Process for producing 2,4,6-triiodophenol derivative

Abstract

The present invention relates to a novel compound represented by formula (I), and its ions, stereoisomers, tautomers, hydrates, solvates, pharmaceutically acceptable salts, or mixtures thereof. The compound of formula (I) is a ligand capable of chelating Fe(III) ions, thereby forming an Fe(III) complex, and due to its high relaxation ability, thermodynamic stability, kinetic inertness and redox stability, it is particularly suitable as a contrast agent for diagnostic imaging, such as magnetic resonance imaging (MRI). JPEG2025524769000274.jpg72123

Description

Technical Field

[0001] The present invention relates to novel compounds capable of forming complexes with Fe(III), and complexes thereof with Fe(III). These complexes are particularly suitable as contrast agents for magnetic resonance imaging (MRI).

Background Art

[0002] Background of the Invention Magnetic resonance imaging (MRI) contrast agents currently used clinically are small, hydrophilic paramagnetic Gd(III) complexes or chelates, which accelerate the relaxation rates (R1 and R2) of neighboring tissue water protons in the region where the drug accumulates. These clinically used Gd(III) complexes are generally very safe and well tolerated by patients. However, recently, there are concerns about contraindications for patients with significantly reduced renal function (nephrogenic systemic fibrosis), the small amount of Gd(III) remaining in the tissues of patients exposed to multiple MRI examinations (although there is no evidence that this is related to clinical harmfulness), and the environmental impact caused by the difficulty of removing gadolinium-based contrast agents (GBCA) in wastewater treatment plants. Therefore, alternative contrast agents based on chemical species different from Gd(III) have been studied.

[0003] Among these, complexes that chelate endogenous paramagnetic metals such as iron can be candidates. In fact, iron complexes, particularly Fe(III) complexes, have been studied for use in MRI. Since Fe(II) complexes are characterized by lower relaxation ability compared to Fe(III) complexes, they are generally not suitable for MRI contrast.

[0004] The ideal Fe(III) complexes for clinical use in MRI have high relaxivity to obtain high contrast in vivo, high thermodynamic stability and kinetic inertness to minimize, and in some cases avoid, hydrolysis, transmetalation, and transchelation reactions with endogenous metal ions and ligands, and stability against reduction to avoid triggering the Fenton reaction (reduction of Fe(III) to Fe(II)) in vivo caused by antioxidants such as ascorbic acid (Baranyai et al. Chem. Sci. 2021, 12, 11138). This reduction can decrease the relaxivity of the administered iron complex (by formation of Fe(II)-complexes) and may generate toxic OH· radicals in vivo.

[0005] Schellenberger et al. (Radiology, 2018, 286, 537) disclosed low-molecular-weight Fe(III) complexes such as the Fe(III) chelate of pentetic acid (Fe(DTPA)) and the Fe(III) chelate of trans-cyclohexanediaminetetraacetic acid (Fe(CDTA)), which provide image contrast in vivo and exhibit an enhancement kinetics very similar to that of the clinically used GBCA, Gd(DTPA) 2- (Magnevist®). However, these complexes are characterized by unsatisfactory redox stability and relaxivity (Baranyai et al., Chem. Sci. 2021, 12, 11138).

[0006] Gale et al. (J. Am. Chem. Soc., 2019, 141, 5916) disclosed the redox-active iron complex Fe-PyC3A, which is characterized by a relatively high relaxivity in the imaging field and exchange of Fe 3+ / 2+ (mediated by biochemical processes. For example, Fe 3+ is rapidly reduced to Fe 2+ by L-cysteine). Thus, this complex is Fe 3+ / 2+To enable exchange, it is intentionally characterized by very low redox stability, which is a very special application for imaging acute inflammation and not ideal for a wide range of MRI applications.

[0007] Morrow et al. (Angew. Chem. Int. Ed., 2020, 59, 2414 and WO 2018 / 213853) disclose a series of substituted macrocyclic ligands used for Fe(III) complexation and their use as MRI contrast agents.

Summary of the Invention

Problems to be Solved by the Invention

[0008] From the above viewpoints, there is a lack of Fe(III) complexes for use in magnetic resonance imaging that exhibit high relaxivity, kinetic inertness, thermodynamic stability, and stability to reduction.

[0009] The ligand of the present invention has been found to have surprisingly advantageous properties when complexed with Fe(III) ions, i.e., forming the complex of the present invention. In particular, this ligand has been found to have a well-balanced profile of high relaxivity, kinetic inertness, thermodynamic stability, and stability to reduction. Therefore, the complex of the present invention can be advantageously used as an MRI contrast agent.

Means for Solving the Problems

[0010] Summary of the Invention The present invention relates to a compound of formula (I), or an ion, stereoisomer, tautomer, hydrate, solvate or salt thereof, or a mixture thereof, as described in the claims. The compound of formula (I) is a ligand that forms an Fe(III) complex (the subject of the present invention as described in the claims) having a well-balanced profile of high relaxivity, kinetic inertness, thermodynamic stability, and stability to reduction when complexed with Fe(III) ions. The present invention further relates to a process for preparing the compounds and complexes of the invention, as well as their use as MRI contrast agents and their use in diagnostic (MRI) imaging, as set forth in the claims.

[0011] Detailed Description of the Invention According to a first aspect, the present invention provides a compound of formula (I):

Chemical formula

Chemical formula

[0012] According to the present invention, the term "alkyl" means a straight-chain or branched hydrocarbon chain. In particular, "C1-C4-alkyl" means a straight or branched chain containing 1 to 4 carbon atoms, such as methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, etc. Similarly, the term "C1-C3-alkyl" refers to a straight or branched chain containing 1 to 3 carbon atoms, such as methyl, ethyl, propyl and iso-propyl, for example, and the term "C1-C2-alkyl" refers to a straight or branched chain containing 1 to 2 carbon atoms, such as methyl and ethyl, and the term "C1-alkyl" refers to a methyl group (-CH3); the term "C1-C6-alkyl" refers to, in addition to methyl, ethyl, propyl, iso-propyl, butyl, iso-butyl, tert-butyl, etc., n-pentyl and its isomers (isopentane, neopentane, etc.), n-hexyl and its isomers (2-methylpentane, 3-methylpentane, 2,3-dimethylbutane, etc.).

[0013] According to the present invention, the term "alkylaminyl" refers to an alkyl as defined above in which one of the hydrogen atoms is substituted with an amine group, and the alkylaminyl is bonded to both (i) the phenolic moiety of the compound of the present invention and (ii) the Z 1 group, Z 2 or Z 3 group (if present). The term "C x -C y -alkylaminyl" refers to an alkylaminyl as defined above having x to y carbon atoms, where x and y represent two integers.

[0014] According to the present invention, the term "alkylamidyl" refers to an alkyl as defined above in which one of the carbon atoms is directly bonded to a carbonyl group (C=O) through a nitrogen atom, and the alkylamidyl is bonded to both (i) the phenolic moiety of the compound of the present invention and (ii) the Z 1 group, Z 2 or Z 3 group (if present). The term "C x -C y -alkylamidyl" refers to an alkylamidyl as defined above having x to y carbon atoms, where x and y represent two integers.

[0015] According to the present invention, the term "alkyl ether" refers to an alkyl as defined above in which one of the hydrogen atoms is substituted with an ether group (-O-), and the alkyl ether is bonded to both (i) the phenolic moiety of the compound of the present invention and (ii) the Z 1 group, Z 2 or Z 3 group (if present). The term "C x -C y -alkyl ether" refers to an alkyl ether as defined above having x to y carbon atoms, where x and y represent two integers.

[0016] According to the present invention, the term "aryl" refers to an aromatic hydrocarbon, preferably a phenyl ring. Unless otherwise specified, in the present invention, aryl may be unsubstituted or, simultaneously or independently of one another, substituted with one or more substituents selected from hydroxyl (-OH), halogen, and optionally C1-C4-alkyl substituted with one or more hydroxyl (-OH); preferably, the term "aryl" refers to an unsubstituted aromatic hydrocarbon, such as unsubstituted phenyl.

[0017] According to the present invention, the term "L-Z" when referring to a substituent generally refers to the substituent L 1 -Z 1 、L 2 -Z 2 and L 3 -Z 3 (if present) either or all of which are meant.

[0018] As used herein, the term macrocycle or macrocyclic cage when referring to a triazacyclononane (9-membered ring), triazacyclodecane (10-membered ring), triazacycloundecane (11-membered ring), or triazacyclododecane (12-membered ring) refers to a macrocycle having the following structure:

Chemical formula

[0019] As used herein, the term "protecting group" means a protecting group suitable for retaining the function of the group and / or atom to which it is attached. Specifically, a protecting group can be used to retain the function of an amino, hydroxyl or carboxyl. Thus, suitable carboxyl protecting groups include, for example, benzyl, alkyl, such as tert-butyl or benzyl esters, or other substituents commonly used for the protection of such functions, all of which are well known to those skilled in the art (e.g., T. W. Greene and P. G. M. Wuts; "Protective Groups in Organic Synthesis", Wiley, N.Y. 1999, 3rd edition).

[0020] The compound of formula (I) may have one or more asymmetric carbon atoms, also called chiral carbon atoms, and thus can give rise to diastereomers, optical isomers and enantiomers. The present invention further includes all possible geometric isomers including all such possible diastereomers, optical isomers and enantiomers, as well as racemic mixtures thereof and substantially pure separated enantiomers. Individual stereoisomers of the compound of formula (I), such as specific diastereomers, can be isolated by any conventional means, such as chromatography, optionally chiral chromatography.

[0021] The term "pharmaceutically acceptable salt", as used herein, refers to derivatives of the compounds of the present invention in which the free acidic or basic groups (if any) of the original compound are suitably modified by conversion to the corresponding addition salts with any base or acid which is customarily intended as pharmaceutically acceptable (e.g. as disclosed in S.M. Berge. et al., J. Pharm. Sci., 1977, 66, 1-19).

[0022] According to one embodiment, Y 1 and Y 2 and, if present, Y 3 are independently selected from the group consisting of hydrogen and C1-C3-alkyl, preferably hydrogen and C1-C2-alkyl, more preferably hydrogen and C1-alkyl (i.e., methyl). Preferably, Y 1 and Y 2 and, if present, Y 3 are simultaneously the same group, most preferably hydrogen.

[0023] According to one embodiment, R 1 R 2 and, if present, R 3is independently selected from the group consisting of hydrogen and C1-C3-alkyl, preferably hydrogen and C1-C2-alkyl, more preferably hydrogen and C1-alkyl, and even more preferably C1-alkyl (i.e., methyl (-CH3)). According to a preferred embodiment, R 1 , R 2 , and when present, R 3 are the same group simultaneously.

[0024] According to one embodiment, L 1 , L 2 , and when present, L 3 are independently selected from the group consisting of C1-C3-alkylaminyl, C1-C3-alkylamidyl, and C1-C3-alkyl ether; preferably, C1-C2-alkylaminyl, C1-C2-alkylamidyl, and C1-C2-alkyl ether; and more preferably, C1-alkylaminyl, C1-alkylamidyl, and C1-alkyl ether; according to a more preferred embodiment, L 1 , L 2 , and when present, L 3 are independently * -CH2-NH-·, * -C(O)NH-·, * -NHC(O)-· and * -CH2-O-·, preferably, * -CH2-NH-·, * -C(O)-NH-· and * -CH2-O-·, more preferably, * -CH2-NH-· and * -C(O)-NH-· are selected, the asterisk (*) represents the phenol moiety, and the midpoint (·) represents the Z 1 group, the Z 2 group, or when present, the Z 3 group. According to a preferred embodiment, L 1 , L 2 , and when present, L 3 are the same group simultaneously.

[0025] Alkylaminyl and alkylamidyl groups L 1 , L 2 and L 3 (when present), the nitrogen atom preferably has at least one hydrogen; in other words, L 1 , L 2 and L 3 (when present), the amine of the alkylaminyl group and / or the amide of the alkylamidyl group are preferably primary or secondary; more preferably secondary.

[0026] According to a preferred embodiment, Z 1 , Z 2 , and when present Z 3 is directly bonded to (respectively) the nitrogen of the alkylaminyl or alkylamidyl group of L 1 , L 2 , and L 3 , the carbonyl (C=O) moiety of the alkylamidyl group, or the oxygen of the alkyl ether group.

[0027] According to a preferred embodiment, Z 1 , Z 2 , and when present Z 3 is independently selected from the group consisting of hydrogen, C4-C6-alkyl substituted with two or more hydroxyl (-OH) groups, and C1-C3-alkyl substituted with at least one group selected from the group consisting of hydroxyl (-OH), carboxyl (-COOH) and phosphonate (PO3H2). According to a more preferred embodiment, Z 1 , Z 2 , and when present Z 3 is independently selected from the group consisting of hydrogen, C6-alkyl substituted with two or more, for example 2 to 5 (preferably 5) hydroxyl (-OH) groups, C1-C3-alkyl substituted with at least one, for example 2, hydroxyl (-OH) groups, and C1-alkyl substituted with carboxyl (COOH) or phosphonate (PO3H2).

[0028] 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 optionally substituted by aryl (such as substituted or unsubstituted aryl), preferably phenyl, more preferably C1-C2-alkyl, or C1-C2-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), preferably phenyl, and even more preferably C1-alkyl, or C1-alkyl optionally substituted by aryl (such as substituted or unsubstituted aryl), preferably phenyl (i.e., benzyl group -CH2-C6H5).

[0029] According to a preferred embodiment, R is hydrogen, C1-alkyl, C1-alkyl substituted by aryl (such as substituted or unsubstituted aryl), preferably phenyl (i.e., benzyl group -CH2-C6H5), and the formula (IA) (wherein Y 3 、R 3 、L 3 and Z 3 are each selected from the group consisting of the moieties represented by Y 1 、R 1 、L 1 and Z 1 of formula (I), and having the same meanings as described above for any of their embodiments).

[0030] According to one embodiment, n, m and o of formula (I) are 1, whereby the compound of the invention has a triazacyclononane macrocyclic cage and has the following formula (II).

Chemical formula

[0031] According to another embodiment, only one of n, m, and o in formula (I) is 2, and the other two are 1, whereby the compound of the present invention has a triazacyclodecane macrocyclic cage and has any one of formulae (IIIA), (IIIB), or (IIIC).

Chemical formula

[0032] According to a further embodiment, only one of n, m, and o in formula (I) is 1, and the other two are 2, whereby the compound of the present invention has a triazacycloundecane macrocyclic cage and has any one of formulae (IVA), (IVB), or (IVC):

Chemical formula

[0033] According to a fourth embodiment, n, m and o of formula (I) are 2, whereby the compound of the invention has a triazacyclododecane macrocyclic cage and has the following formula (V): [Chemical formula] [wherein, R, R 1 , R 2 , Y 1 , Y 2 , L 1 , L 2 , Z 1 and Z 2 are as defined above for formula (I) or any of its embodiments.

