

[0254]

[0255] Compound 91 (3,3'-[1,5,9-triazacyclododecane-1,5-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0256]

[0257] Compound 92 (2,2'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0258]

[0259] Compound 93 (3,3',3''-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0260]

[0261] Compound 94 (3,3'-[1,5,9-triazacyclododecane-1,5-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0262]

[0263] Compound 95 (2,2',2''-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0264]

[0265] Compound 96 (2,2'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0266]

[0267] Compound 97 ({1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}tri(phosphonic acid)),

[0268]

[0269] Compound 98 ({1,5,9-triazacyclododecane-1,5-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid)),

[0270]

[0271] Compound 99 ({1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}tri(phosphonic acid)),

[0272]

[0273] Compound 100 ({1,5,9-triazacyclododecane-1,5-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0274]

[0275] Compound 101 (3,3',3''-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)]tri[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0276]

[0277] Compound 102 (1,1',1''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethylene-1,2-diol)),

[0278]

[0279] Compound 103 (3,3'-[1,5,9-triazacyclododecane-1,5-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0280]

[0281] Compound 104 (1,1'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0282]

[0283] Compound 105 ( N , N ', N ''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide)),

[0284]

[0285] Compound 106 (N , N '-{1,5,9-triazacyclododecane-1,5-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0286]

[0287] Compound 107 ( N , N ', N ''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0288]

[0289] Compound 108 ( N , N '-{1,5,9-triazacyclododecane-1,5-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0290]

[0291] Compound 109 ({1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}tri(phosphonic acid)),

[0292]

[0293] Compound 110 ({1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0294]

[0295] Compound 111 (3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0296]

[0297] Compound 112 (2,2'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0298]

[0299] Compound 113 (3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0300]

[0301] Compound 114 (2,2'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0302]

[0303] Compound 115 ({(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid)),

[0304]

[0305] Compound 116 ({(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0306]

[0307] Compound 117 (3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0308]

[0309] Compound 118 (1,1'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0310]

[0311] Compound 119 ( N , N '-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0312]

[0313] Compound 120 ( N , N '-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0314]

[0315] Compound 121 ({(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0316]

[0317] Compound 122 (3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0318]

[0319] Compound 123 (3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0320]

[0321] Compound 124 (2,2'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0322]

[0323] Compound 125 (2,2'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0324]

[0325] Compound 126 (3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0326]

[0327] Compound 127 (3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0328]

[0329] Compound 128 (2,2'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0330]

[0331] Compound 129 (2,2'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0332]

[0333] Compound 130 ({(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}bis(phosphonic acid)),

[0334]

[0335] Compound 131 ({(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid)),

[0336]

[0337] Compound 132 ({(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0338]

[0339] Compound 133 ({(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0340]

[0341] Compound 134 (3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0342]

[0343] Compound 135 (3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0344]

[0345] Compound 136 (1,1'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0346]

[0347] Compound 137 (1,1'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0348]

[0349] Compound 138 ( N , N'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0350]

[0351] Compound 139 ( N , N '-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0352]

[0353] Compound 140 ( N , N '-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0354]

[0355] Compound 141 ( N , N '-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0356]

[0357] Compound 142 ({(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0358]

[0359] Compound 143 ({(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0360]

[0361] Compound 144 (3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0362]

[0363] Compound 145 (3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0364]

[0365] Compound 146 (2,2'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0366]

[0367] Compound 147 (2,2'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0368]

[0369] Compound 148 (3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0370]

[0371] Compound 149 (3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0372]

[0373] Compound 150 (2,2'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0374]

[0375] Compound 151 (2,2'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0376]

[0377] Compound 152 ({(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}bis(phosphonic acid)),

[0378]

[0379] Compound 153 ({(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}bis(phosphonic acid)),

[0380]

[0381] Compound 154 ({(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0382]

[0383] Compound 155 ({(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0384]

[0385] Compound 156 (3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0386]

[0387] Compound 157 (3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0388]

[0389] Compound 158 (1,1'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0390]

[0391] Compound 159 (1,1'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0392]

[0393] Compound 160 ( N , N '-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0394]

[0395] Compound 161 ( N , N '-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0396]

[0397] Compound 162 ( N , N '-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0398]

[0399] Compound 163 ( N , N '-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0400]

[0401] Compound 164 ({(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0402]

[0403] Compound 165 ({(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)),

[0404]

[0405] Compound 166 (3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]),

[0406]

[0407] Compound 167 (2,2'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol)),

[0408]

[0409] Compound 168 (3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0410]

[0411] Compound 169 (2,2'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0412]

[0413] Compound 170 ({(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}bis(phosphonic acid)),

[0414]

[0415] Compound 171 ({(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanedimethylmethylene]}bis(phosphonic acid)),

[0416]

[0417] Compound 172 (3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0418]

[0419] Compound 173 (1,1'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol)),

[0420]

[0421] Compound 174 ( N , N '-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0422]

[0423] Compound 175 ( N , N '-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0424]

[0425] Compound 176 ({(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid)), and

[0426]

[0427] Compound 177 ( N , N ', N ''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}triacetamide),

[0428]

[0429] Compound 178 (3-{[4,7-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0430]

[0431] Compound 179 (6,6',6''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexyl-1,2,3,4,5-pentaol)),

[0432]

[0433] Compound 180 (2-hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0434]

[0435] Compound 181 (6,6'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0436]

[0437] Compound 182 (3-{[4,7-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0438]

[0439] Compound 183 (6,6',6''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexyl-1,2,3,4,5-pentaol)),

[0440]

[0441] Compound 184 (2-hydroxy-3-{[7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0442]

[0443] Compound 185 (2-hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0444]

[0445] Compound 186 (3-{[1,4-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-8-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0446]

[0447] Compound 187 (6,6',6''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexyl-1,2,3,4,5-pentaol)),

[0448]

[0449] Compound 188 (2-hydroxy-3-{[1-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-8-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0450]

[0451] Compound 189 (2-hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0452]

[0453] Compound 190 (6,6'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0454]

[0455] Compound 191 (6,6'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0456]

[0457] Compound 192 (3-{[5,9-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0458]

[0459] Compound 193 (6,6',6''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexyl-1,2,3,4,5-pentaol)),

[0460]

[0461] Compound 194 (2-hydroxy-3-{[5-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0462]

[0463] Compound 195 (6,6'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0464]

[0465] Compound 196 (3-{[4-benzyl-7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0466]

[0467] Compound 197 (6,6'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0468]

[0469] Compound 198 (3-{[4-benzyl-7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0470]

[0471] Compound 199 (3-{[7-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0472]

[0473] Compound 200 (6,6'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0474]

[0475] Compound 201 (6,6'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0476]

[0477] Compound 202 (3-{[1-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-8-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0478]

[0479] Compound 203 (3-{[8-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0480]

[0481] Compound 204 (6,6'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0482]

[0483] Compound 205 (6,6'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0484]

[0485] Compound 206 (3-{[5-benzyl-9-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0486]

[0487] Compound 207 (6,6'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0488]

[0489] Compound 208 (6,6'-{1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0490]

[0491] Compound 209 (6,6'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol)),

[0492]

[0493] Compound 210 (2,2',2''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(prop-1,3-diol)),

[0494]

[0495] Compound 211 (2,2'-{1,4,7-triazacyclononane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0496]

[0497] Compound 212 (2,2',2''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(prop-1,3-diol)),

[0498]

[0499] Compound 213 (2,2'-{1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0500]

[0501] Compound 214 (2,2'-{1,4,7-triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0502]

[0503] Compound 215 (2,2',2''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(prop-1,3-diol)),

[0504]

[0505] Compound 216 (2,2'-{1,4,8-triazacycloundecane-1,8-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0506]

[0507] Compound 217 (2,2'-{1,4,8-triazacycloundecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0508]

[0509] Compound 218 (2,2',2''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(prop-1,3-diol)),

[0510]

[0511] Compound 219 (2,2'-{1,5,9-triazacyclododecane-1,5-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0512]

[0513] Compound 220 (2,2'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0514]

[0515] Compound 221 (2,2'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0516]

[0517] Compound 222 (2,2'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0518]

[0519] Compound 223 (2,2'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)),

[0520]

[0521] Compound 224 (2,2'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)), and

[0522]

[0523] Compound 225 (2,2'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol)).

[0524] The chemical names of the above compounds were generated using software ACD / ChemSketch 2021.2.2 (ACD / Labs2021.2.2 (file version C35H41, Build 126536, March 2, 2022)). These chemical names may differ slightly from standard IUPAC nomenclature. For clarity, in cases where there are differences between chemical structures and corresponding chemical names, the above compounds are uniquely identified by their chemical structures.

[0525] According to another aspect, the present invention relates to pharmaceutical compositions comprising a compound of formula (I) as defined above according to any embodiment thereof, and thus including compounds of formulas (II) to (V) as defined above, or ions thereof, or stereoisomers, or tautomers, or hydrates, or solvates, or pharmaceutically acceptable complexes, such as pharmaceutically acceptable complexes formed with a metal ion, provided that said metal ion is not an iron ion, particularly not Fe. 3+ and / or Fe 2+ An ion, or a pharmaceutically acceptable salt, or a mixture thereof, and at least one pharmaceutically acceptable excipient, provided that the pharmaceutically acceptable complex is not an iron complex, particularly not an Fe complex. 3+ and / or Fe 2+ Coordination compounds.

[0526] Preferably, the pharmaceutical composition of the present invention, according to any embodiment thereof, is used as a medicine, preferably for the treatment or prevention of diseases caused by excess and / or accumulation of iron ions in the body, preferably in the human body, such as iron poisoning and / or iron overload.

[0527] Another aspect of the invention is a method for treating or preventing diseases caused by excess and / or accumulation of iron ions in the body, preferably in the human body, such as iron poisoning and / or iron overload, in a subject requiring such treatment, said method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition described herein.

[0528] This document describes a method for preparing compounds as defined above in any of its embodiments (and therefore including compounds of formulas (I) to (V) as defined above). This method is generally carried out by coupling a macrocyclic compound selected from triazacyclononane, triazacyclodecane, triazacycloundecane, and triazacyclododecane to one or more suitable moieties, said macrocyclic compound possibly being suitably protected on one or more nitrogen atoms with one or more protecting groups, to obtain the compounds as defined above, or to obtain intermediates thereof, which can then be converted (e.g., by further coupling and / or reduction reactions) to the compounds as defined above.

[0529] The compounds defined above can be prepared according to the following general synthetic steps:

[0530] a) A phenol is provided which, at least at its ortho position (i), is substituted with a C1-C5-alkyl group bonded to a suitable leaving group, such as a methanesulfonate (MsO) or a halogen, for example, thereby providing a halo-C1-C5-alkyl group, such as a chloro-C1-C5-alkyl or a bromo-C1-C5-alkyl group; and (ii) is substituted with an LZ group or a suitable substituent that can subsequently be converted to an LZ group, such as a substituent selected from C1-C4-alkyl-aldehydes, C1-C4-alkyl-esters and C1-C4-alkyl-carboxyl groups; for example, the phenol may be a compound of formula (VI).

[0531] Formula (VI)

[0532] Where Y 1 and R 1 It has the same meaning as that provided for equation (I) or any of its embodiments;

[0533] X is a leaving group, such as a methanesulfonate (MsO) or a halogen, preferably Cl or Br, and

[0534] L 4 It is a group selected from C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl;

[0535] b) Provides a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, which is optionally properly protected on one or more of its nitrogen atoms by one or more protecting groups, and / or optionally has a C1-C4 alkyl group on one of its nitrogen atoms that is optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group);

[0536] c) React the phenol provided in step a), such as the compound of formula (VI), with the macrocyclic compound provided in step b) to obtain the compound as defined above, or an intermediate of the compound as defined above, such as an intermediate with at least two suitable substituents that can be converted to LZ groups in a later step. Such suitable substituents are, for example, at least two L... 4 Part of it can be advantageously converted into the L group in subsequent steps. 1 -Z 1 L 2 -Z 2 , and the final L 3 -Z 3 (If present). Such intermediates are, for example, compounds of formula (VII).

[0537] Equation (VII)

[0538] Where R 1 , R 2 Y 1 Y 2 m, n, and o have the same meaning for equation (I) or any of its implementations.

[0539] L 4 A group selected from C1-C4-alkyl-aldehydes, C1-C4-alkyl-esters, and C1-C4-alkyl-carboxyl groups; and

[0540] R'' is selected from hydrogen, C1-C4 alkyl groups optionally substituted with aryl groups (e.g., substituted or unsubstituted aryl groups), and the part of formula (VIIA):

[0541] Equation (VIIA)

[0542] Among them: asterisk ( ) represents the connection point between the portion of formula (VIIA) and the nitrogen containing the R' group;

[0543] Y 3 Having the above for Y 1 and Y 2 The same meaning provided;

[0544] R 3 Having the above for R 1 and R 2 The same meaning provided; and

[0545] L 4 A group selected from C1-C4-alkyl-aldehydes, C1-C4-alkyl-esters, and C1-C4-alkyl-carboxyl groups; and

[0546] d) Convert the intermediate from step c) into the compound defined above, for example, L 4 Partially converted to group L 1 -Z 1 L 2 -Z 2 , and L 3 -Z 3 (If present), thereby obtaining the compound as defined above, the transformation being carried out, for example by reacting the intermediate obtained in step c), such as the compound of formula (VII), with one or more suitable substrates, and optionally by reducing the compound thus obtained.

[0547] In this specification, the term "C1-C4-alkyl-aldehyde" refers to an alkyl group as defined above, containing 1 to 4 carbons, one of which is an aldehyde group. Therefore, the group C1-C4-alkyl-aldehyde contains at most four carbons.

[0548] In this specification, the term "C1-C4-alkyl-ester" refers to an alkyl group containing 1 to 4 carbons as defined above, where one carbon is a carboxylic acid ester bonded to the alkyl group (i.e., one carbon is -C(O)OR). 0 , where R 0 It is an alkyl group, preferably a C1-C2 alkyl group. Therefore, the C1-C4 alkyl ester group contains at most four carbons (excluding the alkyl R group bonded to oxygen). 0 ).

[0549] In this specification, the term "C1-C4-alkyl-carboxyl" refers to an alkyl group containing 1 to 4 carbons as defined above, where one carbon is a carboxyl (-COOH) group. Therefore, the group C1-C4-alkyl-carboxyl contains at most four carbons.

[0550] Step a) comprises providing a phenol, which is advantageously substituted at one of its ortho positions with a leaving group -C1-C5-alkyl, preferably a halomethyl such as chloromethyl, or MsO-methyl. This group allows the phenol to couple with one or more, possibly two or three nitrogen atoms of a macrocycle in step c). The phenol further comprises a group at its ortho position that can be advantageously converted to L in a subsequent step. 1 -Z 1 , L 2 -Z 2 And the final L 3 -Z 3 (If present) a group, such as a group selected from C1-C4-alkyl-aldehydes, C1-C4-alkyl-esters, and C1-C4-alkyl-carboxyl groups. Alternatively, in addition to a leaving-C1-C5-alkyl group, such as a halo-C1-C5-alkyl group, the phenol may further include an LZ group, such as an L... 1 -Z1 The group, thus directly yielding the compound when the phenol is coupled with the macrocycle provided in step b). Advantageously, the phenol of step a), such as the compound of formula (VI), can be obtained by reacting the corresponding non-methylene halogenated compound with paraformaldehyde in concentrated hydrohalic acid, preferably hydrochloric acid or hydrobromic acid, at a temperature of 30 to 70°C, preferably 40 to 60°C, more preferably 50°C.

[0551] Step b) comprises providing a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane, and triazacyclododecane, which optionally has one or more nitrogen atoms suitably protected by one or more protecting groups, and / or optionally has a C1-C4 alkyl group optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group) on one nitrogen atom. Such a macrocycle will be coupled to the phenol of step a) in step c) to provide an intermediate of the compound of the invention (later converted to the compound of the invention), or directly to provide the compound of the invention.

