BR112017026135B1 - GADOLINIUM CHELEATE COMPOUNDS, THEIR INTERMEDIATES, THEIR USES AND THEIR METHOD OF PREPARATION, AND METHOD FOR IMAGING BODY TISSUE IN A PATIENT - Google Patents

Abstract

GADOLINIUM CHELATED COMPOUNDS, THEIR INTERMEDIATES, THEIR USES AND THEIR METHOD OF PREPARATION, AND METHOD FOR IMAGING BODY TISSUE IN A PATIENT. The present invention relates to a new class of high relaxivity extracellular gadolinium chelate complexes, to methods of preparing said compounds and to the use of said compounds as MRI contrast agents.

Description

FIELD OF INVENTION

[001] The present invention refers to the items characterized in the patent claims, that is, new extracellular gadolinium chelates of high relaxivity based on low molecular weight core polyamines, to methods of preparing said compounds, to the use of said compounds as MRI (magnetic resonance imaging) contrast agents and their use in a mammalian body.

BACKGROUND OF THE INVENTION 1. Introduction

[002] Nine gadolinium-based contrast agents (GBCAs) have been approved for clinical use: gadopentetate dimeglumine (Magnevist®), gadoterate meglumine (Dotarem®), gadoteridol (ProHance®), gadodiamide (Omniscan®), gadobutrol ( Gadovist®), gadoversetamide (OptiMARK®), gadoxetic acid (Primovist®), gadobenate dimeglumine (MultiHance®) and trisodium gadofosveset (Vasovist®/Ablavar®). With the exception of gadoxetic acid, gadobenate dimeglumine, and gadofosveset trisodium, GBCAs exhibit a strictly extracellular passive distribution in the body and are excreted exclusively via the kidney.

[003] Gadoxetic acid and gadobenate dimeglumine exhibit a pharmacokinetic profile different from that of other agents. In addition to extracellular distribution, they are absorbed and also partially excreted through the liver. This allows, in addition to the classic imaging possibilities (e.g. central nervous system, angiography, extremities, heart, head/face/neck, abdomen and breast imaging), also images of the liver due to the enlargement of the liver parenchyma caused by the absorption of GBCAa in hepatocytes.

[004] In contrast to other GBCAa, trisodium gadofosveset does not present passive diffusion in the body and remains in the vascular space. The prolonged period in the blood vessels caused by the reversible binding to HSA (human serum albumin) allows high-resolution MR angiography.

[005] The various GBCAs differ in their effectiveness, given by their longitudinal relaxivity (r1) and transverse relaxivity (r2) and depends on the strengths of the magnetic field, temperature and different intrinsic factors of metal chelates. The influencing parameters of intrinsic relaxivity are mainly the number of water molecules directly bound to the gadolinium (the so-called inner sphere water, q), the average residence time of the inner sphere water molecules (im), the number and residence times of water molecules in the second hydration sphere (the so-called second water sphere) and rotational diffusion (ir) (Helm L. et. al., Future Med Chem. 2010; 2: 385-396). In terms of their relaxivity, all commercially available GBCAs are very similar to each other and fall within a range of 4 to 7 L mmol-1s-1.

[006] Strategies to increase the sensitivity of GBCAs are frequently described in the literature (Caravan P. et. al. Chem. Soc. Rev., 2006, 35, 512-523, Helm et.al. Future Med Chem. 2010; 2:385-396, Jacques V. Invest Radiol. 2010;45:613-624). One of the strategies is the increase of water molecules in the inner sphere (q) which are water molecules directly coordinated with the gadolinium ion in the chelate. As the examples of AAZTA- and HOPO-based ligands show, increasing the inner sphere water molecules from one to two leads to a significant increase in relaxivity. Another strategy to increase relaxivity is to slow down the rotational diffusion of the molecule. The so-called rotation rate (TT, see introduction) describes the drop of the molecule in solution and is mainly affected by the molecular size and protein binding of the GBCA (Merbach A.S. et. al., The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, 2013, ISBN: 978-1-119-99176-2).

[007] Another important characteristic of GBCAs is their complex stability. The potential of GBCAs to release free toxic Gd3+ ions is an important safety issue and is of utmost importance in particular for patients with end-stage renal disease. Nephrogenic systemic fibrosis (NSF) is a rare and serious syndrome that is associated with exposure to GBCAs in patients with severe renal failure. NSF involves fibrotic changes in the skin and many organs. In 2010, the Food and Drug Administration (FDA) published revised labeling recommendations for four GBCAs that have been primarily implicated in NSF, including gadodiamide (Omniscan®), gadobenate dimeglumine (MultiHance®), gadopentetate dimeglumine (Magnevist®), and gadoversetamide (OptiMARK®) (Yang L et. al. Radiology. 2012;265:248-253). At first glance, the stability of all GBCAs is very high, but there are significant differences between linear and macrocyclic agents and between ionic and nonionic representatives of linear agents. Macrocyclic GBCAs have the highest complex stabilities (Frenzel T. et. al. Invest Radiol. 2008; 43:817-828). Due to increased awareness among at-risk patients, the use of lower doses, and the more widespread use of macrocyclic GBCAs, the incidence of NSF has decreased in recent years (Wang Y. et.al. Radiology. 2011;260:105-111 and Becker S. et.al. Nephron Clin Pract. 2012; 121:c91-c94).

[008] The crucial issue for clinical applications is in vivo stability. Kinetic inertia combined with thermodynamic stability particularly concerns the risk of nephrogenic systemic fibrosis (NSF), the best indicator of the in vivo toxicity of q=2 chelates (Merbach A.S. et. al., The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging, 2013, ISBN: 978-1-119-99176-2, pages 157208). Complexes with q=2 show twice the increase in relaxivity, but unfortunately, they have lower stability than compounds q=1 (Hermann P. et.al. Dalton Trans., 2008, 3027-3047).

2. Description of the prior art, problem to be solved and its solution

[009] Various macrocyclic compounds are described in the prior art. EP1931673 B1 and EP2457914 B1 are related to the compounds pyDO3A (q=2), DO3A and DOTA which consist of short amino alcohol chains and metal complexes for medical imaging.

[010] GBCAs similar to macrocyclic lanthanides DO3A and DOTA with high relaxivities are described in the prior art.

[011] Ranganathan R.S. et.al. (Investigative Radiology 1998;33:779-797) analyzed the effect of multimerization on the relaxivity of macrocyclic gadolinium chelates. WO199531444 refers to monomeric and multimeric compounds with increased relaxivities.

[012] Document US 5679810 refers to linear oligomer polychelate compounds and chelates formed therewith, having alternating chelating and linker portions joined together by starch or ester parts and their use in diagnostic images.

[013] Document US 5650133 refers to dechelators, in particular compounds having two groups of macrocyclic chelators linked by a bridge containing an ester or amide bond, and their metal chelates and their use in diagnostic images.

[014] WO 97/32862 A1 describes gadolinium polychelators as magnetic resonance imaging agents that are linking at least two chelating units to the amino groups of a target carrier structure (such as, for example, a protein , amino acid or peptide).

[015] Document US 2007/202047 refers to gadolinium chelate compounds for use in magnetic resonance imaging, which are derived from a chelating molecule selected from 1,4,7,10-tetra-azacyclododecane-1,4,7 acid ,10-tetraacetic acid (DOPA) and diethylentriamine-pentaacetic acid (DTPA), in which at least one of the carboxylic groups of the chelating molecule reacts with an amine.

[016] GBCAs with greater relaxivity offer, on the one hand, the opportunity for a significant dose reduction and, on the other hand, a greater sensitivity in the MRI examination of many diseases using the standard dose (Giesel FL. et.al. Eur Radiol 2010, 20: 2461-2474).

[017] However, there is an unmet medical need to provide GBCAs for general use in magnetic resonance imaging that can: - exhibit high relaxivity, - show a favorable pharmacokinetic profile, - be completely excreted, - be chemically stable - exhibit high solubility in water, - offer potential for significant dose reduction, - be suitable for imaging different regions of the body, and - be very well tolerated.

[018] The current knowledge described above does not describe the high relaxivity extracellular gadolinium chelate compounds of General Formula (I) of the present invention as defined in this document or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate or salt thereof, or a mixture thereof, as described and defined herein and as referred to herein as "compounds of the present invention". It has been found, and this forms the basis of the present invention, that the aforementioned compounds of the present invention have surprising and advantageous properties.

[019] In particular, said compounds of the present invention showed a balanced profile of high relaxivity, a favorable pharmacokinetic profile, complete excretion, high stability, high solubility, the potential for a significant dose reduction and the potential of whole-body imaging and can therefore be used as contrast agents for magnetic resonance imaging (MRI).

SUMMARY

[020] The present invention describes a new class of high relaxivity extracellular gadolinium chelate complexes, methods for their preparation and their use as MRI contrast agents.