[0034] According to a preferred embodiment, the compound of the invention is selected from the group consisting of.

[0035] [Chemical formula] Compound 1 (3,3’,3’’-[1,4,7-triazanonane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]),

[0036] [Chemistry] Compound 2 (2,2’,2’’-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenazanediyl]}tri(propane-1,3-diol)),

[0037] [Chemistry] Compound 3 (3,3’-[1,4,7-triazonane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]),

[0038] [Chemistry] Compound 4 (2,2’-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenazanediyl]}di(propane-1,3-diol)),

[0039] [Chemistry] Compound 5 (3,3’,3’’-[1,4,7-triazonane-1,4,7-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0040] [Chemistry] Compound 6 (3,3’-[1,4,7-triazonane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide),

[0041] [Chemistry] Compound 7 (2,2’,2’’-[1,4,7-triazonane-1,4,7-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol])

[0042]

Chemical Structure

[0043]

Chemical Structure

[0044]

Chemical Structure

[0045]

Chemical Structure

[0046]

Chemical Structure

[0047] [Chemistry] Compound 13 (3,3’,3’’-[1,4,7-triazonane-1,4,7-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0048] [Chemistry] Compound 14 (1,1’,1’’-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenediazanediyl]}tri(ethane-1,2-diol)),

[0049] [Chemistry] Compound 15 (3,3’-[1,4,7-triazonane-1,4-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0050] [Chemistry] Compound 16 (1,1’-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenediazanediyl]}di(ethane-1,2-diol)),

[0051] [Chemistry] Compound 17 (N,N’,N’’-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropanamide)),

[0052] [Chemistry] Compound 18 (N,N’-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide))

[0053]

Chemical Structure

[0054]

Chemical Structure

[0055]

Chemical Structure

[0056]

Chemical Structure

[0057]

Chemical Structure

[0058] [Chemical formula] Compound 24 (2,2’,2’’-{1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenediazanediyl]}tri(propan-1,3-diol))

[0059] [Chemical formula] Compound 25 (3,3’-[1,4,7-triazecane-1,7-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide])

[0060] [Chemical formula] Compound 26 (3,3’-[1,4,7-triazecane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide])

[0061] [Chemical formula] Compound 27 (2,2’-{1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenediazanediyl]}di(propan-1,3-diol))

[0062] [Chemical formula] Compound 28 (2,2’-{1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propan-1,3-diol))

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

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Chemical Structure

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Chemical Structure

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Chemical Structure

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Chemical Structure

[0084]

Chemical Structure

[0085] [Chemical formula] Compound 51 (N,N’-{1,4,7-triazacyclodecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide])

[0086] [Chemical formula] Compound 52 (N,N’-{1,4,7-triazacyclodecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide])

[0087] [Chemical formula] 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))

[0088] [Chemical formula] 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))

[0089] [Chemical formula] 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))

[0090] [Chemical Structure] Compound 56 (3,3’,3’’-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide])

[0091] [Chemical Structure] Compound 57 (2,2’,2’’-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(propan-1,3-diol))

[0092] [Chemical Structure] Compound 58 (3,3’-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide])

[0093] [Chemical Structure] Compound 59 (3,3’-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide])

[0094] [Chemical Structure] Compound 60 (2,2’-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propan-1,3-diol)),

[0095] [Chemical formula] Compound 61 (2,2’-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propan-1,3-diol)),

[0096] [Chemical formula] Compound 62 (3,3’,3’’-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide)),

[0097] [Chemical formula] Compound 63 (3,3’-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0098] [Chemical formula] Compound 64 (3,3’-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0099] [Chemical formula] Compound 65 (2,2’,2’’-[1,4,8-triazacycloundecane-1,4,8-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]),

[0100] [Chem.] Compound 66 (2,2’-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0101] [Chem.] Compound 67 (2,2’-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0102] [Chem.] Compound 68 ({1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid)),

[0103] [Chem.] Compound 69 ({1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0104] [Chem.] Compound 70 ({1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0105] [Chem.] Compound 71 ({1,4,8-triazaspiro[undecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(phosphonic acid)),

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Chem.

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Chem.

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Chem.

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Chem.

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Chem.

[0111] [Chemical formula] Compound 77 (3,3’-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide])

[0112] [Chemical formula] Compound 78 (1,1’-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-1,2-diol))

[0113] [Chemical formula] Compound 79 (1,1’-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-1,2-diol))

[0114] [Chemical formula] Compound 80 (N,N’,N’’-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropanamide))

[0115] [Chemical formula] Compound 81 (N,N’-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide)),

[0116] [Chemical formula] Compound 82 (N,N’-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide)),

[0117] [Chemical formula] 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)propanamide]),

[0118] [Chemical formula] Compound 84 (N,N’-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]),

[0119] [Chemical formula] Compound 85 (N,N’-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]),

[0120] [Chemical formula] Compound 86 ({1,4,8-triazasacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid))

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Chem.

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Chem.

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Chem.

[0126] [Chemical formula] Compound 92 (2,2’-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propan-1,3-diol))

[0127] [Chemical formula] Compound 93 (3,3’,3’’-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide))

[0128] [Chemical formula] Compound 94 (3,3’-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide))

[0129] [Chemical formula] Compound 95 (2,2’,2’’-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol])

[0130] [Chemical formula] Compound 96 (2,2’-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol])

[0131] [Chemistry] Compound 97 ({1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid)),

[0132] [Chemistry] Compound 98 ({1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid)),

[0133] [Chemistry] Compound 99 ({1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenazanediylmethylene]}tris(phosphonic acid)),

[0134] [Chemistry] Compound 100 ({1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenazanediylmethylene]}bis(phosphonic acid)),

[0135] [Chemistry] [[ID=4l]] Compound 101 (3,3’,3’’-[1,5,9-triazacyclododecane-1,5,9-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]),

[0136] [Chemistry] Compound 102 (1,1’,1’’-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethane-1,2-diol)),

[0137]

Chemical Structure

[0138]

Chemical Structure

[0139]

Chemical Structure

[0140]

Chemical Structure

[0141]

Chemical Structure

[0142]

Chem.

[0143]

Chem.

[0144]

Chem.

[0145]

Chem.

[0146]

Chem.

[0147]

Chemical formula

[0148]

Chemical formula

[0149]

Chemical formula

[0150]

Chemical formula

[0151]

Chemical formula

[0152]

Chem.

[0153]

Chem.

[0154]

Chem.

[0155]

Chem.

[0156]

Chem.

[0157] [Chemical formula] Compound 123 (3,3'-[(7-Benzyl-1,4,7-triazecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide])

[0158] [Chemical formula] Compound 124 (2,2'-{(4-Benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenediazanediyl]}di(propan-1,3-diol))

[0159] [Chemical formula] Compound 125 (2,2'-{(7-Benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenediazanediyl]}di(propan-1,3-diol))

[0160] [Chemical formula] Compound 126 (3,3'-[(4-Benzyl-1,4,7-triazecane-1,7-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide))

[0161] [Chemical formula] Compound 127 (3,3’-[(7-Benzyl-1,4,7-triazecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide))

[0162]

Chem.

[0163]

Chem.

[0164]

Chem.

[0165]

Chem.

[0166]

Chem.

[0167]

Chem.

[0168]

Chem.

[0169]

Chem.

[0170]

Chem.

[0171]

Chem.

[0172] [Chemistry] Compound 138 (N,N’-{(4-Benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide)),

[0173] [Chemistry] Compound 139 (N,N’-{(7-Benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide)),

[0174] [Chemistry] Compound 140 (N,N’-{(4-Benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]),

[0175] [Chemistry] Compound 141 (N,N’-{(7-Benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]),

[0176] [Chemistry] Compound 142 ({(4-Benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid)),

[0177] [Chemistry] 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)),

[0178] [Chemistry] Compound 144 (3,3'-[(4-Benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]),

[0179] [Chemistry] Compound 145 (3,3'-[(8-Benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]),

[0180] [Chemistry] Compound 146 (2,2'-{(4-Benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propan-1,3-diol)),

[0181] [Chemistry] Compound 147 (2,2'-{(8-Benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propan-1,3-diol)),

[0182] [Chemistry] Compound 148 (3,3'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0183] [Chemistry] Compound 149 (3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide)),

[0184] [Chemistry] Compound 150 (2,2'-[(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0185] [Chemistry] Compound 151 (2,2'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]),

[0186] [Chemistry] Compound 152 ({(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanylmethylene]}bis(phosphonic acid)),

[0187] [Chemistry] Compound 153 ({(8-Benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid))

[0188]

Chem.

[0189]

Chem.

[0190]

Chem.

[0191]

Chem.

[0192]

Chem.

[0193]

Chem.

[0194]

Chem.

[0195]

Chem.

[0196]

Chem.

[0197]

Chem.

[0198]

Chemical Structure

[0199]

Chemical Structure

[0200]

Chemical Structure

[0201]

Chemical Structure

[0202]

Chemical Structure

[0203]

Chem.

[0204]

Chem.

[0205]

Chem.

[0206]

Chem.

[0207]

Chem.

[0208]

Chem.

[0209]

Chem.

[0210]

Chem.

[0211]

Chem.

[0212]

Chem.

[0213]

Chem.

[0214]

Chem.

[0215]

Chem.

[0216]

Chem.

[0217]

Chem.

[0218]

Chem.

[0219]

Chem.

[0220]

Chem.

[0221] [Chemical formula] Compound 187 (6,6’,6’’-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenazanediyl]}tri(hexane-1,2,3,4,5-pentol)),

[0222] [Chemical formula] Compound 188 (2-hydroxy-3-{[1-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecan-8-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0223] [Chemical formula] Compound 189 (2-hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecan-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0224] [Chemical formula] Compound 190 (6,6’-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol))

[0225] [Chemical formula] Compound 191 (6,6’-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol))

[0226] [Chemical formula] Compound 192 (3-{[5,9-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide)

[0227] [Chemical formula] Compound 193 (6,6’,6’’-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexane-1,2,3,4,5-pentol))

[0228] [Chemical formula] Compound 194 (2-Hydroxy-3-{[5-({2-Hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecan-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0229] [Chemical Formula] Compound 195 (6,6’-{1,5,9-Triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenazanediyl]}di(hexane-1,2,3,4,5-pentol)),

[0230] [Chemical Formula] Compound 196 (3-{[4-Benzyl-7-({2-Hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazonan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0231] [Chemical Formula] Compound 197 (6,6’-{(7-Benzyl-1,4,7-triazonan-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenazanediyl]}di(hexane-1,2,3,4,5-pentol)),

[0232] [Chemical Formula] Compound 198 (3-{[4-Benzyl-7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazecan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide),

[0233]

Chem.

[0234]

Chem.

[0235]

Chem.

[0236]

Chem.

[0237]

Chem.

[0238]

Chem.

[0239]

Chem.

[0240]

Chem.

[0241] [Chem.] Compound 207 (6,6’-{(9-Benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol)),

[0242] [Chem.] Compound 208 (6,6’-{1,4,7-Triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol)),

[0243] [Chem.] Compound 209 (6,6’-{1,4,7-Triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol)),

[0244] [Chem.] Compound 210 (2,2’,2’’-{1,4,7-Triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(propan-1,3-diol)),

[0245] [Chemistry] Compound 211 (2,2’-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenoxy]}di(propan-1,3-diol)),

[0246] [Chemistry] Compound 212 (2,2’,2’’-{1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenoxy]}tri(propan-1,3-diol)),

[0247] [Chemistry] Compound 213 (2,2’-{1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenoxy]}di(propan-1,3-diol)),

[0248] [Chemistry] Compound 214 (2,2’-{1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenoxy]}di(propan-1,3-diol)),

[0249] [Chemistry] Compound 215 (2,2’,2’’-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenoxy]}tri(propan-1,3-diol)),

[0250] [Chemistry] Compound 216 (2,2’-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methylenoxy]}di(propane-1,3-diol)),

[0251]

Chemical Structure

[0252]

Chemical Structure

[0253]

Chemical Structure

[0254]

Chemical Structure

[0255]

Chemical Structure

[0256]

Chem.

[0257]

Chem.

[0258]

Chem.

[0259]

Chem.

[0260] The chemical names of the compounds of the present invention described above were generated using the software ACD / ChemSketch 2021.2.2 (ACD / Labs 2021.2.2 (File Version C35H41, Build 126536, 02 Mar 2022)). These chemical names may be slightly different from the standard IUPAC nomenclature. For clarity, in case of a discrepancy between the chemical structure and the corresponding chemical name, the compounds of the present invention are uniquely identified by their chemical structure.

[0261] According to a further aspect, the present invention relates to a complex of a compound of formula (I) as defined above in any of its embodiments, and thus a compound of formula (II)-(V) as defined above, with Fe 3+ and its salts, which are physiologically acceptable. As shown in the experimental section, the complexes of the present invention have a balanced profile of high relaxivity, kinetic inertness, thermodynamic stability and stability towards reduction, and are very suitable for use as contrast agents in the diagnostic field, particularly magnetic resonance imaging (MRI).

[0262] According to another aspect, the present invention relates to a complex as defined above or a physiologically acceptable salt thereof, preferably for use in a diagnostic method in vivo; more preferably, the complex or a physiologically acceptable salt thereof is for use in a method for diagnosing a medical condition in vivo by, for example, magnetic resonance imaging (MRI). The use of the complex as defined above or a physiologically acceptable salt thereof, for example, in a diagnostic method in vivo, preferably for diagnosing a medical condition in vivo by magnetic resonance imaging (MRI), is also an aspect of the present invention. A further aspect of the present invention is the use of the complex or a salt thereof of the present invention as defined above as a contrast agent, preferably for MRI.

[0263] According to a further aspect, the present invention relates to the use of a complex as defined above or a physiologically acceptable salt thereof for the manufacture of a diagnostic agent such as a contrast agent, preferably for magnetic resonance imaging (MRI), for example for in vivo use.

[0264] According to a further aspect, the present invention relates to a method for imaging a patient's body tissue, comprising the steps of administering to the patient an effective amount of the complex as defined above or a physiologically acceptable salt thereof in a pharmaceutically acceptable carrier, and subjecting the patient to magnetic resonance imaging (MRI).

[0265] According to another aspect, the present invention relates to a pharmaceutical composition comprising the complex as defined above or a physiologically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

[0266] In any of the embodiments, the method for producing the compound of the present invention, which encompasses the compounds of formulas (I)-(V) as defined above, is a further aspect of the present invention. Generally, the production method involves coupling a macrocyclic compound selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane, and triazacyclododecane, optionally appropriately protected with one or more protecting groups on one or more nitrogen atoms, with one or more suitable moieties to obtain the compound of the present invention or an intermediate, which can then be converted to the compound of the present invention (e.g., by further coupling reactions and / or reduction reactions).