[0552] The macrocyclic compound in step b) may be unprotected. Specifically, the nitrogen atoms of the macrocycle may be unprotected when the compound to be obtained has all three nitrogen atoms of the macrocycle bonded to a phenol with an LZ group (i.e., when R is a group of formula (IA)). In fact, in this way, the coupling reaction in step c) may involve all three unprotected nitrogen atoms of the macrocycle, thereby obtaining the compound or intermediate of the invention, such as an intermediate of formula (VII), where R'' is a part of formula (VIIA); this intermediate may then be converted to the compound of the invention in subsequent steps, where R is a group of formula (IA). Furthermore, the nitrogen atoms of the macrocycle may also be unprotected when the compound to be obtained has only two nitrogen atoms of the macrocycle alkylated by a phenol with an LZ group, i.e., when the compound to be obtained has R or R' which is hydrogen or optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group) in a C1-C4 alkyl group (or the preferred embodiments disclosed above). In fact, based on the reaction conditions of step c), which can be selected according to conventional and standard knowledge in the art, the reaction between the phenol and the macrocycle (step c) may involve only the two unprotected nitrogen atoms of the macrocycle instead of all three unprotected nitrogen atoms, and thus the product of such a reaction is a macrocycle of phenol with only two (not three) LZ groups bonded together, as described, for example, in Example 6. For example, during step c), particularly for macrocyclic triazacyclodecane and triazacycloundecane, all three or two of the three nitrogen atoms of the macrocycle can be deprotonated by appropriately adjusting the basicity of the reaction mixture in step c), thereby alkylating two of all three or only three nitrogen atoms during step c); for example, when a base such as DIPEA is added to the reaction mixture in step c), all three nitrogen atoms of macrocyclic triazacycloundecane or triazacyclododecane are deprotonated, thus obtaining a trialkylated macrocycle in step c); while if only a carbonate is used in the reaction mixture, one nitrogen atom of macrocyclic triazacycloundecane or triazacyclododecane remains protonated and will not participate in the alkylation step c), thus providing a dialkylated macrocycle (see, for example, Example 6).

[0553] According to step b), the macrocyclic compound may also be suitably protected with one or more protecting groups on one or more nitrogen atoms. In particular, when R or R' of the compound to be obtained is hydrogen or a C1-C4-alkyl group optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), one or more nitrogen atoms of the macrocycle may be suitably protected with one or more protecting groups. For example, compound 4 (having R=hydrogen) can be synthesized as follows: first, a mono-Boc (tert-butoxycarbonyl) protected macrocycle (e.g., as described by SJ Butler, BK McMahon, R. Pal, D. Parker, JW Walton, ...) is prepared. Chem. Eur J., The method disclosed in 2013, 19, 9511-9517 is then carried out by coupling it with the side group of hydroxybenzaldehyde, followed by reductive amination with serine (2-amino-1,3-propanediol), and finally by deprotection with TFA, as shown in Scheme 1 below.

[0554]

[0555] Option 1

[0556] Furthermore, due to the (potentially selective) deprotection reaction, the possibility of providing a macrocycle with one or more protecting groups on one or more nitrogen atoms in step b) allows for the selection of which and how many nitrogen atoms of the macrocycle will react with the ortho-substituted phenol in the coupling reaction of step c). In particular: any macrocycle described herein with one or more protecting groups on one or more nitrogen atoms can be, for example, from suitable dialkyltriamines (e.g., diethylenetriamine, dipropyltriamine, (2-aminoethyl)-1,3-propanediamine, etc.) (e.g., as described in M. Devreux, C. Henoumont, F. Dioury, D. Stanicki, S. Boutry, L. Larbanoix, C. Ferroud, RN Muller, S. Laurent, Eur. J. Inorg. Chem. The synthesis begins with the method disclosed in 2019, 3354-3365, particularly by protecting the primary amine of the diallyltriamine with a p-nitrobenzenesulfonyl (Ns) group and the secondary amine of the diallyltriamine with a Boc group; then, a suitably protected macrocycle can be obtained by Richman and Atkins cyclization of the protected diallyltriamine using a suitable xylyl diol and appropriate reaction conditions, for example as shown in Scheme 2:

[0557]

[0558] Option 2

[0559] Once a properly protected macrocycle is obtained, for example according to Scheme 2, the two p-nitrobenzenesulfonyl groups (Ns) can be removed by using thiophenol in the presence of carbonate, thereby alkylating the two deprotected amines of the macrocycle with appropriate side arms, for example as disclosed in step c), and finally by converting the groups on the side arms, for example as disclosed in step d); Boc can be finally removed, for example as disclosed in Scheme 1 above, to obtain the compound of the present invention wherein R or R' is hydrogen, or by finally further alkylating the deprotected nitrogen that was previously bonded to Boc.

[0560] The compounds of the present invention, wherein R or R' is a C1-C4 alkyl group optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), can be obtained, for example, by the operation as described in Scheme 2 above. However, instead of a secondary amine protected with Boc, such a secondary amine can be reacted with, for example, benzyl bromide (to insert a benzyl group) or with, for example, a C1-C4 alkyl-aldehyde (e.g., formaldehyde) and NaBH4 (reductive amination) (to insert a C1-C4 alkyl group, e.g., methyl group); this allows for the obtaining of a macrocycle with two p-nitrobenzenesulfonyl groups (Ns) and one C1-C4 alkyl group optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group). The remaining steps for obtaining the compounds of the present invention can then be carried out as detailed above (i.e., according to step c) to remove the Ns group and alkylate. The compounds of the present invention, wherein R or R' is a C1-C4 alkyl group optionally substituted with an aryl group (e.g., substituted or unsubstituted aryl group), can also be obtained from commercially available monoalkylated macrocycles, such as Scheme 3 below for the preparation of compound 112:

[0561]

[0562] Option 3

[0563] Step c) provides to react the phenol of step a) with the macrocycle of step b) to directly obtain the compound of the present invention, or to obtain an intermediate of the compound of the present invention, which is actually reacted in the next step d) to obtain the final product.

[0564] Step c) can be carried out in an organic solvent, such as toluene or acetonitrile. Salts, such as potassium salts, such as KI, KOH, and K₂CO₃, can be included in such an organic solvent, preferably in an amount four times the molar equivalent of the macrocycle provided in step b). KI can also be used in an amount of 0.05 to 0.4 molar equivalents, for example, 0.1 to 0.2 molar equivalents, compared to the macrocycle provided in step b).

[0565] Step c) can advantageously be carried out without heating the reaction mixture. In particular, to reduce the risk of undesirable polyalkylation reactions, step c) can be carried out at a temperature equal to or below room temperature (i.e., below 25°C), for example, at a temperature in the range of 0°C to 25°C.

[0566] Step d) is optional and may be performed optionally when step c) provides an intermediate of the compound of the invention. Step d) includes adding a group of the intermediate, such as the group L. 4 Transform into L 1 -Z 1 , L 2 -Z 2 And the final L 3 -Z 3 (If present) a group. This can be achieved, for example, by making L 4 This is achieved by reacting a group with one or more suitable substrates. For example, if L 1 It is a C1-C4-alkylamino and Z 1 If it is a C1-C6 alkyl group substituted with one or more hydroxyl groups, then L in formulas (VII) and (VIIA) 4 The substrate can be a C1-C4 alkyl-aldehyde, and the suitable substrate can be a C1-C6 alkyl-amine substituted with two or more hydroxyl groups, such as serine or glucosamine, whereby coupling of the two provides an imide, which is subsequently reduced to obtain the desired L. 1 -Z 1 Partial (e.g., disclosed in Example 2 below). Or, when L 1 It is a C1-C4-alkylamino and Z 1 When the C1-C6 alkyl group is substituted with a phosphonate group, L in formulas (VII) and (VIIA) 4 It can be a C1-C4 alkyl-aldehyde, and the suitable substrate can be, for example, diethyl 2-aminomethylphosphonate, as shown in Scheme 4 below for obtaining compound 11.

[0567]

[0568] Option 4

[0569] As a further illustrative example, when L 1 It is a C1-C4-alkylamide and Z 1 When it is hydrogen, L in formulas (VII) and (VIIA) 4 It can be a C1-C4 alkyl ester, and the suitable substrate can be, for example, ammonia, as shown in Scheme 5 below for obtaining compound 5.

[0570]

[0571] Option 5

[0572] As another illustrative example, when L 1 It is a C1-C4 alkyl ether and Z 1 When it is a C1-C6-alkyl group substituted with one or more hydroxyl groups, L in formulas (VII) and (VIIA) 4 It can be a C1-C4 alkyl-aldehyde, which can be reduced to obtain a hydroxyl group, which can then be converted into an alkoxide; this alkoxide can participate in the well-known Williamson synthesis of ethers, thereby reacting with a suitable substrate, such as an alkyl-hydroxy-halide whose hydroxyl group is appropriately protected, for example 2-chloro-1,3-propanediol or 2-bromo-1,3-propanediol whose hydroxyl group is appropriately protected.

[0573] The compounds of the present invention can also be prepared by providing, in step a), a phenol as defined above and having, in particular, the LZ group at its ortho position. In this case, the compounds of the present invention can be obtained directly by reacting such ortho-substituted phenol with the macrocycle provided in step b) in step c). This can be illustrated, for example, according to scheme 6 below, which is used to obtain compounds having the following groups -NHC(O)-·as L 1 And Z 1 The compound of the present invention, which is hydrogen (i.e., compound 177), wherein the asterisk ( The dot (·) indicates the phenolic component, and the dot in the middle indicates Z. 1 Group:

[0574]

[0575] Option 6

[0576] The compounds of the present invention can also be obtained by providing a phenol according to step a) in any embodiment, and by obtaining them in the following ways:

[0577] b') Provide macrocyclic oroamide derivatives selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, i.e. tricyclic triaminomethane derivatives, such as the oroamide derivative of formula (VIII):

[0578] Formula (VIII)

[0579] Where m, n and o have the same meaning for equation (I) or any of its implementations;

[0580] c') React one or two phenols provided in step a), such as compounds of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, with the oroamide derivative, such as an oroamide derivative of formula (VIII), to obtain an oroamide derivative coupled with one or two phenols provided in step a), such as compounds of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde;

[0581] d') The oramide derivative obtained in step c') by hydrolysis, for example by acid hydrolysis, yields one or two phenols provided in step a), such as compounds of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, and macrocycles selected from triazacyclononane, triazacyclodecane, triazacycloundecane, and triazacyclododecane coupled with a formyl (-C(O)H) group;

[0582] e') Optionally, the additional phenol provided in step a), such as a compound of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, is reacted with the macrocycle obtained in step d') to obtain a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane, and triazacyclododecane coupled with the two phenols provided in step a), such as a compound of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, and a formyl group (-C(O)H) coupled with a formyl group;

[0583] f') Hydrolyzing the macrocycle obtained in step d') or e') and optionally transforming it into a possible C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester, or C1-C4-alkyl-carboxyl group, wherein the hydrolysis and optional transformation in step f') are carried out in any order to obtain the compound of the present invention (wherein two nitrogen atoms of the macrocycle are bonded to a phenol with an LZ group, and one is bonded to a hydrogen group); and

[0584] g') Optionally, the additional phenol provided in step a), such as a compound of formula (VI), like 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, is reacted with the macrocyclic compound obtained in step f'), and optionally, possible C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester, or C1-C4-alkyl-carboxyl group is converted to obtain the compound of the present invention (wherein all three nitrogen atoms of the macrocyclic compound are bonded to a phenol with an LZ group).

[0585] Scheme 7 below illustrates a possible manner of carrying out the above, particularly in the following cases: step c') provides reacting a phenol with an oroamide derivative to carry out step e') (and thus provides reacting another phenol with the macrocyclic compound obtained in step d'), step f') provides first performing a conversion of a possible C1-C4-alkyl-aldehyde, followed by a hydrolysis step to obtain the compound of the present invention, and without performing step g'):

[0586]

[0587] Option 7

[0588] According to Scheme 7, the compound of the present invention in which two nitrogen atoms of the macrocycle are bonded to a phenolic compound with an LZ group and one nitrogen atom is bonded to a hydrogen atom can be synthesized. If the additional step g') is performed, the compound of the present invention in which three nitrogen atoms of the macrocycle are bonded to a phenolic compound with an LZ group can also be synthesized.

[0589] The oroamide derivative provided in step b') can be obtained according to standard methods in the art, for example by reacting a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane with formaldehyde dimethyl acetal, or as T. Atkins, J. Am. Chem. Soc. 1980, 102, 6364-6365; RW Alderet et al. J. Chem. Soc. Chem. Commun. As reported in 1992, 507-508, starting from, for example, 1,4,6-triazabicyclo[3.3.0]oct-4-ene and 1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0590] The hydrolysis in step d') transforms the orthoamide derivative into a macrocycle bonded with a formyl group (and a phenol bonded in the previous reaction in step c'). The formyl group appears to primarily bond to the nitrogen atom of a less sterically hindered macrocycle, such as one of the two nitrogen atoms between the ethylene and propylene moieties of a macrocycle triazacycloundecane (rather than one between the two propylene moieties).

[0591] Step d') can be performed before step c'); in this case, step c') is carried out by reacting one or both phenols provided in step a) with the macrocycle obtained by hydrolysis of step d'), i.e. with a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane coupled with a formyl (-C(O)H) group.

[0592] To obtain the Fe(III) complex of the compound of the present invention, which is also an aspect of the present invention, a step of providing coordination of the compound of the present invention with Fe(III) can be performed, for example after step c) or step d), or after step f') or g'); the coordination step can be performed, for example, according to the following steps:

[0593] e) React the compound of the present invention obtained, for example, in step c), d), f'), or g') with a Fe(III) salt, such as FeCl3, Fe(NO3)3, Fe(OH)3, and FeO(OH), to obtain a Fe(III) complex of the compound of the present invention.

[0594] Step e) can be carried out in a non-aqueous polar solvent, such as a lower alcohol, such as methanol, ethanol, n-propanol, isopropanol and mixtures thereof.

[0595] Preferred compounds of the present invention and non-limiting examples of the preparation of intermediates for their preparation are reported in the following sections, which are intended to illustrate the invention in more detail rather than to limit its scope.

[0596] Experimental Section

[0597] Materials and methods

[0598] The reactants and / or solvents used in the following examples that were not specifically synthesized in these examples are all known and readily available. If they are not commercially available, they can be prepared according to methods known in the literature.

[0599] 1 H and 13 The C10 NMR spectra were recorded on a Bruker Avance III spectrometer (Bruker, Milano, Italy), which was operated at 11.74 T and 298 K, corresponding to a proton resonance frequency of 499.8 MHz. 1 H and 13 The 12C NMR chemical shifts are relative to the TMS report and referenced using residual proton solvent resonances. Samples were prepared in 5 mm NMR tubes by dissolving the compounds in a suitable deuterated solvent.

[0600] Analytical and semi-preparative HPLC-MS runs were performed on a Waters modular system (Waters Corporation, Milford, MA, USA) equipped with a Waters 1525 binary pump, a Waters 2487 UV / Vis detector, and a Waters SQD 3100 (ESCI ionization mode) detector. UPLC was performed using an UPLC Acquity H-Class coupled with a QDa and TUV detector (Waters Corporation, Milford, MA, USA). - MS analysis. ESI-MS was recorded on Waters SQD 3100 (Waters Corporation, Milford, MA, USA).

[0601] Example 1 - Synthesis of Compound 1

[0602] The synthesis of compound 1 was carried out according to scheme 8 below:

[0603]

[0604] Option 8.

[0605] Details of the synthesis in this embodiment are provided in the following paragraphs.

[0606] A) Synthesis of methyl benzoate (2-hydroxy-5-methyl)

[0607] 2-Hydroxy-5-methylbenzoic acid (0.5 g, 3.28 mmol) was dissolved in 5 mL of MeOH, and a few drops of HCl were added. The solution was stirred overnight at reflux. The final product was used without further purification. Quantitative yield.

[0608] 1 H NMR (CDCl3, 500MHz): δ (ppm)=2.27 (s, -C-CH3, 3H), 3.92 (s, -O-CH3,3H), 6.87 (d, -CH- CH -COH, 1H, J3=8.5 Hz), 7.24 (dd, -CCH3-CH-CH-, 1H, J3=8.5Hz, J4=2.1 Hz), 7.62 (d, -C-CH-CCH3, 1H, J4=2.1MHz), 10.51 (bs, -OH). 13 C NMR (CDCl3, 125MHz): δ (ppm)=20.4 (-CH3), 52.2 (-O-CH3), 111.9 (-CH- C -CH-), 117.3(-COH- CH -), 129.4 (-CH- C -COH-), 129.6 (-CH- CH -CCH3), 136.6 (-C- CH -C-), 160.2(-C-OH), 170.6 (-C=O-). ESI-MS (m / z): 167.2 (M+H + (Calculated value C9H) 10 O3: 166.2).

[0609] B) Synthesis of (2-hydroxy-5-methyl-3-methylchloro)carboxylic acid

[0610] The methyl benzoate (2-hydroxy-5-methyl) ester (0.5 g, 3.01 mmol) obtained in the previous step was dissolved in 4 mL of concentrated HCl and heated to 50 °C. Paraformaldehyde (0.181 g, 6.02 mmol) was then added in portions, and the reaction mixture was stirred at room temperature for 72 h. The solution was then washed with DCM (3 x 15 mL), and the organic layer was washed with brine (2 x 15 mL). The organic phase was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. Yield: 72%.