Description of the invention

[021] According to a first aspect, the present invention encompasses compounds of General Formula (I), comprising 4, 5, 6, 7 or 8 gadolinium groups [4,7,10-tris (carboxylatomethyl)-1,4 ,7,10-tetra-azacyclododecane-1-yl], on what : represents a selected group of: x; where groups a and b represent, independently of each other, an integer 1 or 2; and wherein the groups * indicate the connection point of the said group with R1; R1 represents, independently of one another, a hydrogen atom or a group selected from: that the groups * indicate the connection point of the aforementioned group with A, with the condition that only one of the R1 substituents can represent a hydrogen atom; n represents an integer of 3 or 4; R2 represents, independently of one another, a hydrogen atom or a methyl group; R3 represents a selected group of: groups * indicate the connection point of the mentioned group with the rest of the molecule; R4 represents, independently of one another, a hydrogen atom or a methyl group; R5 represents, independently of one another, a hydrogen atom or a methyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate or salt thereof or a mixture thereof.

[022] The compounds of this invention may contain one or more asymmetric centers, depending on the location and nature of the various desired substituents. Asymmetric carbon atoms can be present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric center and diastereomeric mixtures in the case of several asymmetric centers. In certain instances, asymmetry may also be present due to restricted rotation about a particular bond, for example, the central bond adjacent to two substituted aromatic rings of the specified compounds.

[023] Preferred compounds are those that produce the most desirable biological activity. Separate, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of this invention are also included within the scope of the present invention. Purification and separation of these materials can be carried out by standard techniques known in the art.

[024] Optical isomers can be obtained by resolving racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers. Examples of suitable acids are tartaric, diacetyltartaric, Ditoluoyltartaric and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into their individual diastereoisomers based on their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallization. Optically active bases or acids are released from the separated diastereomeric salts. A different process for separating optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without derivatization, optimally chosen to maximize separation of the enantiomers. Suitable chiral HPLC columns are manufactured by Diacel, e.g. Chiracel OD and Chiracel OJ among many others, all routinely selectable. Enzymatic separations, with or without derivatization, are also useful. The optically active compounds of this invention can also be obtained by chiral syntheses using optically active starting materials.

[025] To limit the different types of isomers of each other, reference is made to the IUPAC Rules, section E (Pure Appl Chem 45, 11-30, 1976).

[026] The present invention includes all possible stereoisomers of the compounds of the invention, as single stereoisomers or any mixture of the aforementioned stereoisomers, e.g., (R) or (S) isomers or (E) or (Z) isomers in any proportion. Isolation of a single stereoisomer, e.g., a single enantiomer or diastereomer of a compound of the present invention can be obtained by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.

[027] Furthermore, the compounds of the present invention can exist as N-oxides which are defined in the case where at least one nitrogen of the compounds of the present invention is oxidized. The present invention includes all such possible N-oxides.

[028] The present invention also relates to useful forms of the compounds as disclosed herein, such as metabolites, hydrates, solvates, salts, in particular pharmaceutically acceptable salts, esters - hydrolysable and coprecipitates.

[029] The compounds of the present invention can exist as a hydrate, or as a solvate, in which the compounds of the present invention contain polar solvents, in particular, water, methanol or ethanol, for example, as a structural element of the crystalline structure of the compounds . The amount of polar solvents, in particular water, can exist in a stoichiometric or non-stoichiometric proportion. In the case of stoichiometric solvates, e.g., a hydrate, hemi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., the solvates or hydrates, respectively, are possible. The present invention includes all such hydrates or solvates.

[030] Furthermore, the compounds of the present invention can exist in the form of a salt. Said salt may be organic or inorganic addition salt, particularly any organic or inorganic salt acceptable pharmaceutically or generally used in pharmacy.

[031] The term "pharmaceutically acceptable salt" refers to a non-toxic inorganic or organic acid addition salt of a compound of the present invention. For example, see S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci. 1977, 66, 1-19. The production of especially neutral salts is described in document US 5,560,903.

[032] Pharmaceutically acceptable salts of the compounds according to the invention include salts of mineral acids and carboxylic acids, for example, without being limited to these, salts of hydrochloric acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, lactic acid, tartaric acid, malic acid, citric acid, fumaric acid, maleic acid, aspartic acid and glutamic acid.

[033] Those skilled in the art will recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with the appropriate inorganic or organic acid by any of several known methods.

[034] The present invention includes all possible salts of the compounds of the invention, as single salts or any mixture of the aforementioned salts in any proportion.

[035] In this text, in particular in the Experimental Section, for the synthesis of intermediates and examples of the present invention, when a compound is cited as a salt form with the corresponding base or acid, the exact stoichiometric composition of the salt form cited, as obtained by the respective preparation and/or purification process is, in most cases, unknown.

[036] This applies in a similar way to cases in which the synthesis intermediates or the example compounds or their salts were obtained, by the described preparation and/or purification processes, as solvates, e.g. hydrates with (if defined ) unknown stoichiometric composition.

[037] According to a second embodiment of the first aspect, the present invention encompasses compounds of General Formula (I), above, comprising 4, 5 or 6 gadolinium groups [4,7,10-tris(carboxylatomethyl) -1,4,7, 10-tetra-azacyclododecane-1-yl], where: represents a selected group of: pos a and b represent, independently of each other, an integer 1 or 2; and, where the groups * indicate the point of connection of the group mentioned with R1; R1 represents, independently of one another, a hydrogen atom or a group selected from: that the groups * indicate the connection point of the aforementioned group with A, with the condition that only one of the R1 substituents can represent a hydrogen atom; n represents an integer of 3 or 4; R2 represents, independently of one another, a hydrogen atom or a methyl group; R3 represents a selected group of: groups * indicate the connection point of the mentioned group with the rest of the molecule; R4 represents, independently of one another, a hydrogen atom or a methyl group; R5 represents, independently of one another, a hydrogen atom or a methyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate or salt thereof or a mixture thereof.

[038] According to a third embodiment of the first aspect, the present invention encompasses compounds of General Formula (I), above, comprising 4, 5 or 6 gadolinium groups [4,7,10- tris(carboxylatomethyl)- 1,4,7, 10-tetra-azacyclododecane-1-yl], where: represents a selected group of: where groups a and b represent an integer of 1; and, where the groups * indicate the point of connection of the group mentioned with R1; R1 represents, independently of one another, a hydrogen atom or a group selected from: that the groups * indicate the connection point of the aforementioned group with A, with the condition that only one of the R1 substituents can represent a hydrogen atom; n represents an integer of 3 or 4; R2 represents a hydrogen atom; R3 represents a selected group of: in which the groups * indicate the connection point of the mentioned group with the rest of the molecule; R4 represents a hydrogen atom; R5 represents a hydrogen atom or a methyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate or salt thereof or a mixture thereof.

[039] According to a fourth embodiment of the first aspect, the present invention encompasses compounds of General Formula (I), above, comprising 4, 5 or 6 gadolinium groups [4,7,10-tris(carboxylatomethyl) -1,4,7, 10-tetra-azacyclododecane-1-yl], where: represents a selected group of: pos a and b represent an integer of 1; and, where the groups * indicate the point of connection of the group mentioned with R1; R1 represents, independently of each other, an atom of hydrogen or a group selected in: that the groups * indicate the point of connection of the said group with A, with the condition that only one of the R1 substituents can represent a hydrogen atom; n represents an integer of 3 or 4; R2 represents a hydrogen atom; R3 represents a selected group of: groups * indicate the connection point of the mentioned group with the rest of the molecule; R4 represents a hydrogen atom; R5 represents a methyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate or salt thereof or a mixture thereof.

[040] According to another aspect, the present invention covers the compounds of General Formula (I), (I), where: represents a group , where the group * indicates the connection point of the group mentioned with R1; R1 represents a group R3; n represents an integer of 4; R2 represents a hydrogen atom; R3 represents a selected group of: indicate the connection point of the mentioned group with the rest of the molecule; R4 represents a hydrogen atom; R5 represents a hydrogen atom or a methyl group; or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate or salt thereof or a mixture thereof.

[041] In another embodiment of the aforementioned aspect, the invention refers to compounds of Formula (I), comprising 4, 5, 6, 7 or 8 gadolinium groups [4,7,10-tris (carboxylatomethyl)-1,4,7,10-tetra-azacyclododecane-1-yl].

[042] In another embodiment of the aforementioned aspect, the invention refers to compounds of Formula (I), comprising 4, 5 or 6 gadolinium groups [4,7,10-tris (carboxylatomethyl)- 1,4,7,10-tetra-azacyclododecane-1-yl].

[043] In another embodiment of the aforementioned aspect, the invention refers to compounds of Formula (I), comprising 4 gadolinium groups [4,7,10-tris (carboxylatomethyl)- 1,4,7 ,10-tetra-azacyclododecane-1-yl].