[0267] In one embodiment, the compounds of the present invention can be prepared according to the following general synthetic procedure: a) providing a phenol substituted, at least at its ortho position, with (i) a C1-C5-alkyl bonded to a suitable leaving group such as mesylate (MsO) or halo, e.g., halo-C1-C5-alkyl such as chloro-C1-C5-alkyl or bromo-C1-C5-alkyl; and (ii) an L-Z group or a suitable substituent that can be converted to an L-Z group later, e.g., a substituent selected from the group consisting of C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester, and C1-C4-alkyl-carboxyl; For example, the phenol has the formula (VI): [Chemical formula] [Wherein, Y 1 and R 1 have the same meaning as described for formula (I) or any of its embodiments; X is a leaving group such as mesylate (MsO) or halogen, preferably Cl or Br: L 4 is a group selected from the group consisting of C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl.] It may be a compound represented by; b) A macrocyclic compound selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, optionally with one or more of its nitrogen atoms appropriately protected by one or more protecting groups and / or optionally having a C1-C4 alkyl group substituted, optionally with aryl (such as substituted or unsubstituted aryl), on one or more of its nitrogen atoms; c) Reacting the phenol provided in step a), for example a compound of formula (VI), with the macrocyclic compound provided in step b) to obtain a compound of the present invention or an intermediate of a compound of the present invention, for example an intermediate having at least two suitable substituents that can be converted to an L-Z group in a later step, such suitable substituents being, for example, at least two L 4 moieties, and preferably, in a later step, the group L 1 -Z 1 、L 2 -Z 2 、finally L 3 -Z 3 (if present) can be converted, and such an intermediate is, for example, of formula (VII): [Chemical formula] [Wherein, R 1 、R 2 、Y 1 、Y 2, m, n and o have the same meaning as described for formula (I) or any of its embodiments; L 4 is a group selected from the group consisting of C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester, and C1-C4-alkyl-carboxyl; and R’’ is hydrogen, C1-C4 alkyl optionally substituted with aryl (such as substituted or unsubstituted aryl), and the moiety represented by formula (VIIA):

Chemical formula

[0268] According to the present invention, the term "C1-C4-alkyl-aldehyde" means an alkyl group as defined above, which comprises from 1 to 4 carbons, one of which is an aldehyde group. Thus, C1-C4-alkyl-aldehyde comprises at most 4 carbons.

[0269] According to the present invention, the term "C1-C4-alkyl-ester" means an alkyl group as defined above, which comprises from 1 to 4 carbons, one of which is a carboxylate bonded to the alkyl group (i.e., one of which is C(O)O-R 0 where R 0 is an alkyl group, preferably a C1-C2-alkyl group), and thus C1-C4-alkyl-ester comprises at most 4 carbons (the alkyl group R 0 bonded to the oxygen is not counted).

[0270] According to the present invention, the term "C1-C4-alkyl-carboxyl" means an alkyl group as defined above, which comprises from 1 to 4 carbons, one of which is a carboxyl (-COOH) group. Thus, C1-C4-alkyl-carboxyl comprises at most 4 carbons.

[0271] Step a) provides a phenol which is preferably substituted in one of its ortho positions by a leaving group -C1-C5-alkyl group, preferably a halomethyl group such as chloromethyl or a MsO-methyl group. This group enables, in step c), the bonding of the phenol to one or more, optionally two or three, of the nitrogen atoms of the macrocycle. The phenol is further substituted in its ortho position by L 1 -Z 1 L 2 -Z 2 and finally L 3 -Z 3(If present) a group that can be advantageously converted to a base, for example, a group selected from the group consisting of C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester and C1-C4-alkyl-carboxyl. Alternatively, in addition to the leaving group -C1-C5-alkyl group, for example a halo-C1-C5-alkyl group, phenol may further contain an L-Z group, for example L 1 -Z 1 group, so that the compound of the present invention can be directly obtained when the phenol is bonded to the macrocycle provided in step b). Advantageously, the phenol in step a), for example the compound of formula (VI), can be obtained by reacting the corresponding non-methylene-halogenated compound with paraformaldehyde in concentrated hydrohalic acid, preferably hydrochloric acid or hydrobromic acid, at a temperature of 30-70 °C, preferably 40-60 °C, more preferably 50 °C.

[0272] Step b) is selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, optionally one or more of its nitrogen atoms being appropriately protected by one or more protecting groups, and / or optionally one of its nitrogen atoms being a C1-C4 alkyl group optionally substituted with aryl (such as substituted or unsubstituted aryl), to provide a macrocyclic compound. Such a macrocycle is coupled with the phenol of step a) in step c) to obtain an intermediate of the compound of the present invention (which will be converted to the compound of the present invention later) or to directly obtain the compound of the present invention.

[0273] According to one embodiment of step b), the macrocycle may not be protected. In particular, when a phenol having an L-Z group is bonded to all three nitrogen atoms of the macrocycle of the resulting compound of the present invention (i.e., when R is a group of formula (IA)), the nitrogen atoms of the macrocycle may not be protected. In fact, in this way, the coupling reaction of step c) can involve all three unprotected nitrogen atoms of the macrocycle, whereby a compound of the present invention, or an intermediate of formula (VII) in which R’’ is a moiety of formula (VIIA) can be obtained; this intermediate can be converted in subsequent steps into a compound of the present invention in which R is a group of formula (IA). Also, when only two nitrogen atoms of the macrocycle of the resulting compound are alkylated by a phenol having an L-Z group, i.e., when R or R’ of the resulting compound is hydrogen, or optionally C1-C4-alkyl substituted by aryl (such as substituted or unsubstituted aryl), etc. (or its preferred embodiments disclosed above), the nitrogen atoms of the macrocycle may not be protected. In fact, based on the reaction conditions of step c), for example, reaction conditions that can be selected according to conventional and standard knowledge in the art, the reaction between the phenol and the macrocycle (step c)) can involve only two unprotected nitrogen atoms of the macrocycle instead of all three unprotected nitrogen atoms, whereby the product of such a reaction is, for example, a macrocycle in which only two (not three) phenols having an L-Z group are bonded, as shown in Example 6.For example, in step c), particularly when the macrocycle is triazacyclodecane and triazacycloundecane, by appropriately adjusting the basicity of the reaction mixture in step c), all three or any two of the three nitrogen atoms of the macrocycle can be deprotonated, whereby in step c), all three or only two of the three nitrogen atoms are alkylated; when a base such as DIPEA is added to the reaction mixture in step c), all three nitrogen atoms of the macrocycle of triazacycloundecane or triazacyclododecane are deprotonated, and thus a macrocycle trialkylated in step c) is obtained; on the other hand, when only carbonate is used in the reaction mixture, one nitrogen atom of the macrocycle of triazacycloundecane or triazacyclododecane remains protonated and does not participate in the alkylation step c), whereby a macrocycle dialkylated is obtained (see, for example, Example 6).

[0274] According to step b), one or more of the nitrogen atoms of the macrocycle may be appropriately protected with one or more protecting groups. In particular, when R or R' of the compound of the present invention to be obtained is hydrogen or C1-C4-alkyl optionally substituted with aryl (such as substituted or unsubstituted aryl) (or its preferred embodiments disclosed above), one or more of the nitrogen atoms of the macrocycle can be appropriately protected with one or more protecting groups. For example, compound 4 (where R = hydrogen) can be synthesized by first preparing a macrocyclic body protected with mono-Boc (tert-butyloxycarbonyl) as shown in Scheme 1 below (as disclosed, for example, in S. J. Butler, B. K. McMahon, R. Pal, D. Parker, J. W. Walton, Chem. Eur J., 2013, 19, 9511-9517), then coupling with hydroxybenzaldehyde pendant, followed by reductive amination with serinol (2-amino-1,3-propanediol), and finally deprotection with TFA.

Chemical formula

[0275] Furthermore, in step b), this embodiment of providing a macrocyclic compound in which one or more of the nitrogen atoms are appropriately protected with one or more protecting groups allows, thanks to the (possibly optional) deprotection reaction, to select in the coupling reaction of step c) which nitrogen atom, and how many nitrogen atoms, of the macrocyclic compound to react with the ortho-substituted phenol. Specifically: for example, as shown in Scheme 2, the macrocyclic compounds described herein in which one or more of the nitrogen atoms of the macrocycle are appropriately protected with one or more protecting groups can be, for example, appropriately protected (for example, as described in M. Devreux, C. Henoumont, F. Dioury, D. Stanicki, S. Boutry, L. Larbanoix, C. Ferroud, R. N. Muller, S. Laurent, Eur. J. Inorg. Chem. 2019, 3354-3365), starting from a suitable dialkylenetriamine (such as diethylenetriamine, dipropylenetriamine, (2-aminoethyl)-1,3-propanediamine, etc.), protecting the primary amine of the dialkylenetriamine with a nosyl group (Ns), protecting the secondary amine of the dialkylenetriamine with Boc, and then performing a Richman and Atkins cyclization reaction on the protected dialkylenetriamine using a suitable ditosylated diol and suitable reaction conditions to obtain an appropriately protected macrocyclic compound.

Chemical formula

[0276] For example, according to Scheme 2, if a properly protected macrocyclic compound is obtained, in the presence of carbonate, using thiophenol, two nosyl groups (Ns) are eliminated, and the two amines of the deprotected macrocycle are alkylated with appropriate pendant arms as described, for example, in step c), and further, as described, for example, in step d), the groups on the pendant arms are converted; finally, Boc is eliminated as disclosed, for example, in Scheme 1 above, or the deprotected nitrogen that was bonded to Boc is finally further alkylated to obtain the compound of the present invention in which R or R’ is hydrogen.

[0277] The compound of the present invention in which R or R’ is C1-C4 alkyl optionally substituted with aryl (such as substituted or unsubstituted aryl) can be obtained, for example, by carrying out as in Scheme 2 above. Instead of protecting the secondary amine of the dialkylene triamine with Boc, such a secondary amine can be reacted (reductive amination) with, for example, benzyl bromide (for inserting a benzyl group) or a C1-C4-alkyl-aldehyde such as formaldehyde and NaBH4 (for inserting a C1-C4-alkyl group such as a methyl group); thereby, a macrocyclic compound having two nosyl groups (Ns) and one C1-C4 alkyl optionally substituted with aryl (such as substituted or unsubstituted aryl) can be obtained. Next, the remaining steps for obtaining the compound of the present invention can be carried out as detailed above (i.e., elimination of the Ns group and alkylation according to step c). The compound of the present invention in which R or R’ is C1-C4 alkyl optionally substituted with aryl (such as substituted or unsubstituted aryl) can also be obtained, for example, starting from a commercially available monoalkylated macrocyclic compound as shown in Scheme 3 below for the production of compound 112:

Chemical formula

[0278] In step c), the phenol of step a) is reacted with the macrocyclic body of step b) to directly obtain the compound of the present invention or to obtain an intermediate of the compound of the present invention, and this intermediate is reacted in the next step d) to obtain the final product.

[0279] Step c) can be carried out in an organic solvent such as toluene or acetonitrile. Salts, such as potassium salts, such as KI, KOH and K2CO3, are included in such an organic solvent, preferably in an amount of 4-fold molar equivalent with respect to the macrocyclic body provided in step b). KI can also be used in an amount of 0.05 to 0.4 molar equivalent, for example 0.1 to 0.2 molar equivalent, with respect to the macrocyclic body provided in step b).

[0280] Step c) can advantageously be carried out without heating the reaction mixture. In particular, in order to reduce the risk of unwanted polyalkylation reactions, step c) can be carried out at a temperature equal to or lower than room temperature, i.e., a temperature lower than 25 °C, for example a temperature of 0 °C to 25 °C.

[0281] Step d) is optional and can be carried out when step c) provides an intermediate of the compound of the present invention. Step d) includes converting a group of the intermediate, such as group L 4 to a group of L 1 -Z 1 、L 2 -Z 2 、and finally L 3 -Z 3 (if present). This can be done, for example, by reacting the L 4 group with one or more suitable substrates. For example, when L 1 is C1-C4-alkylaminyl and Z 1 is C1-C6 alkyl substituted with one or more hydroxyl groups, L of formulas (VII) and (VIIA) 4can be a C1-C4-alkyl-aldehyde, and a suitable substrate can be a C1-C6-alkyl-amine substituted with two or more hydroxyl groups such as serinol or glucamine. By coupling the two and then reducing, the intended L 1 -Z 1 an imide is formed which gives a moiety (for example, as disclosed in Example 2 below). Alternatively, L 1 is a C1-C4-alkylaminyl and Z 1 is a C1-C6-alkyl substituted with a phosphonate group, L in formulas (VII) and (VIIA) 4 can be a C1-C4-alkyl-aldehyde, and a suitable substrate can be, for example, diethyl-2-aminomethylphosphonate as shown in Scheme 4 below for obtaining Compound 11.

Chemical formula

[0282] As a further illustration, L 1 is a C1-C4-alkylamidyl and Z 1 is hydrogen, L in formulas (VII) and (VIIA) 4 can be a C1-C4-alkyl ester, and a suitable substrate can be, for example, ammonia as shown in Scheme 5 below for obtaining Compound 5.

Chemical formula

[0283] As another illustration, L 1 is a C1-C4-alkyl ether and Z 1 is a C1-C6-alkyl substituted with one or more hydroxyl groups, L in formulas (VII) and (VIIA) 4can be a C1-C4-alkyl-aldehyde, which is reduced to give a hydroxyl group, which can then be converted to an alkoxide; such an alkoxide can be subjected to the well-known Williamson ether synthesis to react with a suitable substrate, such as an alkyl-hydroxyl-halide in which the hydroxyl groups are suitably protected, e.g., 2-chloro-1,3-propanediol or 2-bromo-1,3-propanediol in which the hydroxyl groups are suitably protected.