[0611] 1 H NMR (CDCl3, 500MHz): δ (ppm)=2.29 (s, -CH3, 3H), 3.94 (s, -O-CH3,3H), 4.67 (s, -CH2-Cl, 2H), 7.37 (s, -C- CH -C-CH2Cl, 1H), 7.63 (s, -C- CH -C-CH3,1H), 11.01 (bs, -OH). 13 C NMR (CDCl3, 125MHz): δ (ppm)=20.4 (-CH3), 40.8 (-O-CH3), 52.4 (-CH2-Cl), 112.5 (-CH- C -CH3), 125.5 (- C -CH2Cl), 128.2 (-CH- C -COH), 130.4 (-CCH3- CH -C-), 137.4 (-CCH3- CH -CC=O-), 157.5 (-COH), 170.6 (-C=O-). ESI-MS (m / z): n.d.

[0612] C) Synthesis of 1,4,7-tris-(3-carboxymethyl-2-hydroxy-5-methylbenzyl)-1,4,7-triazacyclononane

[0613] Triazacyclononane·3HCl (0.095 g, 0.4 mmol, TACN) was dissolved in a small amount of toluene. KI (0.007 g, 0.04 mmol) and KOH (0.067 g, 1.2 mmol) were added, and the solution was cooled to 0 °C. Methyl benzoate (2-hydroxy-5-methyl-3-chloromethyl) obtained in the previous step (0.258 g, 1.2 mmol) was dissolved in 2 mL of toluene and added dropwise over approximately 15 min to minimize polyalkylation. The reaction mixture was then stirred at room temperature for 2 h. The product was characterized by HPLC-MS analysis (XBridge Phenyl 3.5 μm (4.6 x 150 mm); A = H₂O / 0.1% TFA; B = MeOH; flow rate = 1 mL / min; 0–1 min = 30% B; 1–15 min = 30%–100% B; 15–19 min = 100% B; 19–20 min = 100%–30% B). Retention time: 13.79 min. Yield: 80%.

[0614] 1 H NMR (CDCl3, 500MHz): δ (ppm)=2.26 (s, -CH3-, 3H), 2.86 (bs, macrocycle), 3.70 (bs, -CH2-N-, 6H), 3.92 (-O-CH3, 9H), 7.16(s, -C- CH -CCH3-, 1H), 7.23 (s,-CCH3- CH -C-, 1H). 13 C NMR (CDCl3, 125MHz): δ (ppm)=20.5 (-CH3), 52.2 (-O-CH3),35.5 (-N-CH2-), 122.7 (-CH2- C -CH-) 125.3 (-CCH3- CH -C-), 128.3 (-CH- C -CH3),129.1 (-C- CH -CCH3), 137.9 (-COH- C -CH-)158.0 (-C-OH), 170.2 (C=O). ESI-MS (m / z): 636.7 (M+H + (Calculated value C) 34 H 41 N3O9: 635.7).

[0615] D) 3,3',3''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tri[ N Synthesis of [(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide] (Compound 1)

[0616] Serine alcohol (2-amino-1,3-propanediol, 0.045 g, 0.5 mmol) was dissolved in DMF (1 mL) and added to a DMF (2 mL) solution of 1,4,7-tris-(3-carboxymethyl-2-hydroxy-5-methylbenzyl)-1,4,7-triazacyclononane (0.066 g, 0.1 mmol, obtained in the previous step). The reaction mixture was heated to 50 °C and stirred overnight. HPLC-MS analysis was performed to examine the reaction (XBridge Phenyl 3.5 μm (4.6 x 150 mm); A = H₂O / 0.1% TFA; B = MeOH; flow rate = 1 mL / min; 0–1 min = 30% B; 1–15 min = from 30% to 100% B; 15–19 min = 100% B; 19–20 min = from 100% to 30% B). Retention time: 10.25 min. The solvent was then removed, and the crude product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5μm (19x100mm); A=H2O / 0.1%TFA; B=MeOH; flow rate=20mL / min; 0-4min=30%B; 4-12min=30% to 57%B; 12-13min=100%B; 13-14min=100%B; 14-15min=100% to 30%B; 15-17min=30%B). Yield: 67%.

[0617] 1 H NMR (D2O, 500MHz): δ (ppm)=2.19 (s, -CH3-, 9H), 3.26 (bs, macrocycle, 12H), 3.66-3.75 (m, -CH- CH2 -OH, 12H), 4.10 (s, -N- CH2 -Ph-, 6H), 4.18-4.28 (m, -NH-) CH -CH2-OH, 3H), 7.22 (s, -CH, 1H), 7.60 (s, -CH, 1H). 13 C NMR (D2O,125MHz): δ (ppm)=19.4 (-CH3-), 49.9 (-CH- CH2 -OH-), 53.1 (-N- CH2 -Ph-), 56.6 (-NH- CH -CH2-OH), 60.6 (macrocyclic), 115.2 (-CH2- C -C-OH), 117.5 (-CH- C -CH3), 128.8 (-CH2-C- CH -), 129.6 (-C- CH -), 137.5 (-CH- C -CO), 156.1 (-C-OH), 170.6 (-C=O). ESI-MS (m / z): 841.4 (M+H + (Calculated value C) 42 H 60 N6O 12 : 840.4).

[0618] Example 2 - Synthesis of Compound 2

[0619] The synthesis of compound 2 was carried out according to scheme 9 below:

[0620]

[0621] Option 9.

[0622] Details of the synthesis in this embodiment are provided in the following paragraphs.

[0623] A) Synthesis of 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde

[0624] 2-Hydroxy-5-methylbenzaldehyde (0.51 g, 3.7 mmol) was dissolved in 4 mL of 48% HBr and heated to 50 °C. Paraformaldehyde (0.166 g, 5.55 mmol) was then added, and the reaction mixture was stirred at room temperature for 72 h. The solution was then extracted with DCM (3 x 15 mL), and the organic layer was washed with brine (2 x 15 mL). The organic phase was dried over Na₂SO₄, filtered, and the solvent was evaporated under reduced pressure. After removal of DCM, the product crystallized immediately. Yield: 69%.

[0625] 1H NMR (CDCl3, 500MHz): δ (ppm)=2.34 (s, -CH3, 3H), 4.55 (s, -CH2-Br,2H), 7.32 (s, -C- CH -CHO, 1H), 7.43 (s, -CCH3- CH -CH2Br, 1H), 9.85 (s, -CHO,1H), 11.29 (s, -OH, 1H). 13 C NMR (CDCl3, 125MHz): δ (ppm)=20.2 (-CH3), 26.6 (-CH2-Br), 126.3 (-C-CH3), 129.3 (-CH- C -CH2Br), 134.2 (-CCH3- CH -C-, -CH- C -CHO), 138.9 (-CHO- CH -C-), 157.3 (-COH), 196.4 (-CHO).

[0626] B) Synthesis of 1,4,7-tris-(3-formyl-2-hydroxy-5-methylbenzyl)-1,4,7-triazacyclononane

[0627] Triazacyclononane (0.042 g, 0.18 mmol, TACN) was dissolved in 3 mL of acetonitrile, and KI (0.003 g, 0.018 mmol) and KOH (0.030 g, 0.54 mmol) were added. 2-Hydroxy-3-chloromethyl-5-methylbenzaldehyde (0.21 g, 0.9 mmol), obtained in the previous step, was added dropwise to the solution dissolved in 1 mL of acetonitrile. The reaction mixture was heated to 60 °C and stirred overnight. The solution was then filtered, and the crude product was precipitated in diethyl ether. Yield: 81%. HPLC-MS analysis was performed to examine the reaction (XBridge Phenyl 3.5 μm (4.6 x 150 mm); A = H₂O / 0.1% TFA; B = MeOH; flow rate = 1 mL / min; 0–2 min = 60% B; 2–12 min = from 60% to 100% B; 12–16 min = 100% B; 16–17 min = from 100% to 60% B). Retention time: 5.60 min.

[0628] 1H NMR (CDCl3, 500MHz): δ (ppm)=2.39 (s, -CH3-, 3H), 2.46, 2.98 (bs, macrocycle), 3.93 (bs, -CH2-N-, 6H), 7.40 (s, -C- CH -CCH3-, 3H), 7.50 (s, -CCH3- CH -C-, 3H), 9.89 (s, CHO, 3H). 13 C NMR (CDCl3, 125MHz): δ (ppm) = 20.4 (-CH3), 50.1-49.3 (-N-CH2- macrocyclic ring), 53.3 (-N-CH2), 115.2 (-CH2- C -CH-) 120.0 (-CCH3- CH -C-),131.0 (-CH- C -CH3), 136.0 (-C- CH -CCH3), 143.5 (-COH- C -CH-), 158.7 (-C-OH), 196.6 (C=O). ESI-MS (m / z): 574.7 (M+H + (Calculated value C) 33 H 39 N3O6: 573.7).

[0629] C) Synthesis of 2,2',2''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol) (compound 2)

[0630] The 1,4,7-tris-(3-formyl-2-hydroxy-5-methylbenzyl)-1,4,7-triazacyclononane (0.07 g, 0.12 mmol) obtained in the previous step was dissolved in 1 mL of MeOH, and excess 2-amino-1,3-propanediol (0.055 g, 0.61 mmol) was added. The solution was stirred at room temperature for 1 h. The imine intermediate was examined by MS spectroscopy: ESI-MS (m / z): 794.0 (M+H) + (Calculated value C) 42 H 60The mixture was used without purification. The solution was cooled to 0°C, and sodium borohydride (0.045 g, 1.8 mmol) was added slowly in portions. The reaction mixture was then stirred for 3 hours. The reducing agent sodium borohydride was quenched by adding 2 mL of MeOH dropwise, waiting 15 minutes, and finally the precipitate was removed by filtration. The final product was characterized by HPLC-MS (XBridge Phenyl 3.5 μm (4.6 x 150 mm); A = H₂O / 0.1% TFA; B = MeOH; flow rate = 1 mL / min; 0–1 min = 30% B; 1–15 min = from 30% to 100% B; 15–19 min = 100% B; 19–20 min = from 100% to 30% B). Retention time: 6.93 min.

[0631] The solvent was removed under reduced pressure, and the crude product was purified by semi-preparative HPLC-MS (XBridge PrepPhenyl OBD 5μm (19x100mm); A=H2O / 0.1%TFA; B=MeOH; flow rate=20mL / min; 0-4min=20%B; 4-10min=20% to 43%B; 10-11min=100%B; 11-12min=100%B; 12-13min=100% to 20%B; 13-15min=20%B). Yield: 80%.

[0632] 1 H NMR (D2O, 500MHz): δ (ppm)=2.17 (s, -CH3, 9H), 3.27-3.29 (m, -NH- CH -CH2-OH, 3H), 3.68-3.71 (m, -CH- CH2 -OH, 6H), 3.72-3.82 (m, -CH- CH’2 -OH, 6H), 4.11 (bs, macrocycle, 12H), 4.27 (s, -N-) CH2 -Ph-, 6H), 7.11 (s, -CH, 3H), 7.21 (s, -CH, 3H). 13 C NMR (D2O, 125MHz): δ (ppm)=19.5 (-CH3-), 44.8 (- CH2 -NH-C), 49.5 (-N- CH2 -Ph), 55.5 (-CH- CH2 -OH), 57.5 (macrocyclic), 59.8 (-NH-) CH -CH2-OH), 115.2 (-CH2- C -C-OH), 117.5 (-CH- C -CH3), 128.8 (-CH2-C- CH -), 129.6 (-C- CH -), 137.5 (-CH- C -CO), 156.1 (-C-OH). ESI-MS (m / z): 800.0 (M+H + (Calculated value C) 42 H 60 N6O 12 : 799.0).

[0633] Example 3 - Synthesis of Compound 4

[0634] The synthesis of compound 4 was carried out according to scheme 10 below:

[0635]

[0636] Option 10

[0637] Details of the synthesis in this embodiment are provided in the following paragraphs.

[0638] A) Synthesis of 1,4-bis-(3-formyl-2-hydroxy-5-methylbenzyl)-7-tert-butoxycarbonyl-1,4,7-triazacyclononane

[0639] 1-tert-butoxycarbonyl-1,4,7-triazacyclononane (0.122 g, 0.53 mmol) was dissolved in 3 mL of acetonitrile, and KI (0.009 g, 0.053 mmol) and K₂CO₃ (0.207 g, 1.59 mmol) were added. 2-hydroxy-3-chloromethyl-5-methylbenzaldehyde (0.293 g, 1.59 mmol) dissolved in 1 mL of acetonitrile was added dropwise to the solution. The reaction mixture was heated to 60 °C and stirred overnight. The solution was then filtered, and the crude product was purified by silica gel column chromatography (97:3 CH₂Cl₂ / MeOH; TLC detected at 95:5 CH₂Cl₂ / MeOH, Rf = 0.2) to give 0.264 g of product (95% yield). The final product was characterized by HPLC-MS (XBridge Phenyl 3.5 μm (4.6 x 150 mm); A = H₂O / 0.1% TFA; B = ACN; flow rate = 1 mL / min; 0-1 min = 50% B; 1-15 min = from 50% to 100% B; 15-19 min = 100% B; 19-20 min = from 100% to 50% B). Retention time: 5.60 min.

[0640] 1 H NMR (500MHz, CDCl3): δ=1.44 (s, 9H, C-(C H3 )3), 2.29 / 2.31 (s, 3H,C H3 -Ph), 2.75-2.88 (m, 8H, C H2 -N), 3.25-3.30 (m, 4H, C H2 -N), 3.80 / 3.83 (s, 4H,NC H2 -Ph), 7.37 / 7.39 (s, 2H, ArH), 7.31 / 7.42 (s, 2H, ArH), 10.13 / 10.22 (s, 2H, CHO). 13 C NMR (125MHz, CDCl3): δ=20.4 (Ph- C H3), 28.6 (C-( C H3)3), 52.1 / 52.6( C H2-N), 53.4 ( C H2-N), 55.1 / 55.5 ( C H2-N), 57.0 / 57.9 (N- C H2-Ph), 79.8 (O- C-(CH3)3), 121.6 / 121.9 (N-CH2- C -CH), 125.4 / 125.8 (CH3-C- C HC), 128.5 ( C -CHO), 129.4 / 130.2 (CH- C -CH), 137.6 / 138.1 (CH2-C- C HC-CH3), 155.3 (N- C =O), 158.8 / 159.2 ( C -OH), 193.2 / 194.0 (C- C HO). ESI-MS (m / z): 526.3 (M+H + (Calculated value C) 29 H 39 N3O6:525.6).

[0641] B) 1,4-double-{[3-( N Synthesis of [-1,3-dihydroxypropyl-2-yl)aminomethyl]-2-hydroxy-5-methylbenzyl]-7-tert-butoxycarbonyl-1,4,7-triazacyclononane

[0642] 1,4-bis-(3-formyl-2-hydroxy-5-methylbenzyl)-7-tert-butoxycarbonyl-1,4,7-triazacyclononane (0.104 g, 0.20 mmol) was dissolved in 1 mL of MeOH, and excess 2-amino-1,3-propanediol (0.054 g, 0.60 mmol) was added. The solution was stirred at room temperature for 1 h. The imine intermediate was examined by MS spectroscopy: ESI-MS (m / z): 672.4 (M+H) + (Calculated value C) 35 H 53 The mixture was used without purification. The solution was cooled to 0°C, and sodium borohydride (0.030 g, 0.79 mmol) was added slowly in portions. The reaction mixture was then stirred at room temperature for 3 hours. The reducing agent was quenched by adding 2 mL of MeOH dropwise, waiting 15 minutes, and finally the precipitate was removed by filtration. The final product was characterized by HPLC-MS (XBridge Phenyl 3.5 μm (4.6 x 150 mm); A = H₂O / 0.1% TFA; B = ACN; flow rate = 1 mL / min; 0–1 min = 10% B; 1–15 min = from 10% to 100% B; 15–19 min = 100% B; 19–20 min = from 100% to 10% B). Retention time: 8.50 min.

[0643] 1 H NMR (500MHz, CDCl3): δ=1.45 (s, 9H, C-(C H3 )3), 2.21 (s, 6H, C H3 -Ph), 2.56-2.93 (bs, 12H, C H2 -N), 2.93 (m, 2H, NC H -CH2-), 3.58 (m, 8H, N-CH-C H2 -), 3.65 (m, 4H, NC H2 -Ph), 3.72 (m, 4H, Ph-C H2 -N), 6.88-6.89 (bs, 4H, Ar H ). 13 CNMR (125MHz, CDCl3): δ=20.9 (Ph- C H3), 27.6 (C-( C H3)3), 48.3 ( C H2-N), 54.1 (Ph-CH2-N), 56.9 ( C H2-N), 61.0 (N- C H2-Ph), 63.3 (N-CH- C H2-OH), 66.6 (N- C H-CH2-OH), 79.8 (O- C -(CH3)3), 123.6 (N-CH2- C -), 125.3 ( C -CH2-N), 127.1 ( C -CH3), 128.7 (-CH), 129.4 (-CH), 154.6 (-C=O), 155.6 (-C-OH). ESI-MS (m / z): 676.4 (M+H + (Calculated value C) 33 H 57 N5O8: 675.8).