[044] In another embodiment of the aforementioned aspect, the invention refers to compounds of Formula (I), comprising 5 gadolinium groups [4,7,10-tris (carboxylatomethyl)- 1,4,7 ,10-tetra-azacyclododecane-1-yl].

[045] In another embodiment of the aforementioned aspect, the invention refers to compounds of Formula (I), comprising 6 gadolinium groups [4,7,10-tris (carboxylatomethyl)-1,4, 7,10- tetra-azacyclododecane-1-yl].

[046] In another embodiment of the aforementioned aspect, the invention refers to compounds of Formula (I), comprising 7 gadolinium groups [4,7,10-tris (carboxylatomethyl)-1,4, 7,10- tetra-azacyclododecane-1-yl].

[047] In another embodiment of the aforementioned aspect, the invention relates to compounds of Formula (I), comprising 8 gadolinium groups [4,7,10-tris (carboxylatomethyl)-1,4, 7,10- tetra-azacyclododecane-1-yl].

[048] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a selected group of: ; where groups a and b represent, independently of each other, an integer 1 or 2; and where the groups * indicate the point of connection of the group mentioned with R1.

[049] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a selected group of: where groups a and b represent, independently of each other, an integer 1 or 2; and, where the groups * indicate the connection point of the group mentioned with R1.

[050] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a selected group of: where groups a and b represent an integer of 1; and, where the groups * indicate the connection point of the group mentioned with R1.

[051] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group where groups a and b represent, independently of each other, an integer 1 or 2; and, where the group * indicates the connection point of the group mentioned with R1.

[052] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group m where groups a and b represent an integer of 1; and, where the group * indicates the connection point of the group mentioned with R1.

[053] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group , where the group * indicates the connection point of the group mentioned with R1.

[054] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group where the group * indicates the connection point of the aforementioned group with R1, and R2 represents a hydrogen atom.

[055] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group where the group * indicates the connection point of the group mentioned with R1.

[056] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which represents a group where the group * indicates the connection point of the group mentioned with R1.

[057] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group where the group * indicates the connection point of the group mentioned with R1.

[058] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group where the group * indicates the connection point of the group mentioned with R1.

[059] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group , where the group * indicates the connection point of the group mentioned with R1.

[060] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: represents a group where the group * indicates the connection point of the group mentioned with R1.

[061] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R1 represents, independently of one another, a hydrogen atom or a group selected from: that the groups * indicate the connection point of the aforementioned group with A, with the condition that only one of the R1 substituents can represent a hydrogen atom.

[062] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R1 represents, independently of each other, a group selected from: that the group * indicates the connection point of the group mentioned with A.

[063] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R1 represents, independently of each other, a selected group in: , where the group * indicates the connection point of the group mentioned with A.

[064] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R1 represents, independently of each other, a group selected from: , where the group * indicates the connection point of the group mentioned with A.

[065] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R1 represents, independently of each other, a group selected from: , where the group * indicates the connection point of the group mentioned with A.

[066] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R1 represents an R3 group.

[067] In another representation of the aspect mentioned above, a represents a group of wherein the group * indi- invention is related to compounds of Formula (I), where: ca is the connection point of the group mentioned with A.

[068] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R1 represents a group of , where the group * indicates the connection point of the group mentioned with A.

[069] In another representation of the aspect mentioned above, a represents a group of , where the group * indicates the connection point of the group mentioned with A.

[070] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R1 represents, independently of one another, a hydrogen atom or a group of R3; with the condition that only one of the R1 substituents can represent a hydrogen atom.

[071] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R1 represents, independently of each other, a hydrogen atom or a hydrogen group where the group * indicates the connection point of the aforementioned group with A, with the condition that only one of the R1 substituents can represent a hydrogen atom.

[072] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R1 represents, independently of each other, a hydrogen atom or a group of R R; where the group * indicates the connection point of the aforementioned group with A, with the condition that only one of the R1 substituents can represent a hydrogen atom.

[073] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R1 represents, independently of each other, a R hydrogen atom or a group of group * indicates the point of connection of the aforementioned group with A, with the condition that only one of the R1 substituents can represent a hydrogen atom.

[074] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: n represents an integer of 3 or 4.

[075] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: n represents an integer of 3.

[076] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: n represents an integer of 4.

[077] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R2 represents, independently of one another, a hydrogen atom or a methyl group.

[078] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R2 represents a hydrogen atom.

[079] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R2 represents a methyl group.

[080] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R3 represents a group selected from: group * indicates the point of connection of the group mentioned with the rest of the molecule.

[081] In another representation of the aspect mentioned above, R3 represents a group of , in which the invention relates to compounds of Formula (I), where: the group * indicates the connection point of the aforementioned group with the rest of the molecule.

[082] In another representation of the aspect mentioned above, R3 represents a group of The invention relates to compounds of Formula (I), where: which group * indicates the point of connection of the aforementioned group with the rest of the molecule.

[083] In another representation of the aspect mentioned above, R3 represents a group of invention is related to compounds of Formula (I), in which: which group * indicates the connection point of the aforementioned group with the rest of the molecule; and R5 represents a hydrogen atom or a methyl group.

[084] In another representation of the aspect mentioned above, R3 represents a group of invention is related to compounds of Formula (I), in which: which group * indicates the connection point of the aforementioned group with the rest of the molecule; and R5 represents a hydrogen atom.

[085] In another representation of the aspect mentioned above, a represents a group of invention relates to compounds of Formula (I), wherein: ; in which the group * indicates the connection point of the aforementioned group with the rest of the molecule; and R5 represents a methyl group.

[086] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), in which: R4 represents, independently of one another, a hydrogen atom or a methyl group.

[087] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R4 represents hydrogen atom.

[088] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R4 represents a methyl group.

[089] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R5 represents, independently of one another, a hydrogen atom or a methyl group.

[090] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R5 represents hydrogen atom.

[091] In another representation of the aspect mentioned above, the invention is related to compounds of Formula (I), where: R5 represents a methyl group.

[092] It should be understood that the present invention also relates to any combination of the representations described above.

[093] Another embodiment of the first aspect are the compounds of Formula (I) selected from the group consisting of: Pentagadolinium [4,10-bis (carboxylatomethyl)-7- {3,6,10,18,22,25 -hexaoxo-26- [4,7,10-tris(carboxylatomethyl)-1,4,7,10- tetra-azacyclododecane-1-yl]-14- [({2- [4,7,10-tris( carboxylatemethyl)-1,4,7,10- tetraazacyclododecan-1-yl] propanoyl} amino)acetyl]-9,19-bis({ [({2- [4,7,10- tris(carboxylatomethyl)-1, 4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14,17,21,24-heptaazaheptacosan-2-yl}-1,4, 7,10-tetraazacyclododecan-1-yl]acetate, Hexagadolinium [4,10-bis(carboxylatomethyl)-7-{3,6,10,15,19,22- hexaoxo-23- [4,7,10-tris (carboxylatomethyl)-1,4,7,10-tetra-azacyclododecane-1-yl]-9,16-bis({ [({2- [4,7,10-tris(carboxylatomethyl)- 1,4,7 ,10-tetra-azacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)- 11-(2-{ [3-{ [({2- [4,7,10-tris(carboxylatomethyl)-1 ,4,7,10-tetra-azacyclododecan-1-yl]propanoyl}amino)acetyl]amino}-2-({ [({2- [4,7,10- tris(carboxylatomethyl) -1,4,7 ,10-tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) propanoyl] amino} ethyl) -4,7,11,14,18,21-hexa-azatetracosan-2-yl} -1,4,7,10-tetra-azacyclododecan-1-yl] acetate, Tetragadolinium [4,10-bis(carboxylatomethyl) -7- {3,6,12,15- tetraoxo-16- [4,7, 10-tris(carboxylatomethyl)azacyclododecan-1-yl]-9,9-bis({[({2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan-1 -yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2-yl} -1,4,7,10-tetra-azacyclododecan-1-yl] acetate, Tetragadolinium {4,10-bis(carboxylatomethyl)-7-[(2R, 16R)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxylatomethyl)-1,4,7, 10 -tetra- azacyclododecan-1-yl] -9,9-bis ({ [({(2R) -2- [4,7,10-tris (carboxylatomethyl) - 1,4,7,10-tetra-azacyclododecan- 1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2-yl] acetate, Tetragadolinium {4,10-bis 3,6,12,15-tetraoxo- 16- [4,7,10-tris azacyclododecan-1-yl] -9,9-bis ({ [({(2S) -2- [4,7,10-tris (carboxylatomethyl) - 1,4,7 ,10-tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2-yl] -1,4,7,10-tetra-azacyclododecan -1-yl} acetate, Pentatriadinol [4- (1 - { [2- (bis {2 - [({1,4-bis [({2- [4,7,10-tris(carboxylatomethyl) -1, 4,7,10-tetra-azacyclododecane -1-yl] propanoyl} amino) acetyl] -1,4-diazepan-6-yl} carbonyl) amino] ethyl} amino) -2-oxoethyl] amino} -1-oxopropan-2-yl) -7,10 -bis(carboxylatomethyl) -1,4,7,10-tetra-azacyclododecane-1-yl] acetate, Hexagadolinium 2,2',2'',2'' ',2'''',2''''',2'''''',2''''''',2 '''''''''''',2''' ''''''''''''',2''''''''''''''''' 2 2' 2''2'''2'''' 2'' '''2''''''2'''''''2''''''''2'''''''''2'''''''''' 2' ''''''''''2'''''''''''' 2'''''''''''''2'''''''''''' ''2''',2,2-(1,4,7-triazonane-1,4,7-triyltris{carbonyl-1,4-diazepane-6,1,4-triylbis[(2-oxoethyl-2 ,1-diyl) imino (1-oxopropane-1,2-diyl) - 1,4,7,10-tetra-azacyclododecane-10,1,4,7-tetrail]}) octadeca-acetate, Tetragadolinium 2,2 ,2 ,2 ,2 ,2 ,2 ,2 ,2 ,2 ,2 ,2 -{1,4,7,10- azacyclododecane-1,4,7,10-tetrailtetracis [(2-oxoethyl-2,1 -diyl) imino (1- oxopropane-1,2-diyl) -1,4,7,10-tetra-azacyclododecane-10,1, 4,7-tetrail]} dodeca-acetate, Hexagadolinium 22 2 2 2 2 2 2 2 2 2 2 2 2 2 2 ,2 ,2 - {3,7,10-triazatricyclo [3.3.3.01,5] undecane-3,7,10- triyltris [carbonyl(3,6,11,14- tetraoxo-4,7,10,13-tetra-azahexadecane - 8,2,15-triyl)di-1,4,7,10-tetra-azacyclododecane-10,1,4,7-tetrail]}octadeca- acetate , Tetragadolinium 2,2',2'',2''',2'''',2''''',2'''''',2''''''',2''' ''''',2''''''''',2'''''''''',2'''''''''''-(3,7,9-triazabicycle 3.3.1] nonane-3,7-diylbis {carbonyl-1,4-diazepane-6,1,4-triylbis [(2-oxoethyl- 2,1-diyl) -1,4,7,10-tetra- azacyclododecane- 10,1,4,7-tetrail]}) dodeca- acetate, Tetragadolinium {4,10-bis (carboxylatomethyl)-7- [2-oxo-2-({3- ({ [4,7,10 -tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecane-1-yl]acetyl}amino)-2,2-bis[({[4,7,10-tris(carboxylatomethyl)-1,4 ,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) methyl] propyl} amino)ethyl] -1,4,7,10- tetra-azacyclododecan-1-yl} acetate and Tetragadolinium [4,10- bis(carboxylatomethyl)-7-{2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]-8 ,8-bis ({ [({ [4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) acetyl] amino} methyl) - 3, 6,10,13-tetra-azapentadec-1-yl}-1,4,7,10-tetra-azacyclododecan-1-yl] acetate, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate or its salt or a mixture thereof.