[0284] The compounds of the present invention can also be prepared in step a) by providing a phenol as defined above, bearing an LZ group in its ortho position. In this case, the compounds of the present invention can be obtained directly in step c) by reacting such an ortho-substituted phenol with the macrocycle provided in step b). This embodiment can be used, for example, in the case of L 1 The following bases * -NHC(O)-·, where the asterisk (*) represents the phenol moiety and the midpoint (·) represents Z 1 represents a group, and Z 1 is hydrogen to obtain a compound of the present invention (i.e., compound 177), which can be illustrated according to Scheme 6 shown below. [ka]

[0285] According to one embodiment, the compounds of the present invention can be obtained by the following steps: providing phenol in any of its embodiments according to step a), and b') macrocyclic orthoamide derivatives selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, i.e. tricyclic trisaminomethane derivatives, such as those of formula (VIII): [ka] wherein m, n, and o have the same meanings as described for formula (I) or any embodiment thereof. providing an orthoamide derivative of the formula: c') reacting one or two phenols provided in step a), such as a compound of formula (VI), for example, 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, with an orthoamide derivative, for example, an orthoamide derivative represented by formula (VIII), to obtain an orthoamide derivative to which one or two phenols provided in step a), such as a compound of formula (VI), for example, 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, are bound; d') hydrolyzing the orthoamide derivative obtained in step c'), for example by acid hydrolysis, to obtain a macrocycle selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, in which one or two phenols provided in step a), for example a compound represented by formula (VI), for example 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, and a formyl (C(O)H) group are bonded; e') optionally reacting a further phenol provided in step a), for example a compound of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, with the macrocycle obtained in step d') to obtain a macrocycle comprising two phenols provided in step a), for example a compound of formula (VI), for example 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, and a formyl (-C(O)H) group bonded thereto, selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane; f') hydrolyzing the macrocycle obtained in step d') or e') and optionally converting the C1-C4-alkyl-aldehyde, C1-C4-alkyl-ester or C1-C4-alkyl-carboxyl, where the hydrolysis and conversion in this step f') can be carried out in any order to obtain a compound of the present invention (wherein two nitrogen atoms of the macrocycle are bound to a phenol bearing an LZ group and one nitrogen atom is bound to a hydrogen atom); and g') Optionally, a further phenol provided in step a), for example a compound of formula (VI), such as 2-hydroxy-3-bromomethyl-5-methylbenzaldehyde, is reacted with the macrocycle obtained in step f'), optionally converting the C-C-alkyl-aldehyde, C-C-alkyl-ester or C-C-alkyl-carboxyl to give a compound of the invention in which a phenol bearing an LZ group is attached to all three nitrogen atoms of the macrocycle.

[0286] Scheme 7 below illustrates how the above embodiment can be carried out, specifically when: In step c'), one phenol is reacted with an orthoamide derivative, Carrying out step e') (i.e., reacting a further phenol with the macrocycle obtained in step d')), In step f'), a step of converting a C1-C4-alkylaldehyde is carried out first, followed by a hydrolysis step to obtain the compound of the invention, Step g') is not performed. [ka]

[0287] According to Scheme 7, compounds of the invention can be synthesized in which phenols bearing LZ groups are attached to two nitrogen atoms of the macrocycle and hydrogen is attached to one nitrogen atom. If a further step g') is carried out, compounds of the invention can be synthesized in the same way in which phenols bearing LZ groups are attached to three nitrogen atoms of the macrocycle.

[0288] The orthoamide derivatives provided in step b') can be obtained according to standard procedures in the art, for example by reacting a macrocycle selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane starting from 1,4,6-triazabicyclo[3.3.0]octan-4-ene or 1,5,7-triazabicyclo[4.4.0]decane-5-ene with formaldehyde dimethyl acetal, or as described by T. Atkins, J. Am. Chem. Soc. 1980, 102, 6364-6365; R.W. Alder et al., J. Chem. Soc. Chem. Commun. 1992, 507-508.

[0289] The orthoamide derivative can be converted to a macrocycle with a formyl group attached by hydrolysis in step d') (also containing the phenol previously reacted in step c'). The formyl group is likely to be attached primarily to the nitrogen atom of the macrocycle that is less sterically hindered, such as one of the two nitrogen atoms between the ethylene and propylene moieties of the triazacycloundecane macrocycle (rather than the nitrogen atom between the two propylene moieties).

[0290] 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 two phenols provided in step a) with a macrocyclic compound obtained by the hydrolysis step d’), i.e., a macrocyclic compound selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane, and triazacyclododecane, which is bonded to a formyl (C(O)H) group.

[0291] In order to obtain an Fe(III) complex of a compound of the present invention, which is also an aspect of the present invention, the step of complexing a compound of the present invention with Fe(III) can be carried out, for example, after step c) or step d), or after step f’) or step g’); the complexing step can be carried out, for example, according to the following steps: e) Reacting a compound of the present invention obtained, for example, in step c), step d), step f’) or step g’) with an Fe(III) salt (e.g., FeCl3, Fe(NO3)3, Fe(OH)3, FeO(OH)) to obtain an Fe(III) complex of the compound of the present invention.

[0292] Step e) can be carried out in a non-aqueous polar solvent, such as a lower alcohol, such as methanol, ethanol, n-propanol, i-propanol, and mixtures thereof.

[0293] Non-limiting examples of the preparation of preferred compounds of the present invention and intermediates therefor are described below for the purpose of explaining the present invention in more detail without limiting its scope.

[0294] Experimental Section Materials and Methods Among the reaction reagents and / or solvents used in the following examples, those not specifically synthesized in the following examples are known and readily available. If it is not commercially available itself, it can be prepared according to known methods described in the literature.

[0295] 1 H and 13 The 1H and 13C NMR spectra were recorded on a Bruker Avance III spectrometer (Bruker, Milano, Italy) at 11.74 T and 298 K (corresponding to a proton resonance frequency of 499.8 MHz). 1 H and 13 The chemical shifts of 1H and 13C NMR are reported relative to TMS and referenced using the residual proton solvent resonance. Samples were prepared in 5 mm NMR tubes by dissolving the compound in a suitable deuterated solvent.

[0296] Analytical and semi-preparative HPLC-MS were performed on a Waters modular system (Waters Corporation, Milford, MA, USA) equipped with a Waters 1525 binary pump, Waters 2487 UV / Vis, and Waters SQD 3100 (ESCI ionization mode) detectors. UPLC-MS analysis was performed using an UPLC Acquity H-Class (Waters Corporation, Milford, MA, USA) equipped with QDa and TUV detectors. ESI-MS was recorded on a Waters SQD 3100 (Waters Corporation, Milford, MA, USA).

Example

[0297] Example 1 - Synthesis of Compound 1 Compound 1 was synthesized according to the following Scheme 8.

Chem.

[0298] B) Synthesis of (2-Hydroxy-5-methyl-3-methylchloro)carboxylic acid Methyl (2-hydroxy-5-methyl)benzoate (0.5 g, 3.01 mmol) obtained in the previous step was dissolved in concentrated hydrochloric acid (4 mL), and the temperature was raised to 50 °C. Next, paraformaldehyde (0.181 g, 6.02 mmol) was added little by little, and the reaction mixture was stirred at room temperature for 72 hours. Then, the solution was washed with DCM (3 × 15 ml), and the organic layer was washed with brine (2 × 15 ml). The organic phase was dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure. Yield: 72%. 1 1H NMR (CDCl3, 500 MHz): 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 13C NMR (CDCl3, 125 MHz): 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.

[0299] C) Synthesis of 1,4,7-tris-(3-carboxymethyl-2-hydroxy-5-methylbenzyl)-1,4,7-triazacyclononane 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 (2-hydroxy-5-methyl-3-chloromethyl)benzoate (0.258 g, 1.2 mmol) obtained in the previous step was dissolved in 2 ml of toluene and added dropwise over about 15 minutes to avoid polyalkylation reaction as much as possible. Next, the reaction mixture was stirred at room temperature for 2 hours. HPLC-MS analysis was performed to characterize the product (XBridge Phenyl 3.5 μm (4.6 × 150 mm); A = H2O / 0.1% TFA; B = MeOH; flow rate = 1 mL / min; 0 - 1 min = 30% B; 1 - 15 min = 30% to 100% B; 15 - 19 min = 100% B; 19 - 20 min = 100% to 30% B). Retention time: 13.79 min. Yield: 80%. 11H NMR (CDCl3, 500 MHz): 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 13C NMR (CDCl3, 125 MHz): 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 N3O9 calculated value: 635.7).

[0300] D) 3,3’,3’’-[1,4,7-Triazonane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide (Compound 1) 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 confirm the reaction (XBridge Phenyl 3.5 μm (4.6×150 mm); A = H2O / 0.1% TFA; B = MeOH; flow rate = 1 mL / min; 0 - 1 min = 30% B; 1 - 15 min = 30% to 100% B; 15 - 19 min = 100% B; 19 - 20 min = 100% to 30% B). Retention time: 10.25 min. Then, the solvent was removed and the crude product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5 μm (19x100 mm); A = H2O / 0.1% TFA; B = MeOH; flow rate = 20 mL / min; 0 - 4 min = 30% B; 4 - 12 min = 30% to 57% B; 12 - 13 min = 100% B; 13 - 14 min = 100% B; 14 - 15 min = 100% to 30% B; 15 - 17 min = 30% B). Yield: 67%. 1 H NMR (D2O, 500 MHz): δ (ppm) = 2.19 (s, -CH3-, 9H), 3.26 (bs, macrocycle, 12H), 3.66 - 3.75 (m, -CH- CH 2-OH, 12H), 4.10 (s, -N- CH 2-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, 125 MHz): δ (ppm) = 19.4 (-CH3-), 49.9 (-CH- CH 2-OH-), 53.1 (-N- CH 2-Ph-), 56.6 (-NH- CH -CH2-OH), 60.6 (macrocycle), 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).

[0301] Example 2 - Synthesis of Compound 2 Compound 2 was synthesized according to the following Scheme 9.

Chemical Structure

[0302] B) Synthesis of 1,4,7-tris-(3-formyl-2-hydroxy-5-methylbenzyl)-1,4,7-triazacyclononane Triazacyclononane (0.042 g, 0.18 mmol, TACN) was dissolved in 3 ml of acetonitrile, and KI (0.003 g, 0.018 mmol) and KOH (0.030 g, 0.54 mmol) were added. 2-Hydroxy-3-chloromethyl-5-methylbenzaldehyde (0.21 g, 0.9 mmol) obtained in the previous step was dissolved in 1 ml of acetonitrile, and the solution was added dropwise. The reaction mixture was heated to 60 °C and stirred overnight. The solution was then filtered, and the crude product was precipitated in diethyl ether. Yield: 81%. To confirm the reaction, HPLC-MS analysis was performed (XBridge Phenyl 3.5 μm (4.6 × 150 mm); A = HO / 0.1% TFA; B = MeOH; flow rate = 1 mL / min; 0-2 min = 60% B; 2-12 min = 60% to 100% B; 12-16 min = 100% B; 16-17 min = 100% to 60% B). Retention time: 5.60 min. 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). 1313C NMR (CDCl3, 125 MHz): 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 N3O6 calculated value: 573.7).

[0303] C) 2,2’,2’’-{1,4,7 - Triazonane - 1,4,7 - triyltris[methylene(2 - hydroxy - 5 - methyl - 3,1 - phenylene)methylenazanediyl]}tri(propan - 1,3 - diol) (Compound 2) Synthesis Dissolve 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 in 1 ml of MeOH, and add an excess of 2 - amino - 1,3 - propanediol (0.055 g, 0.61 mmol). Stir the solution at room temperature for 1 hour. Confirm the imine intermediate by MS spectrometry: ESI - MS (m / z): 794.0 (M + H + )(C 42 H 60Calculated value of 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 slowly added portionwise. The reaction mixture was then stirred for 3 hours. The reducing agent sodium borohydride was quenched by dropwise addition of 2 ml of MeOH, waited for 15 minutes, and finally, the precipitate was removed by filtration. The final product was characterized by HPLC-MS (XBridge Phenyl 3.5 μm (4.6×150 mm); A = H2O / 0.1% TFA; B = MeOH; flow rate = 1 mL / min; 0 - 1 min = 30% B; 1 - 15 min = 30% to 100% B; 15 - 19 min = 100% B; 19 - 20 min = 100% to 30% B). Retention time: 6.93 minutes. The solvent was removed under reduced pressure, and the crude product was purified by semi-preparative HPLC-MS (XBridge Prep Phenyl OBD 5 μm (19x100 mm); A = H2O / 0.1% TFA; B = MeOH; flow rate = 20 mL / min; 0 - 4 min = 20% B; 4 - 10 min = 20% to 43% B; 10 - 11 min = 100% B; 11 - 12 min = 100% B; 12 - 13 min = 100% to 20% B; 13 - 15 min = 20% B). Yield: 80%. 1 H NMR (D2O, 500 MHz): δ (ppm) = 2.17 (s, -CH3, 9H), 3.27 - 3.29 (m, -NH- CH -CH2-OH, 3H), 3.68 - 3.71 (m, -CH- CH 2-OH, 6H), 3.72 - 3.82 (m, -CH- CH’ 2-OH, 6H), 4.11 (bs, macrocycle, 12H), 4.27 (s, -N- CH 2-Ph-, 6H), 7.11 (s, -CH, 3H), 7.21 (s, -CH, 3H). 13 C NMR (D2O, 125 MHz): δ (ppm) = 19.5 (-CH3-), 44.8 (- CH 2-NH-C), 49.5 (-N- CH 2-Ph), 55.5 (-CH- CH2-OH), 57.5 (macrocycle), 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).

[0304] Example 3 - Synthesis of Compound 4 Compound 4 was synthesized according to the following Scheme 10.

Chemical Structure

[0305] B) Synthesis of 1,4-bis-{[3-(N-1,3-dihydroxypropan-2-yl)aminomethyl]-2-hydroxy-5-methylbenzyl}-7-tert-butyloxycarbonyl-1,4,7-triazacyclononane 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 excess 2-amino-1,3-propanediol (0.054 g, 0.60 mmol) was added. The solution was stirred at room temperature for 1 hour. The imine intermediate was confirmed by MS spectrometry: ESI-MS (m / z): 672.4 (M+H + )(C 35 H 53Calculated for NO: 671.8), and the mixture was used without further purification. The solution was cooled to 0 °C, and sodium borohydride (0.030 g, 0.79 mmol) was added portionwise. The reaction mixture was stirred at room temperature for 3 h. The reducing agent was quenched by the dropwise addition of 2 ml of MeOH, followed by a 15 min wait, and finally the precipitate was removed by filtration. The final product was characterized by HPLC-MS (XBridge Phenyl 3.5 μm (4.6 × 150 mm); A = HO / 0.1% TFA; B = ACN; flow rate = 1 mL / min; 0-1 min = 10% B; 1-15 min = 10% to 100% B; 15-19 min = 100% B; 19-20 min = 100% to 10% B). Retention time: 8.50 min. 1 H NMR (500 MHz, CDCl3): δ = 1.45 (s, 9H, C-(C H 3)3), 2.21 (s, 6H, C H 3-Ph), 2.56-2.93 (bs, 12H, C H 2-N), 2.93 (m, 2H, NC H -CH2-), 3.58 (m, 8H, N-CH-C H 2-), 3.65 (m, 4H, NC H 2-Ph), 3.72 (m, 4H, Ph-C H 2-N), 6.88-6.89 (bs, 4H, Ar H ). 13 C NMR (125 MHz, 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 of C15H25N5O8: 675.8).