[0644] C) Synthesis of compound 4 (2,2'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol)

[0645] 1,4-double-{[3-(N [1,3-Dihydroxypropyl-2-yl)aminomethyl]-2-hydroxy-5-methylbenzyl]-7-tert-butoxycarbonyl-1,4,7-triazacyclononane (0.92 g, 0.16 mmol) was dissolved in a 1:1 mixture (4 mL) of TFA and CH2Cl2, and the mixture was stirred at room temperature for 3 h. The solvent was evaporated under reduced pressure, and the residue was dissolved in water. The solution was filtered through a 0.2 μm filter to remove solid residue. The product was purified by semi-preparative HPLC-MS and lyophilized to give a white monotrifluoroacetate (0.16 g, 53%). XBridge Prep Phenyl OBD 5μm (19x100mm); A=H2O / 0.1%TFA; B=ACN; Flow rate=20mL / min; 0-1min=1%B; 1-6min=from 1% to 100%B; 6-7min=100%B; 7-9min=100%B; 9-10min=from 100% to 1%B; 10-12min=1%B. The final product was characterized by HPLC-MS (XBridge Phenyl 3.5μm (4.6x150mm); A=H2O / 0.1%TFA; B=ACN; Flow rate=1mL / min; 0-1min=1%B; 1-15min=from 1% to 100%B; 15-19min=100%B; 19-20min=from 100% to 1%B). Retention time: 9.08 minutes.

[0646] 1 H NMR (500MHz, D2O): δ=2.17 (s, 6H, CC H3 ), 2.93 (bs, 4H, C H2 -N), 3.26 (quint, 2H, J=,NC H -CH2), 3.33 (m, 4H, C H2 -N), 3.37 (m, 4H, C H2 -N), 3.67-3.80 (m, 8H, N-CH-C H2 ), 3.99 (s, 4H, NC H2 -Ph), 4.26 (s, 4H, Ph-C H2 -N-CH),7.07 (s, 2H, ArH), 7.19 (s, 2H, ArH). 13 C NMR (125MHz, D2O): δ=19.4 (Ph- C H3), 42.6 (C H2-N), 44.9 (Ph-CH2-N), 49.1 ( C H2-N), 54.8 (N- C H2-Ph), 57.5 (N-CH- C H2-OH), 59.7 (N- C H-CH2-OH), 120.6 (N-CH2- C -), 121.8 (C- C H2-N), 132.5 ( C -CH3), 133.5 (-CH), 134.4 (-CH), 151.2 (-C-OH). ESI-MS (m / z): 576.4 (M+H + (Calculated value C) 30 H 49 N5O6: 575.7).

[0647] Example 4 - Synthesis of Compound 57

[0648] The synthesis of compound 57 was carried out according to scheme 11 below:

[0649]

[0650] Option 11

[0651] Synthesis of 2,2',2''-{1,4,8-triazacyclononane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol) (compound 57)

[0652] 1,4,8-Triazacycloundecane (0.05 g, 0.32 mmol, TACUD) was dissolved in 1.5 mL of acetonitrile, and KI (0.005 g, 0.032 mmol) and K₂CO₃ (0.176 g, 1.27 mmol) were added dropwise to the acetonitrile / dichloromethane 1:1 solution. The reaction mixture was heated to 60 °C and stirred for 4 h. Then, diisopropylethylamine (DIPEA 57 μL, 0.32 mmol) was added, and the reaction mixture was stirred at 60 °C for 27 h. The solvent was removed under reduced pressure. The product was then dissolved in 20 mL of dichloromethane and washed with water (10 mL x 2) and brine (10 mL x 1); the organic phase was dehydrated with sodium sulfate, filtered, and the solvent was evaporated. The product was characterized by UPLC-MS. (Acquity UPLC BEH C18 1.7μm (2.1x50mm); A=H2O / 0.1%TFA; B=ACN / 0.1%TFA; Flow rate=0.4mL / min; 0-14min=from 30% to 100%B; 14-15min=100%B). Retention time: 4.50 min. MS(m / z): 602.5 (M+H + (Calculated value C) 35 H 43 N3O6: 601.7).

[0653] The product was used in the next step without further purification. Therefore, the solid was dissolved in 20 mL of MeOH, and excess 2-amino-1,3-propanediol (0.118 g, 1.29 mmol) dissolved in 5 mL of anhydrous methanol was added. The solution was stirred overnight at room temperature. The imine intermediate was examined by MS spectroscopy: ESI-MS (m / z): 822.0 (M+H) + (Calculated value C) 44 H 64N6O9: 822.3). The solution was cooled to 0°C and sodium borohydride (0.147 g, 3.87 mmol) was added slowly in portions. The reaction mixture was then stirred at room temperature for 48 h. Excess reducing agent was then quenched by adding 1 mL of H2O dropwise and the solvent was removed under reduced pressure. The product was redissolved in 20 mL of ethanol. The precipitate was removed by filtration. The solvent was removed under reduced pressure and the crude product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5 μm (19 x 100 mm); A = H2O / 0.1% TFA; B = MeOH; flow rate = 8 mL / min; 0–4 min = 20% B; 4–10 min = from 20% to 40% B; 10–11 min = 100% B; 11–14 min = 100% B; 14–15 min = from 100% to 20% B). The final product (58 mg, 0.07 mmol, 22% yield) was characterized by UPLC-MS (Acquity UPLC BEH C18 1.7 μm (2.1 x 50 mm); A = H₂O / 0.1% TFA; B = ACN / 0.1% TFA; flow rate = 0.4 mL / min; 0–14 min = from 2% to 100% B; 14–15 min = 100% B); retention time: 3.47 min. ESI-MS (m / z): 828.3. (M+H) + (Calculated value C) 44 H 70 N6O9: 827.1).

[0654] 1 H NMR (D2O, 500MHz, pD=2): δ (ppm)=2.05 (br, CH2 CH 2CH2, 4H), 2.20 (s,-CH3, 9H), 3.01 (br, NCH2CH2N macrocycle, 4H), 3.32 (m, -NH- CH -CH2-OH, 3H), 3.65-3.70 (m, -CH- CH2 -OH, 6H), 3.72-3.82 (m, -CH- CH’2 -OH, 6H), 3.9 (br, N CH 2CH2CH2 macrocyclic ring (8H), 4.25, 4.30 (s, -N- CH2 -Ph-, 12H), 7.21 (s, -CH, 3H), 7.28 (s, -CH,3H). 13C NMR (D2O, 125MHz): δ (ppm)=19.5 (-CH3-), 20 (br, CH2 CH 2CH2), 45.1 (- CH2 -NH-Ph), 54 (br, N-CH2 macrocycle), 57.2 (-CH- CH2 -OH-), 59.8 (N- CH -CH2-OH-), 118.2(C Ar ), 120.5 (C Ar ), 132.8 (ArH), 135.6 (ArH), 137.5 (C Ar ), 154.1 (-C Ar -OH).

[0655] Example 5 - Synthesis of Compound 60

[0656] The synthesis of compound 60 was carried out according to scheme 12 below:

[0657]

[0658] Option 12

[0659] A) 1,5,7-triazabicyclo[4.4.0]dec-5-ene (340 mg, 2.17 mmol) was dissolved in anhydrous THF (5.0 mL). The solution was placed in an ice bath and NaH (221 mg, 1.7 eq) was added; the mixture was stirred under a nitrogen atmosphere for 20 min. 2-(2-bromoethoxy)tetrahydropyran (680 mg, 1.5 eq) dissolved in 5.0 mL of anhydrous THF was added, and the mixture was stirred at room temperature under a nitrogen atmosphere for 48 h. The reaction was quenched with EtOH (2.0 mL) and stirred for another 1 h; finally, the mixture was filtered and the solvent was evaporated. The product was used without further purification. Crude product: 921 mg ESI + MS: m / z=268.4 [MH + ],(Calculated value C 14 H 25 N3O2: 267.4).

[0660] B) 7-(2-(2-tetrahydropyranoxy)ethyl)-1,5,7-triazabicyclo[4.4.0]dec-5-ene (921 mg) was dissolved in 1M HCl (15.0 mL), and the mixture was stirred at room temperature for 6 h. NaOH granules were added to achieve a pH >11. The solvent was evaporated, and the product was redissolved in DCM, filtered, and dried. The intermediate was used without further purification (663 mg, crude). The solid was dissolved in anhydrous DCM (15.0 mL) and placed in an ice bath. Et3N (0.626 mL, 2.5 eq) and methanesulfonyl chloride (0.541 mL, 1.2 eq) were added to the mixture, and it was stirred at room temperature under a nitrogen atmosphere for 1 h. The reaction was quenched with deionized water and stirred for another 10 min. The solvent was removed under reduced pressure, and the product was used without further purification. ESI + MS: m / z=166.8 [M + ] (Calculated value C9H) 16 N3 + : 166.2).

[0661] C) The product obtained in the previous step was dissolved in anhydrous THF (20.0 mL); the solution was cooled in an ice bath, and LiAlH4 (3.25 mL of 1 M solution in THF, 1 eq) was added. The mixture was stirred under a nitrogen atmosphere for 1.5 h, and then the reaction was quenched with MeOH (2.0 mL), with stirring maintained for about 15 min (until effervescence ceased). The solvent was removed under reduced pressure. The product was dissolved in DCM (35 mL) and washed with 1 M Na2CO3 (3 x 10 mL); the organic phase was dehydrated with Na2SO4, filtered, and the solvent was evaporated. Crude product: 350 mg. ESI + MS: m / z=168.2 [MH + ](Calculated value C9H 17 N3: 167.2).

[0662] D) Tricycloorhodium (350 mg, 2.09 mmol) was dissolved in ACN (30 mL), and then 3-bromomethyl-5-methyl-2-hydroxybenzaldehyde (527 mg, 1.1 eq) was added. The mixture was stirred overnight at room temperature. The solvent was then removed under reduced pressure. The product was confirmed by HPLC-MS analysis (Waters XBridge Phenyl 3.5 μm 4.6 x 150 mm), A = H₂O; B = MeOH; flow rate = 1 mL / min; 0–2 min = 15% B; 2–16 min = from 15% to 100% B; 16–19 min = 100% B; 19–20 min = from 100% to 15% B. Retention time: 14.8 min. ESI +MS: m / z=316.4 [M + ] (Calculated value C) 18 H 26 N3O2 + : 316.2). The product was purified by rapid chromatography (Sepachrom Purezza Phenyl 25μL 15g), A=H2O; B=MeOH; flow rate=15mL / min; 1 column volume (CV) 40%B; 10 CV from 40% to 100%B; 2 CV 100%B. Retention time: 3.7 min. 11 mg of pure product was obtained.

[0663] E) The monoalkylated product (11 mg, 0.028 mmol) was dissolved in 0.1 M HCl (3.0 mL), and the mixture was stirred at room temperature for 24 h. The acid was neutralized with 2 M NaOH (0.150 mL), and the solvent was removed under reduced pressure. The product was used without further purification. The product was confirmed by HPLC-MS analysis (Waters XBridge Phenyl 3.5 μm 4.6 x 150 mm), A = H₂O; B = MeOH; flow rate = 1 mL / min; 0–2 min = 10% B; 2–16 min = from 10% to 100% B; 16–19 min = 100% B; 19–20 min = from 100% to 10% B. Retention time: 10.3 min. ESI + MS: m / z=334.5 [MH + ] (Calculated value C) 18 H 27 N3O3: 333.5).

[0664] F) The crude product (11 mg, 0.028 mmol) was dissolved in ACN (5.0 mL); then K₂CO₃ (12 mg, 3 eq) and 3-bromomethyl-5-methyl-2-hydroxybenzaldehyde (9 mg, 1.5 eq) were added. The mixture was stirred at room temperature for 6 h, and then the solvent was evaporated under reduced pressure. The product (15 mg) was used for the next step without further purification. ESI + MS: m / z=482.6 [MH + ] (Calculated value C) 27 H 35 N3O5: 481.6).

[0665] G) The previous intermediate (15 mg, 0.031 mmol) was dissolved in anhydrous MeOH (5.0 mL), and then serine (7 mg, 2.5 eq) was added. The mixture was stirred overnight at room temperature. NaBH4 (6 mg, 5 eq) was added (0 °C, ice bath) and stirred for 2 h. The reaction was quenched with deionized water (a few drops) and stirred for another 30 min. The solvent was evaporated, the product was redissolved in EtOH, filtered, and dried again under reduced pressure. The product (41 mg) was used without further purification. UPLC-MS (Acquity UPLC BEH C18 1.7 μm (2.1 x 50 mm); A = H2O / 0.1% TFA; B = ACN / 0.1% TFA; flow rate = 0.4 mL / min; 0–14 min = from 2% to 100% B; 14–15 min = 100% B); retention time: 3.12 min. ESI + MS: m / z=632.8 [MH + ] (Calculated value C) 33 H 53 N5O7: 631.8).

[0666] H) The preceding intermediate was dissolved in 4M HCl (1.0 mL) and stirred at room temperature for 24 h. The solvent was then removed under reduced pressure to give 39 mg of crude product. UPLC-MS (Acquity UPLC BEH C18 1.7 μm (2.1 x 50 mm); A = H₂O / 0.1% TFA; B = ACN / 0.1% TFA; flow rate = 0.4 mL / min; 0–14 min = from 2% to 100% B; 14–15 min = 100% B); retention time: 3.34 min. ESI + MS: m / z=604.8 [MH + ](Calculated value C) 32 H 53 N5O6: 603.8).

[0667] 1 H NMR (D2O, 500MHz): δ (ppm)=2.12, 2.19 (s, -CH3, 6H), 2.0 (br,CH2 CH 2CH2 (4H), 3.0-3.2 (br, NCH2CH2N macrocycle, 8H), 3.29 (m, -NH- CH -CH2-OH, 2H), 3.6 (br, N CH 2CH2CH2 macrocycle, 4H), 3.71-3.74 (m, -CH- CH2 -OH, 4H), 3.81-3.85 (m, -CH- CH’2 -OH, 4H), 4.25, 4.29 (s, -N- CH2 -Ph-, 8H), 6.90 (s, -CH, 2H), 7.04 (s, -CH, 2H). 13 C NMR (D2O, 125MHz): δ (ppm)=19.4 (-CH3-), 20 (br, CH2 CH 2CH2), 45.6(- CH -CH2-OH-), 55, 56 (br, N-CH2 macrocycle), 57,4 and 57.6 (-NH-) CH -CH2-OH), 59.5 (- CH2 -NH-C), 70.7 (-N- CH2 -Ph-), 119.4 (C Ar ), 128.2 (C Ar ), 130.2 (ArH), 131.8(ArH), 132.3 (C Ar ), 149.9 (-C Ar -OH).

[0668] Example 6 - Synthesis of Compound 61

[0669] The synthesis of compound 61 was carried out according to scheme 13 below:

[0670]

[0671] Option 13

[0672] 1,4,8-Triazacycloundecane (0.030 g, 0.192 mmol, TACUD) was dissolved in 1.5 mL of acetonitrile, and KI (0.003 g, 0.019 mmol) and K₂CO₃ (0.066 g, 0.48 mmol) were added. 2-Hydroxy-3-bromomethyl-5-methylbenzaldehyde (0.11 g, 0.48 mmol), dissolved in 3 mL of acetonitrile / dichloromethane 1:1 solution, was added dropwise to the solution. The reaction mixture was heated to 60 °C and stirred for 24 h. The solvent was then removed under reduced pressure to give 0.16 g of crude product. The product was characterized by UPLC-MS. (Acquity UPLC BEH C18 1.7μm (2.1x50mm); A=H2O / 0.1%TFA; B=ACN / 0.1%TFA; Flow rate=0.4mL / min; 0-14min=from 30% to 100%B; 14-15min=100%B); Retention time: 1.44 min. ESI-MS (m / z): 454.5 (M+H) + (Calculated value C) 26 H 36 N3O4: 454.6). The product was used in the next step without further purification. Therefore, the solid was dissolved in 15 ml MeOH, and excess 2-amino-1,3-propanediol (0.096 g, 1.05 mmol) dissolved in 5 ml anhydrous methanol was added. The solution was stirred overnight at room temperature. The imine intermediate was examined by MS spectroscopy: ESI-MS (m / z): 600.4 (M+H) + (Calculated value C) 32 H 49N5O6: 599.8). The solution was cooled to 0°C and NaBH4 (0.12 g, 3.2 mmol) was added slowly in portions. The reaction mixture was then stirred at room temperature for 48 h. The reducing agent was quenched dropwise by adding 1 mL of water, and the solvent was removed under reduced pressure. The product was redissolved in 20 mL of ethanol, the precipitate was removed by filtration, and the solvent was finally removed under reduced pressure. The crude product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5 μm (19 x 100 mm); A = H2O / 0.1% TFA; B = MeOH; flow rate = 8 mL / min; 0-3 min = 30% B; 3-6 min = from 30% to 60% B; 6-11 min = 100% B; 11-14 min = 100% B; 14-15 min = from 100% to 30% B). The final product (72 mg, 0.12 mmol, 62% yield) was characterized by UPLC-MS (Acquity UPLC BEH C18 1.7 μm (2.1 x 50 mm); A = H₂O / 0.1% TFA; B = ACN / 0.1% TFA; flow rate = 0.4 mL / min; 0–14 min = from 30% to 100% B; 14–15 min = 100% B); retention time: 3.17 min. ESI-MS (m / z): 604.5 (M+H + (Calculated value C) 32 H 53 N5O6: 603.8).

