1, 4-bis-(2-hydroxy-benzyl)-1, 4, 7-triazacyclononane derivatives and similar compounds as ligands in iron (iii) complexes for use as MRI contrast agents

Abstract

The present invention relates to novel compounds of formula (I) and ions, stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts thereof, or mixtures thereof. The compounds of formula (I) are ligands capable of sequestering Fe (III) ions, thereby producing Fe (III) complexes which are particularly suitable for diagnostic imaging due to their high relaxation rate, thermodynamic stability, kinetic inertness and redox stability, for example as contrast agents for magnetic resonance imaging (MRI). # imgabs0 #

Description

Technical Field

[0001] The present invention relates to novel compounds capable of complexing with Fe(III) and to their complexes with Fe(III). These complexes are particularly suitable for use as contrast agents for magnetic resonance imaging (MRI). Background of the Invention

[0003] Magnetic resonance imaging (MRI) contrast agents currently used in clinical practice are small, hydrophilic, paramagnetic Gd(III) complexes or chelates that accelerate the relaxation rates (R1 and R2) of proximal tissue water protons in the region of agent accumulation. Despite the fact that these clinically used Gd(III) complexes are generally very safe and very well tolerated by patients, there have been recent concerns that they are contraindicated in patients with severely impaired renal function (nephrogenic systemic fibrosis), that small amounts of Gd(III) are retained in the tissues of patients exposed to multiple MRI scans (although there is no evidence that this is associated with clinical harm), and that there may be environmental impacts (as gadolinium-based contrast agents or GBCAs are difficult to remove from wastewater treatment plants). Therefore, alternative contrast agents based on chemistries other than Gd(III) have been sought.

[0004] Among these alternatives, complexes that chelate endogenous paramagnetic metals such as iron are possible candidates. Indeed, iron complexes, especially Fe(III) complexes, have been investigated for use in MRI. Fe(II) complexes are generally less suitable for providing MRI contrast because they are characterized by lower relaxivity compared to Fe(III) complexes.

[0005] For clinical use in MRI, the ideal Fe(III) complex has a high relaxivity to obtain high contrast in vivo, high thermodynamic stability and kinetic inertness to minimize and possibly avoid hydrolysis, metal transfer, and transchelation reactions with challenging endogenous metal ions and ligands, and has reduction stability to avoid initiating the Fenton reaction, which is the reduction of Fe(III) to Fe(II) in vivo, for example, initiated by antioxidants such as ascorbic acid (Baranyai et al. (Chem. Sci. 2021, 12, 11138)). This reduction does reduce the relaxivity of the administered iron complex (due to the formation of the Fe(II)-complex) and may generate toxic OH· radicals in vivo.

[0006] Schellenberger et al. (Radiology, 2018, 286, 537) disclosed low molecular weight Fe(III) complexes such as Fe(III) chelate of pentetic acid (Fe(DTPA)) and Fe(III) chelate of trans-cyclohexanediaminetetraacetic acid (Fe(CDTA)) that provide image contrast in vivo and show comparable performance to Gd(DTPA) 2- (a clinically used GBCA) with very similar enhancement kinetics. However, these complexes are characterized by unsatisfactory redox stability and relaxivity (as reported in Baranyai et al., Chem. Sci. 2021, 12, 11138).

[0007] Gale et al. (J. Am. Chem. Soc., 2019, 141, 5916) disclosed a redox-active iron complex Fe-PyC3A, characterized by a relatively high relaxation rate in the imaging field and Fe 3+ / 2+ Exchange (mediated by biochemical processes; e.g. Fe 3+ Rapidly reduced to Fe by L-cysteine 2+ ). Therefore, the design of this complex features a very low redox stability to allow Fe 3+ / 2+ exchange, which is a very specific application for imaging acute inflammation and is not suitable for broad MRI applications.

[0008] Morrow et al. (Angew. Chem. Int. ed., 2020, 59, 2414 and WO 2018 / 213853) disclosed a series of substituted macrocyclic ligands for Fe(III) complexation and their use as MRI contrast agents.

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

[0010] It has now been found that the ligands of the present invention have surprising and advantageous properties when complexed with Fe(III) ions to form the complexes of the present invention. In particular, the ligands have been found to have a balance of high relaxivity, kinetic inertness, thermodynamic stability and reduction stability. Therefore, the complexes of the present invention can be advantageously used as contrast agents for MRI. SUMMARY OF THE INVENTION

[0012] The present invention relates to a compound of formula (I) as described in the claims or an ion, stereoisomer, tautomer, hydrate, solvate or salt or mixture thereof. The compound of formula (I) is a ligand which, when complexed with Fe(III) ions, forms an Fe(III) complex (also an object of the present invention, as described in the claims) having a balance of properties of high relaxivity, kinetic inertness, thermodynamic stability and reduction stability.

[0013] The invention further relates to processes for the preparation of the compounds and complexes of the invention, and their use as MRI contrast agents and in diagnostic (MRI) imaging, as described in the claims. DETAILED DESCRIPTION OF THE INVENTION

[0015] According to a first aspect, the present invention relates to a compound of formula (I) or an ion, or a stereoisomer, or a tautomer, or a hydrate, or a solvate, or a pharmaceutically acceptable salt, or a mixture thereof:

[0016]

[0017] Wherein: n, m and o are independently selected from integers between 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 (aminyl), C1-C4-alkylamide (amidyl) and C1-C4-alkyl ether; preferably C1-C4-alkylamino and C1-C4-alkylamide;

[0021] Z 1 and Z 2 Independently selected from hydrogen and C1-C6-alkyl, preferably C1-C4-alkyl, 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 optionally substituted by aryl (such as substituted or unsubstituted aryl) and a moiety of formula (IA):

[0023]

[0024] Wherein: the asterisk (*) indicates the point of attachment of the moiety of formula (IA) to the nitrogen carrying the R group;

[0025] Y 3 With the above about Y 1 and Y 2 The same meaning provided;

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

[0027] L 3 With the above about L 1 and L 2 the same meaning as provided; and

[0028] Z 3 With the above about Z 1 and Z 2 Same meaning provided.

[0029] According to the present invention, the term "alkyl" means any straight or branched hydrocarbon chain. Specifically, "C1-C4-alkyl" includes in its meaning a straight 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" means a straight or branched chain containing 1 to 3 carbon atoms, such as, for example, methyl, ethyl, propyl and isopropyl; the term "C1-C2-alkyl" means a straight or branched chain containing 1 to 2 carbon atoms, such as methyl and ethyl; the term "C1-alkyl" means a methyl (-CH3) group; and the term "C1-C6-alkyl" means 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.).

[0030] According to the present invention, the term "alkylamino" means an alkyl group as defined above, wherein one of the hydrogen atoms is replaced by an amine group, said alkylamino group being linked to (i) the phenolic part of the compound of the present invention and (ii) Z 1 , Z 2 or Z 3 The term "C x -C y -alkylamino", wherein x and y represent two integers, represents an alkylamino group as defined above having a carbon number comprised between x and y.

[0031] According to the present invention, the term "alkylamide" means an alkyl group as defined above, wherein one of the carbon atoms is a carbonyl group (C=O) directly bonded to a nitrogen atom, said alkylamide group being linked to (i) the phenolic part of the compound of the present invention and (ii) Z 1 , Z 2 or Z 3 The term "C x -C y -alkylamide", wherein x and y represent two integers, represents an alkylamide as defined above having a carbon number comprised between x and y.

[0032] According to the present invention, the term "alkyl ether" means an alkyl group as defined above, wherein one of the hydrogen atoms is replaced by an ether group (-O-), said alkyl ether being linked to (i) the phenolic part of the compound of the present invention and (ii) Z 1 , Z 2 or Z 3 The term "C x -C y -alkyl ether", wherein x and y represent two integers, means an alkyl ether as defined above having a carbon number comprised between x and y.

[0033] According to the present invention, the term "aryl" means aromatic hydrocarbons, and preferably means a phenyl ring. Unless otherwise specifically provided, the aryl according to the present invention may be unsubstituted or substituted by one or more substituents, the substituents being selected from hydroxyl (-OH), halogen and C1-C4-alkyl optionally substituted by one or more hydroxyl (-OH) groups simultaneously or independently; preferably, the term "aryl" means unsubstituted aromatic hydrocarbons, such as unsubstituted phenyl.

[0034] According to the present invention, the term "LZ" when representing a substituent generally means L 1 -Z 1 , L 2 -Z 2 and L 3 -Z 3 (if any) any or all of the substituents.

[0035] In the present specification, the term macrocycle or macrocyclic cage, when referring to triazacyclononane (or [9]-membered ring), triazacyclodecane (or

[10] -membered ring), triazacycloundecane (or

[11] -membered ring) or triazacyclododecane (or

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

[0036]

[0037] In this specification, the term "blocking group" refers to a blocking group suitable for retaining the function of the group and / or atom to which it is bonded. Specifically, the blocking group can be used to retain amino, hydroxyl or carboxyl functions. Therefore, a suitable carboxyl blocking group can include, for example, benzyl, alkyl (e.g. tert-butyl or benzyl) esters or other substituents that are usually used to protect such functions, 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).

[0038] The compound of above formula (I) may have one or more asymmetric carbon atoms, which are additionally referred to as chiral carbon atoms, and may therefore produce diastereomers, optical isomers and enantiomers. The present invention further includes all such possible diastereomers, optical isomers and enantiomers, as well as their racemic mixtures, their substantially pure enantiomers of resolution. All possible geometric isomers are also included. The single stereoisomer of the compound of formula (I), for example a specific diastereomer, can be separated by any conventional means (e.g. chromatography, possible chiral chromatography).

[0039] The term "pharmaceutically acceptable salts" as used herein refers to derivatives of the compounds of the present invention wherein the parent compound is appropriately modified by converting any free acid or base group (if present) into the corresponding addition salt using any base or acid conventionally considered to be pharmaceutically acceptable (e.g., as disclosed in SM Berge. et al., J. Pharm. Sci. 1977, 66, 1-19).

[0040] According to one embodiment, Y 1 and Y 2 and Y 3 (if present) are independently selected from hydrogen and C1-C3-alkyl, preferably hydrogen and C1-C2-alkyl, and more preferably hydrogen and C1-alkyl (that is, methyl). Preferably, Y 1 and Y 2 and Y 3 (if present) are simultaneously the same radical, most preferably hydrogen.

[0041] According to one embodiment, R 1 , R 2 and R 3 (if present) is 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 (that is to say, methyl (-CH3)). According to a preferred embodiment, R1 , R 2 and R 3 (if present) are at the same time the same group.

[0042] According to one embodiment, L 1 , L 2 and L 3 (if present) is 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 present) is independently selected from *-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-·, wherein the asterisk (*) represents a phenolic moiety and the intermediate dot (·) represents Z 1 Group, Z 2 Group or Z 3 According to a preferred embodiment, L 1 , L 2 and L 3 (if present) are at the same time the same group.

[0043] Alkylamino and alkylamido groups L 1 , L 2 and L 3 The nitrogen atom (if present) preferably carries at least one hydrogen; in other words, the amine and / or alkylamide group L of the alkylamino group 1 , L 2 and L 3 The amide (if present) is preferably primary or secondary; more preferably secondary.

[0044] According to a preferred embodiment, Z 1 , Z 2 and Z 3 (if present) directly bonded to the nitrogen of an alkylamino or alkylamido group, the carbonyl (C=O) portion of an alkylamido group, or (respectively) L 1 , L 2 and L 3 The oxygen of the alkyl ether group.

[0045] According to a preferred embodiment, Z 1 , Z 2 and Z 3 (if present) is independently selected from hydrogen, C4-C6-alkyl substituted by two or more hydroxyl (-OH) groups, and C1-C3-alkyl substituted by 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 by two or more, such as 2 to 5 (preferably 5), hydroxyl (-OH) groups, C1-C3-alkyl substituted by at least one (such as 2) hydroxyl (-OH) group, and C1-alkyl substituted by carboxyl (-COOH) or phosphonate (-PO3H2).

[0046] According to one embodiment, when R is C1-C4-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), R is preferably C1-C3-alkyl or C1-C3-alkyl substituted by aryl (such as substituted or unsubstituted aryl), preferably phenyl, more preferably C1-C2-alkyl or C1-C2-alkyl substituted by aryl (such as substituted or unsubstituted aryl), preferably phenyl, and even more preferably C1-alkyl or C1-alkyl substituted by aryl (such as substituted or unsubstituted aryl), preferably phenyl (thereby providing a benzyl group -CH2-C6H5).

[0047] According to a preferred embodiment, R is selected from hydrogen, C1-alkyl, C1-alkyl substituted by aryl (such as substituted or unsubstituted aryl), preferably phenyl (thus providing a benzyl group -CH2-C6H5), and a moiety of formula (IA) wherein Y 3 , R 3 , L 3 and Z 3 With the above Y of formula (I) 1 , R 1 , L 1 and Z 1 and any embodiments thereof provide the same meaning.

[0048] According to one embodiment, n, m and o of formula (I) are 1, whereby the compound of the present invention has a triazacyclononane macrocyclic cage and has the following formula (II):

[0049]

[0050] Among them, R 1 , R 2 , Y1 , Y 2 , L 1 , L 2 , Z 1 and Z 2 As defined above for formula (I) or for any embodiment thereof.

[0051] According to another embodiment, only one of n, m and o of formula (I) is 2, and the other two are 1, whereby the compound of the present invention has a triazacyclodecane macrocyclic cage and has one of formula (IIIA), (IIIB) or (IIIC)

[0052]

[0053]

[0054] Wherein, for formula (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 for any embodiment thereof, and R' is hydrogen or C1-C4-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), preferably hydrogen or C1-C3-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), more preferably hydrogen or C1-C2-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), and even more preferably hydrogen or C1-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl).

[0055] According to another embodiment, only one of n, m and o of formula (I) is 1, and the other two are 2, whereby the compound of the present invention has a triazacycloundecane macrocyclic cage and has one of formula (IVA), (IVB) or (IVC)

[0056]

[0057]

[0058] Wherein, for formula (IVA), (IVB) and (IVC), R 1 , R 2 , R 3 , Y1 , Y 2 , Y 3 , L 1 , L 2 , L 3 , Z 1 , Z 2 and Z 3 As defined above for formula (I) or for any embodiment thereof, and R' is hydrogen or C1-C4-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), preferably hydrogen or C1-C3-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), more preferably hydrogen or C1-C2-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), and even more preferably hydrogen or C1-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl).