[0306] C) Synthesis of Compound 4 (2,2’-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propan-1,3-diol)) 1,4-Bis-{[3-(N-1,3-dihydroxypropan-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 mixed solvent of TFA and CH2Cl2 (4 mL), and the mixture was stirred at room temperature for 3 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in water, and the solution was filtered through a 0.2 μm filter to remove the solid residue. 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 = 20 mL / min; 0-1 min = 1% B; 1-6 min = 1% to 100% B; 6-7 min = 100% B; 7-9 min = 100% B; 9-10 min = 100% to 1% B; 10-12 min = 1% B). The final product was characterized by HPLC-MS (XBridge Phenyl 3.5μm (4.6×150mm); A = H2O / 0.1% TFA; B = ACN; flow rate = 1 mL / min; 0-1 min = 1% B; 1-15 min = 1% to 100% B; 15-19 min = 100% B; 19-20 min = 100% to 1% B). Retention time: 9.08 min. 1 1H NMR (500 MHz, D2O): δ = 2.17 (s, 6H, C-C H 3), 2.93 (bs, 4H, C H2-N), 3.26 (quint, 2H, J =,N-C H -CH2), 3.33 (m, 4H, C H 2-N), 3.37 (m, 4H, C H 2-N), 3.67 - 3.80 (m, 8H, N-CH-C H 2), 3.99 (s, 4H, N-C H 2-Ph), 4.26 (s, 4H, Ph-C H 2-N-CH), 7.07 (s, 2H, ArH), 7.19 (s, 2H, ArH). 13 C NMR (125 MHz, D2O): δ = 19.4 (Ph- C H3), 42.6 ( C H2-N), 44.9 (Ph-CH2-N), 49.1 ( C H2-N), 54.8 (N- C H2-Ph), 57.5 (N-CH- C H2-OH), 59.7 (N- C H-CH2-OH), 120.6 (N-CH2- C -), 121.8 (C- C H2-N), 132.5 ( C -CH3), 133.5 (-CH), 134.4 (-CH), 151.2 (-C-OH). ESI-MS (m / z): 576.4 (M+H + ) (C 30 H 49 N5O6 calculated value: 575.7).

[0307] Synthesis of Example 4 - Compound 57 Compound 57 was synthesized according to the following Scheme 11.

Chemical Structure

[0308] Synthesis of Example 5 - Compound 60 Compound 60 was synthesized according to the following Scheme 12.

Chemical Structure

[0309] B) 7-(2-(2-Tetrahydropyranoxy)ethyl)-1,5,7-triazabicyclo[4.4.0]dec-5-ene (921 mg) was dissolved in 1 M hydrochloric acid (15.0 mL), and the mixture was stirred at room temperature for 6 hours. The solvent was evaporated, and the product was redissolved in DCM, filtered, and dried. This intermediate was used without further purification (663 mg, crude weight). The solid was dissolved in anhydrous DCM (15.0 mL) and placed in an ice bath. Et3N (0.626 mL, 2.5 equiv) and methanesulfonyl chloride (0.541 mL, 1.2 equiv) were added to the mixture, and the mixture was stirred at room temperature for 1 hour under a nitrogen atmosphere. 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: 166.2).

[0310] 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 was added (3.25 mL of a 1 M solution in THF, 1 equiv). The mixture was stirred under a nitrogen atmosphere for 1.5 hours, then the reaction was quenched with MeOH (2.0 mL) and stirred for about 15 minutes (until foaming ceased). The solvent was removed under reduced pressure. The product was dissolved in DCM (35 mL) and washed with 1 M Na2CO3 (3 × 10 mL); the organic phase was dried over Na2SO4, filtered, and the solvent was evaporated. Crude product: 350 mg. ESI + MS: m / z = 168.2 [MH + (C9H 17 N3 calculated: 167.2).

[0311] D) The tricyclic orthoamide (350 mg, 2.09 mmol) was dissolved in ACN (30 mL), and 3-bromomethyl-5-methyl-2-hydroxybenzaldehyde (527 mg, 1.1 equiv) was added. The mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure. The product was confirmed by HPLC-MS analysis (Waters XBridge Phenyl 3.5μm 4.6x150mm), A = H2O; B = MeOH; flow rate = 1 mL / min; 0 - 2 min = 15% B; 2 - 16 min = 15% to 100% B; 16 - 19 min = 100% B; 19 - 20 min = 100% to 15% B). Retention time: 14.8 min. ESI + MS: m / z = 316.4 [M + (C 18 H 26 N3O2 + (calculated value for: 316.2). The product was purified by flash chromatography (Sepachrom Purezza Phenyl 25μ 15g, A = H2O; B = MeOH; flow rate = 15 mL / min; 1 column volume (CV) 40% B; 40 to 100% B for 10 CV; 100% B for 2 CV). Retention time: 3.7 min. 11 mg of pure product was obtained.

[0312] E) The monoalkylated product (11 mg, 0.028 mmol) was dissolved in 0.1 M HCl (3.0 mL), and the mixture was stirred at room temperature for 24 h. The acid was neutralized with 2 M NaOH (0.150 mL), and the solvent was distilled off under reduced pressure. The product was used without further purification. The product was confirmed by HPLC-MS analysis (Waters XBridge Phenyl 3.5μm 4.6×150mm), A = H2O; B = MeOH; flow rate = 1 mL / min; 0 - 2 min = 10% B; 2 - 16 min = 10% to 100% B; 16 - 19 min = 100% B; 19 - 20 min = 100% to 10% B). Retention time: 10.3 min. ESI + MS: m / z = 334.5 [MH + (C 18 H 27 (calculated value for N3O3: 333.5).

[0313] (F) The crude product (11 mg, 0.028 mmol) was dissolved in ACN (5.0 mL), and K2CO3 (12 mg, 3 equivalents) and 3-bromomethyl-5-methyl-2-hydroxybenzaldehyde (9 mg, 1.5 equivalents) were added. The mixture was stirred at room temperature for 6 hours, 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 N3O5 calculated value: 481.6).

[0314] (G) The intermediate obtained in the previous step (15 mg, 0.031 mmol) was dissolved in anhydrous MeOH (5.0 mL), and serinol (7 mg, 2.5 equivalents) was added. The mixture was stirred at room temperature overnight. NaBH4 (6 mg, 5 equivalents) was added (0 °C, ice bath), and the mixture was stirred for 2 hours. The reaction was quenched with deionized water (a few drops), and the mixture was stirred for an additional 30 minutes. The solvent was evaporated, the product was redissolved in EtOH, filtered, and dried again under reduced pressure. The product (41 mg) was used without further purification. UPLC-MS (Acquity UPLC BEH C18 1.7 μm (2.1×50 mm); A = H2O / 0.1% TFA; B = ACN / 0.1% TFA; flow rate = 0.4 mL / min; 0 - 14 min = 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 N5O7 calculated value: 631.8).

[0315] (H) The intermediate obtained in the previous step was dissolved in 4M hydrochloric acid (1.0 mL) and stirred at room temperature for 24 hours. Then, the solvent was distilled off under reduced pressure to obtain 39 mg of a crude product. UPLC-MS (Acquity UPLC BEH C18 1.7 μm (2.1×50 mm); A = H2O / 0.1% TFA; B = ACN / 0.1% TFA; flow rate = 0.4 mL / min; 0 - 14 min = 2% to 100% B; 14 - 15 min = 100% B); retention time: 3.34 min. ESI + MS: m / z = 604.8 [MH +(C 32 H 53 Calculated value of H5N5O6: 603.8). 1 1H NMR (D2O, 500 MHz): 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- CH 2-OH, 4H), 3.81 - 3.85 (m, -CH- CH’ 2-OH, 4H), 4.25, 4.29 (s, -N- CH 2-Ph-, 8H), 6.90 (s, -CH, 2H), 7.04 (s, -CH, 2H). 13 13C NMR (D2O, 125 MHz): 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 (- CH 2-NH-C), 70.7 (-N- CH 2-Ph-), 119.4 (C Ar ), 128.2 (C Ar ), 130.2 (ArH), 131.8 (ArH), 132.3 (C Ar ), 149.9 (-C Ar -OH).

[0316] Example 6 - Synthesis of Compound 61 Compound 61 was synthesized according to the following Scheme 13.

Chemical Structure

[0317] Example 7 - Synthesis of Compound 112 Compound 112 was synthesized according to the following Scheme 14.

Chemical Structure

[0318] Example 8 - Synthesis of Compound 177 The synthesis of compound 177 was carried out according to Scheme 15 below and in the following details. [ka] A) Synthesis of 2-hydroxymethyl-4-methyl-6-nitrophenol 4-Methyl-2-nitrophenol (0.1 g, 0.65 mmol) was dissolved in 2 mL of 4 M KOH and the temperature was brought to 80 °C. Once this 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 hydrochloric acid and extracted with HO / DCM. The organic phase was then dried over MgSO, filtered, and the solvent was removed under reduced pressure to give a pale yellow oil (0.106 g, 90% yield). 11H NMR (500 MHz, 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 13C NMR (125 MHz, CDCl3): δ = 20.4 (Ph- C H3), 60.4 (- C H2), 124.9 (-CH), 128.6 (-CCH2), 129.7 (-CNO2), 134.2 (-CCH3) 139.3 (-CH), 151.3 (-COH). Calculated value of MS C8H9NO4: 183.05.

[0319] B) Synthesis of 3-hydroxymethyl-2-hydroxy-5-methylphenylacetamide 2-Hydroxymethyl-4-methyl-6-nitrophenol (0.106 g, 0.58 mmol) was dissolved in 3 ml of acetonitrile, 20 w / w% Pd / C (0.014 g) was added, and the suspension was stirred at room temperature for 2 hours under a H2 atmosphere. The mixture was filtered through a PTFE filter to minimize air contact with the compound. Next, acetyl chloride was added to the solution under a N2 atmosphere (41 μl, 0.58 mmol), and the reaction mixture was stirred overnight. Finally, the solvent was removed under reduced pressure to obtain a pale yellow oil (34 mg, yield 30%). 1 1H NMR (500 MHz, CDCl3): δ = 2.13 (s, 3H, -CH3), 2.14 (s, 3H, -CH3), 4.65 (s, 2H, -CH2-), 6.23 (s, 1H, -CH), 6.44 (s, 1H, -CH). MS C 10 H 13 NO3 calculated value: 195.2.

[0320] C) Synthesis of N,N’,N’’-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}triacetamide (Compound 177) 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 hour. The product was extracted with 3×H2O while washing the organic layer, and the organic phase was dried over MgSO4, filtered, and the solvent was removed under reduced pressure. This product was used without further purification. A solution of this mesylate in ACN (1 ml) 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). The reaction mixture was then stirred at room temperature overnight. The final compound was observed by ESI-MS (m / z): 661.4 (M+H + )(Calculated for C 29 H 39 N3O6: 660.8).

[0321] Example 9 - Fe(III) Complexation The ligands obtained in Examples 1, 2, 7, and 8 were dissolved in ethanol, and the ligands obtained in Examples 3 - 6 were dissolved in water. An equimolar amount of Fe 3+ containing FeCl3 or Fe(NO3)3 was added to prepare Fe(III) chelates by a complexation reaction. The reaction was carried out at 298 K for 18 hours. For the complexes obtained using Examples 1, 2, 7, and 8 as starting materials, the solvent was removed, the product was dissolved in water, and the pH of the solution was adjusted to 8.5 with diluted NaOH (for all complexes), and the precipitation of excess free Fe 3+ was promoted.

[0322] Example 10 - Relaxometry Analysis The relaxation ability values of some complexes of the present invention were evaluated by measuring them at 298 K in magnetic fields relevant to the clinical setting, namely 1.5 T and 3.0 T, as follows. 1The 1H NMRD profiles were measured in aqueous solution using a variable field relaxometer equipped with an HTS-110 3T Metrology Cryogen-free Superconducting Magnet (Mede, Italy) operating over the full range of proton Larmor frequencies from 20 - 120 MHz (0.47 - 3.00 T). Measurements were performed using a standard inversion recovery sequence with a 90° pulse width of 3.5 μs (20 experiments, 2 scans), and the data reproducibility was within ±0.5%. The temperature was controlled with a Stelar VTC-91 heater air flow. Additional points in the frequency range of 0.01 - 10 MHz were collected with a Fast-Field Cycling (FFC) Stelar SmarTracer Relaxometer. T1 values at 500 MHz were collected on a Bruker NMR spectrometer operating at 11.7 T. Also, the longitudinal and transverse relaxation rate values (R 1 and R 2 ) in pure water and reconstituted human serum (Seronorm matrix) at 1.5 T and 3.0 T were measured at 298 K and 310 K. The concentration of Fe 3+ in various solutions was determined using bulk magnetic susceptibility (BMS) shift measurements performed at 11.7 T (D. F. Evans, J. Chem. Soc., 1959, 2003), and confirmed by ICP-MS analysis after mineralization of the sample with 65% HNO3 at 408 K.

[0323] Compounds 1 (concentration 0.40 mM), 2 (concentration 0.60 mM), 4 (concentration 0.65 mM), 57 (concentration 0.50 mM), 60 (concentration 0.47 mM), 61 (concentration 0.60 mM) and 112 (concentration 0.78 mM) were measured as described above at 1.5 T and 3.0 T magnetic flux densities, pH = 7.4 and 310 K in 0.15 M NaCl, in 0.15 M NaCl and 25 mM NaHCO3, and in Seronorm® (lyophilized human serum), and are shown in Table 1.

Table 1

[0324] Example 11 - Thermodynamic Stability Analysis To evaluate the thermodynamic stability of the Fe(III) complex of the present invention and the comparative examples, first the protonation constants of each ligand were determined, and then the protonation constants of the Fe(III) complex were determined by pH-potentiometry and / or UV spectrophotometry. Finally, based on the protonation constants, the thermodynamic stability constants of the Fe(III) complex of the present invention were 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 Vis spectrophotometry for Compound 4. A similar method for evaluating the thermodynamic stability of different metal complexes is implemented in WO 2020 / 099398. HBED represented by the following formula is a ligand that forms a complex with Fe(III) and has a very low relaxation ability (r1 of 0.49 mM at 60 MHz and 40 °C in PBS buffer as described in Bales et al., Contrast Media & Molecular Imaging, Volume 2019, Article ID 8356931). -1 ·s -1 of r1).