[0673] 1 H NMR (D2O, 500MHz): δ (ppm)=2.16 (s, -CH3, 6H), 2.20 (br, CH2 CH 2CH2,4H), 3.20 (br, NCH2CH2N macrocycle, 4H), 3.25 (m, -NH- CH -CH2-OH, 2H), 3.69-3.74 (m,-CH- CH2 -OH, 4H), 3.79-3.84 (m, -CH- CH’2 -OH, 4H), 4.25, 4.30 (s, 8H, Ph-C H2 -N), 4.3 (br, N CH 2CH2CH2 macrocycle (8H), 7.06 (s, -CH, 2H), 7.09 (s, -CH, 2H). 13C NMR (D2O, 125MHz): δ (ppm)=19 (br, CH2 CH 2CH2), 19.3 (-CH3-), 45.3 (- N -CH2-Ph-), 56(br, N-CH2 macrocycle), 57,4 and 57.6 (-NH-) CH -CH2-OH), 59.5 (- CH- C H2 -OH), 118.6 (C Ar ),124.0 (C Ar ), 131.0 (ArH), 132.0 (ArH), 132.4 (C Ar ), 151.2 (-C Ar -OH).

[0674] Example 7 - Synthesis of Compound 112

[0675] The synthesis of compound 112 was carried out according to the following scheme 14:

[0676]

[0677] Option 14

[0678] Details of the synthesis in this embodiment are provided below.

[0679] 1-Benzyl-1,4,7-triazacyclononane (0.08 g, 0.036 mmol) was dissolved in 3 mL of acetonitrile, and KI (0.006 g, 0.036 mmol) and K₂CO₃ (0.151 g, 1.09 mmol) were added. 2-Hydroxy-3-chloromethyl-5-methylbenzaldehyde (0.251 g, 1.09 mmol) dissolved in 1 mL of acetonitrile was added dropwise to this solution. The reaction mixture was heated to 60 °C and stirred overnight. The solution was then filtered, and the crude product was precipitated in diethyl ether. The crude 1,4-bis-(3-formyl-2-hydroxy-5-methylbenzyl)-7-benzyl-1,4,7-triazacyclononane (0.19 g, 0.37 mmol) obtained in the previous step was then dissolved in 1 mL of MeOH, and excess 2-amino-1,3-propanediol (0.10 g, 1.12 mmol) was added. The solution was stirred at room temperature for 1 hour. The imine intermediate was examined by MS spectroscopy: ESI-MS (m / z): 662.4 (M+H) + (Calculated value C) 37 H 51The mixture (N5O6: 661.8) was used without purification. The solution was cooled to 0°C, and NaBH4 (0.06 g, 1.5 mmol) was added slowly in portions. The reaction mixture was then stirred for 3 hours. The reducing agent was quenched by adding 2 mL of MeOH dropwise, waiting 15 minutes, and finally the precipitate was removed by filtration. The final product was characterized by HPLC-MS (XBridge Phenyl 3.5 μm (4.6 x 150 mm); A = H2O / 0.1% TFA; B = ACN; flow rate = 1 mL / min; 0–2 min = 10% B; 2–16 min = from 10% to 100% B; 16–19 min = 100% B; 19–20 min = from 100% to 10% B). Retention time: 8.80 min.

[0680] The solvent was removed under reduced pressure, and the crude product was purified by semi-preparative HPLC-MS (XBridge PrepPhenyl OBD 5μm (19x100mm); A=H2O / 0.1%TFA; B=ACN; flow rate=20mL / min; 0-1min=90% A; 1-9min=10% to 54% B; 9-11min=54% to 100% B; 11-13min=100% B; 13-14min=100% to 10% B; 14-16min=10% B). Yield: 82%.

[0681] 1 H NMR(500MHz, CDCl3): δ=2.34 (s, 6H, CC H 3), 2.87 (bs, 8H, C H 2-N), 3.03 (m, 4H, C H 2-N), 3.81 (m, 2H, NC H -CH2), 3.87-3.88 (m, 8H, N-CH-C H2 ), 4.05(s, 2H, NC H 2-Bz), 4.43 (s, 4H, NC H 2-Ph), 4.97 (s, 4H, Ph-C H2 -N-CH), 7.23 (s,2H, ArH), 7.32 (s, 2H, ArH), 7.38 (s, 5H, ArH). 13 C NMR (125MHz, CDCl3): δ=19.1(Ph- C H3), 44.9 (Bz-C H2-N), 49.3 (Ph-CH2-N), 49.6 ( C H2-N), 49.9 ( C H2-N), 54.9(N- C H2-Ph), 57.7 (N-CH- C H2-OH), 60.2 (N- C H-CH2-OH), 115.1 (Bz- C -CH2-N), 117.4(Bz-CH), 120.3 (Bz-CH), 122.9 (Bz-CH), 128.3 ( C -CH3), 128.7 (-CH), 129.8 (-CH), 131.1 (-CH2-C-COH), 131.1 (-C-CH2-N-), 152.4 (-C-OH). ESI-MS (m / z): 666.4(M+H + (Calculated value C) 37 H 55 N5O6: 665.9).

[0682] Example 8 - Synthesis of Compound 177

[0683] The synthesis of compound 177 is as described in Scheme 15 below, and is carried out in the following details:

[0684]

[0685] Option 15

[0686] A) Synthesis of 2-hydroxymethyl-4-methyl-6-nitrophenol

[0687] 4-Methyl-2-nitrophenol (0.1 g, 0.65 mmol) was dissolved in 2 mL of 4M KOH and the temperature was set at 80 °C. When this temperature was reached, p-formaldehyde (0.029 g, 0.98 mmol) was added, and the reaction mixture was stirred for another 48 h. The solution was neutralized with HCl and extracted with H₂O / DCM. The organic phase was then dried over MgSO₄, filtered, and the solvent was removed under reduced pressure to give a pale yellow oil (0.106 g, 90% yield).

[0688] 1H NMR (500MHz, CDCl3): δ=2.36 (s, 3H, -CH3), 4.69 (s, 2H, -CH2-), 7.54 (s, 1H, -CH), 7.90 (s, 1H, -CH), 10.86 (s, 1H, -COH). 13 C NMR (125MHz, CDCl3): δ=20.4 (Ph- C H3), 60.4 (- C H2), 124.9 (-CH), 128.6 (-CCH2), 129.7 (-CNO2), 134.2 (-CCH3), 139.3 (-CH), 151.3 (-COH). MS calculated C8H9NO4: 183.05.

[0689] B) Synthesis of 3-hydroxymethyl-2-hydroxy-5-methylphenylacetamide

[0690] 2-Hydroxymethyl-4-methyl-6-nitrophenol (0.106 g, 0.58 mmol) was dissolved in 3 mL of acetonitrile, and 20 w / w% Pd / C (0.014 g) was added. The suspension was stirred at room temperature for 2 h under a H2 atmosphere. The mixture was filtered through a PTFE filter to minimize the compound's contact with air. Acetyl chloride (41 μL, 0.58 mmol) was then added to the solution under a N2 atmosphere, and the reaction mixture was stirred overnight. Finally, the solvent was removed under reduced pressure to give a pale yellow oil (34 mg, 30% yield).

[0691] 1 ¹H NMR (500MHz, CDCl₃): δ=2.13 (s, 3H, -CH₃), 2.14 (s, 3H, -CH₃), 4.65 (s, 2H, -CH₂-), 6.23 (s, 1H, -CH), 6.44 (s, 1H, -CH). MS calculated C 10 H 13 NO3: 195.2.

[0692] C) N , N ', N Synthesis of ''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}triacetamide (compound 177)

[0693] 3-Hydroxymethyl-2-hydroxy-5-methylphenylacetamide (0.017 g, 0.087 mmol) was dissolved in CH₂Cl₂ (2 mL) and triethylamine (159 μL, 0.013 g, 0.128 mmol) was added. Methanesulfonyl chloride (89 μL, 0.015 g, 0.131 mmol) was added at 0 °C (ice bath), and the reaction mixture was stirred at room temperature for 1 h. The product was extracted, the organic layer was washed with 3x H₂O, and the organic phase was dried over MgSO₄, filtered, and the solvent was removed under reduced pressure. This product was used without further purification. Therefore, a solution of methanesulfonate in 1 mL ACN was added dropwise to a solution of 1,4,7-triazacyclononane (1 mg, 0.01 mmol) and sodium carbonate (3 mg, 0.03 mmol) in 1 mL ACN. The reaction mixture was then stirred overnight at room temperature. The final compound was observed by ESI-MS (m / z): 661.4 (M+H + (Calculated value C) 29 H 39 N3O6: 660.8).

[0694] Example 9 - Thermodynamic Stability Analysis

[0695] To assess the thermodynamic stability of Fe(III) complexes formed from compounds of formula (I), the protonation constants of the ligands were first determined by pH-potential titration and / or by UV-Vis spectrophotometry, followed by the protonation constants of the corresponding Fe(III) complexes formed from said ligands. Finally, based on these protonation constants, the thermodynamic stability constants of the Fe(III) complexes were determined by monitoring the competitive reaction between the Fe(III) complexes and the N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) ligand using capillary zone electrophoresis (CZE) on compound 2 and UV-Vis spectrophotometry on compound 4. A similar method for assessing the thermodynamic stability of different metal complexes was performed in WO2020 / 099398. This example demonstrates the high affinity of compounds of formula (I) for Fe(III), thus proving the high thermodynamic stability of Fe(III)-complexes formed from compounds of formula (I). Complexes with high thermodynamic stability are not easily bound by competing endogenous metal ions (e.g., Cu). 2+ Zn 2+ and Ca 2+ The compounds of this invention undergo metal transfer and chelate transfer reactions with ligands (e.g., transferrin), thereby making it difficult for them to release Fe(III)- ions once they are coordinated, for example, in vivo. HBED is a ligand having the following formula that forms a complex with Fe(III):

[0696]

[0697] HBED

[0698] A) Determination of the protonation constant of ligands

[0699] Solid Fe(NO3)3 was dissolved in 0.1 M HNO3 solution. The concentration of the Fe(NO3)3 solution was determined by using an excess of standardized Na2H2EDTA. The excess of Na2H2EDTA was measured using standardized ZnCl2 solution and xylenol orange as indicators. The H2O concentration of the Fe(NO3)3 solution was... + Concentrations were determined by pH potentiometric titration in the presence of Na₂H₂EDTA in excess. The concentrations of ligands 2, 4, H₃NOTA (reference – see formula below), and H₄HBED (reference) were determined in the presence and absence of 40-fold excess Ca. 2+ In this case, the pH is determined by potentiometric titration. pH potentiometric titration is performed using standardized 0.2M NaOH (the ligand concentration is typically 0.002M). For pH measurement and titration, a Metrohm 888 Titrando titration workstation with a Metrohm-6.0234.110 combination electrode is used.

[0700]

[0701] H3NOTA (Reference)

[0702] The protonation constants (Ka) of compounds 2, NOA (reference), and HBED (reference) obtained by the above pH potentiometric titration method are... i H =[H i [ligand] / ([H] i-1 [ligand]x[H + It was later used to determine the protonation constant and thermodynamic stability of the corresponding Fe(III) complexes.

[0703] The protonation constant of compound 2 was analyzed by UV-Vis spectrophotometry (using instrumentation). PerkinElmer Lambda 365 The assay was confirmed using a UV-Vis spectrophotometer in the wavelength range of 210–390 nm ([Compound 2] = 87 μm, 0.15 M NaClO4, 25 °C). The phenolic-OH and isoserine-NH2 groups of Compound 2 were investigated by spectrophotometry at 243 and 303 nm, monitoring the absorbance values ​​at these wavelengths along the absorption bands of the aromatic groups of the ligands. + Deprotonation of the group. The absorbance of the ligand is a combination of the absorbance of each protonated substance and is expressed by the following formula (Beck, MT). et al. , Chemistry of Complex Equilibria, Akadémia Kiadó Budapest and Nostrand Reinhold Company Ltd. London, 1990):

[0704]

[0705] Where A is the absorbance at a given wavelength, and c i , ε i and l represent the concentration of the substance, the molar absorptivity, and the optical path length of the cuvette, respectively. The absorbance value (A) has been fitted to the above formula (the concentrations of different protonated ligands have been determined by the protonation constant). K i H express).

[0706] The protonation constant of compound 4 was determined using a Bruker Avance III (9.4T) spectrometer. 1 The H-NMR spectroscopy measurements were performed using a Bruker variable temperature unit (BVT), a Bruker cooling unit (BCU), and a BB inverse z-gradient probe (5 mm). The measurements were performed by recording the chemical shift changes of unstable protons in 0.15 M NaNO3 solution at 25 °C as a function of pH. Since protonation / deprotonation is rapid on the NMR timescale, the observed chemical shifts of the signal represent a weighted average of the shifts of different substances with different protonation states, expressed by the following formula (JLSudmeier, CN Reilley, Anal. Chem. 1964, 36, 1698-1706):

[0707]

[0708] Where δ H(obs) It is the chemical shift of the observed given signal, c i and δ H HiL These are the concentrations and chemical shifts of the substances involved. The observed chemical shift values ​​(δ) have been... H(obs) The formula above was fitted (the concentrations of different protonated ligands were determined by the protonation constant). K i H express).

[0709] B) Determination of the protonation constant of Fe(III) complexes

[0710] The protonation constants (Ka) of the Fe(III) complexes of compounds 2, 4, NOTA (reference), and HBED (reference) were determined by pH potentiometric titration and / or spectrophotometry. Mhi配体 =[MH i [ligand] / ([MH] i-1 [ligand]x[H + ])).

[0711] Specifically, the protonation constants of the Fe(NOTA) and Fe(HBED) complexes were determined using pH-potential titration by titrating the pre-prepared complexes from pH 1.7 to pH 12.0 ([FeL] = 0.002 M) with 0.2 M NaOH. For pH measurement and titration, [the following method was used]. Metrohm 888 Titrando A Metrohm-6.0234.110 titration workstation with a combined electrode was used. Equilibrium measurements were performed in 6 ml of sample at 25°C under constant ionic strength (0.15 M NaNO3 or NaClO4). The solution was stirred and N2 was bubbled into it. Titrations were performed within a pH range of 1.7–12.0. KH-phthalate (pH=4.005) and borax (pH=9.177) buffer solutions were used to calibrate the pH meter. [H+] was calculated from the measured pH value. + The following uses Irving et al Anal.Chim. Acta , 1967, 38 The method disclosed in 475-488 involves titrating a 0.01 M HNO3 or HClO4 solution with a standardized NaOH solution of 0.15 M NaNO3 ionic strength. The measured pH value is... read ) and calculated pH(-log[H + The difference between the values ​​( A Used to obtain equilibrium H from pH values ​​measured in titration experiments. + Concentration (A = 0.02 for 0.15 M NaNO3, 0.01 for 0.15 M NaClO4). For equilibrium calculations, the stoichiometric water ion product is also required ( pK w To calculate [OH] under alkaline conditions - Value. The V obtained by titration of HNO3-NaOH within the pH range of 10.5-12.0. NaOH -pH read Data pairs are used to calculate p K w value (p) K w =13.76).

[0712] According to the method disclosed in Example 9A above, the protonation constants of the Fe(compound 2) and Fe(compound 4) complexes were determined by UV spectrophotometry in the wavelength range of 210-700 nm ([Fe(compound 2)] = 43 μM, [Fe(compound 4)] = 100 μM, 0.15 M NaClO4, 25 °C).