[094] According to another aspect, the present invention covers methods of preparing compounds of the present invention, the methods consisting of the steps as described in the Experimentation Section of this document.

[095] According to another aspect, the present invention covers intermediate compounds that are useful for the preparation of the compounds of General Formula (I), supra.

[096] In particular, the inventions cover the compounds of General Formula (II-a): on what is as defined for the compounds of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 and their salts; and compounds of General Formula (II-b): on what is as defined for the compounds of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 and their salts; and compounds of General Formula (II-c): on what is as defined for the compounds of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 and their salts.

[097] Even more particularly, the present invention covers the intermediate compounds that are disclosed in the example section of this text, infra.

[098] According to another aspect, the present invention covers the use of compounds of General Formula (ll-a): on what is as defined for compounds of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 and salts thereof for the preparation of a compound of General Formula (I) as defined supra.

[099] According to another aspect, the present invention covers the use of compounds of General Formula (II-b): on what is as defined for compounds of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 and salts thereof for the preparation of a compound of General Formula (I) as defined supra.

[0100] According to another aspect, the present invention covers the use of compounds of General Formula (II-c): on what is as defined for compounds of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 and salts thereof for the preparation of a compound of General Formula (I) as defined supra.

[0101] According to another aspect, the present invention covers the use of compounds of General Formula (III): wherein R5 is as defined for the compounds of General Formula (I), above, and LG represents an activating leaving group, such as, for example, 4-nitrophenol, or a group as defined for the synthesis of compounds of the General Formula ( Ia) below, for the preparation of a compound of General Formula (I) as defined above.

[0102] According to another aspect, the present invention covers the use of compounds of General Formula (IV): wherein R4 is as defined for the compound of General Formula (I), above and represents a tetraamine as defined for the compounds of General Formula (I), supra, for the preparation of a compound of General Formula (I) as defined above.

[0103] Another aspect of the invention is the use of a compound of General Formula (I) for diagnostic imaging.

[0104] Preferably, the use of a compound of the invention in diagnosis is carried out using magnetic resonance imaging (MRI).

[0105] Another aspect of the invention are compounds of General Formula (I) for use in diagnostic images.

[0106] Another aspect of the invention are compounds of General Formula (I) for use in magnetic resonance imaging (MRI).

[0107] The invention also contains compounds of General Formula (I) for the manufacture of diagnostic agents.

[0108] Another aspect of the invention is the use of compounds of General Formula (I) or mixtures thereof for the manufacture of diagnostic agents.

[0109] Another aspect of the invention is the use of the compounds of General Formula (I) or mixtures thereof for the manufacture of diagnostic agents for magnetic resonance imaging (MRI).

[0110] Another aspect of the invention is a method of imaging body tissue in a patient, comprising the steps of administering to the patient an effective amount of one or more compounds of General Formula (I) in a pharmaceutically acceptable carrier and subjecting the patient to NMR tomography. This method is described in US 5,560,903.

[0111] For the manufacture of diagnostic agents, for example, administration to human subjects or animals, the compounds of General Formula (I) or mixtures will be conveniently formulated together with pharmaceutical carriers or excipients. The contrast medium of the invention may conveniently contain pharmaceutical formulation auxiliaries, for example, stabilizers, antioxidants, pH-adjusting agents, flavors and the like. The production of the diagnostic means according to the invention is also carried out in a manner known in the art, see US 5,560,903. They can be formulated for parenteral or enteral administration or for direct administration into body cavities. For example, parenteral formulations contain a sterile solution or suspension at a dose of 0.0001-5 mmol gadolinium/kg body weight, especially 0.005-0.5 mmol gadolinium/kg body weight of the compound of Formula (I) according to this invention. Thus, the medium of the invention can be in conventional pharmaceutical formulations, such as solutions, suspensions, dispersions, syrups, etc. in physiologically acceptable carrier media, preferably in water for injections. When the contrast medium is formulated for parenteral administration, it will preferably be isotonic or hypertonic and close to pH 7.4.

[0112] In another aspect, the invention is directed to a method of diagnosing and monitoring the health of patients. This method comprises a) administering to a person in need of such diagnosis a compound of the invention to detect the compound in the patient, as described above and here and b) measuring the signal resulting from administration of the compound to the patient, preferably by resonance imaging. -cyamagnetic (RM). GENERAL SUMMARY

[0113] The compounds according to the invention can be prepared according to the following schemes 1 to 12.

[0114] The schemes and procedures described below illustrate the synthetic routes for the compounds of General Formula (I) of the invention and should not be limiting. It is obvious to one skilled in the art that the order of transformations, as exemplified in the drawings, can be modified in a number of ways. The order of transformations exemplified in the schemes should not, therefore, be limiting. Appropriate protecting groups and their introduction and cleavage are well known to one skilled in the art (see, for example, T.W. Greene and P.G.M. Wuts in Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999). Specific examples are described in subsequent paragraphs.

[0115] The term "amine protecting group", as used herein alone or as part of another group, is known or obvious to one skilled in the art, which is chosen from other protecting groups, i.e., carbamate groups, amides , imides, N-alkylamines, N-arylamines, imines, enamines, boranes, N-P, N-sulfenyl, N-sulfonyl and N-silyl protecting groups and which is chosen, without limitation, among others described in the textbook Greene and Wuts , Protecting Groups in Organic Synthesis, Third Edition, pages 494-653, included here by reference. The "amine protecting group" is preferably carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxycarbonyl (FMOC), benzyl (Bn), p-methoxybenzyl ( PMB) 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), triphenylmethyl (Tri-tyl), methoxyphenyl diphenylmethyl (MMT) or the protected amino group is a 1,3-dioxo-1,3-di- hydro-2H-isoindol-2-yl (phthalimido) or an azido group.