Chemical formula

[0325] A) Determination of the protonation constant of the ligand Solid Fe(NO3)3 was dissolved in 0.1 M 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 standardized ZnCl2 solution and xylenol orange as an indicator. The H of the Fe(NO3)3 solution was + The concentrations of the ligands Compound 2, Compound 4, H3NOTA (comparative example - see formula below) and H4HBED (comparative example) were determined by pH-potentiometric titration in the presence of excess Na2H2EDTA. 2+ The pH was determined by potentiometric titration in the presence and absence of HCl. The pH was measured using standardized 0.2 M NaOH (the ligand concentration was uniformly set at 0.002 M). A Metrohm 888 Titrando titration workstation with a Metrohm-6.0234.110 combination electrode was used for pH measurements and titrations. [ka] The protonation constants (K) of Compound 2, NOTA (comparative example), and HBED (comparative example) obtained by the pH potentiometry method described above i H =[H i ligand] / ([H i-1 Ligand] × [H + ]) was subsequently used to determine the protonation constants and thermodynamic stabilities of the corresponding Fe(III) complexes. The protonation constant of compound 2 was confirmed by ultraviolet spectrophotometry in the wavelength range of 210-390 nm (using a PerkinElmer Lambda 365 UV-Vis spectrophotometer) ([compound 2] = 87 μM, 0.15 M NaClO4, 25 °C). The protonation constant of compound 2 was confirmed by ultraviolet spectrophotometry in the wavelength range of 210-390 nm (using a PerkinElmer Lambda 365 UV-Vis spectrophotometer) ([compound 2] = 87 μM, 0.15 M NaClO4, 25 °C). 2+The deprotonation of the base was examined spectrophotometrically by following the absorption bands of the aromatic groups of the ligand according to the absorbance values at 243 nm and 303 nm. The absorbance of the ligand is a combination of the absorbances of the individual protonated species and is given by the following equation: [Equation] (where A is the absorbance at a given wavelength, c i , ε i , and l are the concentration, the molar absorptivity of the species, and the cell path length, respectively). (Beck, M. T. et al., Chemistry of Comple× Equilibria, Akademia Kiado Budapest and Nostrand Reinhold Company Ltd., 1990, London. London, 1990). The absorbance (A) conformed to the above equation (the concentrations of the various protonated ligands were expressed in terms of the protonation constant K i H ). The protonation constant of compound 4 was determined by recording the chemical shift changes of the non-labile protons as a function of pH at 25 °C in a 0.15 M NaNO3 solution by 1H-NMR spectroscopy on a Bruker Avance III spectrometer (9.4 T) equipped with a Bruker variable temperature unit (BVT), a Bruker cooling unit (BCU), and a BB inverse Z-gradient probe (5 mm). Since protonation / deprotonation is fast on the NMR time scale, the chemical shift of the observed signal is given by the weighted average of the shifts of the different species having different protonation states and is given by the following equation: 1 (where δ [Equation] (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 species involved, respectively). represented by (Pagado, J. M; Goldberg, D. E; Fernelius, W. C; J. Phys. Chem., 1961, 65, 1062). The observed chemical shift values (δ H(obs) ) were in agreement with the above equation (the concentrations of different protonated ligands are the protonation constant K i H represented by).

[0326] B) Determination of the protonation constant of the Fe(III) complex The protonation constants (K MHiLigand = [MH i Ligand] / ([MH i-1 Ligand] × [H + ) of the Fe(III) complexes of Compound 2, Compound 4, NOTA (comparative example), and HBED (comparative example) were determined by the pH-potentiometric method and / or spectrophotometric method. Specifically, the protonation constants of the Fe(NOTA) and Fe(HBED) complexes were determined by titrating the pre-prepared complexes with 0.2 M NaOH ([FeL] = 0.002 M) from pH = 1.7 to pH = 12.0 using pH-potentiometry. For pH measurement and titration, a Metrohm 888 Titrando titration workstation and a Metrohm-6.0234.110 combined electrode were used. The equilibrium measurements were carried out at 25 °C in a 6 ml sample with a constant ionic strength (0.15 M NaNO3 or NaClO4). The solution was stirred and N2 was bubbled through. The titration was carried out in the pH range of 1.7 - 12.0. The pH meter was calibrated using a KH-phthalate buffer solution (pH = 4.005) and a borax buffer solution (pH = 9.177). To calculate [H + from the measured pH values, the method disclosed in Irving et al. Anal. Chim. Acta, 1967, 38, 475 - 488 was used as follows: A 0.01 M HNO3 or HClO4 solution was titrated with a standardized NaOH solution at an ionic strength of 0.15 M NaNO3. The measured pH value (pH read ) and the calculated value (-log[H +]) (A) is used to calculate the equilibrium H from the pH measured in the titration experiment. + The concentrations were calculated (A = 0.02 for 0.15 M NaNO3, A = 0.01 for 0.15 M NaClO4). Equilibrium calculations showed that under basic conditions, [OH - To calculate the stoichiometric water ion product (pK w ) was required. V of HNO3-NaOH titration obtained in the pH range 10.5-12.0 NaOH -pH read Using data pairs, pK w The values were calculated (pK w =13.76). Following the method disclosed in Example 11A above, the protonation constants of the Fe(Compound 2) and Fe(Compound 4) complexes were determined by ultraviolet spectrophotometric analysis in the wavelength range of 210–700 nm ([Fe(Compound 2)] = 43 μM, [Fe(Compound 4)] = 100 μM, 0.15 M NaClO, 25°C). The protonation constants of the Fe(III) complexes of Compound 2, Compound 4, NOTA (comparative), and HBED (comparative) were used to subsequently determine the thermodynamic stability of these Fe(III) complexes.

[0327] C) Determination of thermodynamic stability of Fe(III) complexes Thermodynamic stability constants (K MLigand = ([MLigand] / ([M] × [Ligand])) was determined as follows: The stability constant of the Fe(NOTA) complex is 3+ Spectrophotometric measurement of the -NOTA system revealed that [H + ]=0.01 to 3.0 M Fe III The absorption band of the complex was determined. 3+ The concentration of NOTA was 0.002M. + The concentration is calculated from the volume of a 6M solution of HNO3 (I = [Na + ]+[H + ]=0.15,[H +(≤0.15 M) was added and adjusted. The samples were stored at 25 °C for 2 weeks. The absorbance of the samples was measured at a wavelength of 11 (370, 380, 390, 395, 400, 405, 410, 415, 420, 425, 430 nm). For the calculation of the thermodynamic stability constant of Fe(NOTA), the molar absorbances of Fe 3+ and Fe(NOTA) were determined by recording the spectra of solutions of Fe 3+ and Fe(NOTA) (1.0×10 -3 , 1.5×10 -3 , 2.0×10 -3 and 2.5×10 -3 M). The absorption spectrum of the Fe(NOTA) solution was recorded in the pH range of 1.7 - 7.5. All spectrophotometric measurements were carried out at 25 °C in a 0.15 M NaNO3 solution. The pH was adjusted by adding concentrated NaOH or HNO3 solution little by little.

[0328] The stability constant of the Fe(HBED) complex was determined using a spectrophotometer by tracking the competitive reaction between the ligands HBED and NOTA for Fe 3+ ions in the absorption band of the Fe(HBED) complex in the wavelength range of 400 - 700 nm. In the Fe 3+ -HBED-NOTA system, six types of samples were prepared (in 0.15 M NaNO3 solution, [Fe 3+ =0.1 mM, [HBED]=0.2 mM, [NOTA]=0.0, 2.0, 4.0, 6.0, 8.0, 10.0 mM). The pH of the samples was adjusted to 5.0 by adding concentrated NaOH and HNO3 solutions little by little. The samples were allowed to stand at 25 °C for 4 weeks for equilibration. The time required to reach equilibrium was measured with a spectrophotometer. The absorbance of the samples was measured at the absorption band of the Fe(HBED) complex ([Fe(HBED)] - species is dominant at pH = 5.0). For the calculation of the thermodynamic stability constant of the Fe(HBED) complex, the molar absorbances of the [Fe(HBED)] - species were measured at pH = 5 in the presence of 0.15 M NaNO3 at 0.5, 0.1, 0.2 mM of [Fe(HBED)] -It was determined by recording the spectrum of the solution. Spectrophotometric measurements were carried out using a 1.0 cm cell and a PerkinElmer Lambda 365 UV-Vis spectrophotometer. The thermodynamic stability constants were calculated with the PSEQUAD program (L. Zekany et al., Computational Method for Determination of Formation Constants, Ed. Legett D J, Plenum, New York, 1985, p. 291).

[0329] The thermodynamic stability constant of the Fe(Compound 2) complex was determined for the signal of the Fe(Compound 2) complex using capillary zone electrophoresis (CZE). 3+It was determined by tracking the competitive reaction between compound 2 and the HBED ligand for ions. CZE separation was performed on an Agilent 7100 Capillary Electrophoresis system using a 64 cm × 50 μm (inner diameter) bare fused silica capillary (Agilent). Before using the capillary for the first time, the capillary was washed with 1.0 M NaOH (15 minutes), 0.1 M NaOH (30 minutes), and buffer electrolyte (30 minutes). Prior to CZE analysis, all buffers were filtered through a 0.45 μm syringe filter and stored in a +4°C refrigerator. In CZE, the sample solution was introduced into the anode end of the capillary in normal mode (50 mbar, 20 seconds). The effective length of the capillary was 56 cm. The capillary was pretreated with buffer electrolyte (150 mM sodium bicarbonate, pH = 8.2) for 3 minutes. Separation was carried out at 37°C with an applied voltage of 30 kV. After analysis, post-treatment (0.1 M NaOH (3 minutes) and buffer (3 minutes)) was performed to desorb all substances adsorbed from the capillary. In all measurements, 5 mM DMSO was applied as an internal standard to correct the migration time of electrophoretic components. Detection was performed by on-column DAD measurement at 500 nm. Recording and processing of the electropherogram were performed with the ChemStation computer program (Agilent), version B.04.02. For the calculation of the equilibrium, the molar integral value of Fe (compound 2) was used. The molar integral value of Fe (compound 2) was determined by recording the electropherograms of 22 μM, 44 μM, and 87 μM Fe (compound 2) solutions at pH = 6.0, 25°C in the presence of an ionic strength of 0.15 M NaNO3. Linear regression equations (reaction - concentration) were determined individually for the three concentrations of Fe (compound 2). The peak area was linear (R 2 >0.998) in the concentration range of 22 - 87 μM (accuracy better than 4%). The LOD was 2.7 μM and the molar integral value was 133294 mAU -1 M -1 (LOD = 3σ / molar integral value).

[0330] Fe 3+- For the 2-HBED system of the compound, five types of samples ([Fe(compound 2)] = 87 μM, [HBED] = 0.0, 4.0, 16.0, 30.0, 50.0 mM in 0.15 M NaNO3 solution) were prepared. The pH of the samples was adjusted to 11.0 by adding concentrated NaOH and HNO3 solutions little by little. The samples were left standing at 25 °C for 4 weeks for equilibration. The time required to reach equilibrium was determined by CZE test. The amount of the Fe(compound 2) complex decreases according to the competition reaction between compound 2 and HBED for Fe 3+ - ions (Equation 1). The signals of the negatively charged Fe(HBED) and the ligand of compound 2 did not appear in the electrophoretogram.

Equation

[0331] The stability constant of the Fe(Compound 4) complex was determined by using a spectrophotometer to follow the competitive reaction between Compound 4 and the HBED ligand for Fe 3+ ions in the absorption bands of Fe(Compound 4) and the Fe(HBED) complex in the wavelength range of 400 - 700 nm. For the Fe 3+ -Compound 4-HBED system, six types of samples were prepared (in a 0.15 M NaNO3 solution, [Fe 3+ ​=0.1 mM, [Compound 4]=0.1 mM, [HBED]=0.0, 0.05, 0.1, 0.2, 0.4, 0.5, 1.0, 2.0 mM). The pH of the sample was adjusted to 12.0 by adding concentrated NaOH and HNO3 solutions little by little. To equilibrate, the sample was left standing at 25 °C for 4 weeks. The time required to reach equilibrium was measured with a spectrophotometer. The absorbance of the sample was measured for the absorption bands of the Fe(Compound 4) and Fe(HBED) complexes ([Fe(Compound 4)H -1 , [Fe(HBED)] - and [Fe(HBED)H -1 -2 species are dominant at pH = 12.0). To calculate the thermodynamic stability constants of the Fe(Compound 4) complex, solutions of 0.5 mM, 0.1 mM, 0.2 mM of [Fe(Compound 4)] and [Fe(HBED)] - were determined by recording spectra in the range of pH 7.0 - 12.5 in the presence of 0.15 M NaNO3. Spectrophotometric measurements were carried out using a PerkinElmer Lambda 365 UV-Vis spectrophotometer with a 1.0 cm cell. The thermodynamic stability constants were calculated with the PSEQUAD program (L. Zekany et al., Computational Method for Determination of Formation Constants, Ed. Legett D J, Plenum, New York, 1985, p.291).

[0332] D) Protonation constants and thermodynamic stability of Fe(III) complexes The thermodynamic stabilities and protonation constants (determined according to the above experiments) of the Fe(III)-complexes of Compound 2 and Compound 4 and the NOTA complex and HBED complex as comparative examples are shown in Table 2 below.

Table 2

[0333] Example 12 - Kinetic Inertness Analysis ​​To obtain data on the kinetic inertness of Fe(Compound 2), Fe(Compound 4) and Fe(NOTA) (comparative example), 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, the transchelation reaction (outlined below) was investigated by VIS-spectrophotometry (for Fe(Compound 4) and Fe(NOTA)) and capillary zone electrophoresis (CZE) (for Fe(Compound 2)). [Chemical formula] (L = Compound 2, Compound 4 or NOTA)

[0334] A) Determination of the kinetic inertness of the Fe(III) complex For the transchelation reaction of Fe(Compound 4) and Fe(NOTA) (comparative example), the formation of the Fe(HBED) complex was followed at 472 nm and 470 nm using a Perkin Elmer Lambda 365 UV-Vis spectrophotometer and investigated by spectrophotometry. The concentrations of the Fe(Compound 4) and Fe(NOTA) complexes were 0.1 and 0.2 mM, and the concentration of HBED was 10 to 200 times that to ensure pseudo-first-order conditions. The temperature was kept at 25 °C and the ionic strength of the solution was kept constant (0.15 M NaNO3). The exchange rate was investigated in the pH range of 9.5 to 14.0. At pH < 12, since the excess HBED could maintain a constant pH value, no buffer was used. At pH > 12, the calculated amount of 19 M NaOH was added to adjust the OH - concentration in the sample (I = [NaNO3] + [NaOH] = 0.15, [NaOH] ≤ 0.15 M). The pseudo-first-order rate constant (k d ) was calculated by fitting the absorbance-time data pairs to Equation 2. [Number] (wherein, A t , A0, A p are the absorbances at time t, at the start of the reaction, and at equilibrium, respectively) The ligand exchange reaction in the Fe(Compound 2)-HBED reaction system was examined by capillary zone electrophoresis (CZE) in the pH range of 9.5 to 11.5. The transchelation reaction of Fe(Compound 2) was examined by tracking the dissociation of the Fe(Compound 2) complex using an Agilent 7100 capillary electrophoresis system (using the same conditions as the CZE experiment in Example 11). The concentration of the Fe(Compound 2) complex was set to 87 μM, and the concentrations of HBED were set to 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 (1.0 M NaClO4). The pseudo-first-order rate constant (k d ) was calculated by fitting the pair of area-time data to the above Equation 2 (wherein, A t , A0, A p are the area values at time t, at the start of the reaction, and at equilibrium, respectively). The calculations were performed using the Micromath Scientist computer program (version 2.0, Salt Lake City, Utah, USA).