[0713] The thermodynamic stability of the same Fe(III) complexes was then determined using the protonation constants of Fe(III) complexes of compounds 2, 4, NOTA (reference), and HBED (reference).

[0714] C) Determination of the thermodynamic stability of Fe(III) complexes

[0715] Thermodynamic stability constant (K) of Fe(III) complexes M配体 =([M ligand] / ([M]x[ligand])) is determined as follows.

[0716] The stability constant of Fe(NOTA) complexes is obtained through Fe 3+ The determination was performed using UV-Vis spectrophotometry on the -NOTA system, and the determination was carried out in Fe III The absorption band of the complex is in [H + The experiment was conducted at 0.01-3.0 M in the wavelength range of 350-800 nm. (Fe) 3+ The concentration of NOA was 0.002 M. The H+ in the sample was adjusted by adding a calculated amount of 6 M HNO3 solution. + Concentration is adjusted (I=[Na) + ]+[H + ]=0.15, [H + [≤0.15M]. Samples were stored at 25°C for two weeks. The absorbance of the samples was measured at 11 wavelengths (370, 380, 390, 395, 400, 405, 410, 415, 420, 425, and 430 nm). To calculate the thermodynamic stability constant of Fe(NOTA), the absorbance was recorded at 1.0 x 10⁻⁶ nm. -3 1.5x10 -3 2.0x10 -3 and 2.5x10 -3 M of Fe 3+ The spectra of Fe(NOTA) solution and Fe(NOTA) solution were used to determine Fe 3+The molar absorptivity of Fe(NOTA) was determined. Absorption spectra of Fe(NOTA) solutions were recorded within a pH range of 1.7–7.5. All spectrophotometric measurements were performed at 25 °C in 0.15 M NaNO3 solution. pH was adjusted by stepwise addition of concentrated NaOH or HNO3 solution.

[0717] By monitoring the Fe-related interactions between HBED and Nota ligands 3+ The stability constant of Fe(HBED) complexes was determined by competitive reactions of -ions using spectrophotometry at the absorption bands of Fe(HBED) complexes in the wavelength range of 400-700 nm. For Fe 3+ The -HBED-NOTA system was used to prepare six samples in 0.15 M NaNO3 solution, among which [Fe 3+ The concentrations of [Fe(HBED)] were 0.1 mM, [HBED] was 0.2 mM, and [NOTA] was 0.0, 2.0, 4.0, 6.0, 8.0, and 10.0 mM. The pH of the sample was adjusted to 5.0 by stepwise addition of concentrated NaOH and HNO3 solutions. The sample was stored at 25°C for four weeks to reach equilibrium. The time required to reach equilibrium was determined spectrophotometrically. The absorbance of the sample was measured at the absorption band of the Fe(HBED) complex (at pH 5.0, [Fe(HBED)]). - (Material dominance). To calculate the thermodynamic stability constant of the Fe(HBED) complex, [Fe(HBED)] was recorded in the presence of 0.15 M NaNO3 at pH=5. - The spectra of 0.5, 0.1, and 0.2 mM solutions were used to determine [Fe(HBED)]. - The molar absorptivity of a substance. (Used) PerkinElmer Lambda 365 A UV-Vis spectrophotometer was used for spectrophotometric measurements with a 1.0 cm cuvette. Thermodynamic stability constants were calculated using the PSEQUAD program. (L. Zékány) et al. , Computational Method for Determination of Formation Constants, Ed.Legett DJ, Plenum, New York, 1985, p. 291.)

[0718] By monitoring the Fe-related interactions between compound 2 and HBED ligand 3+The thermodynamic stability constant of the Fe(compound 2) complex was determined by competitive reactions of -ions, using capillary zone electrophoresis (CZE) to monitor the signal of the Fe(compound 2) complex. A bare fused silica capillary (Agilent) measuring 64 cm x 50 μm id was used. Agilent 7100 CZE separation was performed using a capillary electrophoresis system. Before the first use of the capillary, the sample solution was washed with 1.0 M NaOH (15 min), followed by washing with 0.1 M NaOH (30 min) and then with a buffered electrolyte (30 min). All buffers were filtered through a 0.45 μm syringe filter and stored at +4 °C before CZE analysis. In CZE, the sample solution was introduced into the anode of the capillary in normal mode (50 mbar, 20 s). The effective length of the capillary was 56 cm. The capillary was pretreated with a buffered electrolyte (150 mM sodium bicarbonate, pH 8.2) for 3 min. Separation was performed at 37 °C with a voltage of 30 kV. After analysis, post-treatment (0.1 M NaOH (3 min) and buffer (3 min)) was performed to remove any potentially adsorbed substances from the capillary. In all measurements, 5 mM DMSO was used as an internal standard to correct for the migration time of components on the electrophoresis pattern. Detection was performed by on-column DAD measurement at 500 nm. Electrophoresis plots were recorded and processed using ChemStation computer program (Agilent) version B.04.02. For equilibrium calculations, the molar integral value of Fe(compound 2) was used. The molar integral value of Fe(compound 2) was determined by recording electrophoresis plots of 22, 44, and 87 μM Fe(compound 2) solutions at pH 6.0 and in the presence of 0.15 M NaNO3 at 25 °C. Individual linear regression equations (response-concentration) for Fe(compound 2) were determined based on the three concentrations. A linear relationship (R² > 0.998) was found in the peak area over the 22–87 μM concentration range, with a precision better than 4%. The LOD and molar integral values ​​were found to be 2.7 μM and 133294 mAU, respectively. -1 M -1 (LOD = 3σ / molar integral).

[0719] For Fe 3+ Five samples were prepared in the compound 2-HBED system in 0.15 M NaNO3 solution, with [Fe(compound 2)] = 87 μM and [HBED] = 0.0, 4.0, 16.0, 30.0, and 50.0 mM. The pH of the samples was adjusted to 11.0 by stepwise addition of concentrated NaOH and HNO3 solutions. The samples were stored at 25 °C for four weeks to reach equilibration. The time required to reach equilibration was determined by CZE studies. The amount of Fe(compound 2) complex was determined based on the interaction between compound 2 and HBED. 3+- The competitive reaction of ions reduces (Formula 1). No signals of negatively charged Fe(HBED) and compound 2 ligands were observed in the electrophoresis diagram.

[0720]

[0721] Formula 1

[0722] in α H = K 1 H [H + ]+ K 1 H K 2 H [H + ] 2 +…+ K 1 H K 2 H … K n H [H + ] n and K 1 H , K 2 H ,… K n H It is the protonation constant of the free ligand determined in Example 9A, while α Fe(Cpd2) = K FeHL [H + ]+ K FeHL K FeH2L [H + ] 2 + K FeHL K FeH2L K FeH3L [H + ] 3 It is the protonation constant of the Fe(compound 2) complex measured in 0.15M NaNO3 solution at 25°C in Example 9B (Fe(HBED) substance is dominant in 0.15M NaNO3 at 25°C and pH=11).

[0723] By considering the molar integral values ​​of the Fe(compound 2) complex obtained by recording electrophoresis patterns of 22, 44, and 87 μM Fe(compound 2) solutions, and HBED([HBED]), tot =[Hx HBED]+[Fe(HBED)]), Fe 3+ Ions ([Fe) 3+ ] tot =[Fe(H z Compound 2]+[Fe(HBED)] and Compound 2([Compound 2]) tot =[Fe(H z Compound 2)]+[H y The total concentration of compound 2) was found to be... K FeNB The value is (3.5±0.2)x10 -4 By considering the stability constant (log) of Fe(HBED) K Fe(HBED) =40.2, 0.15M NaNO3, 25℃), the protonation constants of compound 2 and HBED ligands, and the protonation constant of the Fe (compound 2) complex (Table 1, 25℃, 0.15M NaNO3), were found to be log 40.2, 0.15M NaNO3, 25℃. The thermodynamic stability constant of the Fe (compound 2) complex in 0.15M NaNO3 solution at 25℃ was log 40.2, 0.15M NaNO3, 25℃. K Fe(化合物2) =44.0 (3).

[0724] By monitoring the Fe-related interactions between compound 4 and HBED ligand. 3+ The stability constant of the Fe(compound 4) complex was determined by competitive reactions of -ions using spectrophotometry at the absorption bands of the Fe(compound 4) and Fe(HBED) complexes in the wavelength range of 400-700 nm. For Fe 3+ The compound 4-HBED system was used to prepare six samples in 0.15 M NaNO3 solution, among which [Fe 3+ [Compound 4] = 0.1 mM, and [HBED] = 0.0, 0.05, 0.1, 0.2, 0.4, 0.5, 1.0, and 2.0 mM, respectively. The pH of the samples was adjusted to 12.0 by gradually adding concentrated NaOH and HNO3 solutions. The samples were stored at 25°C for four weeks to reach equilibrium. The time required to reach equilibrium was determined spectrophotometrically. The absorbance values ​​of the samples were measured at the absorption bands of the Fe(Compound 4) and Fe(HBED) complexes (at pH = 12.0, [Fe(Compound 4)H⁻¹], [Fe(HBED)]). - and [Fe(HBED)H -1 ] 2-(Material dominance). To calculate the thermodynamic stability constants of the Fe(compound 4) complexes, [Fe(compound 4)] and [Fe(HBED)] were recorded in the presence of 0.15 M NaNO3 within a pH range of 7.0–12.5. - The spectra of 0.5, 0.1, and 0.2 mM solutions were used to determine the [Fe(compound 4)H] content. -1 ], [Fe(HBED)] - and [Fe(HBED)H -1 ] 2- The molar absorptivity of a substance. (Used) PerkinElmer Lambda 365 Spectrophotometric measurements were performed using a UV-Vis spectrophotometer with a 1.0 cm cuvette. Thermodynamic stability constants (L. Zékány) were calculated using the PSEQUAD program. et al. , Computational Method for Determination of Formation Constants, Ed.Legett DJ, Plenum, New York, 1985, p. 291).

[0725] D) Protonation constant and thermodynamic stability of Fe(III) complexes

[0726] The thermodynamic stability and protonation constants (determined from the experiments described above) of the Fe(III)-complexes of compounds 2 and 4, as well as the reference iron complexes Nota and HBED, are summarized in Table 1 below.

[0727]

[0728] Table 1

[0729] a Capillary zone electrophoresis (0.15M NaNO3, 25℃) b Spectrophotometry (0.15M NaClO4, 25℃) c Spectrophotometry (0.15M NaNO3, 25℃) d Reference compounds were used to determine the thermodynamic stability of the Fe(III)-complexes of H4HBED, compound 2, and / or compound 4.

[0730] At pH 7.4, at 1 μM Fe 3+ In the presence of a 10 μM ligand, the pFe values ​​of Fe (compound 2) and Fe (compound 4) were calculated (pFe = -log[Fe...]). 3+ ] 游离 , [Fe 3+ ]tot =1μM, [L] tot =10μM, pH=7.4.; S. Hajela et al. , J.Am. Chem. Soc . , 2000, 122, 11228-11229).

[0731] For comparison, this article reports the thermodynamic and conditional stability ([Fe2+]) of commercially available drugs DFO, DFP, and DFX. 3+ ] tot =1μM, [L] tot =10μM, pH=7.4, where [L] tot (This refers to the total concentration of free commercially available drugs):

[0732] - Fe(DFO): log K FeL =30.4, log K FeHL =10.61, 0.2M KCl, 25℃, such as E. Farkas, Polyhedron The value reported in 1999, 18, 2391-2398; pFe=26.51;

[0733] - Fe(DFP)3: log K FeL =15.11, log K FeL2 =11.51, log K FeL3 =9.27, 0.1M KCl, 25℃, as reported by R. Ma, Inorganica Chimica Acta, 1994, 223, 21-29; pFe = 19.31; and

[0734] - Fe(DFX)2: log K FeL =22.00, log K FeL2 =14.9, 0.1M KCl, 25℃, as reported by S. Steinhauser, Eur. J. Inorg. Chem. 2004, 4177-4192; pFe=23.47.

[0735] Based on the pFe values, as can be observed from the data in Table 1, Fe (compound 2) exhibits the highest thermodynamic stability, confirming the in vivo safety of the Fe(III) complex formed with compound (I) (compound 2); this high thermodynamic stability is even higher than that of the comparative iron complexes formed by the commercially available drugs DFO, DFP, and DFX. Based on the pFe values, Fe (compound 4) also shows very high thermodynamic stability; this value is higher than the pFe values ​​of the comparative iron complexes of DFP and DFX, and comparable to the pFe value of the comparative iron complex of DFO.

[0736] This embodiment demonstrates that compounds of formula (I) have a high affinity for Fe(III), and therefore Fe(III)-complexes formed from such compounds are not easily bound by competing endogenous metal ions (e.g., Cu). 2+ Zn 2+ and Ca 2+ The compound undergoes metal transfer and chelate transfer reactions with ligands (e.g., transferrin). Therefore, once the compound of the present invention is coordinated with Fe(III)- ions in vivo, it is not easily released, especially under physiological conditions, and the Fe(III)- complex thus formed can be excreted as is, and the iron ions can be successfully removed from the body.

[0737] Example 10 - Dynamic Inertia Analysis

[0738] To obtain data relating to the kinetic inertness of the Fe(III) complexes formed from compounds (compounds 2 and 4) of formula (I) (Fe(compound 2) and Fe(compound 4) respectively), the chelate transfer reaction was studied by UV-VIS spectrophotometry (for Fe(compound 4)) and by capillary zone electrophoresis (CZE) (for Fe(compound 2)) in the presence of a large excess of HBED as an exchange ligand (as shown below) (Fe(compound 2): [Fe(compound 2)] = 87 μM, [HBED] = 0.1 and 0.2 M, 1.0 M NaClO4, 25 °C; Fe(compound 4): [Fe(compound 4)] = 100 μM, [HBED] = 0.002 and 0.02 M, 0.15 M NaNO3, 25 °C) to ensure pseudo-first-order kinetic conditions.

[0739]

[0740] Where L = compound 2 or compound 4. This example aims to demonstrate that the Fe(III) complexes formed from compounds of formula (I) are highly kinetically inert, and thus the dissociation of such Fe(III) complexes hardly occurs under physiological conditions.

[0741] A) Determination of the kinetic inertness of Fe(III) complexes

[0742] The chelation transfer reaction of Fe (compound 4) was studied by spectrophotometry. PerkinElmer Lambda 365 The formation of the Fe(HBED) complex at 472 nm was monitored using a UV-Vis spectrophotometer. The concentration of the Fe(compound 4) complex was 0.1 mM, while the concentration of HBED was 10-200 times higher to ensure pseudo-first-order conditions. The temperature was maintained at 25 °C, and the ionic strength of the solution was kept constant, with 0.15 M NaNO3. The exchange rate was studied in a pH range of approximately 9.5-14.0. Buffer solutions were not used because excess HBED could maintain a constant pH at pH < 12. At pH > 12, the OH- concentration in the sample was adjusted by adding a calculated amount of 19 M NaOH (I = [NaNO3] + [NaOH] = 0.15, [NaOH] ≤ 0.15 M). - Concentration. The pseudo-first-order rate constant was calculated by fitting absorbance-time data to Equation 2. k d ).

[0743] Formula 2

[0744] in A t , A 0 and A p These represent time t, the absorbance values ​​at the start of the reaction, and the equilibrium point, respectively.

[0745] The ligand exchange reactions of the Fe(compound 2)-HBED reaction system were studied by capillary zone electrophoresis (CZE) in the pH range of 9.5–11.5. Agilent 7100 The chelate transfer reaction of Fe(compound 2) was studied by monitoring the dissociation of the Fe(compound 2) complex using a capillary electrophoresis system (under the same conditions as the CZE experiment in Example 9). The concentration of the Fe(compound 2) complex was 87 μM, while the concentrations of HBED were 0.1 and 0.2 M to ensure pseudo-first-order conditions. The temperature was maintained at 25 °C, and the ionic strength of the solution was kept constant, with NaClO4 at 1.0 M. The pseudo-first-order rate constant was calculated by fitting the area-time data to Equation 2 above. k d ),in A t , A 0 and A p These represent time t, the area at the start of the reaction, and the area at equilibrium, respectively.

[0746] use Micromath Scientist The calculations were performed using a computer program (version 2.0, Salt Lake City, UT, USA).

[0747] B) Kinetic inertness of Fe(III) complexes

[0748] The kinetic inertness results of the Fe(III)-complexes of compounds 2 and 4 (in terms of dissociation rate constants) k d and half-life t 1 / 2 The following is a summary in Table 2.

[0749]

[0750] Table 2

[0751] The dissociation half-life of Fe(III)-compound 2 and Fe(III)-compound 4 complexes ( t 1 / 2 =ln(2) / k d The shelf life is approximately 11.3 years and 0.65 years, close to physiological conditions (pH=7.4, 25°C), which could be an indication of their safe application in vivo.