[0059] According to a fourth embodiment, n, m and o of formula (I) are 2, whereby the compound of the present invention has a triazacyclododecane macrocyclic cage and has the following formula (V)

[0060]

[0061] Among them, R 1 , R 2 , Y 1 , Y 2 , L 1 , L 2 , Z 1 and Z 2 As defined above for formula (I) or for any embodiment thereof.

[0062] According to a preferred embodiment, the compounds of the present invention are selected from:

[0063]

[0064] Compound 1 (3,3',3"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0065]

[0066] Compound 2 (2,2',2"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(propane-1,3-diol)),

[0067]

[0068] Compound 3 (3,3'-[1,4,7-triazacyclononane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0069]

[0070] Compound 4 (2,2'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0071]

[0072] Compound 5 (3,3',3"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0073]

[0074] Compound 6 (3,3'-[1,4,7-triazacyclononane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0075]

[0076] Compound 7 (2,2',2"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0077]

[0078] Compound 8 (2,2'-[1,4,7-triazacyclononane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0079]

[0080] Compound 9 ({1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid)),

[0081]

[0082] Compound 10 ({1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0083]

[0084] Compound 11 ({1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(phosphonic acid)),

[0085]

[0086] Compound 12 ({1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0087]

[0088] Compound 13 (3,3',3"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0089]

[0090] Compound 14 (1,1',1"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(ethane-1,2-diol)),

[0091]

[0092] Compound 15 (3,3'-[1,4,7-triazacyclononane-1,4-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0093]

[0094] Compound 16 (1,1'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0095]

[0096] 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)),

[0097]

[0098] Compound 18 (N,N'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0099]

[0100] 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]),

[0101]

[0102] 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]),

[0103]

[0104] Compound 21 ({1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid)),

[0105]

[0106] Compound 22 ({1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0107]

[0108] Compound 23 (3,3',3"-[1,4,7-triazacyclodecane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0109]

[0110] Compound 24 (2,2',2"-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(propane-1,3-diol)),

[0111]

[0112] Compound 25 (3,3'-[1,4,7-triazacyclodecane-1,7-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0113]

[0114] Compound 26 (3,3'-[1,4,7-triazacyclodecane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0115]

[0116] Compound 27 (2,2'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0117]

[0118] Compound 28 (2,2'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0119]

[0120] Compound 29 (3,3',3"-[1,4,7-triazacyclodecane-1,4,7-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0121]

[0122] Compound 30 (3,3'-[1,4,7-triazacyclodecane-1,7-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0123]

[0124] Compound 31 (3,3'-[1,4,7-triazacyclodecane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0125]

[0126] Compound 32 (2,2',2"-[1,4,7-triazacyclodecane-1,4,7-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0127]

[0128] Compound 33 (2,2'-[1,4,7-triazacyclodecane-1,7-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0129]

[0130] Compound 34 (2,2'-[1,4,7-triazacyclodecane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0131]

[0132] Compound 35 ({1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid)),

[0133]

[0134] Compound 36 ({1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid),

[0135]

[0136] Compound 37 ({1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0137]

[0138] Compound 38 ({1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(phosphonic acid)),

[0139]

[0140] Compound 39 ({1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0141]

[0142] Compound 40 ({1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0143]

[0144] Compound 41 (3,3',3"-[1,4,7-triazacyclodecane-1,4,7-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0145]

[0146] Compound 42 (1,1',1"-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(ethane-1,2-diol)),

[0147]

[0148] Compound 43 (3,3'-[1,4,7-triazacyclodecane-1,7-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0149]

[0150] Compound 44 (3,3'-[1,4,7-triazacyclodecane-1,4-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0151]

[0152] Compound 45 (1,1'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0153]

[0154] Compound 46 (1,1'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0155]

[0156] 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)),

[0157]

[0158] Compound 48 (N,N'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0159]

[0160] Compound 49 (N,N'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0161]

[0162] 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]),

[0163]

[0164] Compound 51 (N,N'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0165]

[0166] Compound 52 (N,N'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0167]

[0168] Compound 53 ({1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid)),

[0169]

[0170] Compound 54 ({1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0171]

[0172] Compound 55 ({1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0173]

[0174] Compound 56 (3,3',3"-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0175]

[0176] Compound 57 (2,2',2"-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(propane-1,3-diol)),

[0177]

[0178] Compound 58 (3,3'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0179]

[0180] Compound 59 (3,3'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0181]

[0182] Compound 60 (2,2'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0183]

[0184] Compound 61 (2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0185]

[0186] Compound 62 (3,3',3"-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0187]

[0188] Compound 63 (3,3'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0189]

[0190] Compound 64 (3,3'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0191]

[0192] Compound 65 (2,2',2"-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0193]

[0194] Compound 66 (2,2'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0195]

[0196] Compound 67 (2,2'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0197]

[0198] Compound 68 ({1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid)),

[0199]

[0200] Compound 69 ({1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0201]

[0202] Compound 70 ({1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0203]

[0204] Compound 71 ({1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(phosphonic acid)),

[0205]

[0206] Compound 72 ({1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0207]

[0208] Compound 73 ({1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0209]

[0210] Compound 74 (3,3',3"-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0211]

[0212] Compound 75 (1,1',1"-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(ethane-1,2-diol)),

[0213]

[0214] Compound 76 (3,3'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0215]

[0216] Compound 77 (3,3'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0217]

[0218] Compound 78 (1,1'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0219]

[0220] Compound 79 (1,1'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0221]

[0222] 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)),

[0223]

[0224] Compound 81 (N,N'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0225]

[0226] Compound 82 (N,N'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0227]

[0228] 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]),

[0229]

[0230] Compound 84 (N,N'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0231]

[0232] 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]),

[0233]

[0234] Compound 86 ({1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid)),

[0235]

[0236] Compound 87 ({1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0237]

[0238] Compound 88 ({1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0239]

[0240] Compound 89 (3,3',3"-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0241]

[0242] Compound 90 (2,2',2"-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(propane-1,3-diol)),

[0243]

[0244] Compound 91 (3,3'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0245]

[0246] Compound 92 (2,2'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0247]

[0248] Compound 93 (3,3',3"-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0249]

[0250] Compound 94 (3,3'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0251]

[0252] Compound 95 (2,2',2"-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0253]

[0254] Compound 96 (2,2'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0255]

[0256] Compound 97 ({1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid)),

[0257]

[0258] Compound 98 ({1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0259]

[0260] Compound 99 ({1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(phosphonic acid)),

[0261]

[0262] Compound 100 ({1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0263]

[0264] Compound 101 (3,3',3"-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0265]

[0266] Compound 102 (1,1',1"-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(ethane-1,2-diol)),

[0267]

[0268] Compound 103 (3,3'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0269]

[0270] Compound 104 (1,1'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0271]

[0272] 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)),

[0273]

[0274] Compound 106 (N,N'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide)),

[0275]

[0276] 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]),

[0277]

[0278] Compound 108 (N,N'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]),

[0279]

[0280] Compound 109 ({1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid)),

[0281]

[0282] Compound 110 ({1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0283]

[0284] Compound 111 (3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0285]

[0286] Compound 112 (2,2'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0287]

[0288] Compound 113 (3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0289]

[0290] Compound 114 (2,2'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0291]

[0292] Compound 115 ({(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0293]

[0294] Compound 116 ({(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0295]

[0296] Compound 117 (3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0297]

[0298] Compound 118 (1,1'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0299]

[0300] 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)),

[0301]

[0302] 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]),

[0303]

[0304] Compound 121 ({(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0305]

[0306] Compound 122 (3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0307]

[0308] Compound 123 (3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0309]

[0310] Compound 124 (2,2'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0311]

[0312] Compound 125 (2,2'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0313]

[0314] Compound 126 (3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0315]

[0316] Compound 127 (3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0317]

[0318] Compound 128 (2,2'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0319]

[0320] Compound 129 (2,2'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0321]

[0322] Compound 130 ({(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0323]

[0324] Compound 131 ({(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0325]

[0326] Compound 132 ({(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0327]

[0328] Compound 133 ({(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0329]

[0330] Compound 134 (3,3'-[(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0331]

[0332] Compound 135 (3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0333]

[0334] Compound 136 (1,1'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0335]

[0336] Compound 137 (1,1'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0337]

[0338] 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)),

[0339]

[0340] 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)),

[0341]

[0342] 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]),

[0343]

[0344] 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]),

[0345]

[0346] Compound 142 ({(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0347] Compound 143 ({(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0348]

[0349] Compound 144 (3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0350]

[0351] Compound 145 (3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0352]

[0353] Compound 146 (2,2'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0354]

[0355] Compound 147 (2,2'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0356]

[0357] Compound 148 (3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0358]

[0359] Compound 149 (3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0360]

[0361] Compound 150 (2,2'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0362]

[0363] Compound 151 (2,2'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0364]

[0365] Compound 152 ({(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0366]

[0367] Compound 153 ({(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0368]

[0369] Compound 154 ({(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0370]

[0371] Compound 155 ({(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0372]

[0373] Compound 156 (3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0374]

[0375] Compound 157 (3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0376]

[0377] Compound 158 (1,1'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0378]

[0379] Compound 159 (1,1'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0380]

[0381] 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)),

[0382]

[0383] 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)),

[0384]

[0385] 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]),

[0386]

[0387] 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]),

[0388]

[0389] Compound 164 ({(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0390]

[0391] Compound 165 ({(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0392]

[0393] Compound 166 (3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]),

[0394]

[0395] Compound 167 (2,2'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)),

[0396]

[0397] Compound 168 (3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0398]

[0399] Compound 169 (2,2'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0400]

[0401] Compound 170 ({(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0402]

[0403] Compound 171 ({(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid)),

[0404]

[0405] Compound 172 (3,3'-[(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0406]

[0407] Compound 173 (1,1'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol)),

[0408]

[0409] 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)),

[0410]

[0411] 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]),

[0412]

[0413] Compound 176 ({(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)), and

[0414]

[0415] Compound 177 (N,N',N"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}triacetamide),

[0416]

[0417] Compound 178 (3-{[4,7-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0418]

[0419] Compound 179 (6,6',6"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(hexane-1,2,3,4,5-pentaol)),

[0420]

[0421] Compound 180 (2-hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononan-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0422]

[0423] Compound 181 (6,6'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0424]

[0425] 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),

[0426]

[0427] Compound 183 (6,6',6"-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(hexane-1,2,3,4,5-pentaol)),

[0428]

[0429] 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),

[0430]

[0431] 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),

[0432]

[0433] Compound 186 (3-{[1,4-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundec-8-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0434]

[0435] Compound 187 (6,6',6"-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(hexane-1,2,3,4,5-pentaol)),

[0436]

[0437] Compound 188 (2-hydroxy-3-{[1-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundec-8-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0438]

[0439] Compound 189 (2-hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundec-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0440]

[0441] Compound 190 (6,6'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0442]

[0443] Compound 191 (6,6'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0444]

[0445] Compound 192 (3-{[5,9-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododec-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0446]

[0447] Compound 193 (6,6',6"-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(hexane-1,2,3,4,5-pentaol)),

[0448]

[0449] Compound 194 (2-hydroxy-3-{[5-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododec-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0450]

[0451] Compound 195 (6,6'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0452]

[0453] Compound 196 (3-{[4-benzyl-7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazacyclononan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0454]

[0455] Compound 197 (6,6'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0456]

[0457] 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),

[0458]

[0459] 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),

[0460]

[0461] Compound 200 (6,6'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0462]

[0463] Compound 201 (6,6'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0464]

[0465] Compound 202 (3-{[1-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundec-8-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0466]

[0467] Compound 203 (3-{[8-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundec-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0468]

[0469] Compound 204 (6,6'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0470]

[0471] Compound 205 (6,6'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0472]

[0473] Compound 206 (3-{[5-benzyl-9-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododec-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0474]

[0475] Compound 207 (6,6'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0476]

[0477] Compound 208 (6,6'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0478]

[0479] Compound 209 (6,6'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol)),

[0480]

[0481] Compound 210 (2,2',2"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tris(propane-1,3-diol)),

[0482]

[0483] Compound 211 (2,2'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0484]

[0485] Compound 212 (2,2',2"-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tris(propane-1,3-diol)),

[0486]

[0487] Compound 213 (2,2'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0488]

[0489] Compound 214 (2,2'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0490]

[0491] Compound 215 (2,2',2"-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tris(propane-1,3-diol)),

[0492]

[0493] Compound 216 (2,2'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0494]

[0495] Compound 217 (2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0496]

[0497] Compound 218 (2,2',2"-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tris(propane-1,3-diol)),

[0498]

[0499] Compound 219 (2,2'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0500]

[0501] Compound 220 (2,2'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0502]

[0503] Compound 221 (2,2'-{(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0504]

[0505] Compound 222 (2,2'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0506]

[0507] Compound 223 (2,2'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)),

[0508]

[0509] Compound 224 (2,2'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)), and

[0510]

[0511] Compound 225 (2,2'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol)).

[0512] The chemical names provided for the compounds of the present invention listed above were generated by the software ACD / ChemSketch 2021.2.2 (ACD / Labs 2021.2.2 (File Version C35H41, Build 126536, March 2, 2022)). These chemical names may differ slightly from standard IUPAC nomenclature. For clarity, when the chemical structure is inconsistent with the corresponding chemical name, the compounds of the present invention are uniquely identified by their chemical structure.

[0513] According to another aspect, the present invention relates to a compound of formula (I) as defined above in any of its embodiments (thus encompassing compounds of formulae (II) to (V) as defined above) and Fe 3+ As demonstrated in the experimental part, the complexes of the invention have a balance of properties of high relaxivity, kinetic inertness, thermodynamic stability and reduction stability, making them very suitable for their application in the field of diagnosis, in particular, as contrast agents for magnetic resonance imaging (MRI).

[0514] According to another aspect, the present invention relates to a complex as defined above or a physiologically acceptable salt thereof for use in a method of diagnosis (preferably in vivo); more preferably, the complex or a physiologically acceptable salt thereof is for use in a method of diagnosis (e.g. in vivo) of a pathology by magnetic resonance imaging (MRI). The use of a complex as defined above or a physiologically acceptable salt thereof for a method of diagnosis (e.g. in vivo), preferably for diagnosis (e.g. in vivo) of a pathology by magnetic resonance imaging (MRI) is also an aspect of the present invention. Another aspect of the present invention is the use of a complex of the present invention as defined above or a salt thereof as a contrast agent, preferably for MRI.