[0335] B) Kinetic Inertness of Fe(III) Complex The results of the kinetic inertness (dissociation rate constant k d and half-life t 1 / 2 ) of the Fe(III)-complex of Compound 2, as well as the complexes NOTA (determined according to the above experiments), EDTA, and CDTA (Baranyai Z. et al., Chem. Sci., 2021, 12, 11138-11145) of the comparative examples are shown in Table 3 below. [Table 3] Dissociation rate constant (k d)(Calculated by extrapolating the kinetic data obtained at pH > 9.0) is approximately twice lower than the dissociation rate constant of Fe(NOTA), and the complex of the present invention is less active than the comparative example of Fe(NOTA). The dissociation half-lives (t 1 / 2 = ln(2) / k d ) of Fe(III)-Compound 2 and Fe(III)-Compound 4 complexes are about 11.3 years and 0.65 years near physiological conditions (pH = 7.4, 25 °C), which indicates that the in vivo application is safe.

[0336] Example 13 - Transferrin Challenge Reaction Transferrin is an Fe 3+ binding transport protein. Human serum transferrin (sTf) is known to bind Fe 3+ with high affinity (logK FeTf = 21.44, logK Fe2Tf = 20.34) (W. R. Harris, Y. Chen, K. Wein, Inorg. Chem., 1994, 33, 4991). Serum transferrin is usually only 30% saturated with Fe 3+ , so it retains a relatively high ability to bind Fe 3+ released by other Fe(III)-complexes, and further promotes the release of Fe 3+ from the Fe(III)-complex, and as a result, promotes the dissociation of such Fe(III)-complexes. To investigate the possibility of the role of transferrin in the dissociation of the Fe(III)-complexes of the present invention, the reaction between 22.6% saturated human serum transferrin (Sigma) and Fe(III)-Compound 2, Fe(III)-Compound 4, Fe(III)-Compound 57, Fe(III)-Compound 60 and Fe(IIII)-Compound 61 complexes was investigated by following the formation of Fe 3+ saturated human serum transferrin and the dissociation of Fe(III)-Compound 2, Fe(III)-Compound 4, Fe(III)-Compound 57, Fe(III)-Compound 60 and Fe(IIII)-Compound 61 complexes. The Fe 3+ of human serum transferrin 3+The saturation was determined as described in Z. Baranyai, F. Uggeri, A. Maiocchi, G. B. Giovenzana, C. Cavallotti, A. Takacs, I. Toth, I. Banyai, E. Brucher, S. Aime, Eur. J. Inorg. Chem. 2013, 147 - 162; the binding of sTf to Fe 3+ Since the binding requires the cooperative binding of anions (bicarbonate in vivo) (G. W. Bates, M. R. Schlabach, J. Biol. Chem., 1975, 250, 2177 - 2181), all measurements were carried out at pH = 7.4 and 25 °C in the presence of 25 mM NaHCO3. The molar absorbances of the Fe(III)-complexes and Fe 3+ -human serum transferrin species are different, so for the metal exchange reaction between the Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61 complexes and Fe 3+ 22.6% saturated human serum transferrin, the dissociation of the Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60 and Fe(III)-compound 61 complexes and the formation of Fe 3+ saturated human serum transferrin were investigated by following, in the wavelength range of 400 - 700 nm, a spectrophotometric method using a PerkinElmer Lambda 365 UV-Vis spectrophotometer in the presence of equimolar human transferrin. The complexes of Fe(III)-compound 2, Fe(III)-compound 4, Fe(III)-compound 57, Fe(III)-compound 60, Fe(III)-compound 61 and Fe 3+The concentration of 22.6% saturated human serum transferrin was set at 0.1 mM. The temperature was maintained at 25 °C and the ionic strength of the solution was kept constant (0.15 M NaCl). The pH of the sample was adjusted by adding concentrated NaOH and HCl solutions little by little. At a reaction time of 1100 minutes, no change was observed in the absorption spectra 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, that is, the Fe(III)-complexes formed by Compound 2, Compound 4, Compound 57, Compound 60, and Compound 61 have very high kinetic inertness and / or high conditional stability compared to the Fe(III)-complex of sTf. In fact, the complexes of the present invention are Fe 3+ Even in the presence of 22.6% saturated sTf (i.e., near physiological conditions, pH = 7.4, 25 °C, 25 mM NaHCO3, 0.15 M NaCl), they did 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 Fe(III)-Compound 2, Fe(III)-Compound 4, Fe(III)-Compound 57, Fe(III)-Compound 60, and Fe(III)-Compound 61.

[0337] Example 14 - Redox Stability Analysis To characterize the redox stability of the Fe(III) complexes, the reactions of ascorbic acid with Fe(III)-Compound 2, Fe(III)-Compound 4, Fe(III)-Compound 57, Fe(III)-Compound 60, Fe(III)-Compound 61, and Fe(III)(NOTA) (comparative example) were examined as follows. In the presence of a large excess of ascorbic acid, the reduction of the Fe(III)-complex was traced by a spectrophotometer ([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).

[0338] A) Determination of the Redox Stability of the Fe(III) Complex The redox stabilities 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 were characterized by evaluating the reduction rate by ascorbic acid by tracking the formation of the Fe(II)-ligand complex and observing the reduction reaction with a spectrophotometer at 375 nm for Fe(III)(NOTA), 480 nm for Fe(III)-Compound 2 and Fe(III)-Compound 57, 471 nm for Fe(III)-Compound 4, and 500 nm for Fe(III)-Compound 60 and Fe(III)-Compound 61. The concentrations of the Fe(III)(NOTA), 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 μM, 100 μM, 25 μM, 100 μM, and 100 μM, respectively, and ascorbic acid was used in a large excess ([ascorbic acid] = 20 mM) to ensure pseudo-first-order conditions. In the experiment of Fe(III)(NOTA), Fe released from Fe(III)(NOTA) after reduction may be released by Fe(II)NOTA 2+As a scavenger for complexing ions, a 4-fold excess of free NOTA ligand was added (the stability of Fe(II)NOTA is low and Fe 2+ ions can be released by the complex). The temperature was maintained at 25 °C and the ionic strength of the solution was kept constant (0.15 M NaNO3). The reduction rate was investigated at pH = 7.4. To keep the pH constant, HEPES buffer ([HEPES] = 0.01 M) was used. In sample preparation, all solutions were bubbled with air to maintain an oxygen-free state. The pseudo-first-order rate constant (k obs = k d ) was calculated by fitting pairs of absorbance-time data to Equation 2 using the Micromath Scientist computer program (version 2.0, Salt Lake City, UT, USA).

[0339] B) Redox stability data of Fe(III) complexes The absorption spectra of the above experiments showed that for Fe(III)(NOTA), the absorbance value decreased as a function of time due to the reduction of Fe(III)(NOTA) by ascorbic acid. In fact, the reduction half-life (t 1 / 2 = ln2 / k obs ) that characterizes the reduction of Fe(III)(NOTA) by ascorbic acid was t 1 / 2It was found to be 2.7 minutes (in the case of ascorbic acid excess described in the above (A)). Considering the in vivo concentration of ascorbic acid ([ascorbic acid] = 43 μM, P. M. May, D. R. Williams, P. W. 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.; Horvath, D.; Tei, L.; Platas-Iglesias, C.; Botta, M. Chem. Sci. 2021, 12, 11138 - 11145), the reduction of Fe(III)(NOTA) by ascorbic acid is under physiological conditions ([ascorbic acid] = 43 μM, pH = 7.4, 0.01 M HEPES, 0.15 M NaNO3, 25 °C) with t 1 / 2 was found to be 19.5 hours.

[0340] Furthermore, the absorbance of the reaction systems of Fe(III)-compound 4-ascorbic acid, Fe(III)-compound 60-ascorbic acid, and Fe(III)-compound 61-ascorbic acid decreases slowly as a function of time, that is, even in the presence of a 200-fold excess of ascorbic acid, the decreases in absorbance in one day were observed to be 12%, 35%, and 40%, respectively. Based on such spectral changes, the reduction from 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 seems to occur very slowly in the Fe(III)-compound 4-ascorbic acid, Fe(III)-compound 60-ascorbic acid, and Fe(III)-compound 61-ascorbic acid reaction systems. Considering the in vivo concentration of ascorbic acid ([ascorbic acid] = 43 μM) and assuming that the reduction rate of the Fe(III)-complex is directly proportional to the concentration of ascorbic acid, the reduction of Fe(III)-compound 4, Fe(III)-compound 60, and Fe(III)-compound 61 by ascorbic acid is at physiological conditions ([ascorbic acid] = 43 μM, pH = 7.4, 0.01 M HEPES, 0.15 M NaNO3, 25 °C), t 1 / 2 = 3.5×10 3 、1.6×10 3 および3.0×10 3 hours, respectively. These t 1 / 2 values indicate safe and effective in vivo application.

[0341] Furthermore, it was observed that there was no change in the absorption spectra of the Fe(III)-compound 2-ascorbic acid and Fe(III)-compound 57-ascorbic acid reaction systems at a reaction time of 1 day. This can be explained by the fact that compounds 2 and 57 have a higher selectivity for Fe(III)-ions than for Fe(II)-ions (ΔpFe > 16); in other words, when iron forms a complex with compounds 2 or 57, it tends to maintain a +3 oxidation state without being reduced to +2 even in the presence of a large excess of ascorbic acid (a reducing agent). This also indicates the safe and effective in vivo application of the Fe(III)-complexes of the present invention.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, n, m, and o are independently integers from 1 to 2; Y １ and Y ２ are independently hydrogen and C １ -C ４ - selected from the group consisting of alkyl; R １ and R ２ are independently hydrogen and C １ -C ４ - selected from the group consisting of alkyl; L １ and L ２ are independently １ -C ４ -Alkylaminyl, C １ -C ４ -Alkyl amidyl and C １ -C ４ - selected from the group consisting of alkyl ethers; Z １ and Z ２ are independently hydrogen and C １ -C ６ -alkyl, wherein said C １ -C ６ -Alkyl is optionally hydroxyl (-OH), carboxyl (-COOH) and phosphonate (-PO ３ H ２ substituted with one or more groups selected from the group consisting of: R is hydrogen, optionally aryl-substituted C １ -C ４ alkyl, and formula (IA): 【Chemistry 2】 (In the formula, The asterisk (*) indicates the point of attachment of the moiety of formula (IA) to the nitrogen bearing the R group; Y ３ Is Y １ and Y ２ has the same meaning as given above for R ３ is R １ and R ２ has the same meaning as given above for L ３ Is, L １ and L ２ has the same meaning as given above for Z ３ Is Z １ and Z ２ (The meaning of "is the same as that given above for ") and wherein the moiety is selected from the group consisting of: or a mixture thereof, an ion, a stereoisomer, a tautomer, a hydrate, a solvate or a pharmaceutically acceptable salt thereof.

2. Y １ and Y ２ , and Y, if present ３ are independently hydrogen and C １ -C ３ 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of: - alkyl.

3. Y １ and Y ２ , and Y, if present ３ are independently hydrogen and C １ -C ２ 3. The compound of claim 2, wherein the aryl group is selected from the group consisting of: - alkyl.

4. Y １ and Y ２ , and Y, if present ３ are independently hydrogen and C １ - alkyl.

5. Y １ and Y ２ , and Y, if present ３ The compound of claim 4 , wherein is hydrogen.

6. R １ and R ２ , and R if present ３ are independently hydrogen and C １ -C ３ 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of: - alkyl.

7. R １ and R ２ , and R if present ３ are independently hydrogen and C １ -C ２ - alkyl.

8. R １ and R ２ , and R if present ３ are independently hydrogen and C １ 8. The compound of claim 7, wherein the aryl group is selected from the group consisting of: - alkyl.

9. R １ and R ２ , and R if present ３ is C １ -Alkyl (-CH ３ 9. The compound of claim 8, wherein

10. L １ , L ２ , and L, if present ３ are independently １ -C ３ -Alkylaminyl, C １ -C ３ -Alkyl amidyl and C １ -C ３ - alkyl ether; preferably C １ -C ３ -Alkyl aminyl and C １ -C ３ - alkyl amidyl.

11. L １ , L ２ , and L, if present ３ are independently １ -C ２ -Alkylaminyl, C １ -C ２ -Alkyl amidyl and C １ -C ２ - alkyl ether; preferably C １ -C ２ -Alkyl aminyl and C １ -C ２ - alkyl amidyl.

12. L １ , L ２ , and L, if present ３ are independently １ -Alkylaminyl, C １ -Alkyl amidyl and C １ - alkyl ether; preferably C １ -Alkyl aminyl and C １ - alkyl amidyl.

13. L １ , L ２ , and L, if present ３ is, independently, ＊ -CH ２ -NH-, ＊ -C(O)NH-, ＊ -NHC(O)- and ＊ -CH ２ -O-., where the asterisk (*) represents a phenol moiety and the dot (.) represents Z １ Base, Z ２ group, or Z, if present ３ 13. The compound of claim 12, wherein the compound represents a group.

14. L １ , L ２ , and L, if present ３ is, independently, ＊ -CH ２ -NH-, ＊ -C(O)NH- and ＊ -CH ２ -O-; preferably, ＊ -CH ２ -NH- and ＊ -C(O)-NH-., where the asterisk (*) represents a phenol moiety and the center dot (.) represents Z １ Base, Z ２ group, or Z, if present ３ 14. The compound of claim 13, wherein the compound represents a group.

15. Z １ , Z ２ , and Z, if present ３ are independently hydrogen, C substituted with two or more hydroxyl (—OH) groups, ４ -C ６ -Alkyl, as well as hydroxyl (-OH), carboxyl (-COOH) and phosphonate (PO ３ H ２ C substituted with at least one group selected from the group consisting of １ -C ３ 2. The compound of claim 1, wherein the aryl group is selected from the group consisting of: - alkyl.

16. Z １ , Z ２ , and Z, if present ３ are independently hydrogen, C substituted with 2 to 5 hydroxyl (—OH) groups ６ -alkyl, C substituted with at least one hydroxyl (—OH) group １ -C ３ - alkyl, and carboxyl (COOH) or phosphonate (PO ３ H ２ ) substituted with C １ - alkyl.

17. Z １ , Z ２ , and Z, if present ３ are independently hydrogen and C １ -C ４ -alkyl, wherein said C １ -C ４ -Alkyl is optionally hydroxyl (-OH), carboxyl (COOH) and phosphonate (PO ３ H ２ 10. The compound of claim 1, substituted with one or more groups selected from the group consisting of:

18. R is C １ -C ３ -C substituted with alkyl or aryl １ -C ３ The compound of claim 1, wherein:

19. R is C １ -C ２ -C substituted with alkyl or aryl １ -C ２ - alkyl.

20. R is C １ -C substituted with alkyl or aryl １ - alkyl.

21. R is hydrogen, C １ -C substituted with alkyl, aryl １ -alkyl, and formula (IA): 【Transformation 3】 (In the formula, Y ３ , R ３ , L ３ and Z ３ are respectively, Y １ , R １ , L １ and Z １ has the same meaning as defined in claim 1) 2. The compound of claim 1 selected from the group consisting of:

22. n, m and o are 1, whereby the compound has the following formula (II): 【Chemistry 4】 [In the formula, R, R １ , R ２ , Y １ , Y ２ , L １ , L ２ , Z １ and Z ２ is as defined in claim 1.