[0752] In comparison, the chelation transfer reactions of iron complexes (i.e., Fe(DFO) and Fe(DFP)3) formed with commercially available drugs DFO and DFP with EDTA as an exchange ligand occurred in 250 min and 120 sec, respectively ([FeHDFO] = 0.4 mM, [EDTA] = 10 mM; [FeHDFO] = 0.4 mM, [EDTA] = 10 mM; [FeHDFO] = 0.4 mM, [EDTA] = 10 mM, ... 3+ [H(DFP)] = 0.20 mM, [EDTA] = 5.0 mM; 0.10 M NaClO4, pH = 4.35 (50 mM NaOAc buffer), 25 °C, as reported in James M. Harrington, Dalton Trans., 2018, 47, 6954-6964). Furthermore, kinetic studies of solvent decomposition and dissociation revealed that the iron complex of DFX (i.e., Fe(DFX)2) also exhibits low kinetic inertness. k d =2.67x10 -4 s -1 , t 1 / 2 =ln2 / k d=43.3 min, pH=7.4, 25℃ (as reported by R. Suzuki, Journal of Inorganic Biochemistry, 2023, 241, 112131).

[0753] Table 2 shows that the Fe(III) complexes formed from compounds of formula (I) have an unusually high half-life. t 1 / 2 Furthermore, considering the data provided in Table 2 and the data in the aforementioned literature, it can be demonstrated that the iron complex formed by the compound of formula (I) has a longer half-life compared to the commercially available drugs DFO, DFP, and DFX (250 min, 120 seconds, and 43.3 min, respectively). t 1 / 2 (Approximately 11.3 years for Fe(III)-compound 2 and 0.65 years for Fe(III)-compound 4). Therefore, this example demonstrates that the Fe(III) complexes formed from compounds of formula (I) exhibit almost no dissociation, particularly under physiological conditions, and even less dissociation compared to iron complexes formed from commercially available drugs DFO, DFP, and DFX. This ensures the effective removal of accumulated iron ions upon administration of compounds of formula (I).

[0754] Example 11 - Transferrin Competitive Reaction

[0755] Transferrin is a type of iron (Fe) present in body fluids. 3+ -Binding transport proteins, due to their affinity for Fe... 3+ High affinity (log K FeTf =21.44, log K Fe2Tf =20.34, for human serum transferrin (WR Harris, Y. Chen, K. Wein, Inorg . Chem. , 1994, 33 , 4991) and its conditional stability for the binding of Fe(III) ions (pFe = 22.4, [Fe 3+ [Tf] = 1 μM, [Tf] = 10 μM, pH = 7.4), which represents an in vivo competitor to iron chelators. This is because serum transferrin is typically only 30% bound to Fe. 3+ Saturation, it retains a relatively high level of bound Fe released from other Fe(III)- complexes. 3+ The ability, and even promote Fe 3+ Release from Fe(III)- complexes, thereby promoting the dissociation of such Fe(III)- complexes.

[0756] A) Chelating transfer reaction between Fe(III)-complex and transferrin

[0757] To investigate the possible role of transferrin in the dissociation of the Fe(III)-complex formed from compound (I), 22.6% Fe... 3+ The reaction of saturated human serum transferrin (sTf, Sigma) with complexes of Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61 was measured by monitoring Fe 3+ The possible formation of saturated human serum transferrin and the possible dissociation of Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60, and Fe(III)-compound 61 complexes were investigated. The Fe... 3+ Saturation such as Z. Baranyai, F. Uggeri, A. Maiocchi, GB Giovenzana, C.Cavallotti, A. Takács, I. Tóth, I. Bányai, E. Brücher, S. Aime, Eur . J . Inorg . Chem The determination was performed as disclosed in (2013, 147-162); due to the Fe of sTf 3+ The binding requires the co-binding of a co-anion, which in vivo is bicarbonate (GW Bates, MR Schlabach, ...). J . Biol . Chem., 1975, 250 (2177-2181), all measurements were performed at pH 7.4 and 25°C in the presence of 25 mM NaHCO3. This is because the Fe(III)- complex and Fe... 3+ The molar absorptivity of human serum transferrin varies among Fe(III)-compounds 2, 4, 57, 60, and 61, and is associated with 22.6% Fe. 3+ Possible metal exchange reactions of saturated human serum transferrin were monitored by tracking the final dissociation of the complexes of Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61, as well as Fe...3+ The formation of saturated human serum transferrin was determined by spectrophotometry in the 400-700 nm wavelength range in the presence of equimolar human transferrin using a PerkinElmer Lambda 365 UV-Vis spectrophotometer. The complexes of Fe(III) compounds 2, 4, 57, 60, and 61, and 22.6% Fe... 3+ The concentration of saturated human serum transferrin was 0.1 mM. The temperature was maintained at 25°C, and the ionic strength of the solution was kept constant (0.15 M NaCl). The pH of the sample was adjusted by gradually adding concentrated NaOH and HCl solutions.

[0758] The absorption spectra of the Fe(III)-compound 2-human serum transferrin, Fe(III)-compound 4-human serum transferrin, Fe(III)-compound 57-human serum transferrin, Fe(III)-compound 60-human serum transferrin, and Fe(III)-compound 61-human serum transferrin reaction systems remained unchanged over a reaction time of 1100 min. This indicates that the Fe(III)-complexes formed by compounds 2, 4, 57, 60, and 61 possess very high kinetic inertness and / or higher conditional stability compared to the Fe(III)-complexes of sTf. In fact, the complexes of this invention remain stable even at 22.6% Fe... 3+ Even in the presence of saturated sTf (i.e., near-physiological conditions, namely pH 7.4, 25°C, 25 mM NaHCO3, 0.15 M NaCl), dissociation did not occur. This further demonstrates the high kinetic inertness and / or thermodynamic stability of the compounds of the present invention, such as Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60, and Fe(III)-compound 61, when coordinated with Fe(III).

[0759] B) Chelation transfer reaction between Fe2(sTf) complex and compounds 2 and 4

[0760] To investigate the therapeutic efficacy of compounds 2 and 4 as iron chelators, the kinetics of iron removal from human diferritin (Fe2(sTf)) by compounds of formula (I) (compounds 2 and 4) were monitored. The formation of Fe(III)-compound 2 and Fe(III)-compound 4 complexes was monitored spectrophotometrically after the addition of uncoordinated compounds 2 and 4 to Fe2(sTf) solutions under near-physiological conditions (pH = 7.4, 25°C, 25 mM NaHCO3, 0.15 M NaCl). The rates of metal exchange reactions between Fe2(sTf) and compounds 2 and 4 were determined as follows: in two reaction systems (first reaction system: [Fe2(sTf)] = 0.05 mM, [compound 2] = 0.08 mM; second reaction system: [Fe2(sTf)] = [compound 4] = 0.1 mM), the rates were determined by using… PerkinElmer Lambda 365 The formation of Fe(III)-compounds 2 and 4 was monitored by UV-Vis spectrophotometry at 467 nm on the absorption bands of the resulting Fe(III)-compounds 2 and 4. The temperature was maintained at 25 °C, and the ionic strength of the solution was kept constant (0.15 M NaCl). The reaction was monitored in the presence of 25 mM NaHCO3. The pH of the sample was adjusted by stepwise addition of concentrated NaOH and HCl solutions. The absorption spectra of the Fe2(sTf)-compounds 2 and 4 reaction systems showed an increase in absorbance as a function of time in the 400–650 nm wavelength range, indicating the formation of Fe(III)-complexes of compounds 2 and 4. Therefore, the competitive reaction between Fe2(sTf) and either compound 2 or compound 4 favors the latter two, due to the higher conditional stability constants of Fe(III)-compounds 2 and 4 compared to the Fe(III)-complexes of sTf. Furthermore, the formation of Fe(III)-compound 2 and Fe(III)-compound 4 was observed to be completed within 200 min from the absorption spectrum. This experiment demonstrates that the compound of formula (I) can be effectively used to treat or prevent diseases caused by excess and / or accumulation of iron ions, such as iron poisoning and / or iron overload, because it can bind with iron ions, especially Fe... 3+ Ions form complexes. This can happen even when such iron ions are already coordinated with endogenous proteins such as human serum transferrin. Therefore, once administered, compounds of formula (I) can react with excess and / or accumulated iron ions, particularly Fe. 3+ The ions form complexes and are then excreted as iron complexes, thereby effectively reducing excess and / or accumulated iron ions.

[0761] C) Fe2(sTf) complexes with compounds 2 and 4 in large amounts of Ca 2+ Chelation transfer reaction in excess

[0762] A similar experiment to Example 11B was conducted, however this time in the presence of a large excess of Ca. 2+ The reaction was carried out under ionic conditions, where the latter acted as a reaction between the analyte and Fe. 3+ The role of coordination competitors. By adding the Ca(II) complex of compound 2 to near physiological conditions ([Ca... 2+ In a Fe2(sTf) solution containing [compound 2] = 2.5 mM, pH = 7.4, 25℃, 25 mM NaHCO3, 0.15 M NaCl, the formation of the Fe(III)-compound 2 complex was monitored spectrophotometrically, thereby monitoring the Ca(II) complex of compound 2 (by using [compound 2] = 0.08 mM and [Ca... 2+ (Prepared by adding 2.5 mM to an aqueous solution of 25 mM NaHCO3 and 0.15 M NaCl at pH 7.4 and 25 °C) Kinetics of iron removal from human ferric-transferrin Fe2(sTf). The study investigated the effects of equimolar amounts of Fe2(sTf) and the Ca(II) complex of compound 2, along with a significant amount of Ca... 2+ In the presence of excess ([Fe2(sTf)] = 0.05 mM, [compound 2] = 0.08 mM and [Ca...),... 2+ ]=2.5mM─The latter reflects Ca 2+ The total concentration in body fluids, as mentioned in PM May, J. Chem. Soc. Dalton Trans. 1977, 588-595, is determined by the use of... PerkinElmer Lambda The formation of Fe(III)-compound 2 was monitored spectrophotometrically at 467 nm on the absorption band of the resulting Fe(III)-compound 2 using a 365 UV-Vis spectrophotometer to determine the rate of the metal exchange reaction between Fe2(sTf) and the Ca(II) complex of compound 2. The temperature was maintained at 37 °C, and the ionic strength of the solution was kept constant (0.15 M NaCl). The reaction was monitored in the presence of 25 mM NaHCO3. The pH of the sample was adjusted by stepwise addition of concentrated NaOH and HCl solutions. The absorption spectra of the Fe2(sTf)-Ca(II)-compound 2 reaction system showed that the absorbance increased as a function of time in the wavelength range of 400–650 nm. The spectral changes in the Fe2(sTf)-compound 2 Ca(II) complex and the Fe2(sTf)-compound 2 (Example 11B) reaction system are very similar, which means that the Fe(III)-complex of compound 2 is even formed through a competitive reaction between Fe2(sTf) and the Ca(II) complex of compound 2, even at 50 times the Ca 2+ In the presence of excess ions (compared to compound 2), this demonstrates the high selectivity of the compounds of the present invention for Fe(III), for example, for Fe... 3+ The high selectivity of Ca 2+ Even in large quantities of Ca 2+ Excessive presence.

[0763] Example 12 - Redox Stability Analysis

[0764] To characterize the redox stability of the Fe(III) complexes formed from compounds of formula (I), ascorbic acid was reacted with Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60, and Fe(III)-compound 61 and Fe(III)(NOTA) (comparative) in the presence of a large amount of ascorbic acid in excess ([Fe(III)(NOTA)] = 2.0 mM, [Fe(III)-compound 2] = 25 μm, [Fe(III)-compound 4] = 100 μm, [Fe(III)-compound 57] = 25 μm, [Fe(III)-compound 60] = 100 μm, [Fe(III)-compound 61] = 100 μm, [ascorbic acid] = 20 mM, pH = 7.4, [HEPES] = 0.01 M, 0.15 M The study was conducted by a spectrophotometric method using NaNO3 (25℃) to monitor the reduction of Fe(III)-complexes, as shown below.

[0765] A) Determination of the redox stability of Fe(III) complexes

[0766] The redox stability of Fe(III)(NOTA), Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61 was characterized as follows: their reduction rates with ascorbic acid were assessed by spectrophotometry, and the formation of Fe(II)-ligand complexes was monitored using a PerkinElmer Lambda 365 UV-Vis spectrophotometer at 375 nm for Fe(III)(NOTA), 480 nm for Fe(III)-compound 2 and Fe(III)-compound 57, 471 nm for Fe(III)-compound 4, and 500 nm for Fe(III)-compound 60 and Fe(III)-compound 61. The concentrations of the Fe(III)(NOTA) complexes, Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60, and Fe(III)-compound 61, were 2.0 mM, 25, 100, 25, 100, and 100 μM, respectively, while ascorbic acid was used in high excess ([ascorbic acid] = 20 mM) to ensure pseudo-first-order conditions. For the Fe(III)(NOTA) experiment, four times the excess of free Nota ligand was added as a scavenger to react with any possible Fe... 2+ Ion coordination, Fe 2 + The ions can be released from Fe(II)(NOTA) after its reduction from Fe(III)(NOTA) (Fe(II)NOTA has low stability, thus Fe...). 2+ (Ions can be released from such complexes). The temperature was maintained at 25°C, and the ionic strength of the solution was kept constant, with NaNO3 at 0.15 M. The reduction rate was studied at pH 7.4. To maintain a constant pH, HEPES buffer ([HEPES] = 0.01 M) was used. During sample preparation, air was bubbled through all solutions to maintain anaerobic conditions. The pseudo-first-order rate constant was calculated by fitting the absorbance-time data to Equation 2 using the Micromath Scientist computer program (version 2.0, Salt Lake City, UT, USA). k obs = k d ).

[0767] B) Redox stability data of Fe(III) complexes

[0768] The absorption spectra of the above experiments show that, for Fe(III)(NOTA), the absorbance value decreases as a function of time due to the reduction of Fe(III)(NOTA) by ascorbic acid, and in fact, the reduction half-life characterizing the ascorbic acid-mediated reduction of Fe(III)(NOTA) was found to be... t 1 / 2 =ln2 / k obs )for t 1 / 2 =2.7 min (as mentioned in section A above regarding excess ascorbic acid). Considering the in vivo concentration of ascorbic acid ([ascorbic acid] = 43 μm, PM May, DR Williams, PW Linder, J . Chem . Soc . Dalton Trans. (1977, 588-595) and taking into account that the reduction rate of Fe(III)-complexes is proportional to the concentration of ascorbic acid (Baranyai, Z.; Carniato, F.; Nucera, A.; Horváth, D.; Tei, L.; Platas-Iglesias, C.; Botta, M.). Chem . Sci 2021, 12 (11138-11145) It was found that the ascorbic acid-mediated reduction of Fe(III)(NOTA) under physiological conditions ([ascorbic acid] = 43 μM, pH = 7.4, 0.01 M HEPES, 0.15 M NaNO3, 25 °C) is [missing information]. t 1 / 2 =19.5h.

[0769] Further observation revealed that the absorbance values ​​of the Fe(III)-compound 4-ascorbic acid, Fe(III)-compound 60-ascorbic acid, and Fe(III)-compound 61-ascorbic acid reaction systems decreased slowly as a function of time; that is, even in the presence of a 200-fold excess of ascorbic acid, the absorbance values ​​decreased by 12%, 35%, and 40%, respectively, within one day. Based on this spectral change, the reduction of Fe(III)-compound 4, Fe(III)-compound 60, and Fe(III)-compound 61 to Fe(II)-compound 4, Fe(II)-compound 60, and Fe(II)-compound 61 appears to occur very slowly in the Fe(III)-compound 4-ascorbic acid, Fe(III)-compound 60-ascorbic acid, and Fe(III)-compound 61-ascorbic acid reaction systems. Considering the in vivo concentration of ascorbic acid ([ascorbic acid] = 43 μM) and the fact that the reduction rate of Fe(III)-complexes is proportional to the concentration of ascorbic acid, the reduction rates of Fe(III)-complexes 4, 60, and 61 mediated by ascorbic acid under physiological conditions ([ascorbic acid] = 43 μM, pH = 7.4, 0.01 M HEPES, 0.15 M NaNO3, 25 °C) were respectively t 1 / 2 =3.5x10 3 1.6x10 3 and 3.0x10 3 h. These t 1 / 2 The value can indicate the Fe of the Fe(III)-complex formed by the compound of formula (I). 3+ It is hardly reduced to Fe in the body. 2+ (Fenton reaction), thereby reducing or avoiding the formation of toxic free radicals such as OH·. Therefore, this points to the potential safe and effective in vivo application of compounds of formula (I).