[0515] According to a further aspect, the invention relates to the use of a complex as defined above or a physiologically acceptable salt thereof for the preparation of a diagnostic agent, such as a contrast agent, preferably a contrast agent for magnetic resonance imaging (MRI), eg for in vivo application.

[0516] According to another aspect, the present invention relates to a method for imaging a body tissue of a patient, comprising the steps of administering to said patient an effective amount of a complex as defined above or a physiologically acceptable salt thereof in a pharmaceutically acceptable carrier, and performing magnetic resonance imaging (MRI) on said patient.

[0517] According to another aspect, the invention relates to a pharmaceutical composition comprising a complex as defined above or a physiologically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0518] A process for preparing a compound of the invention as defined above in any of its embodiments (thus encompassing compounds of formula (I) to (V) as defined above) represents another aspect of the invention. The process may generally be accomplished by coupling a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane (which may be suitably protected with one or more protecting groups on one or more nitrogen atoms) with one or more suitable moieties to obtain a compound of the invention, or to obtain an intermediate thereof which may then be converted (e.g. by further coupling and / or reduction reactions) to a compound of the invention.

[0519] In one embodiment, the compounds of the present invention can be prepared according to the following general synthetic steps:

[0520] a) providing a phenol substituted at least in its ortho position by: (i) a C1-C5-alkyl group bonded to a suitable leaving group such as mesylate (MsO) or a halogen, for example to provide a halo-C1-C5-alkyl group such as a chloro-C1-C5-alkyl group or a bromo-C1-C5-alkyl group; and (ii) a LZ group or a suitable substituent which can be subsequently converted into a LZ group, for example a substituent selected from the group consisting of a C1-C4-alkyl-aldehyde, a C1-C4-alkyl-ester and a C1-C4-alkyl-carboxyl group; for example, the phenol may be a compound of formula (VI)

[0521]

[0522] where Y 1 and R 1 has the same meanings as provided with respect to formula (I) or any embodiment thereof;

[0523] X is a leaving group such as mesylate (MsO) or a halogen, preferably Cl or Br, and

[0524] L 4 is a group selected from C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl;

[0525] b) providing a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, which is optionally suitably protected on one or more of its nitrogen atoms with one or more protecting groups and / or optionally carries a C1-C4 alkyl group optionally substituted by an aryl group, such as a substituted or unsubstituted aryl group, on one of its nitrogen atoms;

[0526] c) reacting the phenol provided in step a), for example a compound of formula (VI), with the macrocycle provided in step b), to obtain a compound of the invention, or an intermediate of a compound of the invention, such as an intermediate carrying at least two suitable substituents which can be converted into an LZ group in a later step. Such suitable substituents are, for example, at least two L 4 moiety, which can advantageously be converted into the group L in a subsequent step 1 -Z 1 , L 2 -Z 2 And the last L 3 -Z 3 Such intermediates are, for example, compounds of formula (VII)

[0527]

[0528] Where R 1 , R 2 , Y1 , Y 2 , m, n and o have the same meanings as provided with respect to Formula (I) or any embodiment thereof,

[0529] L 4 is a group selected from C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl; and

[0530] R" is selected from hydrogen, C1-C4 alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl) and a moiety of formula (VIIA):

[0531]

[0532] Wherein: the asterisk (*) indicates the point of attachment of the moiety of formula (VIIA) to the nitrogen carrying the R' group;

[0533] Y 3 With the above about Y 1 and Y 2 The same meaning provided;

[0534] R 3 With the above R 1 and R 2 the same meaning as provided; and

[0535] L 4 is a group selected from C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl; and

[0536] d) converting the intermediate of step c) into a compound of the present invention, for example, 4 Partially converted into group L 1 -Z 1 , L 2 -Z 2 and L 3 -Z 3 (if any), thereby obtaining the compounds of the invention, for example by reacting the intermediate obtained in step c) such as a compound of formula (VII) with one or more suitable substrates, and optionally by reducing the compound thus obtained.

[0537] According to the invention, the term "C1-C4-alkyl-aldehyde" means an alkyl group as defined above containing 1 to 4 carbons, one of which is an aldehyde group. Thus, the group C1-C4-alkyl-aldehyde contains up to four carbons.

[0538] According to the present invention, the term "C1-C4-alkyl-ester" means an alkyl group as defined above containing 1 to 4 carbons, one of which is a carboxylate bonded to the alkyl group (i.e. one of which is -C(O)OR 0 , where R 0 is an alkyl group, preferably a C1-C2-alkyl group). Thus, the group C1-C4-alkyl-ester contains at most four carbon atoms (not counting the alkyl group R bonded to the oxygen). 0 ).

[0539] According to the invention, the term "C1-C4-alkyl-carboxyl" means an alkyl group as defined above containing 1 to 4 carbons, one of which is a carboxyl (-COOH) group. Thus, the group C1-C4-alkyl-carboxyl contains up to four carbons.

[0540] Step a) involves providing a phenol which is advantageously substituted in one of its ortho positions with a leaving group -C1-C5-alkyl group, preferably a halomethyl group such as a chloromethyl or MsO-methyl group. This group allows the phenol to be coupled to one or more, possibly two or three nitrogen atoms of the macrocycle in step c). The phenol further comprises in its ortho position a alkyl group which can advantageously be converted into L in a subsequent step. 1 -Z 1 , L 2 -Z 2 And the last L 3 -Z 3 (if present) a group such as a group selected from C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl. Alternatively, in addition to a leaving group-C1-C5-alkyl group such as a halo-C1-C5-alkyl group, the phenol may further comprise an LZ group in its ortho position, for example L 1 -Z 1 The phenol of step a), for example a compound of formula (VI), can be obtained by reacting the corresponding non-methylene-halogenated compound with paraformaldehyde in a concentrated hydrohalic acid, preferably hydrochloric acid or hydrobromic acid, at a temperature comprised in the range of 30 to 70° C., preferably 40 to 60° C., more preferably at 50° C.

[0541] Step b) involves providing a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, which is optionally suitably protected with one or more protecting groups on one or more of its nitrogen atoms, and / or optionally carries a C1-C4 alkyl group optionally substituted by an aryl group (such as a substituted or unsubstituted aryl group) on one of its nitrogen atoms. Such a macrocycle will be coupled in step c) with the phenol of step a) to provide an intermediate of a compound of the invention (which will later be converted into a compound of the invention), or directly provide a compound of the invention.

[0542] According to one embodiment of step b), the macrocycle may be unprotected. Specifically, when all three nitrogen atoms of the macrocycle of the compound of the invention to be obtained are bonded to a phenol carrying an LZ group (that is, when R is a group of formula (IA)), the nitrogen atoms of the macrocycle may be unprotected. In fact, in this way, the coupling reaction of step c) can involve all three unprotected nitrogen atoms of the macrocycle, thereby obtaining a compound or intermediate of the invention, such as one of formula (VII), wherein R "is a moiety of formula (VIIA); this intermediate can later be converted into a compound of the invention in a subsequent step, wherein R is a group of formula (IA). In addition, when only two nitrogen atoms of the macrocycle in the compound to be obtained are alkylated by the phenol carrying the LZ group, i.e. when R or R' in the compound to be obtained is hydrogen or C1-C4-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl) (or its preferred embodiments disclosed above), the nitrogen atoms of the macrocycle can also be unprotected. In fact, based on the reaction conditions of step c), such reaction conditions can be selected according to the routine and standard knowledge in the art, the reaction between phenol and the macrocycle (step c)) can involve only two unprotected nitrogen atoms of the macrocycle, instead of all three. The unprotected nitrogen atom, so that the product of such a reaction is a macrocycle to which only two (rather than three) phenols carrying LZ groups are bonded, as shown, for example, in Example 6. For example, in step c), in particular for macrocyclic triazacyclodecane and triazacycloundecane, all three nitrogen atoms or two of the three nitrogen atoms of the macrocycle can be deprotonated by appropriately adjusting the basicity of the reaction mixture of step c), so that all three nitrogen atoms or only two of the three nitrogen atoms are alkylated in step c); for example, when a base such as DIPEA is added to the reaction mixture of step c), all three nitrogen atoms of the macrocyclic triazacycloundecane or triazacyclododecane are deprotonated, and thus a trialkylated macrocycle is obtained in step c); whereas, if only carbonate is used in the reaction mixture, one nitrogen atom of the macrocyclic triazacycloundecane or triazacyclododecane remains protonated and does not participate in the alkylation step c), thereby providing a dialkylated macrocycle (see, for example, Example 6).

[0543] According to step b), the macrocycle may also be appropriately protected with one or more protecting groups on one or more of its nitrogen atoms. Specifically, when R or R' in the compound of the present invention to be obtained is hydrogen or a C1-C4-alkyl group optionally substituted by an aryl group (such as a substituted or unsubstituted aryl group) (or its preferred embodiment disclosed above), one or more of the nitrogen atoms of the macrocycle may be appropriately protected with one or more protecting groups. For example, compound 4 (with R = hydrogen) can be synthesized as follows: first prepare a mono-Boc (tert-butyloxycarbonyl) protected macrocycle (for example, as disclosed in SJ Butler, BK McMahon, R. Pal, D. Parker, JW Walton, Chem. Eur J., 2013, 19, 9511-9517), then couple it with a hydroxybenzaldehyde side chain, then reductively aminize with serinol (2-amino-1,3-propanediol), and finally deprotect with TFA, as shown in Scheme 1 below.

[0544]

[0545] Furthermore, due to the (possibly selective) deprotection reaction, this embodiment of providing a macrocycle in step b) which is suitably protected with one or more protecting groups on one or more of its nitrogen atoms allows the choice of which and how many nitrogen atoms of the macrocycle will react with the ortho-substituted phenol in the coupling reaction of step c). Specifically: starting from a suitable dialkylene triamine (e.g. diethylene triamine, dipropylene triamine, (2-aminoethyl)-1,3-propane diamine, etc.) which may be suitably protected, any macrocycle described herein (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. 2019, 3354-3365), specifically, by protecting the primary amine of the dialkylene triamine with a p-nitrobenzenesulfonyl group (nosyl, Ns) and protecting the secondary amine of the dialkylene triamine with Boc; then the protected dialkylene triamine can be subjected to Richman and Atkins cyclization using appropriate ditoluenesulfonated diols and appropriate reaction conditions to obtain a suitably protected macrocycle, for example as shown in Scheme 2:

[0546]

[0547] Once the macrocycle has been appropriately protected, for example according to Scheme 2, the two p-nitrobenzenesulfonyl groups (Ns) can be removed using thiophenol in the presence of carbonate, whereby the two deprotected amines of the macrocycle can be alkylated with a suitable side arm, for example as disclosed in step c), ultimately by transforming the groups on the side arms, for example as disclosed in step d); finally the Boc can be removed, for example as disclosed in Scheme 1 above, to give compounds of the invention wherein R or R' is hydrogen, or by ultimately further alkylating the deprotected nitrogen once bonded to the Boc.

[0548] For example, by operating as described in Scheme 2 above, compounds of the invention in which R or R' is a C1-C4-alkyl group optionally substituted by an aryl group (such as a substituted or unsubstituted aryl group) can be obtained, but, instead of protecting the secondary amine of the dialkylene triamine with Boc, such a secondary amine can be reacted with, for example, benzyl bromide (to insert a benzyl group) or, for example, with a C1-C4-alkyl-aldehyde (such as formaldehyde) and NaBH4 (reductive amination) (to insert a C1-C4-alkyl group, such as a methyl group); this allows obtaining a macrocycle carrying two p-nitrobenzenesulfonyl groups (Ns) and one C1-C4-alkyl group optionally substituted by an aryl group (such as a substituted or unsubstituted aryl group). The remaining steps to obtain the compounds of the invention can then be carried out as detailed above (i.e., removal of the Ns group and alkylation according to step c)). Starting from commercially available monoalkylated macrocycles, compounds of the invention wherein R or R' is C1-C4 alkyl optionally substituted with aryl (such as substituted or unsubstituted aryl) can also be obtained, for example as shown in Scheme 3 below for the preparation of compound 112:

[0549]

[0550] Step c) provides for reacting the phenol of step a) with the macrocycle of step b) to directly give the compound of the invention, or to give an intermediate to the compound of the invention which in fact reacts in the following step d) to give the final product.

[0551] Step c) can be carried out in an organic solvent such as toluene or acetonitrile. Salts such as potassium salts, for example 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). It is also possible to use KI 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).

[0552] Step c) can advantageously be carried out without heating the reaction mixture. In particular, in order to reduce the risk of undesired polyalkylation reactions, step c) can be carried out at a temperature equal to or below room temperature (that is to say, below 25°C), for example a temperature comprised in the range of 0°C to 25°C.

[0553] Step d) is optional and may be performed optionally when step c) provides an intermediate of a compound of the invention. Step d) involves the addition of a group (e.g., group L) of the intermediate to 4 ) is converted into L 1 -Z 1 , L 2 -Z 2 And the last L 3 -Z 3 (if present) group. This can be accomplished, for example, by making L 4 The reaction of the group with one or more suitable substrates is accomplished. For example, if L 1 is C1-C4-alkylamino and Z 1 is a C1-C6 alkyl group substituted with one or more hydroxyl groups, then L in formula (VII) and (VIIA) 4 would be a C1-C4-alkyl-aldehyde and the suitable substrate would be a C1-C6-alkyl-amine substituted with two or more hydroxyl groups, such as serinol or reduced glucosamine, whereby coupling of the two provides an imide which is subsequently reduced to give the desired L 1 -Z 1 part (such as disclosed in, for example, Example 2 below). Alternatively, when L 1 is C1-C4-alkylamino and Z 1 When L in formula (VII) and (VIIA) is a C1-C6 alkyl group substituted with a phosphonate group 4 will be a C1-C4 alkyl-aldehyde and the suitable substrate will be, for example, diethyl-2-aminomethylphosphonate, for example as shown in Scheme 4 below for obtaining compound 11.

[0554]

[0555] As a further exemplary embodiment, when L 1 is a C1-C4-alkylamide group and Z 1 When L in formula (VII) and (VIIA) is hydrogen 4 will be a C1-C4 alkyl-ester and the suitable substrate will be, for example, ammonia, for example as shown in Scheme 5 below for obtaining compound 5.