[0116] The term "amine protecting group", as used herein alone or as part of another group, is known or obvious to one skilled in the art, which is chosen from other protecting groups, i.e., esters, amides and hydrazides and which is chosen, without limitation, from among others described in the Greene and Wuts textbook, Protecting Groups in Organic Synthesis, third edition, pages 369-453, incorporated herein by reference. The "carboxyl protecting group" is preferably methyl, ethyl, propyl, butyl, tert-butyl, allyl, benzyl, 4-methoxybenzyl or 4-methoxyphenyl.

[0117] The content of the documents cited here is incorporated by reference.

[0118] A route for preparing compounds of General Formula (Ia) is described in Scheme 1.

[0119] Scheme 1: Route for the preparation of compounds of General Formula (Ia), in which and R5 has the meaning given to General Formula (I), supra, n' represents an integer of 2, 3 and 4, and PG represents an amine protecting group, such as, for example, a tert-butyloxycarbonyl group (BOC) or a group as defined below.

[0120] Starting materials 1 are commercially available polyamines or their salts [for example, CAS 111-40-0, CAS 28634-67-5, CAS 4730-54-5, CAS 4742-00-1, CAS 294- 90-6] or polyamines or their salts known from the literature or which can be prepared in analogy with compounds that are described in the literature or in the experimental part, infra [for example, CAS 41077-50-3].

[0121] A triamine or tetraamine 1 or a salt thereof reacted with a protected 3-amino-2-(aminomethyl)propionic acid 2-a, [for example, CAS 496974-25-5] or a salt thereof, leading to an intermediary 3-a. Suitable amine protecting groups for 3-amino-2-(aminomethyl)propionic acid are, for example, carbobenzyloxy (Cbz), p-methoxybenzyl carbonyl (Moz or MeOZ), tert-butyloxycarbonyl (BOC), 9-fluorenylmethyloxy carbonyl (FMOC ), benzyl (Bn), p-methoxybenzyl (PMB), 3,4-dimethoxybenzyl (DMPM), p-methoxyphenyl (PMP), triphenylmethyl (Trityl), methoxyphenyl diphenylmethyl (MMT) or the protected amino group is a 1, 3-dioxo-1,3-dihydro-2H-isoindol-2-yl (phthalimido) or an azido group. The coupling reaction of polyamines 1 with propionic acid derivatives 2-a is carried out using standard peptide coupling conditions, such as, for example, coupling in the presence of HATU and N,N-diisopropylethylamine, in a suitable solvent, e.g. example, N,N-dimethylformamide, at a temperature range from room temperature to 80 ° C, to provide the intermediates of General Formula 3-a.

[0122] Deprotection of intermediates of General Formula 3-a leading to intermediates of General Formula (II-a) or their salts is carried out in analogy with the methods described in the textbook Greene and Wuts, Protecting groups in Organic Synthesis, second edition, pages 309-405, included here by reference. The amine protecting group, tert-butyloxycarbonyl (BOC), is removed by dissolving a BOC-protected intermediate of General Formula 3-a in a suitable solvent, such as, for example, an alcohol, tetrahydrofuran, dioxane or N. N-dimethylformamide or a mixture thereof, adding suitable acids, such as, for example, aqueous hydrochloric or hydrobromic acid or trifluoroacetic acid in organic solvents, such as dichloromethane. The deprotection reaction is carried out at temperatures ranging from room temperature to the boiling point of the respective solvent or solvent mixture, preferably the reaction is carried out at temperatures ranging between room temperature and 80°C.

[0123] Intermediates of General Formula (II-a) or their salts react with Gd complexes of General Formula (III), which are activated by a leaving group (LG), such as, for example, pentafluorophenol, 4- nitrophenol, 1-hydroxypyrrolidine-2,5-dione, hydroxybenzotriazole or 3H- [1,2,3] triazole [4,5-b] pyridin-3-ol, leading to compounds of General Formula (Ia). The preparation of activated esters is well known to the person skilled in the art and is described in detail, for example, by C.A. Montalbetti and V. Falque in Tetrahedron 61 (2005), pages 10827 10852. For example, the preparation of gadolinium 2,2' ,2''- [10-(1- { [2-(4-nitrophenoxy)-2-oxoethyl]amino}-1-oxopropan-2-yl)-1, 4,7,10-tetra-azacyclododecane-1 ,4,7-triyl] triacetate is described in detail in WO 2001051095 A2. The reaction of intermediates of General Formula (II-a) with the activated Gd complexes of General Formula (III) is carried out in a suitable solvent, such as, for example, dimethylsulfoxide, N,N-dimethylformamide, pyridine or a mixture thereof, Optionally, the reaction is carried out in the presence of a base. Suitable bases are, for example, trialkylamines, such as, for example, triethylamine or N,N-diisopropylethylamine. The reaction is carried out at temperatures ranging from room temperature to 100°C, preferably the reaction is carried out at temperatures ranging from 50°C to 70°C.

[0124] A route for preparing compounds of General Formula (Ib) is described in Scheme 2.

[0125] Scheme 2: Route for the preparation of compounds of General Formula (Ib), in which and R5 have the meaning given for General Formula (I), supra, n' represents an integer of 2, 3 and 4, and PG represents an amine protecting group, such as, for example, a tert-butyloxycarbonyl group (BOC ) or a group as defined for the synthesis of the compounds of General Formula (Ia) above.

[0126] The compounds of General Formula (I-b) are synthesized in analogy with the compounds of General Formula (I-a), as described above.

[0127] Starting materials 1 are commercially available polyamines or salts thereof [e.g., CAS 111-40-0, CAS 28634-67-5, CAS 4730-54-5, CAS 4742-00-1, CAS 294- 90-6] or polyamines or their salts known from the literature or which can be prepared in analogy with compounds that are described in the literature or in the experimental part, infra [for example, CAS 41077-50-3].

[0128] A triamine or tetraamine 1 or salt thereof reacted with a protected 2,3-diaminopropionic acid 2-b [e.g., CAS 20147268-6] or salt thereof, to provide an intermediate of General Formula 3-b, which after deprotection provides an intermediate of the General Formula (II-b) or its salt. In the final step, an intermediate of General Formula (II-b) or its salt reacts with a Gd complex of General Formula (III), leading to a compound of General Formula (I-b).

[0129] A route for preparing compounds of General Formula (Ic) is described in Scheme 3.

[0130] Scheme 3: Route for the preparation of compounds of General Formula (Ic), in which and R5 has the meaning given for General Formula (I), supra, n' represents an integer of 2, 3 and 4, and PG represents an amine protecting group, such as, for example, a tert-butyloxycarbonyl group ( BOC) or a group as defined for the synthesis of the compounds of General Formula (Ia) above.

[0131] The compounds of General Formula (I-c) are synthesized in analogy with the compounds of General Formula (I-a), as described above.

[0132] Starting materials 1 are commercially available polyamines or their salts [for example, CAS 111-40-0, CAS 28634-67-5, CAS 4730-54-5, CAS 4742-00-1, CAS 294- 90-6] or polyamines or their salts known from the literature or which can be prepared in analogy with compounds that are described in the literature or in the experimental part, infra [for example, CAS 41077-50-3].

[0133] A triamine or tetraamine 1 or its salt reacts with a protected 1,4-diazepane-6-carboxylic acid 2-c, which can be synthesized as described in the experimental part below, from methyl 1,4- dibenzyl-1-4-diazepane-6-carboxylate [see US 5,866,562], to provide an intermediate of General Formula 3-c, which upon deprotection provides an intermediate of General Formula (II-c) or its salt. In the final step, an intermediate of General Formula (II-c) or its salt reacts with a Gd complex of General Formula (III), leading to a compound of General Formula (I-c).

[0134] A route for preparing compounds of General Formula (Id) is described in Scheme 4.

[0135] Scheme 4: Route for the preparation of compounds of the General Formula (Id), where R5 has the meaning given in the General Formula (I), above, represents a tetraamine as for General Formula (I), supra, and LG represents an activating leaving group, as, for example, 4-nitrophenol, or a group as defined for the synthesis of compounds of the General Formula ( Ia) above.

[0136] The starting materials 4 are commercially available tetraamines or their salts [e.g., CAS 4742-00-1, CAS 294-90-6] or tetraamines or their salts that are known from the literature or that can be prepared in analogy with the compounds that are described in the literature.

[0137] A tetra-amine 4 or its salt reacts with a Gd complex of General Formula (III), which is activated by a leaving group (LG), such as, for example, pentafluorophenol, 4-nitrophenol, 1-hydroxypyrrolidine - 2,5 -dione, hydroxybenzotriazole or 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol, leading to a compound of the General Formula (Id). The preparation of activated esters is well known to those skilled in the art and is described in detail, for example, by C. A. Montalbetti and V. Falque in Tetrahedron 61 (2005), pages 10827-10852. For example, the preparation of gadolinium 2,2',2''- [10-(1-{ [2-(4-nitrophenoxy)-2-oxoethyl]amino}- 1-oxopropan-2-yl)-1, 4,7,10-tetra-azacyclododecane-1,4,7-triyl] triacetate is described in detail in WO 2001051095 A2. The reaction of polyamine 4 or its salt with the activated Gd complexes of General Formula (III) is carried out in a suitable solvent, such as, for example, dimethylsulfoxide, N,N-dimethylformamide, pyridine or a mixture thereof, optionally, the reaction is carried out in the presence of a base. Suitable bases are, for example, trialkylamines, such as, for example, triethylamine or N,N-diisopropylethylamine. The reaction is carried out at temperatures ranging from room temperature to 100°C, preferably the reaction is carried out at temperatures ranging from 50°C to 70°C.