[0770] Furthermore, the absorption spectra of the Fe(III)-compound 2-ascorbic acid and Fe(III)-compound 57-ascorbic acid reaction system remained unchanged over a 1-day reaction period. This can be explained by the high selectivity of compounds 2 and 57 for Fe(III)-ions compared to Fe(II)-ions (ΔpFe>16); in other words, iron preferably remains in the +3 oxidation state rather than being reduced to +2, even in the presence of a large excess of ascorbic acid (reducing agent) when coordinated with compounds 2 and 57. Moreover, this could be an indication of the safe and effective in vivo application of the Fe(III)-complexes formed from compounds of formula (I).

Claims

1. Compound of formula (I): Equation (I) in: n, m, and o are integers independently selected from 1 and 2; Y 1 and Y 2 Independently selected from hydrogen and C1-C4-alkyl; R 1 and R 2 Independently selected from hydrogen and C1-C4-alkyl; L 1 and L 2 Independently selected from C1-C4-alkylamino, C1-C4-alkylamide and C1-C4-alkyl ether; Z 1 and Z 2 Independently selected from hydrogen and C1-C6-alkyl, wherein the C1-C6-alkyl is optionally substituted by one or more groups selected from hydroxyl (-OH), carboxyl (-COOH) and phosphonate (-PO3H2); R is selected from hydrogen, C1-C4 alkyl groups optionally substituted with aryl groups, and the part of formula (IA): Formula (IA) Among them: asterisk ( ) represents the connection point between a portion of formula (IA) and a nitrogen atom with an R group; Y 3 Having the above for Y 1 and Y 2 The same meaning provided; R 3 Having the above for R 1 and R 2 The same meaning provided; L 3 Having the above for L 1 and L 2 The same meaning provided; and Z 3 Having the above for Z 1 and Z 2 The same meaning provided; Or, an ion thereof, or a stereoisomer thereof, or a tautomer thereof, or a hydrate thereof, or a solvate thereof, forming a pharmaceutically acceptable complex with a metal ion, provided that said metal ion is not an iron ion, or a pharmaceutically acceptable salt thereof, or a mixture thereof, for use as a medicine.

2. The compound according to claim 1, wherein Y 1 and Y 2 and Y 3 (If present), independently selected from hydrogen and C1-C3-alkyl; preferably hydrogen and C1-C2-alkyl; more preferably hydrogen and C1-alkyl; and even more preferably hydrogen.

3. The compound according to claim 1 or 2, wherein R 1 R 2 , and R 3 (If present), independently selected from hydrogen and C1-C3-alkyl; preferably hydrogen and C1-C2-alkyl; more preferably hydrogen and C1-alkyl; and even more preferably methyl (-CH3).

4. The compound according to any one of claims 1 to 3, wherein L 1 L 2 , and L 3 (If present), independently selected from C1-C3-alkylamino, C1-C3-alkylamide and C1-C3-alkyl ether; preferably C1-C2-alkylamino, C1-C2-alkylamide and C1-C2-alkyl ether; and more preferably C1-alkylamino, C1-alkylamide and C1-alkyl ether.

5. The compound according to claim 4, wherein L 1 L 2 , and L 3 (If it exists), select independently -CH2-NH-·, -C(O)-NH-·, -NHC(O)-·and -CH2-O-·; Preferred -CH2-NH-·, -C(O)-NH-· and -CH2-O-·; More preferably -CH2-NH-·and -C(O)-NH-·; where the asterisk ( ) represents the phenolic moiety, and the midpoint (·) represents Z. 1 Z 2 , or Z 3 Group (if present).

6. The compound according to any one of claims 1 to 5, wherein Z 1 Z 2 , and Z 3 (If present), independently selected from hydrogen, C4-C6-alkyl groups substituted with two or more hydroxyl groups (-OH), and C1-C3-alkyl groups substituted with at least one group selected from hydroxyl (-OH), carboxyl (-COOH), and phosphonate (-PO3H2); preferably hydrogen, C6-alkyl groups substituted with two to five hydroxyl (-OH), C1-C3-alkyl groups substituted with at least one hydroxyl (-OH) group, and C1-alkyl groups substituted with carboxyl (-COOH) or phosphonate (-PO3H2).

7. The compound according to any one of claims 1 to 6, wherein R is a C1-C3-alkyl or an aryl-substituted C1-C3-alkyl; preferably a C1-C2-alkyl or an aryl-substituted C1-C2-alkyl; more preferably a C1-alkyl or an aryl-substituted C1-alkyl.

8. The compound according to any one of claims 1 to 7, wherein R is selected from hydrogen, C1-alkyl, aryl-substituted C1-alkyl, and the part of formula (IA). Formula (IA) Where Y 3 R 3 L 3 and Z 3 Each has the Y defined above for any one of claims 1 to 7 1 R 1 L 1 and Z 1 The same meaning provided.

9. The compound according to any one of claims 1 to 8, wherein n, m, and o are 1, thereby the compound having the following formula (II). Equation (II) Where R, R 1 , R 2 , Y 1 , Y 2 , L 1 , L 2 Z 1 and Z 2 As defined above for any one of claims 1 to 8.

10. The compound according to any one of claims 1 to 8, wherein only one of n, m and o is 2 and the other two are 1, thereby the compound having one of formula (IIIA), (IIIB) or (IIIC). Formula (IIIA) Formula (IIIB) Formula (IIIC) in, For equations (IIIA), (IIIB), and (IIIC), R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , L 1 , L 2 , L 3 Z 1 Z 2 and Z 3 As defined above for any one of claims 1 to 8, and R' is hydrogen or optionally a C1-C4-alkyl group substituted with an aryl group.

11. The compound according to claim 10, wherein R' is hydrogen or a C1-C3-alkyl group optionally substituted with an aryl group; preferably hydrogen or a C1-C2-alkyl group optionally substituted with an aryl group; more preferably hydrogen or a C1-alkyl group optionally substituted with an aryl group.

12. The compound according to any one of claims 1 to 8, wherein only one of n, m and o is 1, and the other two are 2, thereby the compound having one of formula (IVA), (IVB) or (IVC). Formula (IVA) Formula (IVB) Formula (IVC) in, For equations (IVA), (IVB), and (IVC), R 1 , R 2 , R 3 , Y 1 , Y 2 , Y 3 , L 1 , L 2 , L 3 Z 1 Z 2 and Z 3 As defined above for any one of claims 1 to 8, and R' is hydrogen or optionally a C1-C4-alkyl group substituted with an aryl group.

13. The compound according to claim 12, wherein R' is hydrogen or a C1-C3-alkyl group optionally substituted with an aryl group; preferably hydrogen or a C1-C2-alkyl group optionally substituted with an aryl group; more preferably hydrogen or a C1-alkyl group optionally substituted with an aryl group.

14. The compound according to any one of claims 1 to 8, wherein n, m, and o are 2, thereby the compound having the following formula (V). Formula (V) Where R, R 1 , R 2 , Y 1 , Y 2 , L 1 , L 2 Z 1 and Z 2 As defined above for any one of claims 1 to 8.

15. The compound according to any one of claims 1 to 14, wherein the compound is selected from: 3,3',3''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tri[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2',2''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol); 3,3'-[1,4,7-triazacyclononane-1,4-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 3,3',3''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,7-triazacyclononane-1,4-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tris[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,7-triazacyclononane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazinedimethylmethylene]}tris(phosphonic acid); {1,4,7-Triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazaalkyldiylmethylene]}bis(phosphonic acid); {1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}tris(phosphonic acid); {1,4,7-Triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldiylmethylene]}bis(phosphonic acid); 3,3',3''-[1,4,7-triazacyclononane-1,4,7-triyltri(methylene)]tri[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1',1''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethylene-1,2-diol); 3,3'-[1,4,7-triazacyclononane-1,4-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); N , N ', N ''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide); N , N '-{1,4,7-triazacyclononane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N ', N ''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]; N , N '-{1,4,7-triazacyclononane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}tris(phosphonic acid); {1,4,7-Triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); 3,3',3''-[1,4,7-triazacyclodecane-1,4,7-triyltri(methylene)]tri[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2',2''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol); 3,3'-[1,4,7-triazacyclodecane-1,7-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,7-triazacyclodecane-1,4-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 2,2'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 3,3',3''-[1,4,7-triazacyclodecane-1,4,7-triyltri(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,7-triazacyclodecane-1,7-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,7-triazacyclodecane-1,4-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2''-[1,4,7-triazacyclodecane-1,4,7-triyltri(methylene)]tris[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,7-triazacyclodecane-1,7-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,7-triazacyclodecane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazinedimethylmethylene]}tris(phosphonic acid); {1,4,7-Triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {1,4,7-Triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}tris(phosphonic acid); {1,4,7-Triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}bis(phosphonic acid); {1,4,7-Triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldiylmethylene]}bis(phosphonic acid); 3,3',3''-[1,4,7-triazacyclodecane-1,4,7-triyltri(methylene)]tri[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1',1''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethylene-1,2-diol); 3,3'-[1,4,7-triazacyclodecane-1,7-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,7-triazacyclodecane-1,4-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); 1,1'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); N , N ', N ''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide); N , N '-{1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N '-{1,4,7-triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N ', N ''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]; N , N '-{1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; N , N '-{1,4,7-triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}tris(phosphonic acid); {1,4,7-Triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); {1,4,7-Triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); 3,3',3''-[1,4,8-triazacycloundecane-1,4,8-triyltri(methylene)]tri[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2',2''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol); 3,3'-[1,4,8-triazacycloundecane-1,8-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 3,3',3''-[1,4,8-triazacycloundecane-1,4,8-triyltri(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,8-triazacycloundecane-1,8-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,8-triazacycloundecane-1,4-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2''-[1,4,8-triazacycloundecane-1,4,8-triyltri(methylene)]tris[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}tris(phosphonic acid); {1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}tri(phosphonic acid); {1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldiylmethylene]}bis(phosphonic acid); {1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldiylmethylene]}bis(phosphonic acid); (3,3',3''-[1,4,8-triazacycloundecane-1,4,8-triyltri(methylene)]tri[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1',1''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethylene-1,2-diol); (3,3'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); 1,1'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); N , N ', N ''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide); N , N '-{1,4,8-triazacycloundecane-1,8-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N '-{1,4,8-triazacycloundecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N ', N ''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]; N , N '-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; N , N '-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}tris(phosphonic acid); {1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); {1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); 3,3',3''-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)]tri[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2',2''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(prop-1,3-diol); 3,3'-[1,5,9-triazacyclododecane-1,5-dimethylbis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 3,3',3''-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,5,9-triazacyclododecane-1,5-dimethylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2''-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)]tri[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethyl]}tris(phosphonic acid); {1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}tris(phosphonic acid); {1,5,9-Triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldiylmethylene]}bis(phosphonic acid); 3,3',3''-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)]tri[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1',1''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethylene-1,2-diol); 3,3'-[1,5,9-triazacyclododecane-1,5-dimethylbis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); N , N ', N ''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide); N , N '-{1,5,9-triazacyclododecane-1,5-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N ', N ''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]; N , N '-{1,5,9-triazacyclododecane-1,5-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}tris(phosphonic acid); {1,5,9-Triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); 3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}bis(phosphonic acid); 3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); N , N '-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N '-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); 3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; 2,2'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}bis(phosphonic acid); 3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); 1,1'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); N , N '-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N '-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N '-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; N , N '-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); 3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 2,2'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; 2,2'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}bis(phosphonic acid); {(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}bis(phosphonic acid); 3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); 1,1'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); N , N '-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N '-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N '-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; N , N '-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); {(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); 3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[ N [-(1,3-dihydroxypropyl-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(prop-1,3-diol); 3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanedimethylmethylene]}bis(phosphonic acid); {(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazaalkyldimethylmethylene]}bis(phosphonic acid); 3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[ N [-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethylene-1,2-diol); N , N '-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N , N '-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azaalkyldiyl(2-oxoethyl-2,1-diyl)]}bis(phosphonic acid); N , N ', N ''-{1,4,7-triazacyclononane-1,4,7-triyltri[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}triacetamide); 3-{[4,7-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6',6''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexyl-1,2,3,4,5-pentaol); 2-Hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol); 3-{[4,7-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6',6''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexyl-1,2,3,4,5-pentaol); 2-Hydroxy-3-{[7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 2-Hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 3-{[1,4-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-8-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6',6''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexyl-1,2,3,4,5-pentaol); 2-Hydroxy-3-{[1-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-8-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 2-Hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 6,6'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 3-{[5,9-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6',6''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexyl-1,2,3,4,5-pentaol); 2-Hydroxy-3-{[5-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecane-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentaol); 3-{[4-benzyl-7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 3-{[4-benzyl-7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 3-{[7-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclodecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 6,6'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 3-{[1-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-8-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 3-{[8-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 6,6'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 3-{[5-benzyl-9-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecane-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 6,6'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 6,6'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexyl-1,2,3,4,5-pentaol); 2,2',2''-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(prop-1,3-diol); 2,2'-{1,4,7-triazacyclononane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2',2''-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(prop-1,3-diol); 2,2'-{1,4,7-triazacyclodecane-1,7-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2'-{1,4,7-triazacyclodecane-1,4-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2',2''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(prop-1,3-diol); 2,2'-{1,4,8-triazacycloundecane-1,8-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2',2''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(prop-1,3-diol); 2,2'-{1,5,9-triazacyclododecane-1,5-dimethylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); 2,2'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol); and 2,2'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(prop-1,3-diol).

16. The compound according to any one of claims 1 to 15, for treating or preventing diseases caused by excess and / or accumulation of iron ions in the body, preferably in the human body; preferably, the disease is iron poisoning and / or iron overload.

17. A pharmaceutical composition comprising a compound of formula (I): Equation (I) in: n, m, and o are integers independently selected from 1 and 2; Y 1 and Y 2 Independently selected from hydrogen and C1-C4-alkyl; R 1 and R 2 Independently selected from hydrogen and C1-C4-alkyl; L 1 and L 2 Independently selected from C1-C4-alkylamino, C1-C4-alkylamide and C1-C4-alkyl ether; Z 1 and Z 2 Independently selected from hydrogen and C1-C6-alkyl, wherein the C1-C6-alkyl is optionally substituted by one or more groups selected from hydroxyl (OH), carboxyl (-COOH) and phosphonate (-PO3H2); R is selected from hydrogen, C1-C4 alkyl groups optionally substituted with aryl groups, and the part of formula (IA): Formula (IA) Among them: asterisk ( ) represents the connection point between a portion of formula (IA) and a nitrogen atom with an R group; Y 3 Having the above for Y 1 and Y 2 The same meaning provided; R 3 Having the above for R 1 and R 2 The same meaning provided; L 3 Having the above for L 1 and L 2 The same meaning provided; and Z 3 Having the above for Z 1 and Z 2 The same meaning provided; Or its ions, or stereoisomers, or tautomers, or hydrates, or solvates, pharmaceutically acceptable complexes, or pharmaceutically acceptable salts, or mixtures thereof; and at least one pharmaceutically acceptable excipient; Preferably, the composition is used as a medicine; more preferably, the composition is used to treat or prevent diseases caused by excess and / or accumulation of iron ions in the body. The condition is that the pharmaceutically acceptable complex is not an iron complex.

18. Complexes of compound (I): Equation (I) in: n, m, and o are integers independently selected from 1 and 2; Y 1 and Y 2 Independently selected from hydrogen and C1-C4-alkyl; R 1 and R 2 Independently selected from hydrogen and C1-C4-alkyl; L 1 and L 2 Independently selected from C1-C4-alkylamino, C1-C4-alkylamide and C1-C4-alkyl ether; Z 1 and Z 2 Independently selected from hydrogen and C1-C6-alkyl, wherein the C1-C6-alkyl is optionally substituted by one or more groups selected from hydroxyl (OH), carboxyl (-COOH) and phosphonate (-PO3H2); R is selected from hydrogen, C1-C4 alkyl groups optionally substituted with aryl groups, and the part of formula (IA): Formula (IA), Among them: asterisk ( ) represents the connection point between a portion of formula (IA) and a nitrogen atom with an R group; Y 3 Having the above for Y 1 and Y 2 The same meaning provided; R 3 Having the above for R 1 and R 2 The same meaning provided; L 3 Having the above for L 1 and L 2 The same meaning provided; and Z 3 Having the above for Z 1 and Z 2 The same meaning provided; Or its ions, or stereoisomers, or tautomers, or hydrates, or solvates, or pharmaceutically acceptable salts, or mixtures thereof; The complex is formed by a compound of formula (I) with a pharmaceutically acceptable ion that is not an iron ion; preferably, with a pharmaceutically acceptable alkali metal ion or alkaline earth metal ion; more preferably, with Ca 2+ ions or Mg 2+ Ion formation.

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