[0556]

[0557] As another exemplary embodiment, when L 1 is a C1-C4-alkyl ether and Z 1 When L is C1-C6-alkyl substituted by one or more hydroxyl groups, L of formula (VII) and (VIIA) 4 will be a C1-C4-alkyl-aldehyde which can be reduced to give a hydroxyl group which can in turn be converted into an alkoxide; such an alkoxide can participate in the well-known Williamson ether synthesis whereby it is reacted with a suitable substrate, such as an alkyl-hydroxy-halide wherein its hydroxyl group is suitably protected, such as 2-chloro-1,3-propanediol or 2-bromo-1,3-propanediol wherein its hydroxyl group is suitably protected.

[0558] The compounds of the invention may also be prepared by providing in step a) a phenol as defined above and specifically carrying an LZ group in its ortho position. In this case, the compounds of the invention can be obtained directly by reacting such an ortho-substituted phenol with the macrocycle provided in step b) in step c). This embodiment can be illustrated, for example, according to the following scheme 6, which is used to obtain a phenol having the following group *-NHC(O)- as L 1 (where the asterisk (*) represents the phenolic moiety and the middle dot (·) represents Z 1 group) and having hydrogen as Z 1 The compound of the present invention (ie, Compound 177):

[0559]

[0560] According to one embodiment, the compounds of the present invention can also be obtained as follows: according to step a) in any of its embodiments, phenol is provided, and:

[0561] b') providing a macrocyclic orthoamide derivative selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, ie a tricyclic triaminomethane derivative, for example an orthoamide derivative of formula (VIII):

[0562]

[0563] wherein m, n and o have the same meanings as provided with respect to formula (I) or any embodiment thereof;

[0564] c') reacting the one or two phenols provided in step a) (e.g., a compound of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde) with an ortho-amino derivative (e.g., an ortho-amino derivative of formula (VIII)) to obtain an ortho-amino derivative coupled with the one or two phenols provided in step a) (e.g., a compound of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde);

[0565] d') hydrolyzing the ortho-amino derivative obtained in step c'), for example by acid hydrolysis, to obtain a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane coupled to one or two phenols provided in step a) (for example a compound of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde) and to a formyl (-C(O)H) group;

[0566] e') optionally reacting another phenol (e.g. a compound of formula (VI) such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde) provided in step a) with the macrocycle obtained in step d') to obtain a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane coupled to the two phenols (e.g. a compound of formula (VI) such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde) provided in step a) and to a formyl (-C(O)H) group;

[0567] f') hydrolysis of the macrocycle obtained in step d') or e') and optionally conversion of the possible C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester or C1-C4-alkyl-carboxyl, wherein the hydrolysis and optional conversion of step f') are carried out in any order to obtain the compound of the invention (in which 2 nitrogen atoms of the macrocycle are bonded to the phenol carrying the LZ group and one is bonded to hydrogen); and

[0568] g') optionally reacting the other phenol provided in step a) (e.g. a compound of formula (VI) such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde) with the macrocycle obtained in step f') and optionally converting the possible C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester or C1-C4-alkyl-carboxyl to obtain a compound according to the invention in which all three nitrogen atoms of the macrocycle are bonded to a phenol carrying an LZ group.

[0569] The following scheme 7 illustrates a possible way to implement the above embodiment, in particular: step c') provides for reacting a phenol with an o-amino derivative, performing step e') (and thereby providing for reacting another phenol with the macrocycle obtained in step d')), step f') provides for first performing a step of converting a possible C1-C4-alkyl-aldehyde, and then performing a hydrolysis step to obtain the compound of the present invention, and not performing step g'):

[0570]

[0571] According to Scheme 7, compounds according to the invention can be synthesized in which two nitrogen atoms of the macrocycle are bonded to a phenol carrying a LZ group and one is bonded to hydrogen. If a further step g') is carried out, compounds according to the invention can also be synthesized in which three nitrogen atoms of the macrocycle are bonded to a phenol carrying a LZ group.

[0572] The ortho-amino derivative provided in step b') can be obtained according to standard procedures in the art, for example by reacting a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane with formaldehyde dimethyl acetal, or as reported in T. Atkins, J. Am. Chem. Soc. 1980, 102, 6364-6365; RW Alder et al. J. Chem. Soc. Chem. Commun. 1992, 507-508, for example starting from 1,4,6-triazabicyclo[3.3.0]oct-4-ene 1,5,7-triazabicyclo[4.4.0]dec-5-ene.

[0573] The hydrolysis of step d') allows the conversion of the ortho-amino derivative into a macrocycle bonded to a formyl group (as well as to the phenol previously reacted in step c'). The formyl group appears to be primarily bonded to nitrogen atoms of the less sterically hindered macrocycle, such as one of the two nitrogen atoms between the ethylene and propylene moieties (rather than one nitrogen atom between the two propylene moieties) of the macrocyclic triazacycloundecane.

[0574] According to one embodiment, step d') can be carried out 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 step d'), i.e. the macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane coupled to a formyl (-C(O)H) group.

[0575] In order to obtain the Fe(III) complex of the compound of the invention, which is also an aspect of the invention, a step of complexing the compound of the invention with Fe(III) can be performed, for example, after step c) or step d) or after step f') or g'); the complexing step can be performed, for example, according to the following steps:

[0576] e) reacting a compound of the present invention (e.g., a compound obtained in step c), step d), step f') or step g') with an Fe(III) salt (such as FeCl3, Fe(NO3)3, Fe(OH)3 and FeO(OH)) to obtain an Fe(III) complex of the compound of the present invention.

[0577] Step e) can be carried out in a non-aqueous polar solvent, such as a lower alcohol, for example methanol, ethanol, n-propanol, isopropanol, and mixtures thereof.

[0578] In the following section non-limiting examples of the preparation of preferred compounds of the invention and of intermediates for their preparation are reported, with the intention of illustrating the invention in more detail without limiting its scope.

[0579] Experimental Section

[0580] Materials and methods

[0581] The reactants and / or solvents employed in the following examples which are not specifically synthesized in the following examples are known and readily available. If they are not commercially available per se, they can be prepared according to methods known in the literature.

[0582] Recorded on a Bruker Avance III spectrometer (Bruker, Milan, Italy) 1 H and 13 C NMR spectra, which were run at 11.74T and 298K, correspond to a proton resonance frequency of 499.8 MHz. Reported relative to TMS 1 H and 13 C NMR chemical shifts were referenced using residual proton solvent resonances. Samples were prepared in 5 mm NMR tubes by dissolving the compound in an appropriate deuterated solvent.

[0583] Analytical and semi-preparative HPLC-MS runs were performed on a Waters modular system equipped with a Waters 1525 binary pump, a Waters 2487 UV / Vis, and a Waters SQD 3100 (ESCI ionization mode) detector (Waters Corporation, Milford, MA, the U.S.). UPLC-MS analysis was performed using a UPLC Acquity H-Class coupled to a QDa and TUV detector (Waters Corporation, Milford, MA, the U.S.). ESI-MS was recorded on a Waters SQD 3100 (Waters Corporation, Milford, MA, the U.S.).

[0584] Example 1 - Synthesis of Compound 1

[0585] The synthesis of compound 1 was carried out according to the following Scheme 8:

[0586]

[0587] Synthetic details for this example are provided in the following paragraphs.

[0588] A) Synthesis of (2-hydroxy-5-methyl)methyl benzoate

[0589] 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 at reflux temperature overnight. The final product was used without further purification. Quantitative yield.

[0590] 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=8.5Hz), 7.24(dd,-CCH3-CH-CH-,1H,J3=8.5Hz, J4=2.1Hz), 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 + )(C9H 10 Calculated value of O3: 166.2).

[0591] B) Synthesis of (2-Hydroxy-5-methyl-3-methylchloro)formic acid

[0592] Benzoic acid (2-hydroxy-5-methyl) methyl ester (0.5g, 3.01mmol) obtained in the previous step was dissolved in 4mL of concentrated HCl and the temperature was raised to 50°C. Then, paraformaldehyde (0.181g, 6.02mmol) was added portion by portion and the reaction mixture was stirred at room temperature for 72h. Then, the solution was washed with DCM (3x 15ml) and the organic layer was washed with brine (2x 15ml). The organic phase was dried with Na2SO4, filtered and the solvent was evaporated under reduced pressure. Yield: 72%.

[0593] 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): nd.

[0594] C) Synthesis of 1,4,7-tris-(3-carboxymethyl-2-hydroxy-5-methylbenzyl)-1,4,7-triazacyclononane

[0595] 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) (0.258 g, 1.2 mmol) obtained in the previous step was dissolved in 2 ml of toluene and added dropwise in about 15 min to avoid polyalkylation as much as possible. Then, the reaction mixture was stirred at room temperature for 2 h. 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 = from 30% to 100% B; 15-19 min = 100% B; 19-20 min = from 100% to 30% B) was performed to characterize the product. Retention time: 13.79 minutes. Yield: 80%.

[0596] 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 CNMR (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 + )(C 34 H 41 Calculated value for N3O9: 635.7).

[0597] D) Synthesis of 3,3',3"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide] (Compound 1)

[0598] Serinol (2-amino-1,3-propanediol, 0.045 g, 0.5 mmol) was dissolved in DMF (1 mL) and added to a 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) in DMF (2 mL). The reaction mixture was heated to 50°C and stirred overnight. HPLC-MS analysis was performed to check 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 minutes. The solvent was then removed and the crude product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5 μm (19×100 mm); A=H2O / 0.1% TFA; B=MeOH; flow rate=20 mL / min; 0-4 min=30% B; 4-12 min=from 30% to 57% B; 12-13 min=100% B; 13-14 min=100% B; 14-15 min=from 100% to 30% B; 15-17 min=30% B). Yield: 67%.

[0599] 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 + )(C 42 H 60 N6O 12 Calculated value: 840.4).

[0600] Example 2-Synthesis of Compound 2

[0601] The synthesis of compound 2 was carried out according to the following Scheme 9:

[0602]

[0603] Synthetic details for this example are provided in the following paragraphs.

[0604] A) Synthesis of 2-hydroxy-3-bromomethyl-5-methyl-benzaldehyde

[0605] 2-Hydroxy-5-methylbenzaldehyde (0.51 g, 3.7 mmol) was dissolved in 4 mL of 48% HBr and heated to 50 ° C. Then, paraformaldehyde (0.166 g, 5.55 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. Then, the solution was extracted with DCM (3 x 15 ml) and the organic layer was washed with brine (2 x 15 ml). The organic phase was dried with Na2SO4, filtered and the solvent was evaporated under reduced pressure. After removing DCM, the product was crystallized immediately. Yield: 69%.

[0606] 1 H 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 CNMR (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).

[0607] B) Synthesis of 1,4,7-tris-(3-formyl-2-hydroxy-5-methylbenzyl)-1,4,7-triazacyclononane

[0608] 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 and dissolved in 1 ml of acetonitrile was added dropwise to the solution. The reaction mixture was heated to 60 ° C and stirred overnight. Then, the solution was filtered and the crude product was precipitated in ether. Yield: 81%. HPLC-MS analysis was performed to check 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.

[0609] 1 H 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-macrocycle), 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 + )(C 33 H 39 Calculated value for N3O6: 573.7).

[0610] C) Synthesis of 2,2',2"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(propane-1,3-diol) (Compound 2)

[0611] 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 an excess of 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 checked by MS spectrometry: ESI-MS (m / z): 794.0 (M+H + )(C 42 H 60 Calculated value for N6O9: 793.0) and the 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 for 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 minutes.

[0612] The solvent was removed under reduced pressure and the crude product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5 μm (19×100 mm); A=H 2 O / 0.1% TFA; B=MeOH; flow rate=20 mL / min; 0-4 min=20% B; 4-10 min=from 20% to 43% B; 10-11 min=100% B; 11-12 min=100% B; 12-13 min=from 100% to 20% B; 13-15 min=20% B). Yield: 80%.

[0613] 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 + )(C 42 H 60 N6O 12 Calculated value: 799.0).

[0614] Example 3 - Synthesis of Compound 4

[0615] The synthesis of compound 4 was carried out according to the following scheme 10:

[0616]

[0617] Synthetic details for this example are provided in the following paragraphs.

[0618] A) Synthesis of 1,4-di-(3-formyl-2-hydroxy-5-methylbenzyl)-7-tert-butyloxycarbonyl-1,4,7-triazacyclononane

[0619] 1-tert-Butyloxycarbonyl-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. Then, the solution was filtered and the crude product was purified by silica gel column (97:3 CH2Cl2 / MeOH; TLC performed in 95:5 CH2Cl2 / MeOH conditions, Rf=0.2) to obtain 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.

[0620] 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 + )(C 29 H 39 Calculated value for N3O6: 525.6).

[0621] B) Synthesis of 1,4-bis-{[3-(N-1,3-dihydroxypropane-2-yl)aminomethyl]-2-hydroxy-5-methylbenzyl}-7-tert-butyloxycarbonyl-1,4,7-triazacyclononane

[0622] 1,4-bis-(3-formyl-2-hydroxy-5-methylbenzyl)-7-tert-butyloxycarbonyl-1,4,7-triazacyclononane (0.104 g, 0.20 mmol) was dissolved in 1 ml of MeOH and an excess of 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 checked by MS spectrometry: ESI-MS (m / z): 672.4 (M+H + )(C 35 H 53 N5O8 calculated value: 671.8) and 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 for 15 minutes, and finally, the precipitate was removed by filtration. The final product was characterized by HPLC-MS (XBridge Phenyl 3.5μm (4.6x 150mm); 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 minutes.

[0623] 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 C NMR (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 + )(C 33 H 57 Calculated value for N5O8: 675.8).

[0624] C) Synthesis of Compound 4 (2,2'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol)

[0625] 1,4-bis-{[3-(N-1,3-dihydroxypropane-2-yl)aminomethyl]-2-hydroxy-5-methylbenzyl}-7-tert-butyloxycarbonyl-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, and the solution was filtered with a 0.2 μm filter to remove solid residues. The product was purified using semi-preparative HPLC-MS and obtained as a white monotrifluoroacetate salt (0.16 g, 53%) after lyophilization. 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 (4.6x 150mm); 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.

[0626] 1 H NMR (500MHz, D2O): δ = 2.17 (s, 6H, CC H3 ),2.93(bs,4H,C H2 -N), 3.26 (quintet, 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 CNMR(125MHz,D2O): δ=19.4(Ph- C H3),42.6( C H2-N),44.9(Ph-CH2-N),49.1( CH2-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 + )(C 30 H 49 Calculated value for N5O6: 575.7).