[0138] A route for preparing compounds of General Formula (Ie) is described in Scheme 5.

[0139] Scheme 5: Route for the preparation of compounds of General Formula (Ie), where R4 R4 has the meaning given in General Formula (I), above, represents a tetraamine as for General Formula (I), supra, and LG represents an activating leaving group, as, for example, 4-nitrophenol, or a group as defined for the synthesis of compounds of the General Formula ( Ia) above.

[0140] The starting materials 4 are commercially available tetraamines or their salts [e.g., cAS 4742-00-1, cAS 294-90-6] or tetraamines or their salts that are known from the literature or that can be prepared in analogy with the compounds that are described in the literature.

[0141] A tetra-amine 4 or its salt reacts with a derivative of [4,7,10-tris (2-tert-butoxy-2-oxoethyl) -1,4,7,10-tetra-azacyclododecan-1- yl]acetic acid 5, which is activated by a leaving group (LG), such as pentafluorophenol, 4-nitrophenol, 1-hydroxypyrrolidine-2,5-dione [e.g., the synthesis of tri-tert-butyl 2,2',2''-(10-{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1,4,7,10-tetraazacyclododecane-1,4 ,7-triyl) triacetate is described in detail by Cong Li et al., J. Am.Chem.Soc. 2006, 128, p.15072-15073; S3-5 and Galibert et al., Biorg. and Med. Chem. Letters 20 (2010), 5422 - 5425] or hydroxybenzotriozole, leading to an intermediate 6. The preparation of activated esters is well known to the person skilled in the art and is described in detail, for example, by C. A. Montalbetti and V. Falque in Tetrahedron 61 (2005), pages 10827-10852. The coupling reaction of polyamines 4 with [4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]acetic acid derivatives 5 is carried out in a suitable solvent, such as, for example, N,N-dimethylformamide or dimethyl sulfoxide, or a mixture thereof, at a temperature range from room temperature to 80°C, to provide intermediates 6. Cleavage of the groups carboxyl protectors of intermediates 6 to produce the intermediates of General Formula (IV) can be achieved as described in the textbook Greene and Wuts, Protecting groups in Organic Synthesis, second edition, pages 245-247. Deprotection is, for example, carried out by dissolving and stirring intermediates 6 in trifluoroacetic acid at room temperature for several hours. The complexation of intermediates of General Formula (IV) with suitable compounds or salts of gadolinium (III), such as, for example, gadolinium trioxide, gadolinium triacetate or hydrates of gadolinium triacetate, gadolinium trichloride or gadolinium trinitrate, is well known to one skilled in the art. The intermediates of General Formula (IV) are dissolved in water and after addition of suitable gadolinium compounds (III), the resulting mixtures are stirred at a temperature range from room temperature to 100°C at pH = 1- 7 for several hours to provide compounds of General Formula (I-e). The intermediates of General Formula (IV) are, for example, dissolved in water, gadolinium triacetate tetrahydrate is added, the pH is adjusted to 3.5 - 5.5 by addition of a suitable base, e.g. example, aqueous sodium hydroxide solution. The reaction is carried out at temperatures ranging from 50°C to 80°C, leading to compounds of the General Formula (I-e).

[0142] A route for preparing compounds of the General Formula (If) is described in Scheme 6.

[0143] Scheme 6: Route for the preparation of compounds of the General Formula (lf), where n' represents an integer of 2, if represents a triamine as defined above, or n' represents an integer of 3, if represents a tetra-amine as defined above, and R5 has the meaning given in General Formula (I), above, and LG represents activation leaving groups such as, for example, 4-nitrophenol or a group as defined below.

[0144] Intermediates of General Formula (II-a) or their salts, as described in Scheme 1 and in the experimental part below, where n' represents an integer of 2 and represents a triamine nucleus as defined above or intermediates of General Formula (II-a) or salts thereof, where n' represents an integer of 3 and represents a tetraamine nucleus as defined above, react with Gd complexes of General Formula (III), which are activated by a leaving group (LG), such as pentafluorophenol, 4-nitrophenol, 1-hydroxypyrrolidine-2 ,5-dione, hydroxybenzotriozole or 3H- [1,2,3] triazole [4,5-b] pyridin-3-ol, leading to compounds of the General Formula (If). The preparation of activated esters is well known to the person skilled in the art and is described in detail, for example, by CA Montalbetti and V. Falque in Tetrahedron 61 (2005), pages 10827-10852. For example, the preparation of gadolinium 2,2',2'' [10-(1-{ [2-(4-nitrophenoxy)-2-oxoethyl]amino}-1-oxopropan-2-yl)-1, 4 ,7,10-tetraazacyclododecane-1,4,7-triyl] triacetate is described in detail in WO 2001051095 A2. The reaction of intermediates of General Formula (II-a) or their salts with the activated Gd complexes of General Formula (III) is carried out in a suitable solvent, such as, for example, dimethylsulfoxide, N,N-dimethylformamide, pyridine or their mixture, optionally, the reaction is carried out in the presence of a base. Suitable bases are, for example, trialkylamines, such as, for example, triethylamine or N,N-diisopropylethylamine. The reaction is carried out at temperatures ranging from room temperature to 100°C, preferably the reaction is carried out at temperatures ranging from 50°C to 70°C.

[0145] A route for preparing compounds of General Formula (Ig) is described in Scheme 7.

[0146] Scheme 7: Route for preparing compounds of the General Formula (lg), where n' represents an integer of 2, whether represents a triamine as defined above, or n' represents an integer of 3 if represents a tetraamine as defined above, and R5 has the meaning given in General Formula (1), above, and LG represents activation leaving groups such as, for example, 4-nitrophenol or a group as defined below.

[0147] The compounds of General Formula (l-g) are synthesized in analogy with the compounds of General Formula (l-f), as described above.

[0148] Intermediates of General Formula (ll-b) or their salts, as described in Scheme 2, where n 'represents an integer of 2 and represents a triamine nucleus as defined above or intermediates of General Formula (II-b) or salts thereof, wherein n' represents an integer of 3 and represents a tetramine nucleus as defined above, react with Gd complexes of General Formula (III), which are activated by a leaving group (LG), such as, for example, pentafluorophenol, 4-nitrophenol, 1-hydroxypyrrolidine-2, 5-dione, hydroxy-benzotriazole or 3H- [1,2,3] triazole [4,5-b] pyridin-3-ol, leading to compounds of the General Formula (Ig).

[0149] A route for preparing compounds of General Formula (Ih) is described in Scheme 8.

[0150] Scheme 8: Route for preparing compounds of the General Formula (Ih), where n' represents an integer of 2, if represents a triamine as defined above, or n' represents an integer of 3, if represents a tetraamine as defined above, and R5 has the meaning given in General Formula (I), above, and LG represents activation leaving groups such as, for example, 4-nitrophenol or a group as defined below.

[0151] The compounds of General Formula (I-h) are synthesized in analogy with the compounds of General Formula (I-f), as described above.

[0152] Intermediates of General Formula (II-c) or their salts, as described in Scheme 3, where n' represents an integer of 2 and represents a triamine nucleus as defined above or intermediates of General Formula (II-c) or salts thereof, wherein n' represents an integer of 3 and represents a tetramine nucleus as defined above, react with Gd complexes of General Formula (III), which are activated by a leaving group (LG), such as, for example, pentafluorophenol, 4-nitrophenol, 1-hydroxypyrrolidine-2, 5-dione, hydroxy-benzotriazole or 3H- [1,2,3] triazole [4,5-b] pyridin-3-ol, leading to compounds of General Formula (Ih).

[0153] A route for preparing compounds of General Formula (Ik) is described in Scheme 9.

[0154] Scheme 9: Route for the preparation of compounds of the General Formula (Ik), in which and R4 have the meaning given in General Formula (I), above, n' represents an integer of 2, 3 and 4, LG represents the activation leaving groups, such as, for example, 1-hydroxypyrrolidine-2, 5-dione or a group as defined for the synthesis of the compounds of General Formula (Ia) above, and PG represents a carboxyl protecting group, such as, for example, a methyl or ethyl group.

[0155] Starting materials 1 are commercially available polyamines or salts thereof [e.g., CAS 111-40-0, CAS 28634-67-5, CAS 4730-54-5, CAS 4742-00-1, CAS 294- 90-6] or polyamines or their salts known from the literature or which can be prepared in analogy with compounds that are described in the literature or in the experimental part, infra [for example, CAS 41077-50-3].