2. The compound of claim 1 having the formula:

23. Only one of n, m, and o is 2 and the other two are 1, thereby providing a compound of formula (IIIA), formula (IIIB), or formula (IIIC): 【Transformation 5】 wherein, for formula (IIIA), formula (IIIB) and formula (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 is as defined in claim 1, and R' is hydrogen or C optionally substituted with aryl. １ -C ４ -alkyl] 2. The compound of claim 1, wherein

24. R' is hydrogen or C optionally substituted with aryl １ -C ３ - alkyl.

25. R' is hydrogen or C optionally substituted with aryl １ -C ２ - alkyl.

26. R' is hydrogen or C optionally substituted with aryl １ - alkyl.

27. Only one of n, m and o is 1 and the other two are 2, whereby the compound has formula (IVA), formula (IVB) or formula (IVC): 【Transformation 6】 [Wherein, for formula (IVA), formula (IVB) and formula (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 is as defined in claim 1, and R' is hydrogen or C optionally substituted with aryl. １ -C ４ -alkyl] 2. The compound of claim 1, wherein

28. R' is hydrogen or C optionally substituted with aryl １ -C ３ - alkyl.

29. R' is hydrogen or C optionally substituted with aryl １ -C ２ - alkyl.

30. R' is hydrogen or C optionally substituted with aryl １ - alkyl.

31. n, m and o are 2, whereby the compound has the following formula (V): 【Transformation 7】 [In the formula, R, R １ , R ２ , Y １ , Y ２ , L １ , L ２ , Z １ and Z ２ is as defined in claim 1.

2. The compound of claim 1 having the formula:

32. The compound of claim 1 selected from the group consisting of: 3,3',3''-[1,4,7-triazonane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2',2''-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(propane-1,3-diol); 3,3'-[1,4,7-triazonane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol); 3,3',3''-[1,4,7-triazonane-1,4,7-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,7-triazonane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2''-[1,4,7-triazonane-1,4,7-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,7-triazonane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid); {1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(phosphonic acid); {1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); 3,3',3''-[1,4,7-triazonane-1,4,7-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1',1''-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethane-1,2-diol); 3,3'-[1,4,7-triazonane-1,4-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-1,2-diol); N,N',N''-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropanamide); N,N'-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N',N''-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propanamide]; N,N'-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; {1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid); {1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); 3,3',3''-[1,4,7-triazecane-1,4,7-triyltris(methylene)]tris[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2',2''-{1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(propane-1,3-diol); 3,3'-[1,4,7-triazecane-1,7-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,7-triazecane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol); 2,2'-{1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol); 3,3',3''-[1,4,7-triazecane-1,4,7-triyltris(methylene)]tris(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,7-triazecane-1,7-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 3,3'-[1,4,7-triazecane-1,4-diylbis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2',2''-[1,4,7-triazecane-1,4,7-triyltris(methylene)]tris[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,7-triazecane-1,7-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; 2,2'-[1,4,7-triazecane-1,4-diylbis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid); {1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(phosphonic acid); {1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); {1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); 3,3',3''-[1,4,7-triazecane-1,4,7-triyltris(methylene)]tris[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1',1''-{1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(ethane-1,2-diol); 3,3'-[1,4,7-triazecane-1,7-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,7-triazecane-1,4-diylbis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-1,2-diol); 1,1'-{1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-1,2-diol); N,N',N''-{1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris(2,3-dihydroxypropanamide); N,N'-{1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N'-{1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N',N''-{1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propanamide]; N,N'-{1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; N,N'-{1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; {1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}tris(phosphonic acid); {1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); {1,4,7-triazecane-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[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2',2''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(propane-1,3-diol); 3,3'-[1,4,8-triazacycloundecane-1,8-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[1,4,8-triazacycloundecane-1,4-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol); 2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(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-methylbenzamide); 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-methyl-3,1-phenylene)carbonylazanediylmethylene]}tris(phosphonic acid); {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]}tris(phosphonic acid); {1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); {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]}tri(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]}di(ethane-1,2-diol); 1,1'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-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-dihydroxypropanamide); N,N'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N',N''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propanamide]; N,N'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; N,N'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; {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); {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-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2',2''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(propane-1,3-diol); 3,3'-[1,5,9-triazacyclododecane-1,5-diylbis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol); 3,3',3''-[1,5,9-triazacyclododecane-1,5,9-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)carbonylazanediylmethylene]}tris(phosphonic acid); {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-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}tris(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-triyltris(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]}tri(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]}di(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-dihydroxypropanamide); N,N'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N',N''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}tris[3-hydroxy-2-(hydroxymethyl)propanamide]; N,N'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; {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-triazonane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{(7-benzyl-1,4,7-triazonane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol); 3,3'-[(7-benzyl-1,4,7-triazonane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2'-[(7-benzyl-1,4,7-triazonane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {(7-benzyl-1,4,7-triazonane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazonane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); 3,3'-[(7-benzyl-1,4,7-triazonane-1,4-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{(7-benzyl-1,4,7-triazonane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-1,2-diol); N,N'-{(7-benzyl-1,4,7-triazonane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N'-{(7-benzyl-1,4,7-triazonane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; {(7-benzyl-1,4,7-triazonane-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-triazecane-1,7-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(7-benzyl-1,4,7-triazecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(propane-1,3-diol); 3,3'-[(4-benzyl-1,4,7-triazecane-1,7-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 3,3'-[(7-benzyl-1,4,7-triazecane-1,4-diyl)bis(methylene)]bis(2-hydroxy-5-methylbenzamide); 2,2'-[(4-benzyl-1,4,7-triazecane-1,7-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; 2,2'-[(7-benzyl-1,4,7-triazecane-1,4-diyl)bis(methylene)]bis[6-(aminomethyl)-4-methylphenol]; {(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediylmethylene]}bis(phosphonic acid); 3,3'-[(4-benzyl-1,4,7-triazecane-1,7-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(7-benzyl-1,4,7-triazecane-1,4-diyl)bis(methylene)]bis[N-(1,2-dihydroxyethyl)-2-hydroxy-5-methylbenzamide]; 1,1'-{(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-1,2-diol); 1,1'-{(7-benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(ethane-1,2-diol); N,N'-{(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N'-{(7-benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); N,N'-{(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; N,N'-{(7-benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis[3-hydroxy-2-(hydroxymethyl)propanamide]; {(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)azanediyl(2-oxoethane-2,1-diyl)]}bis(phosphonic acid); {(7-benzyl-1,4,7-triazecane-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-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 3,3'-[(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis(methylene)]bis[N-(1,3-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(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]}di(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-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)carbonylazanediylmethylene]}bis(phosphonic acid); {(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]}di(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]}di(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-dihydroxypropanamide); N,N'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)]}bis(2,3-dihydroxypropanamide); 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)propanamide]; 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)propanamide]; {(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-dihydroxypropan-2-yl)-2-hydroxy-5-methylbenzamide]; 2,2'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(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]}di(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-dihydroxypropanamide); 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)propanamide]; {(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); N,N',N''-{1,4,7-triazonane-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-triazonan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6',6''-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexane-1,2,3,4,5-pentol); 2-hydroxy-3-{[4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazonan-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 3-{[4,7-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazecan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6',6''-{1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexane-1,2,3,4,5-pentol); 2-hydroxy-3-{[7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazecan-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-triazecan-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 3-{[1,4-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecan-8-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6',6''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexane-1,2,3,4,5-pentol); 2-hydroxy-3-{[1-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecan-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-triazacycloundecan-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 6,6'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 3-{[5,9-bis({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6',6''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}tri(hexane-1,2,3,4,5-pentol); 2-hydroxy-3-{[5-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecan-1-yl]methyl}-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 3-{[4-benzyl-7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazonan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{(7-benzyl-1,4,7-triazonane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 3-{[4-benzyl-7-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,7-triazecan-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-triazecan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 6,6'-{(7-benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 3-{[1-benzyl-4-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,4,8-triazacycloundecan-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-triazacycloundecan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{(4-benzyl-1,4,8-triazacycloundecane-1,8-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 6,6'-{(8-benzyl-1,4,8-triazacycloundecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 3-{[5-benzyl-9-({2-hydroxy-5-methyl-3-[(2,3,4,5,6-pentahydroxyhexyl)carbamoyl]phenyl}methyl)-1,5,9-triazacyclododecan-1-yl]methyl}-2-hydroxy-5-methyl-N-(2,3,4,5,6-pentahydroxyhexyl)benzamide; 6,6'-{(9-benzyl-1,5,9-triazacyclododecane-1,5-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 6,6'-{1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 6,6'-{1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneazanediyl]}di(hexane-1,2,3,4,5-pentol); 2,2',2''-{1,4,7-triazonane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(propane-1,3-diol); 2,2'-{1,4,7-triazonane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(propane-1,3-diol); 2,2',2''-{1,4,7-triazecane-1,4,7-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(propane-1,3-diol); 2,2'-{1,4,7-triazecane-1,7-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(propane-1,3-diol); 2,2'-{1,4,7-triazecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(propane-1,3-diol); 2,2',2''-{1,4,8-triazacycloundecane-1,4,8-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(propane-1,3-diol); 2,2'-{1,4,8-triazacycloundecane-1,8-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(propane-1,3-diol); 2,2'-{1,4,8-triazacycloundecane-1,4-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(propane-1,3-diol); 2,2',2''-{1,5,9-triazacyclododecane-1,5,9-triyltris[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}tri(propane-1,3-diol); 2,2'-{1,5,9-triazacyclododecane-1,5-diylbis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(propane-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazonane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(propane-1,3-diol); 2,2'-{(4-benzyl-1,4,7-triazecane-1,7-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(propane-1,3-diol); 2,2'-{(7-benzyl-1,4,7-triazecane-1,4-diyl)bis[methylene(2-hydroxy-5-methyl-3,1-phenylene)methyleneoxy]}di(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]}di(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]}di(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]}di(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 said complex.

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

35. 34. The complex of claim 33 for use in a method for the diagnosis of a disease state in vivo by magnetic resonance imaging (MRI).

36. 34. A method of imaging bodily tissue in a patient, comprising administering to the patient an effective amount of the complex of claim 33 in a pharmaceutically acceptable carrier, and subjecting the patient to magnetic resonance imaging (MRI).

37. 34. A pharmaceutical composition comprising the complex of claim 33 and at least one pharmaceutically acceptable excipient.

38. A method for preparing a compound according to any one of claims 1 to 32, comprising the steps of: a) at least at its ortho position, (i) a C bonded to a leaving group; １ -C ５ -alkyl; and (ii) an L-Z group, or C １ -C ４ -Alkyl-aldehyde, C １ -C ４ -alkyl-esters and C １ -C ４ -a substituent selected from the group consisting of alkyl-carboxyl; b) a C aryl group selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, optionally having one or more nitrogen atoms suitably protected with one or more protecting groups and / or ... １ -C ４ providing a macrocycle having an alkyl group; c) reacting the phenol provided in step a) with the macrocycle provided in step b) to obtain a compound according to any one of claims 1 to 32, or an intermediate thereof; and d) converting the intermediate of step c) into a compound according to any one of claims 1 to 32.

39. The phenol provided in step a) is reacted with a compound of formula (VI): 【Transformation 8】 [In the formula, Y １ and R １ has the same meaning as defined in any of claims 1 to 32 for formula (I); X is a leaving group: L ４ is C １ -C ４ -Alkyl-aldehyde, C １ -C ４ -alkyl-esters and C １ -C ４ -alkyl-carboxyl.] and The intermediate obtained in step c) has the following formula (VII): 【Chemistry 9】 [In the formula, R １ , R ２ , Y １ , Y ２ , m, n and o have the same meaning as defined in any of claims 1 to 32 for formula (I); L ４ is C １ -C ４ -Alkyl-aldehyde, C １ -C ４ -alkyl-esters, and C １ -C ４ -alkyl-carboxyl; and R″ is hydrogen, optionally aryl-substituted C １ -C ４ alkyl, and a moiety represented by formula (VIIA): 【Chemistry 10】 (In the formula, The asterisk (*) indicates the point of attachment of the moiety of formula (VIIA) to the nitrogen bearing the R′ group; Y ３ Is Y １ and Y ２ has the same meaning as set out above R ３ is R １ and R ２ has the same meaning as set forth above; and L ４ is C １ -C ４ -Alkyl-aldehyde, C １ -C ４ -alkyl-esters and C １ -C ４ -alkyl-carboxyl) selected from the group consisting of and Step d) is L ４ Part, L １ -Z １ , L ２ -Z ２ , and L, if present ３ -Z ３ Convert to the base of The method of claim 38.

40. A method for preparing a compound according to any one of claims 1 to 32, comprising the steps of: a) at least at its ortho position, (i) a C bonded to a leaving group; １ -C ５ -alkyl; and (ii) an L-Z group, or C １ -C ４ -Alkyl-aldehyde, C １ -C ４ -alkyl-esters and C １ -C ４ -a substituent selected from the group consisting of alkyl-carboxyl; b') providing an orthoamide derivative of a macrocycle selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane, and triazacyclododecane; c') reacting one or two phenols provided in step a) with the orthoamide derivative to obtain an orthoamide derivative having one or two phenols provided in step a) attached thereto; d') hydrolyzing the orthoamide derivative obtained in step c') to obtain a macrocycle selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane and triazacyclododecane, in which one or two phenols provided in step a) and a formyl (C(O)H) group are bonded; e') optionally reacting an additional phenol provided in step a) with the macrocycle obtained in step d') to obtain a macrocycle selected from the group consisting of triazacyclononane, triazacyclodecane, triazacycloundecane, and triazacyclododecane, in which a formyl (-C(O)H) group is attached to the two phenols provided in step a); f') hydrolyzing the macrocycle obtained in step d') or e') and optionally １ -C ４ -Alkyl-aldehyde, C １ -C ４ -alkyl-ester or C １ -C ４ -alkyl-carboxyl, wherein the hydrolysis and transformation of this step f') are carried out in any order to obtain a compound according to any one of claims 1 to 32; and g') optionally reacting a further phenol provided in step a) with the macrocycle obtained in step f'), optionally reacting C １ -C ４ -Alkyl-aldehyde, C １ -C ４ -alkyl-ester or C １ -C ４ -alkyl-carboxyl to give a compound according to any one of claims 1 to 32.

41. The orthoamide derivative provided in step b') is represented by the following formula (VIII): 【Chemistry 11】 wherein m, n and o have the same meanings as defined for formula (I) in any one of claims 1 to 32. The method of claim 40, comprising:

42. 34. A method for preparing the complex of claim 33, comprising carrying out the steps of: e) reacting the compound obtained in step c) or step d) as defined in claim 38 with an Fe(III) salt to obtain an Fe(III) complex.

43. A method for producing the complex of claim 33, comprising carrying out the following steps: e) reacting the compound obtained in step f') or step g') as defined in claim 40 with an Fe(III) salt to obtain an Fe(III) complex.

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