[0627] Example 4-Synthesis of Compound 57

[0628] The synthesis of compound 57 was carried out according to the following Scheme 11:

[0629]

[0630] Synthesis of 2,2',2"-{1,4,8-triazacyclononane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(propane-1,3-diol) (Compound 57)

[0631] 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. 2-Hydroxy-3-bromomethyl-5-methylbenzaldehyde (0.291 g, 1.27 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 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. Then, the product was dissolved in 20 ml of dichloromethane and washed with water (10 ml x 2) and brine (10 ml x 1); the organic phase was anhydrified with sodium sulfate, filtered and the solvent was evaporated. The product 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: 4.50 min. ESI-MS (m / z): 602.5 (M+H + )(C 35 H 43 Calculated value for N3O6: 601.7).

[0632] The product was used in the next step without further purification. Therefore, the solid was dissolved in 20 ml of MeOH and an excess of 2-amino-1,3-propanediol (0.118 g, 1.29 mmol) dissolved in 5 ml of anhydrous methanol was added. The solution was stirred at room temperature overnight. The imine intermediate was checked by MS spectrometry: ESI-MS (m / z): 822.0 (M+H + )(C 44 H 64Calculated value of N6O9: 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. The 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 and 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 5μm (19x100mm); 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 BEHC18 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 + )(C 44 H 70 Calculated value for N6O9: 827.1).

[0633] 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 macrocycle, 8H), 4.25, 4.30 (s, -N- CH2 -Ph-,12H),7.21(s,-CH,3H),7.28(s,-CH,3H). 13 C 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).

[0634] Example 5-Synthesis of Compound 60

[0635] The synthesis of compound 60 was carried out according to the following Scheme 12:

[0636]

[0637] 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 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 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 + ],(C 14 H 25 Calculated value for N3O2: 267.4).

[0638] B) 7-(2-(2-tetrahydropyran (piran) oxy) ethyl)-1,5,7-triazabicyclo [4.4.0] dec-5-ene (921 mg) was dissolved in HCl 1M (15.0 mL) and the mixture was stirred at room temperature for 6 h. NaOH pellets were added to reach a pH value > 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, which was then 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 + ](C9H 16 N3 + Calculated value: 166.2).

[0639] 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 a 1 M solution in THF, 1 equivalent) was added. The mixture was stirred under a nitrogen atmosphere for 1.5 h, then the reaction was quenched with MeOH (2.0 mL) and stirring was maintained for about 15 min (until the bubbling ended). The solvent was removed under reduced pressure. The product was dissolved in DCM (35 mL) and washed with 1M Na2CO3 (3x10 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 + ](C9H 17 Calculated value of N3: 167.2).

[0640] D) The tricyclic anthranilide (350 mg, 2.09 mmol) was dissolved in ACN (30 mL) and 3-bromomethyl-5-methyl-2-hydroxybenzaldehyde (527 mg, 1.1 eq.) was added. The mixture was stirred at room temperature overnight. The solvent was then removed under reduced pressure. The product was confirmed by HPLC-MS analysis (Waters XBridge Phenyl 3.5 μm 4.6x150 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 minutes. ESI+ MS: m / z = 316.4 [M + ](C 18 H 26 N3O2 + Calculated value: 316.2). The product was purified by flash chromatography (Sepachrom Purezza Phenyl 25μ15g), A = H2O; B = MeOH; flow rate = 15mL / min; 1 column volume (CV) 40% B; 10CV from 40 to 100% B; 2CV 100% B. Retention time: 3.7 minutes. 11 mg of pure product was obtained.

[0641] E) The monoalkylated product (11 mg, 0.028 mmol) was dissolved in HCl 0.1 M (3.0 mL) and the mixture was stirred at room temperature for 24 h. The acid was neutralized with NaOH 2 M (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 4.6x150 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 minutes. ESI + MS: m / z = 334.5 [MH + ](C 18 H 27 Calculated value for N3O3: 333.5).

[0642] F) The crude product (11 mg, 0.028 mmol) was dissolved in ACN (5.0 mL); K2CO3 (12 mg, 3 eq.) and 3-bromomethyl-5-methyl-2-hydroxybenzaldehyde (9 mg, 1.5 eq.) were then 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 in the next step without further purification. ESI + MS: m / z = 482.6 [MH + ](C 27 H 35 Calculated value for N3O5: 481.6).

[0643] G) The previous intermediate (15 mg, 0.031 mmol) was dissolved in anhydrous MeOH (5.0 mL) and serinol (7 mg, 2.5 eq.) was added. The mixture was stirred at room temperature overnight. NaBH4 (6 mg, 5 eq.) (0°C, ice bath) was added 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 and the product was redissolved in EtOH, filtered and dried again under reduced pressure. The product (41 mg) was used without further purification. UPLC-MS (AcquityUPLC 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 + ](C 33 H 53 Calculated value for N5O7: 631.8).

[0644] H) The previous intermediate was dissolved in HCl 4M (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 material. 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 minutes. ESI + MS: m / z = 604.8 [MH + ](C 32 H 53 Calculated value for N5O6: 603.8).

[0645] 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).

[0646] Example 6-Synthesis of Compound 61

[0647] The synthesis of compound 61 was carried out according to the following Scheme 13:

[0648]

[0649] 1,4,8-triazacycloundecane (0.030 g, 0.192 mmol, TACUD) was dissolved in 1.5 ml 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 acetonitrile / dichloromethane 1:1 solution was added dropwise to the solution. The reaction mixture was heated to 60 ° C and stirred for 24 h. Then, the solvent was removed under reduced pressure to obtain 0.16 g of crude product. The product was characterized by UPLC-MS (AcquityUPLC 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: 1.44 min. ESI-MS (m / z): 454.5 (M+H + )(C 26 H 36Calculated value for N3O4: 454.6). The product was used in the next step without further purification. Therefore, the solid was dissolved in 15 ml of MeOH and an excess of 2-amino-1,3-propanediol (0.096 g, 1.05 mmol) dissolved in 5 ml of anhydrous methanol was added. The solution was stirred at room temperature overnight. The imine intermediate was checked by MS spectrometry: ESI-MS (m / z): 600.4 (M+H + )(C 32 H 49 Calculated value of N5O6: 599.8). The solution was cooled to 0°C and NaBH4 (0.12 g, 3.2 mmol) was slowly added portionwise. The reaction mixture was then stirred at room temperature for 48 h. The reducing agent was quenched by dropwise addition of 1 ml of water and then 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 5μm (19x100mm); 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 + )(C 32 H 53 Calculated value for N5O6: 603.8).

[0650] 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). 13 CNMR (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).

[0651] Example 7-Synthesis of Compound 112

[0652] The synthesis of compound 112 was carried out according to the following Scheme 14:

[0653]

[0654] Synthesis details for this example are provided below.

[0655] 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 the solution. The reaction mixture was heated to 60°C and stirred overnight. Then, the solution was filtered and the crude product was precipitated in ether. Then, the crude 1,4-di-(3-formyl-2-hydroxy-5-methylbenzyl)-7-benzyl-1,4,7-triazacyclononane (0.19 g, 0.37 mmol) obtained in the previous step was dissolved in 1 ml of MeOH and an excess of 2-amino-1,3-propanediol (0.10 g, 1.12 mmol) was added. The solution was stirred at room temperature for 1 h. The imine intermediate was checked by MS spectrometry: ESI-MS (m / z): 662.4 (M+H + )(C 37 H51 N5O6 calculated value: 661.8) and the mixture 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 for 15 minutes, and finally, the precipitate was removed by filtration. The final product was characterized by HPLC-MS (XBridge Phenyl 3.5μm (4.6x 150mm); A = H2O / 0.1% TFA; B = ACN; flow rate = 1 mL / min; 0-2min = 10% B; 2-16min = from 10% to 100% B; 16-19min = 100% B; 19-20min = from 100% to 10% B). Retention time: 8.80 minutes.

[0656] The solvent was removed under reduced pressure and the crude product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5 μm (19×100 mm); A=H 2 O / 0.1% TFA; B=ACN; flow rate=20 mL / min; 0-1 min=90% A; 1-9 min=from 10% to 54% B; 9-11 min=from 54% to 100% B; 11-13 min=100% B; 13-14 min=from 100% to 10% B; 14-16 min=10% B). Yield: 82%.

[0657] 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 + )(C 37 H 55 Calculated value for N5O6: 665.9).

[0658] Example 8-Synthesis of Compound 177

[0659] The synthesis of compound 177 was carried out as described in Scheme 15 below and according to the following details:

[0660]

[0661]

[0662] A) Synthesis of 2-hydroxymethyl-4-methyl-6-nitrophenol

[0663] 4-Methyl-2-nitrophenol (0.1 g, 0.65 mmol) was dissolved in 2 ml of KOH 4M and the temperature was set at 80°C. When the temperature was reached, p-formaldehyde (0.029 g, 0.98 mmol) was added and the reaction mixture was stirred for 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 removed under reduced pressure to give a light yellow oil (0.106 g, 90% yield).

[0664] 1 H 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 CNMR (125MHz, CDCl3): δ=20.4 (Ph- C H3),60.4(- CH2), 124.9(-CH), 128.6(-CCH2), 129.7(-CNO2), 134.2(-CCH3) 139.3(-CH), 151.3(-COH). MS calculated for C8H9NO4: 183.05.

[0665] B) Synthesis of 3-hydroxymethyl-2-hydroxy-5-methylphenylacetamide

[0666] 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, and the suspension was stirred at room temperature for 2 h under H2-atmosphere. The mixture was filtered with a PTFE filter to minimize the air contact of the compound. Then, acetyl chloride (41 μl, 0.58 mmol) was added to the solution under N2 atmosphere and the reaction mixture was stirred overnight. Finally, the solvent was removed under reduced pressure to obtain a light yellow oil (34 mg, 30% yield).

[0667] 1 H 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). C 10 H 13 MS calculated value for NO3: 195.2.

[0668] C) Synthesis of N,N',N"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}triacetamide (Compound 177)

[0669] 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 with MgSO4, filtered and the solvent was removed under reduced pressure. The product was used without further purification. Thus, a solution of the mesylate in 1 ml of 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 ACN (1 mL). Then, the reaction mixture was stirred at room temperature overnight. The final compound was observed by ESI-MS (m / z): 661.4 (M+H + )(C 29 H 39 Calculated value for N3O6: 660.8).

[0670] Example 9 - Fe(III) complexation

[0671] The Fe(III) chelate was prepared by complexation reaction as follows: the ligands obtained in Examples 1, 2, 7, and 8 were dissolved in ethanol, and the ligands obtained in Examples 3 to 6 were dissolved in water, and then an equimolar Fe 3+ The reaction was carried out at 298 K for 18 hours. For the complexes obtained from Examples 1, 2, 7 and 8, the solvent was then removed, the product was dissolved in water, and (for all complexes) the pH of the solution was corrected to 8.5 with dilute NaOH to promote any excess free Fe 3+ of precipitation.

[0672] Example 10 - Relaxometry Analysis

[0673] The relaxivity values ​​of certain complexes of the invention were evaluated by measuring them at 298 K in magnetic fields relevant to clinical practice (i.e. at 1.5 and 3.0 T) as follows: Variable field relaxometry was used in aqueous solution equipped with a HTS-110 3 T metrology cryogenic superconducting magnet (Mede, Italy) 1H NMRD, the relaxometer is operated in the overall range of the proton Larmor frequency of 20-120MHz (0.47-3.00T). Using standard inversion recovery sequence (20 experiments, 2 scans) to measure, typical 90 ° pulse width is 3.5μs, and the reproducibility of data is within ± 0.5%. Temperature is controlled by Stelar VTC-91 heater airflow. Other points in the frequency range of 0.01-10MHz are collected on the fast field cycle (Fast-Field Cycling, FFC) Stelar SmarTracer relaxometer. The T1 value at 500MHz is collected using the Bruker NMR spectrometer operated at 11.7T. The longitudinal and transverse relaxivity values ​​(R1 and R2) at 1.5 and 3.0T in pure water and in reconstructed human serum (Seronorm matrix) are also measured at 298 and 310K. All experiments are repeated three times, and the reproducibility of data is within ± 0.5%. The Fe content in different solutions was determined by bulk magnetic susceptibility (BMS) offset measurements at 11.7 T. 3+ The concentration of (D. F. E. vans, J. Chem. Soc., 1959, 2003) and was confirmed by ICP-MS analysis after mineralization of the sample with 65% HNO3 at 408K.

[0674] Compound 1 (concentration 0.40 mM), Compound 2 (concentration 0.60 mM), Compound 4 (concentration 0.65 mM), Compound 57 (concentration 0.50 mM), Compound 60 (concentration 0.47 mM), Compound 61 (concentration 0.60 mM) and Compound 112 (concentration 0.78 mM) were tested at 1.5 and 3.0 T field strengths, pH = 7.4 and 310 K in 0.15 M NaCl, in 0.15 M NaCl and 25 mM NaHCO3 and in Seronorm TM The relaxivity r1 values ​​of the Fe(III) complexes in (lyophilized human serum) were determined as described above and are shown in Table 1.

[0675]

[0676] Table 1

[0677] Considering the data of Table 1, it can be seen that the complexes of the present invention exhibit high and suitable relaxivity r1 values ​​for MRI imaging, especially under physiological conditions.

[0678] In addition, it can be seen from Table 1 that the complex of the present invention does not substantially interact with proteins in human serum (such as human serum albumin) because in Seronorm TMThe relaxivity values ​​in (lyophilized human serum) were comparable to those in the other two conditions (NaCl 0.15 M and NaCl 0.15 M (HCO3 - For this reason, in vivo, the complexes of the present invention can be cleared faster and evenly distributed in organs and textiles relative to complexes that interact with proteins in human serum, and thus have a wider range of MRI applications.