[0156] Diamines 7 or their salts are commercially available [for example, CAS 1417898-94-2] or can be synthesized by methods that are well known to one skilled in the art. Diamines 7 or their salts can react with a derivative of [4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecane-1-yl]acetic acid 5, which is activated by a leaving group (LG), such as pentafluorophenol, 4-nitrophenol, 1-hydroxypyrrolidine-2,5-dione [e.g., the synthesis of tri-tert-butyl 2,2' ,2''-(10-{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1,4,7,10-tetra-azacyclododecane-1,4,7-triyl )triacetate is described in detail by Cong Li et al., J. Am.Chem.Soc. 2006, 128, p.15072-15073; S3-5 and Galibert et al., Biorg. and Med. Chem. Letters 2010, 20, p.5422-5425] or hydroxybenzotriazole, leading to intermediates 8. The preparation of activated esters is well known to the person skilled in the art and is described in detail, for example, by C.A. Montalbetti and V. Falque in Tetrahedron 2005, 61 pages 10827-10852. The PG protecting group of intermediates 8 can be cleaved under basic conditions, such as by treatment with alkali metal hydroxides, such as lithium hydroxide, in water or a mixture of water and tetrahydrofuran, to produce the corresponding salt of the carboxylic acid salt. This salt can be coupled with polyamines 1 using conventional peptide coupling conditions, such as, for example, coupling in the presence of HATU and 3H-[1,2,3]triazole[4,5-b]pyridin-3-ol in the presence of N,N-diisopropylethylamine, in a suitable solvent, such as dichloromethane, at room temperature, to provide the intermediates of General Formula (V). Cleavage of the carboxyl protecting groups of the intermediates of General Formula (V) can be achieved using standard conditions, such as, for example, by dissolving and stirring intermediates (V) in aqueous hydrochloric acid at room temperature. Subsequent complexation with suitable compounds or salts of gadolinium (III), such as, for example, gadolinium trioxide, gadolinium triacetate or hydrates of gadolinium triacetate, gadolinium trichloride or gadolinium trinitrate, is well known to one skilled in the art. technique and can, for example, be obtained by reacting with suitable gadolinium (III) compounds in a temperature range from room temperature to 100°C at pH = 1-7 for several hours, to provide the compounds of the General Formula ( I-k). Crude carboxylic acids derived from compounds of General Formula (V) react, for example, with gadolinium trioxide at 80°C, leading to compounds of General Formula (I-k).

[0157] A route for preparing compounds of general formulas (Im) and (In) is described in Scheme 10.

[0158] Scheme 10: Route for the preparation of compounds of general Formulas (Im) and (In), in which and R4 have the meaning given in General Formula (I), above, n' represents an integer of 2, 3 and 4, LG represents the activation leaving groups, such as, for example, 1-hydroxypyrrolidine-2,5 -dione or a group as defined for the synthesis of the compounds of General Formula (Ia) above, and PG represents a carboxyl protecting group, such as, for example, a methyl or ethyl group.

[0159] When instead of the diamines of Formula 7, as described in Scheme 9, the diamines of Formulas 9 and 10 or their salts are used in the analogous synthesis as described in Scheme 9, the compounds of general Formulas (Im) and ( In) can be obtained.

[0160] Diamines 9 or their salts are commercially available [for example, CAS 159029-33-1, CAS 440644-06-4] or can be synthesized by methods that are well known to one skilled in the art.

[0161] Diamines 10 or their salts are commercially available [for example, CAS 20610-20-2, CAS 6059-44-5] or can be synthesized by methods that are well known to one skilled in the art.

[0162] An alternative route to that described in Scheme 4 for the preparation of compounds of General Formula (Id) is described in Scheme 11. Scheme 11

[0163] Scheme 11: Alternative route for preparing compounds of the General Formula (Id), where R5 has the meaning given in the General Formula (I), above, represents a tetra-amine as for General Formula (I), above, and LG represents an activating leaving group, such as, for example, 3H- [1,2,3]triazolo [4,5-b]pyridin -3-ol or a group as defined for the synthesis of the compounds of General Formula (Ia) above.

[0164] The starting materials 4 are commercially available tetraamines or their salts [e.g., CAS 4742-00-1, CAS 294-90-6] or tetraamines or their salts that are known from the literature or that can be prepared in analogy with the compounds that are described in the literature. The starting materials 14 are commercially available or known from the literature or can be synthesized in analogy with compounds that are described in the literature, e.g., by gradual alkylation of the cyclene nucleus.

[0165] A tetramine 4 or its salt reacts with an amino acid derivative 11, which is activated by a leaving group (LG), such as, for example, 1 hydroxypyrrolidine-2,5-dione, pentafluorophenol, 4-nitrophenol or 3H - [1,2,3]triazole [4,5-b] pyridin-3-ol, leading to an intermediate 12. The preparation of activated esters is well known to the person skilled in the art and is described in detail, e.g. C.A. Montalbetti and V. Falque in Tetrahedron 61 (2005), pages 10827-10852. Coupling reactions of polyamines 4 with amino acid derivatives 11 are carried out in a suitable solvent, such as, for example, dichloromethane or N,N-dimethylformamide, at a temperature range from room temperature to 50°C, to provide intermediates 12. Cleavage of the amino protecting groups (PG) of intermediates 12 to produce intermediates 13 can be accomplished as described in the Greene and Wuts textbook, Protecting groups in Organic Synthesis, second edition. In the case of tert-butoxycarbonyl protecting groups, deprotection is, for example, carried out by reacting intermediates 12 with HCl in CPME in a suitable solvent, such as, for example, CPME or 1,4-dioxane or a mixture thereof in a range temperatures from 0°C to room temperature for several hours.

[0166] A tetramine 13 or its salt reacts with a derivative of [4,7,10-tris (2-tert-butoxy-2-oxoethyl) -1,4,7,10-tetra-azacyclododecane-1-yl] acetic acid 14, which is activated by a leaving group (LG), such as 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol, 4-nitrophenol or 1- hydroxypyrrolidine-2,5-dione leading to an intermediate 15. The coupling reaction of tetramines 13 with derivatives of [4,7,10-tris(2- tert-butoxy-2-oxoethyl) -1,4,7, 10-tetra-azacyclododecan-1-yl]acetic acid 14 is carried out in a suitable solvent, such as, for example, N,N-dimethylacetamide or dimethyl sulfoxide, or a mixture thereof, at a temperature range from room temperature to 80 °C, to provide the intermediates 15.

[0167] Cleavage of the carboxyl protecting groups of intermediates 15 to produce the intermediates of General Formula (VI) can be accomplished as described in the textbook Greene and Wuts, Protecting groups in Organic Synthesis, second edition, pages 245-247 . Deprotection is, for example, carried out by dissolving and stirring intermediates 15 in trifluoroacetic acid at room temperature for several hours.

[0168] The complexation of intermediates of General Formula (VI) with suitable compounds or salts of gadolinium (III), such as, for example, gadolinium trioxide, gadolinium triacetate or hydrates of gadolinium triacetate, gadolinium trichloride or gadolinium trinitrate, is well known to one skilled in the art. The intermediates of General Formula (VI) are dissolved in water and after addition of suitable gadolinium compounds (III), the resulting mixtures are stirred at a temperature range from room temperature to 100°C at pH = 1-7 for several hours, to provide the compounds of General Formula (I-d). The intermediates of General Formula (VI) are, for example, dissolved in water, gadolinium triacetate tetrahydrate is added, and the pH is adjusted to 3.5 - 5.5 by addition of a suitable base, such as, for example, aqueous sodium hydroxide solution. The reaction is carried out at temperatures ranging from 50°C to 80°C, leading to compounds of General Formula (I-d).

[0169] An alternative route to that described in Scheme 4 for the preparation of compounds of General Formula (Id) is described in Scheme 12.

[0170] Scheme 12: Alternative route for preparing compounds of the General Formula (Id), where R5 has the meaning given in the General Formula (I), above, represents a tetra-amine as for General Formula (I), above, and LG represents an activating leaving group, such as, for example, 3H- [1,2,3]triazolo [4,5-b]pyridin -3-ol or a group as defined for the synthesis of the compounds of General Formula (Ia) above.

[0171] The starting materials 4 are commercially available tetraamines or their salts [e.g., CAS 4742-00-1, CAS 294-90-6] or tetraamines or their salts that are known from the literature or that can be prepared in analogy with the compounds that are described in the literature. The starting materials 16 are known from the literature or can be synthesized in analogy with compounds that are described in the literature, e.g., by gradual alkylation of the cyclene nucleus.