[0679] Example 11 - Thermodynamic Stability Analysis

[0680] In order to evaluate the thermodynamic stability of the Fe(III) complex of the present invention and the Fe(III) complex of the comparative example, the protonation constant of the corresponding ligand is first determined by pH-potentiometric determination and / or by UV spectrophotometry, and then the protonation constant of the Fe(III) complex is determined. Finally, based on the protonation constant, the thermodynamic stability constant of the Fe(III) complex of the present invention is determined by observing the competitive reaction between the Fe(III) complex and the N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED) ligand, using capillary zone electrophoresis (CZE) (for compound 2) and visible light spectrophotometry (for compound 4). A similar method was performed in WO 2020 / 099398 to evaluate the thermodynamic stability of different metal complexes. HBED is a ligand with the following formula, which forms a complex with a very low relaxation rate with Fe(III) (r1 is 0.49 mM at 60 MHz, 40°C in PBS buffer) -1 ·s -1 , as described in Bales et al., Contrast Media & Molecular Imaging, Vol. 2019, Article ID 8356931)

[0681]

[0682] A) Determination of the protonation constant of the ligand

[0683] Solid Fe(NO3)3 was dissolved in 0.1M HNO3 solution. The concentration of the Fe(NO3)3 solution was determined using an excess of standardized Na2H2EDTA. The excess of Na2H2EDTA was measured using a standardized ZnCl2 solution and xylenol orange as an indicator. The H concentration of the Fe(NO3)3 solution was determined by pH potentiometric titration in the presence of excess Na2H2EDTA. + concentration. In the presence and absence of 40-fold excess Ca 2+In the case of , the concentrations of ligand compound 2, compound 4, H3NOTA (comparison - see formula below) and H4HBED (comparison) were determined by pH-potentiometric titration. The pH-potentiometric titration was performed using standardized 0.2M NaOH (the concentration of the ligand was typically 0.002M). For pH measurement and titration, a Metrohm 888 Titrando titration workstation Metrohm-6.0234.110 combination electrode was used.

[0684]

[0685] The protonation constants (K) of compound 2, NOTA (comparison) and HBED (comparison) obtained by the above pH potential measurement method are shown in Table 1. i H =[H i Ligand] / ([H i-1 Ligand]x[H + ])) was subsequently used to determine the protonation constants and thermodynamic stabilities of the corresponding Fe(III) complexes.

[0686] The protonation constant of compound 2 was confirmed by UV spectrophotometric analysis (using the instrument PerkinElmer Lambda 365 UV-Visible spectrophotometer) in the wavelength range of 210-390 nm ([Compound 2] = 87 μM, 0.15 M NaClO4, 25°C). The absorption bands of the aromatic groups of the ligands were studied by spectrophotometry, and the phenol-OH and isoserinol-NH2 of compound 2 were studied based on the absorbance values ​​at 243 and 303 nm. + The absorbance of the ligand is the combination of the absorption of each protonated species and is expressed by the following equation (Beck, MT et al., Chemistry of Complex Equilibria, Akademia Kiadó Budapest and Nostrand Reinhold Company Ltd. London, 1990):

[0687] A=∑c i ε i l

[0688] Where A is the absorbance at a given wavelength, c i , ε i and l are the concentration of the substance, the molar absorptivity and the path length of the cuvette, respectively. The absorbance values ​​(A) have been fitted to the above equation (the concentrations of different protonated ligands have been expressed using the protonation constant K i H express).

[0689] The protonation constant of compound 4 has been determined by 1 H-NMR spectroscopy was determined using a Bruker Avance III (9.4T) spectrometer equipped with a Bruker variable temperature device (BVT), a Bruker cooling unit (BCU) and a BB inverse z-gradient probe (5 mm), wherein the chemical shift changes of non-labile protons in a 0.15 M NaNO3 solution at 25°C were recorded as a function of pH. Since protonation / deprotonation occurs rapidly on the NMR time scale, the chemical shift of the observed signal represents a weighted average of the shifts of different substances with different protonation states and is represented by the following equation (Pagado, JM; Goldberg, DE; Fernelius, WC; J. Phys. Chem., 1961, 65, 1062.):

[0690] δ H(obs) =∑c i δ H HiL

[0691] where δ H(obs) is the observed chemical shift of a given signal, c i and δ H HiL are the concentration and chemical shift of the substances involved. H(obs) ) has been fitted to the above equation (the concentrations of the different protonated ligands have been expressed using the protonation constant K i H express).

[0692] B) Determination of the protonation constant of the Fe(III) complex

[0693] The protonation constants (K) of the Fe(III) complexes of compound 2, compound 4, NOTA (comparative) and HBED (comparative) were determined by pH-potentiometry and / or by spectrophotometric studies. MHi配体 =[MH i Ligand] / ([MH i-1 Ligand]x[H + ])).

[0694] Specifically, the protonation constants of Fe(NOTA) and Fe(HBED) complexes were determined using pH-potentiometric determination by titrating the pre-prepared complexes from pH=1.7 to pH=12.0 with 0.2M NaOH ([FeL]=0.002M). For pH measurement and titration, a Metrohm 888Titrando titration workstation Metrohm-6.0234.110 combined electrode was used. Equilibrium measurements were performed in 6 ml of sample at a constant ionic strength (0.15M NaNO3 or NaClO4) at 25°C. The solution was stirred and bubbled with N2. The titration was performed in a pH range of 1.7-12.0. The pH meter was calibrated using KH-phthalate (pH=4.005) and borax (pH=9.177) buffers. In order to calculate [H + ], using the method disclosed in Irving et al. Anal. Chim. Acta, 1967, 38, 475-488 as follows: titrate a 0.01 M HNO3 or HClO4 solution with a standardized NaOH solution at 0.15 M NaNO3 ionic strength. Use the measured pH (pH 读出 ) and calculated pH (-log [H + The equilibrium H is obtained from the pH value measured in the titration experiment. + concentration (for 0.15M NaNO3, A = 0.02; for 0.15M NaClO4, A = 0.01). For equilibrium calculations, the stoichiometric amount of the water ion product (pK w ) to calculate [OH - ] value. The V of HNO3-NaOH titration obtained in the pH range of 10.5-12.0 NaOH -pH 读出 The data pairs are used to calculate pK w Value (pK w =13.76).

[0695] According to the method disclosed in the above Example 11A, the protonation constants of 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).

[0696] The protonation constants of the Fe(III) complexes of Compound 2, Compound 4, NOTA (comparative) and HBED (comparative) were then used to determine the thermodynamic stability of the same Fe(III) complexes.

[0697] C) Determination of the thermodynamic stability of Fe(III) complexes

[0698] The thermodynamic stability constant (K) of the Fe(III) complex was determined as follows M配体 =([Mligand] / ([M]x[ligand])).

[0699] By Fe 3+ -NOTA system spectrophotometric study in [H + ]=Fe at 0.01-3.0M III The absorption band of the complex in the wavelength range of 350-800 nm determines the stability constant of the Fe(NOTA) complex. 3+ The concentration of NOTA was 0.002 M. The H in the sample was adjusted by adding a calculated amount of 6 M HNO3 solution. + Concentration (I=[Na + ]+[H + ]=0.15,[H + ]≤0.15M). The samples were stored at 25°C for two weeks. The absorbance values ​​of the samples were measured at 11 wavelengths (370, 380, 390, 395, 400, 405, 410, 415, 420, 425 and 430 nm). In order to calculate the thermodynamic stability constant of Fe(NOTA), the Fe 3+ and Fe(NOTA) solution of 1.0x10 -3 , 1.5x10 -3 , 2.0x10 -3 and 2.5x10 -3 The spectrum of M solution was used to determine Fe 3+ and the molar absorption coefficient of Fe(NOTA). The absorption spectra of Fe(NOTA) solutions were recorded in the pH range of 1.7-7.5. All spectrophotometric measurements were performed in 0.15 M NaNO3 solution at 25°C. The pH was adjusted by stepwise addition of concentrated NaOH or HNO3 solution.

[0700] The absorption band of the Fe(HBED) complex was detected by spectrophotometry in the wavelength range of 400-700 nm by following the interaction between HBED and NOTA ligands. 3+ -ions, and the stability constant of the Fe(HBED) complex was determined. 3 + -HBED-NOTA system, six samples were prepared in 0.15 M NaNO3 solution, where [Fe 3+]=0.1mM, [HBED]=0.2mM and [NOTA]=0.0, 2.0, 4.0, 6.0, 8.0 and 10.0mM. The pH value of the sample was adjusted to 5.0 by gradually adding 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 by spectrophotometry. The absorbance value of the sample was measured at the absorption band of the Fe(HBED) complex ([Fe(HBED)] - Thermodynamic stability constants of the Fe(HBED) complex were calculated by recording the concentrations of 0.5, 0.1 and 0.2 mM [Fe(HBED)] - The spectra of the solutions were used to determine [Fe(HBED)] - The molar absorptivity of the substance. Spectrophotometric measurements were performed using a PerkinElmer Lambda 365 UV-Vis spectrophotometer using 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.)

[0701] Capillary zone electrophoresis (CZE) was used to track the Fe(compound 2) complex signal by tracking the interaction between compound 2 and HBED ligand. 3+-ions, and the thermodynamic stability constant of the Fe (compound 2) complex was determined. CZE separation was performed using an Agilent 7100 capillary electrophoresis system using a bare fused silica capillary of 64 cm x 50 μm inner diameter (Agilent). Before the first use of the capillary, the capillary was washed with 1.0 M NaOH (15 min), 0.1 M NaOH (30 min), and buffer electrolyte (30 min). Before CZE analysis, all buffers were filtered through a 0.45 μm syringe filter and stored in a refrigerator at +4°C. In CZE, the sample solution was introduced into the anode end 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 buffer electrolyte (150 mM sodium bicarbonate, pH = 8.2) for 3 minutes. A voltage of 30 kV was applied at 37°C for separation. After analysis, post-treatment (0.1M NaOH (3min) and buffer (3min)) was applied to remove all possible adsorbed substances from the capillary. In all measurements, 5mMDSO was used as an internal standard to correct the migration time of components on the electrophoresis pattern. Detection was performed at 500nm by DAD measurement on the column. The electrophoresis pattern was recorded and processed by the ChemStation computer program (Agilent) of 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 the electrophoresis pattern of 22, 44 and 87 μM Fe (compound 2) solutions at pH=6.0 and 25°C in the presence of 0.15M NaNO3 ionic strength. Each linear regression equation (response-concentration) of Fe (compound 2) was determined according to three concentrations. It was found that the peak area was linear (R2>0.998) in the concentration range of 22-87 μM, with an accuracy better than 4%. The LOD and molar integrated values ​​were found to be 2.7 μM and 133294 mAU, respectively. -1 M -1 (LOD = 3σ / mole integral).

[0702] For Fe 3+ -Compound 2-HBED system, five samples were prepared in 0.15M NaNO3 solution, where [Fe(Compound 2)] = 87 μM, [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 equilibrium. The time required to reach equilibrium was determined by CZE studies. The amount of Fe(Compound 2) complex was determined based on the Fe(Compound 2) complex between Compound 2 and HBED. 3+-ions and reduced by competitive reaction (Equation 1). No signals of negatively charged Fe(HBED) and compound 2 ligands appeared in the electrophoresis spectrum.

[0703]

[0704] where α H =K1 H [H + ]+K1 H K2 H [H + ] 2 +…+K1 H K2 H …K n H [H + ] n And K1 H ,K2 H ,…K n H is the protonation constant of the free ligand determined in Example 11A, and α Fe(Cpd2) =K FeHL [H + ]+K FeHL K FeH2L [H + ] 2 +K FeHL K FeH2L K FeH3L [H + ] 3 is the protonation constant of the Fe(Compound 2) complex determined in Example 11B in 0.15 M NaNO 3 solution at 25° C. (at pH=11 and 25° C. in 0.15 M NaNO 3 , the Fe(HBED) species predominates).

[0705] By considering the molar integral values ​​of Fe(Compound 2) complexes obtained from the electropherograms recorded for 22, 44 and 87 μM Fe(Compound 2) solutions, and the total concentration of HBED ([HBED] tot =[H x HBED]+[Fe(HBED)]),Fe 3+ The total concentration of ions ([Fe 3+ ] tot =[Fe(H z Compound 2] + [Fe(HBED)] and the total concentration of compound 2 ([compound 2] tot =[Fe(H z Compound 2)]+[H y Compound 2]), found K FeNBThe value is (3.5±0.2)x10 -4 By considering the stability constant (logK Fe(HBED) =40.2, 0.15M NaNO3, 25°C), the protonation constants of compound 2 and HBED ligand (Table 1, 25°C, 0.15M NaNO3) and the protonation constant of Fe (compound 2) complex (Table 2, 25°C, 0.15M NaNO3). It was found that the thermodynamic stability constant of Fe (compound 2) complex in 0.15M NaNO3 solution at 25°C is logK Fe(化合物2) =44.0(3).

[0706] The absorption bands of Fe(compound 4) and Fe(HBED) complexes in the wavelength range of 400-700 nm were followed by spectrophotometric tracking of the Fe binding between compound 4 and HBED ligand. 3+ -ions, and the stability constant of the Fe (compound 4) complex was determined. 3+ -Compound 4-HBED system, six samples were prepared in 0.15M NaNO3 solution, where [Fe 3+ ]=0.1mM, [Compound 4]=0.1mM and [HBED]=0.0, 0.05, 0.1, 0.2, 0.4, 0.5, 1.0 and 2.0mM. The pH value of the sample was adjusted to 12.0 by gradually adding 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 by spectrophotometry. The absorbance value of the sample was measured at the absorption band of Fe(Compound 4) and Fe(HBED) complex ([Fe(Compound 4)H -1 ], [Fe(HBED)] - and [Fe(HBED)H -1 ] -2 Thermodynamic stability constants of the Fe(compound 4) complex were calculated by recording the concentrations of 0.5, 0.1 and 0.2 mM [Fe(compound 4)] and [Fe(HBED)] in the presence of 0.15 M NaNO3 over the pH range 7.0-12.5. - The spectra of the solutions were used to determine [Fe(compound 4)H -1 ], [Fe(HBED)] - and [Fe(HBED)H -1 ] 2-The molar absorptivity of the substance. Spectrophotometric measurements were performed using a PerkinElmer Lambda 365 UV-Vis spectrophotometer using 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.)

[0707] D) Protonation constant and thermodynamic stability of Fe(III) complexes

[0708] Thermodynamic stabilities and protonation constants (determined from the above experiments) of the Fe(III)-complexes of Compound 2 and Compound 4 as well as the comparative complexes NOTA and HBED are summarized in Table 2 below.

[0709]

[0710] Table 2

[0711] a Capillary zone electrophoresis (0.15 M NaNO3, 25°C), b Spectrophotometry (0.15M NaClO4, 25℃), c Spectrophotometry (0.15M NaNO3, 25℃), d Reference compound for determining the thermodynamic stability of the Fe(III)-complexes of compounds 2 and 4

[0712] In order to compare the thermodynamic stability of Fe(compound 2), Fe(compound 4), Fe(HBED) and Fe(NOTA) complexes, we have studied the thermodynamic stability of Fe(compound 2), Fe(compound 4), Fe(HBED) and Fe(NOTA) complexes in the presence of 1 μM Fe 3+ The pFe value (pFe = -log [Fe 3+ ] free ,[Fe 3 + ] tot =1μM,[L] tot=10 μM, pH=7.4.; S. Hajela et al., J. Am. Chem. Soc., 2000, 122, 11228-11229), which characterizes the conditional stability of the Fe(III)-complex. Based on the pFe value, it can be seen from the data in Table 2 that Fe(Compound 2) has the highest thermodynamic stability, thereby confirming the in vivo safety of the Fe(III) complex of the present invention; such high thermodynamic stability is even higher than the thermodynamic stability of the comparative Fe(NOTA) complex. In addition, based on the pFe value, Fe(Compound 4) also shows a very high thermodynamic stability, even higher than the thermodynamic stability of the comparative Fe(NOTA) complex.

[0713] Example 12 - Kinetic Inertness Analysis

[0714] In order to obtain data related to the kinetic inertness of Fe(Compound 2), Fe(Compound 4) and Fe(NOTA) (comparative), the transchelation reaction (shown below) was studied by visible spectrophotometry (for Fe(Compound 4) and Fe(NOTA), comparative) and by capillary zone electrophoresis (CZE) (for Fe(Compound 2)) in the presence of a large excess of HBED as the exchange ligand (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 Fe(NOTA): [Fe(NOTA)] = 0.2 mM, [HBED] = 2.0 and 4.0 mM, 0.15 M NaNO3, 25°C) to ensure pseudo-first-order kinetic conditions.

[0715]

[0716] Wherein L = Compound 2, Compound 4 or NOTA.

[0717] A) Determination of the kinetic inertness of Fe(III) complexes

[0718] The transchelation reaction of Fe(compound 4) and Fe(NOTA) (comparative) was studied spectrophotometrically, where the formation of the resulting Fe(HBED) complex was followed at 472 and 470 nm using a PerkinElmer Lambda 365 UV-Vis spectrophotometer. The concentrations of Fe(compound 4) and Fe(NOTA) complexes were 0.1 and 0.2 mM, respectively, whereas the concentration of HBED was 10-200 times higher in order to ensure pseudo-first order conditions. The temperature was maintained at 25 °C and the ionic strength of the solution was kept constant at 0.15 M NaNO3. The exchange rate was studied in the pH range of about 9.5-14.0. No buffer was used, as an excess of HBED was able to maintain the pH at a constant level at pH < 12. At pH > 12, the OH in the sample was adjusted by adding a calculated amount of 19 M NaOH. - concentration (I = [NaNO3] + [NaOH] = 0.15, [NaOH] ≤ 0.15 M). The pseudo-first-order rate constant (k d ).

[0719]

[0720] Among them A t , A0 and A p are the absorbance values ​​at time t, at the beginning of the reaction and at equilibrium, respectively.

[0721] The ligand exchange reaction in the Fe(Compound 2)-HBED reaction system has been studied by capillary zone electrophoresis (CZE) in the pH range of 9.5-11.5. The transchelation reaction of Fe(Compound 2) was studied by following the dissociation of the Fe(Compound 2) complex with an Agilent 7100 capillary electrophoresis system (using the same conditions as the CZE experiment of Example 11). The concentration of the Fe(Compound 2) complex was 87 μM, while the concentration of HBED was 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 at 1.0 M NaClO4. The pseudo-first-order rate constant (k) was calculated by fitting the area-time data to Equation 2 above. d ), where A t , A0 and A p are the area values ​​at time t, at the beginning of the reaction and at equilibrium, respectively.

[0722] Calculations were performed using the Micromath Scientist computer program (version 2.0, Salt Lake City, UT, USA).

[0723] B) Kinetic inertness of Fe(III) complexes

[0724] Kinetic inertness results (measured as dissociation rate constant k) of the Fe(III)-complex of compound 2 and the comparative complexes NOTA (determined according to the above experiments), EDTA and CDTA (as disclosed in Baranyai Z. et al., Chem. Sci., 2021, 12, 11138-11145) d and half-life t 1 / 2 The results are summarized in Table 3 below.

[0725]

[0726]

[0727] Table 3

[0728] The dissociation rate constant (k d The dissociation rate constant of Fe(NOTA) (calculated by extrapolating the kinetic data obtained at pH>9.0) is about two times lower than that of Fe(NOTA), i.e., the complexes of the present invention are more inert than the comparative Fe(NOTA). The dissociation half-life (t 1 / 2 =ln(2) / k d ) were approximately 11.3 and 0.65 years, respectively, which can be used as indicators of their safe application in vivo.

[0729] Example 13 - Transferrin stimulation reaction

[0730] Transferrin is an Fe 3+ - Binding transport proteins. Human serum transferrin (sTf) is known to bind Fe with high affinity 3+ (logK FeTf =21.44,logK Fe2Tf =20.34)(WR Harris, Y. Chen, K. Wein, Inorg. Chem., 1994, 33, 4991). Since only 30% of serum transferrin is Fe 3+ saturated, so it still retains a relatively high amount of Fe released by binding other Fe(III)-complexes 3+ ability, and even promote Fe 3+ In order to investigate the possible role of transferrin in the dissociation of the Fe(III)-complex of the present invention, the Fe(III)-complex was followed. 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. 3+ Saturated human serum transferrin (Sigma) was reacted with Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(IIII)-compound 61 complexes. The Fe content of human serum transferrin was determined as disclosed in Z. Baranyai, F. Uggeri, A. Maiocchi, GB Giovenzana, C. Cavallotti, A. Takács, I. Tóth, I. Bányai, E. Brücher, S. Aime, Eur. J. Inorg. Chem. 2013, 147-162.). 3+ Saturation; because the Fe of sTf 3+ Binding requires the concomitant binding of a co-anion, which in vivo is bicarbonate (GW Bates, MR Schlabach, J. Biol. Chem., 1975, 250, 2177-2181), so all measurements were performed in the presence of 25 mM NaHCO3 at pH = 7.4 and 25°C. 3+ - Human serum transferrin substances have different molar absorptivity, and the final dissociation of Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60, and Fe(III)-compound 61 complexes as well as the Fe(III)-transferrin complexes were followed spectrophotometrically in the presence of equimolar human transferrin in the wavelength range of 400-700 nm using a PerkinElmer Lambda 365 UV-Vis spectrophotometer. 3+ - formation of saturated human serum transferrin, and determination of Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61 complexes with 22.6% Fe 3+ -Possible metal exchange reactions of saturated human serum transferrin. Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61 complexes and 22.6% Fe 3+The concentration of saturated human serum transferrin is 0.1mM. The temperature is maintained at 25°C, and the ionic strength of the solution remains constant (0.15M NaCl). The pH of the sample is adjusted by progressively adding concentrated NaOH and HCl solutions. Observe that the absorption spectrum of the reaction systems of 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 remains unchanged within the reaction time of 1100min, which means that, compared with the Fe (III)-complex of sTf, the Fe (III)-complex formed with compound 2, compound 4, compound 57, compound 60 and compound 61 has very high kinetic inertness and / or higher conditional stability. In fact, even at 22.6% Fe 3+ - In the presence of saturated sTf (i.e., close to physiological conditions, the latter being pH = 7.4, 25°C, 25 mM NaHCO3, 0.15 M NaCl), the complex of the present invention will not dissociate. This further demonstrates the high kinetic inertness and / or thermodynamic stability of the compounds of the present invention when complexed with Fe(III), such as the high kinetic inertness and / or thermodynamic stability of Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61.

[0731] Example 14 - Redox Stability Analysis

[0732] In order to characterize the redox stability of the Fe(III) complex, the reaction of ascorbic acid 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) was studied by following the reduction of the Fe(III) complex by spectrophotometry in the presence of a large excess of ascorbic acid as follows ([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 NaNO3, 25°C).

[0733] A) Determination of the redox stability of Fe(III) complexes

[0734] 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 rate with ascorbic acid was evaluated, the reduction reaction was observed spectrophotometrically, and the formation of Fe(II)-ligand complexes was followed 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 Fe(III) (NOTA), Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61 complexes 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 Fe(III) (NOTA) experiments, a four-fold excess of free NOTA ligand was added as a scavenger to complex possible Fe 2+ ions, the Fe 2+ ions can be released by Fe(II)NOTA after it is possibly reduced from Fe(III)(NOTA) (the stability of Fe(II)NOTA is low, so such complexes can release Fe 2+ ions). The temperature was maintained at 25°C and the ionic strength of the solution was kept constant, NaNO3 was 0.15 M. The reduction rate was studied at pH = 7.4. In order to keep the pH constant, 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 (k) was calculated by fitting the absorbance-time data pairs to equation 2 using the Micromath Scientist computer program (version 2.0, Salt Lake City, UT, USA). obs =k d ).

[0735] B) Redox stability data of Fe(III) complexes

[0736] The absorption spectra of the above experiments show that for Fe(III)(NOTA), the absorbance value decreases over time due to the reduction of Fe(III)(NOTA) by ascorbic acid, and in fact the reduction half-life (t 1 / 2 =ln2 / k obs ) is t 1 / 2 =2.7 min (the ascorbic acid excess mentioned in section A) above). By taking into account 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 considering that the reduction rate of the Fe(III)-complex 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 is t 1 / 2 =19.5h ([ascorbic acid]=43μM, pH=7.4, 0.01M HEPES, 0.15M NaNO3 25°C).

[0737] It was further observed 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 over time, i.e., even in the presence of a 200-fold excess of ascorbic acid, the absorbance values ​​decreased by 12%, 35%, and 40%, respectively, within 1 day. Based on such spectral changes, in the Fe(III)-compound 4-ascorbic acid, Fe(III)-compound 60-ascorbic acid, and Fe(III)-compound 61-ascorbic acid reaction systems, 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 seemed to occur very slowly. By considering the in vivo concentration of ascorbic acid ([ascorbic acid] = 43 μM) and taking into account that the reduction rate of the Fe(III)-complex is proportional to the concentration of ascorbic acid, it was found that the ascorbic acid-mediated reduction of Fe(III)-compound 4, Fe(III)-compound 60, and Fe(III)-compound 61 under physiological conditions is t 1 / 2 =3.5x10 3 , 1.6x10 3and 3.0x10 3 h ([ascorbic acid] = 43 μM, pH = 7.4, 0.01 M HEPES, 0.15 M NaNO3 25°C). 1 / 2 The values ​​can indicate their safe and effective in vivo application.

[0738] Furthermore, it was observed that the absorption spectra of the Fe(III)-compound 2-ascorbic acid and Fe(III)-compound 57-ascorbic acid reaction systems remained unchanged over a reaction time of 1 day, which can be explained by the higher selectivity (ΔpFe>16) of compound 2 and compound 57 for Fe(III)-ions over Fe(II)-ions; in other words, even in the presence of a large excess of ascorbic acid (reducing agent) when complexing with compound 2 and compound 57, iron is preferentially maintained in the +3 oxidation state and is not reduced to +2. Again, this can indicate the safe and effective in vivo application of the Fe(III)-complex of the present invention.

Claims

1. A compound of formula (I) or an ion, stereoisomer, tautomer, hydrate, solvate, pharmaceutically acceptable salt, or mixture thereof: in: n, m and o are independently selected from integers between 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, the C1-C6-alkyl being optionally substituted by one or more groups selected from hydroxyl (-OH), carboxyl (-COOH) and phosphonate (-PO3H2); R is selected from hydrogen, C1-C4 alkyl optionally substituted by aryl and a moiety of formula (IA): Wherein: the asterisk (*) indicates the point of attachment of the moiety of formula (IA) to the nitrogen carrying the R group; Y 3 With the above about Y 1 and Y 2 The same meaning provided; R 3 With the above R 1 and R 2 The same meaning provided; L 3 With the above about L 1 and L 2 the same meaning as provided; and Z 3 With the above about Z 1 and Z 2 Same meaning provided.

2. The compound according to claim 1, wherein Y 1 and Y 2 and Y if present 3 Independently selected from hydrogen and C1-C3-alkyl.

3. The compound according to claim 2, wherein Y 1 and Y 2 and Y if present 3 Independently selected from hydrogen and C1-C2-alkyl.

4. The compound according to claim 3, wherein Y 1 and Y 2 and Y if present 3 are independently selected from hydrogen and C1-alkyl.

5. The compound according to claim 4, wherein Y 1 and Y 2 and Y if present 3 It's hydrogen.

6. The compound according to any one of claims 1 to 5, wherein R 1 , R 2 and R if present 3 Independently selected from hydrogen and C1-C3-alkyl.

7. The compound according to claim 6, wherein R 1 , R 2 and R if present 3 Independently selected from hydrogen and C1-C2-alkyl.

8. The compound according to claim 7, wherein R 1 , R 2 and R if present 3 are independently selected from hydrogen and C1-alkyl.

9. The compound according to claim 8, wherein R 1 , R 2 and R if present 3 It is methyl (-CH3).

10. The compound according to any one of claims 1 to 9, wherein L 1 , L 2 and L if it exists 3 Independently selected from C1-C3-alkylamino, C1-C3-alkylamide and C1-C3-alkyl ether; preferably C1-C3-alkylamino and C1-C3-alkylamide.

11. The compound according to claim 10, wherein L 1 , L 2 and L if it exists 3 Independently selected from C1-C2-alkylamino, C1-C2-alkylamide and C1-C2-alkyl ether; preferably C1-C2-alkylamino and C1-C2-alkylamide.

12. The compound according to claim 11, wherein L 1 , L 2 and L if it exists 3 Independently selected from C1-alkylamino, C1-alkylamide and C1-alkyl ether; preferably C1-alkylamino and C1-alkylamide.

13. The compound according to claim 12, wherein L 1 , L 2 and L if it exists 3 independently selected from *-CH2-NH-·, *-C(O)-NH-·, *-NHC(O)-·, and *-CH2-O-·, wherein the asterisk (*) represents a phenolic moiety and the middle dot (·) represents Z 1 Group, Z 2 The group or Z if present 3 Group.

14. The compound according to claim 13, wherein L 1 , L 2 and L if it exists 3 Independently selected from *-CH2-NH-·, *-C(O)-NH-· and *-CH2-O-·; preferably *-CH2-NH-· and *-C(O)-NH-·, wherein the asterisk (*) represents a phenolic moiety and the middle dot (·) represents Z 1 Group, Z 2 The group or Z if present 3 Group.

15. The compound according to any one of claims 1 to 14, wherein Z 1 , Z 2 and Z if it exists 3 Independently selected from hydrogen, C4-C6-alkyl substituted by two or more hydroxyl (-OH) groups, and C1-C3-alkyl substituted by at least one group selected from hydroxyl (-OH), carboxyl (-COOH) and phosphonate (-PO3H2).

16. The compound according to claim 15, wherein Z 1 , Z 2 and Z if it exists 3 Independently selected from hydrogen, C6-alkyl substituted by 2 to 5 hydroxyl (-OH) groups, C1-C3-alkyl substituted by at least one hydroxyl (-OH) group, and C1-alkyl substituted by carboxyl (-COOH) or phosphonate (-PO3H2).

17. The compound according to any one of claims 1 to 16, wherein Z 1 and Z 2 and Z if it exists 3 Independently selected from hydrogen and C1-C4-alkyl, the C1-C4-alkyl being optionally substituted by one or more groups selected from hydroxyl (-OH), carboxyl (-COOH) and phosphonate (-PO3H2).

18. A compound according to any one of claims 1 to 17, wherein R is C1-C3-alkyl or C1-C3-alkyl substituted by aryl.

19. The compound according to claim 18, wherein R is C1-C2-alkyl or C1-C2-alkyl substituted by aryl.

20. The compound according to claim 19, wherein R is C1-alkyl or C1-alkyl substituted by aryl.

21. The compound according to any one of claims 1 to 17, wherein R is selected from hydrogen, C1-alkyl, C1-alkyl substituted by aryl and a moiety of formula (IA), where Y 3 , R 3 , L 3 and Z 3 As defined in any one of claims 1 to 17, the above respectively with respect to Y 1 , R 1 , L 1 and Z 1 Same meaning as provided.

22. The compound according to any one of claims 1 to 21, wherein n, m and o are 1, whereby the compound has the following formula (II) Among them, R 1 , R 2 , Y 1 , Y 2 , L 1 , L 2 , Z 1 and Z 2 As defined above in relation to any one of claims 1 to 21.

23. A compound according to any one of claims 1 to 21, wherein only one of n, m and o is 2, and the other two are 1, whereby the compound has one of formula (IIIA), (IIIB) or (IIIC) in, For formula (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 in relation to any one of claims 1 to 21, and R' is hydrogen or C1-C4-alkyl optionally substituted by aryl.

24. The compound according to claim 23, wherein R' is hydrogen or C1-C3-alkyl optionally substituted by aryl.

25. The compound according to claim 24, wherein R' is hydrogen or C1-C2-alkyl optionally substituted by aryl.

26. The compound of claim 25, wherein R' is hydrogen or C1-alkyl optionally substituted with aryl.

27. The compound according to any one of claims 1 to 21, wherein only one of n, m and o is 1, and the other two are 2, whereby the compound has one of formula (IVA), (IVB) or (IVC) in, For formulas (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 in relation to any one of claims 1 to 21, and R' is hydrogen or C1-C4-alkyl optionally substituted by aryl.

28. The compound according to claim 27, wherein R' is hydrogen or C1-C3-alkyl optionally substituted by aryl.

29. The compound according to claim 28, wherein R' is hydrogen or C1-C2-alkyl optionally substituted by aryl.

30. The compound of claim 29, wherein R' is hydrogen or C1-alkyl optionally substituted with aryl.

31. A compound according to any one of claims 1 to 21, wherein n, m and o are 2, whereby the compound has the following formula (V) Among them, R 1 , R 2 , Y 1 , Y 2 , L 1 , L 2 , Z 1 and Z 2 As defined above in relation to any one of claims 1 to 21.

32. The compound according to any one of claims 1 to 31, wherein the compound is selected from: 3,3',3"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropane-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]}tris(propane-1,3-diol); 3,3'-[1,4,7-triazacyclononane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide amide]; 2,2'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol); 3,3',3"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,7-triazacyclononane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]; Azacyclononane-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)carbonylazanediylmethylene]}tris(phosphonic acid); {1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(phosphonic acid); {1,4,7-triazacyclononane-1,4-diyl Bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); 3,3',3"-[1,4,7-triazacyclononane-1,4,7-triyltris(methylene)]tris[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]}tris(ethane-1,2-diol); 3,3'-[1,4,7-triazacyclononane-1,4-diylbis(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]}bis(ethane-1,2-diol); N,N',N"-{1,4,7-triazacyclononane-1,4,7-triyltri[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropionamide); N,N'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N,N',N"-{1,4,7-triazacyclononane-1,4,7-triyltri[methylene(2 -hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]; N,N'-{1,4,7-triazacyclononane-1,4-diylbis[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)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid); {1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid); )]}bis(phosphonic acid); 3,3',3"-[1,4,7-triazacyclodecane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropane-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]}tris(propane-1,3-diol); 3,3'-[1,4,7-triazacyclodecane-1,7-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,7-triazacyclodecane- 1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol); 2,2'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol); 3,3',3"-[1,4,7-triazacyclodecane-1,4,7-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide);3,3'-[1,4,7-triazacyclodecane-1,7-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,7-triazacyclodecane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2"-[1,4,7-triazacyclodecane-1,4,7-triyltris(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)carbonylazanediylmethylene]}tris(phosphonic acid); {1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); 3,3',3"-[1,4,7-triazacyclodecane-1,4,7-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1',1"-{1,4,7-triazacyclodecane-1,4,7-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide] 1,1'-{1,4,7-triazacyclodecane-1,7-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{1,4,7-triazacyclodecane-1,7-diylbis(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]}bis(ethane-1,2-diol);1,1'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-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-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N,N'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); -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-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; N,N'-{1,4,7-triazacyclodecane-1,4-diylbis[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)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid); {1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); {1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); 3,3',3"-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris(phosphonic acid); [N-(1,3-dihydroxypropane-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]}tris(propane-1,3-diol); 3,3'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide];2,2'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol); 2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol); 3,3',3"-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis(2-hydroxy-5-methylbenzoyl) amine); 3,3'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2"-[1,4,8-triazacycloundecane-1,4,8-triyltris(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-methylbenzamide {1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tri(phosphonic acid); {1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]} {1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); (3,3',3"-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris[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]}tris(ethane-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]}bis(ethane-1,2-diol); 1,1'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-1,2-diol) 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-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); N,N'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropionamide); Heterocycloundecane-1,4,8-triyl tris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propionamide]; N,N'-{1,4,8-triazacycloundecane-1,8-diyl bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; N,N'-{1,4,8-triazacycloundecane-1,4-diyl bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {1,4,8-triazacycloundecane-1,4,8-triyl tris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide {1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); {1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); 3,3',3"-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris[N-(1,3-dihydroxypropane-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]}tris(propane-1,3-diol); 3,3'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-1,3-diol); 3,3',3"-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide ,5,9-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2"-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris[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)carbonylazane {1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,5,9-triazacyclododecane-1,5,9-triyltri[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tri(phosphonic acid); {1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); 3,3',3"-[1,5,9-triazacyclododecane-1,5,9-triyltri(methylene)] Tris[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]}tris(ethane-1,2-diol); 3,3'-[1,5,9-triazacyclododecane-1,5-diylbis(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]}bis(ethane-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-diylbis[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-diylbis[methylene( {1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid); {1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); 3,3'-[(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2 2,2'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-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 bis(phosphonic acid); bis((7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}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]}bis(ethane-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)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); 3,3'-[(4-benzyl-1, 4,7-Triazacyclodecane-1,7-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-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]}bis(propane-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide bis(methylene)-2-hydroxy-5-methyl-3,1-phenylene)-1-methylazanediyl)bis(propane-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-1,7-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)carbonylazanediylmethylene]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {(4-benzyl-1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid);{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}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) methylene azane diyl]} bis(ethane-1,2-diol); 1,1'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene (2-hydroxy-5-methyl-3,1-phenylene) methylene azane diyl]} bis(ethane-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(ethane-1,2-diol); 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)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide ,1-diyl)]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); 3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-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]}bis(propane-1,3-diol); 2,2'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(propane-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)carbonylazanediylmethylene]}bis(phosphonic acid); {(8-benzyl-1,4,8-triazacycloundecane-1,4 {(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); {(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}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]}bis(ethane-1,2-diol); 1,1'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(ethane-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)]}bis[3-hydroxy-2-(hydroxymethyl)propionamide]; {(4-Benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); {(8-Benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); 3,3'-[(9- Benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropane-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]}bis(propane-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)carbonylazanediylmethylene]}bis(phosphonic acid); {(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}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]}bis(ethane-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 bis(phosphonic acid); N,N',N"-{1,4,7-triazacyclononane-1,4,7-triyltris[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)carbamoyl]phenyl}methyl 6-pentahydroxyhexyl)benzamide; 6,6',6"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(hexane-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',6"-{1,4,7-triazacyclononane-1,4-diyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(hexane-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; 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]}tris(hexane-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 6,6',6"-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tris(hexane-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]}bis(hexane-1,2,3,4,5-pentaol); 6,6'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol) methyl(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-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]}tris(hexane-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]}bis(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-triazacyclododecane-1-yl]methyl 6,6'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(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-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]}bis(hexane-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]}bis(hexane-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-triazacycloundec-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-triazacycloundec-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]}bis(hexane-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]}bis(hexane-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-triazacyclododecanede 6,6'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol); 6,6'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}bis(hexane-1,2,3,4,5-pentaol); 6,6'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2 1,2,3,4,5-pentanol); 2,2',2"-{1,4,7-triazacyclononane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tris(propane-1,3-diol); 2,2'-{1,4,7-triazacyclononane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2',2"-{1,4,7-triazacyclodecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1 -phenylene)methyleneoxy]}tris(propane-1,3-diol); 2,2'-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2'-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2',2"-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tris(propane-1,3-diol);2,2'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2',2"-{1,5,9-triazacyclododecane-1,5,9-triyltri[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol) -3,1-phenylene)methyleneoxy]}tris(propane-1,3-diol); 2,2'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazacyclononane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2'-{(4-benzyl- 1,4,7-triazacyclodecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazacyclodecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-1,3-diol); 2,2'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}bis(propane-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]}bis(propane-1,3-diol). ; 33. A compound according to any one of claims 1 to 32 and Fe 3+ or a physiologically acceptable salt of the complex.

34. Use of the complex according to claim 33 as a contrast agent, preferably a contrast agent for MRI.

35. The complex according to claim 33 for use in a method for diagnosing a pathology in vivo by magnetic resonance imaging (MRI).

36. A method for imaging a body tissue of a patient, the method comprising the steps of administering to the patient an effective amount of a complex according to claim 33 in a pharmaceutically acceptable carrier, and performing magnetic resonance imaging (MRI) on the patient.

37. A pharmaceutical composition comprising a complex as defined in claim 33 and at least one pharmaceutically acceptable excipient.

38. A process for the preparation of a compound as defined in any one of claims 1 to 32, comprising the steps of: a) providing a phenol substituted at least in its ortho position by: (i) a C1-C5-alkyl- group bonded to a leaving group; and (ii) a LZ group, or a substituent selected from the group consisting of a C1-C4-alkyl-aldehyde, a C1-C4-alkyl-ester and a C1-C4-alkyl-carboxyl group; b) providing a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, which is optionally suitably protected on one or more of its nitrogen atoms with one or more protecting groups and / or optionally carries a C1-C4-alkyl group, optionally substituted by an aryl group, on one of its nitrogen atoms; c) reacting the phenol provided in step a) with the macrocycle provided in step b) to obtain a compound as defined in any one of claims 1 to 32 or an intermediate thereof; and d) converting the intermediate of step c) into a compound as defined in any one of claims 1 to 32.

39. The method of claim 38, wherein: The phenol provided in step a) has the following formula (VI): where Y 1 and R 1 has the same meaning as provided with respect to formula (I) as defined in any one of claims 1 to 32; X is a leaving group, and L 4 is a group selected from C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl; The intermediate obtained in step c) has the following formula (VII): Where R 1 , R 2 , Y 1 , Y 2 , m, n and o have the same meanings as provided with respect to formula (I) as defined in any one of claims 1 to 32, L 4 is a group selected from C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl; and R" is selected from hydrogen, C1-C4 alkyl optionally substituted by aryl and a moiety of formula (VIIA): Wherein: the asterisk (*) indicates the point of attachment of the moiety of formula (VIIA) to the nitrogen carrying the R' group; Y 3 With the above about Y 1 and Y 2 The same meaning provided; R 3 With the above R 1 and R 2 the same meaning as provided; and L 4 is a group selected from C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl; and ● Step d) provides for L 4 Partially converted into group L 1 -Z 1 , L 2 -Z 2 and L if it exists 3 -Z 3 .

40. A process for the preparation of a compound as defined in any one of claims 1 to 32, said process comprising the steps of: a) providing a phenol substituted at least in its ortho position by: (i) a C1-C5-alkyl group bonded to a leaving group; and (ii) a LZ group, or a substituent selected from the group consisting of a C1-C4-alkyl-aldehyde, a C1-C4-alkyl-ester and a C1-C4-alkyl-carboxyl group; b') providing an ortho-amide derivative of a macrocycle selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane; c') reacting the one or two phenols provided in step a) with the o-amino derivative to obtain an o-amino derivative coupled with the one or two phenols provided in step a); d') hydrolyzing the ortho-amino derivative obtained in step c') to obtain a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane coupled to one or two phenols provided in step a) and to a formyl (-C(O)H) group; e') optionally reacting the other phenol provided in step a) with the macrocycle obtained in step d') to obtain a macrocycle selected from triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane coupled to the two phenols provided in step a) and to a formyl (-C(O)H) group; f') hydrolyzing the macrocycle obtained in step d') or e') and optionally converting the possible C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester or C1-C4-alkyl-carboxyl, wherein the hydrolysis and the optional conversion of step f') are carried out in any order to obtain the compound according to any one of claims 1 to 32; and g') optionally reacting the further phenol provided in step a) with the macrocycle obtained in step f') and optionally converting a possible C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester or C1-C4-alkyl-carboxyl to obtain a compound according to any one of claims 1 to 32.

41. The method of claim 40, wherein the ortho-amide derivative provided in step b') has the following formula (VIII): wherein m, n and o have the same meanings as provided with respect to formula (I) as defined in any one of claims 1 to 32.

42. A process for preparing the complex as defined in claim 33, said process comprising carrying out the following steps: e) reacting the compound obtained in step c) or step d) as defined in claim 38 or 39 or the compound obtained in step f') or step g') as defined in claim 40 or 41 with an Fe(III) salt to obtain an Fe(III) complex.

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