[0172] A tetramine 4 or its salt reacts with a derivative of [4,7,10-tris (2-tert-butoxy-2-oxoethyl) -1,4,7,10-tetra-azacyclododecane-1-yl] acetic acid 16, which is activated by a leaving group (LG), such as 3H- [1,2,3] triazolo [4,5-b] pyridin-3-ol, 4-nitrophenol or 1- hydroxypyrrolidine-2,5-dione leading to an intermediate 15. The coupling reaction of tetramines 4 with derivatives of [4,7,10-tris (2- tert-butoxy-2-oxoethyl) -1,4,7, 10-tetra-azacyclododecan-1-yl]acetic acid 16 is carried out in a suitable solvent, such as, for example, N,N-dimethylformamide, to provide intermediates 16.

[0173] The complexation of intermediates of General Formula (VI) with suitable compounds or salts of gadolinium (III), such as, for example, gadolinium trioxide, gadolinium triacetate or hydrates of gadolinium triacetate, gadolinium trichloride or trinitrate of gadolinium, is well known to one skilled in the art. The intermediates of General Formula (VI) are dissolved in water and after addition of suitable gadolinium compounds (III), the resulting mixtures are stirred over a temperature range from room temperature to 100°C at pH = 1- 7 for several hours to provide compounds of General Formula (I-d). The intermediates of General Formula (VI) are, for example, dissolved in water, gadolinium triacetate tetrahydrate is added, and the pH is adjusted to 3.5 - 5.5 by addition of a suitable base, such as, for example, aqueous sodium hydroxide solution. The reaction is carried out at temperatures ranging from 50°C to 80°C, leading to compounds of General Formula (I-d).

[0174] According to a representation, the present also relates to a method of preparing a compound of General Formula (I -), as defined above, the cited method consisting of the step in which an intermediate compound of General Formula is allowed (II-a): on what is as defined for the compound of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 or its salt, to react with a compound of General Formula (III): wherein R5 is as defined for the compound of General Formula (I), above and LG represents an activation leaving group, such as, for example, 4-nitrophenol, or a group as defined for the synthesis of the compounds of General Formula (Ia) above, thus providing a compound of General Formula (Ia): on what and R5 are as defined for the compound of General Formula (I) above, and n' represents an integer of 2, 3 and 4.

[0175] According to another representation, the present one also relates to a method of preparing a compound of General Formula (Ib), as defined above, the cited method consisting of the step in which an intermediate compound of Formula General (II-b): on what is as defined for the compound of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 or its salt, to react with a compound of General Formula (III): wherein R5 is as defined for the compound of General Formula (I), above, and LG represents an activating leaving group, such as, for example, 4-nitrophenol, or a group as defined for the synthesis of compounds of General Formula ( Ia) above, thus providing a compound of General Formula (Ib): on what and R5 are as defined for the compound of General Formula (I) above, and n' represents an integer of 2, 3 and 4.

[0176] According to another representation, the present one also relates to a method of preparing a compound of General Formula (Ic), as defined above, the cited method consisting of the step in which an intermediate compound of Formula General (II-c): on what is as defined for the compound of General Formula (I), supra, and n 'represents an integer of 2, 3 and 4 or its salt, to react with a compound of General Formula (III): wherein R5 is as defined for the compound of General Formula (I), above, and LG represents an activating leaving group, such as, for example, 4-nitrophenol, or a group as defined for the synthesis of compounds of General Formula ( Ia) above, thus providing a compound of General Formula (Ic): on what and R5 are as defined for the compound of General Formula (I) above, and n' represents an integer of 2, 3 and 4.

[0177] According to another representation, the present one also relates to a method of preparing a compound of General Formula (Id), as defined above, the cited method consisting of the step in which a compound of Formula 4 is allowed , wherein ^A is a tetramine as defined for the compound of General Formula (I), above, or its salt, to react with a compound of General Formula (III): wherein R5 is as defined for the compound of General Formula (I), supra, and LG represents an activating leaving group, such as, for example, 4-nitrophenol, or a group as defined for the synthesis of compounds of General Formula (Ia). ) above, thus providing a compound of General Formula (Id): wherein R5 is as defined for the compound of General Formula (I) above, and is a tetramine as defined for the compound of General Formula (I), supra.

[0178] According to another representation, the present one also relates to a method of preparing a compound of General Formula (Ie), as defined above, the cited method consisting of the step in which an intermediate compound of Formula General (IV): wherein R4 is as defined for the compound of General Formula (I), above and is a tetramine as defined for the compound of General Formula (I), above, for reacting with a gadolinium compound (III), such as, for example, gadolinium trioxide, gadolinium triacetate or hydrates of gadolinium triacetate, gadolinium trichloride or gadolinium trinitrate or with its salt, thus providing a compound of General Formula (Ie): wherein R4 is as defined for the compound of General Formula (I), above and is a tetramine as defined for the compound of General Formula (I), supra.

[0179] According to another representation, the present one also relates to a method of preparing a compound of General Formula (If), as defined above, the cited method consisting of the step in which an intermediate compound of General Formula (If) is allowed. II-a): on what is a triamine as defined for the compound of General Formula (I), above and n' represents an integer of 2 or its salt or wherein is a tetramine as defined for the compound of General Formula (I), above, and n' represents an integer of 3 or its salt, for reacting with a compound of General Formula (III): wherein R5 is as defined for the compound of General Formula (I), supra, and LG represents an activating leaving group, such as, for example, 4-nitrophenol, or a group as defined for the synthesis of compounds of General Formula (Ia). ) above, thus providing a compound with General Formula (If): wherein R5 is as defined for the compound of General Formula (I), above and wherein is a triamine as defined for the compound d General Formula (I), above and n' represents an integer of 2 or where is a tetramine as defined General (I), above and n' represents an integer of 3.

[0180] According to another representation, the present one also relates to a method of preparing a compound of General Formula (Ih), as defined above, the cited method consisting of the step in which an intermediate compound of Formula General (II-c): on what is a triamine as defined for the compound of General Formula (I), above and n' represents an integer of 2 or its salt or wherein is a tetramine as defined for the compound of General Formula (I), above, and n' represents an integer of 3 or its salt, for reacting with a compound of General Formula (III): wherein R5 is as defined for the compound of General Formula (I), above, and LG represents an activating leaving group, such as, for example, 4-nitrophenol, or a group as defined for the synthesis of compounds of General Formula ( Ia) above, thus providing a compound of General Formula (Ih): wherein R5 is as defined for the compound of General Formula (I), above and wherein is a triamine as defined for the compound of General Formula (I), above and n' represents an integer of 2 or where is a tetramine as defined for the compound of General Formula (I), above and n' represents an integer of 3.

[0181] According to another representation, the present one also relates to a method of preparing a compound of General Formula (Ik), as defined above, the cited method consisting of the step in which an intermediate compound of Formula General (V): on what and R4 are as defined for the compound of General Formula (I), above, and n' represents an integer of 2, 3 and 4, in a first step to react with an acid, such as, for example, aqueous hydrochloric acid and in a second step to react with a gadolinium (III) compound, such as, for example, gadolinium trioxide, gadolinium triacetate or gadolinium triacetate hydrates, gadolinium trichloride or gadolinium trinitrate or with its salt, thereby providing form, a compound of General Formula (Ik): on what and R4 are as defined for the compound of General Formula (I), above, and n' represents an integer of 2, 3 and 4.

BRIEF DESCRIPTION OF FIGURES

[0182] Figure 1 shows the blood plasma kinetics of Example 3 versus Gadovist® in rats. The pharmacokinetic profile of Example 3 is comparable to that of Gadovist®.

[0183] Figure 2 shows the evolution of the relative paramagnetic longitudinal attenuation rate of the water proton R1p(t)/R1p(0) versus time of Example 3, reference compound 1 (Gadovist®), reference compound 2 ( Magnevist®) and reference compound 3 (Primovist ®). The stability of Example 3 is comparable to the high stability macrocyclic reference compound 1 (Gadovist®).

[0184] Figure 3 presents data from magnetic resonance angiography in New Zealand white rabbits: (A) 30 µmol Gd/kg bw Reference compound 1 (Gadovist®); (B) 30 µmol Gd/kg bw Example 3 and (C) 100 µmol Gd/kg bw Reference compound 1. The contrast enhancement of the low dose protocol with Example 3 (B) is comparable to that of the standard dose of reference compound 1 (C). Furthermore, the image quality of the low dose protocol of Example 3 (B) is significantly better than the low dose protocol of reference compound 1 (A). The angiography study demonstrates the potential of Example 3 for significant dose reduction.

[0185] Figure 4 MRI images before and after contrast agent administration. Representative images of the head and neck region before and 1.4 min after administration of Example 3 (A) and reference compound 1 (B). The strong signal enhancement is visible, for example, in the heart, tongue and neck muscle.

[0186] Figure 5 MRI images before and after contrast agent administration. Representative images of the abdominal region before and 0.5 minutes after administration of Example 3 (A) and reference compound 1 (B). Strong signal enhancement is visible, for example, in the aorta, kidneys, liver and spleen.

[0187] Figure 6 MRI images before and after contrast agent administration. Representative images of the pelvic region before and 2.9 min after administration of Example 3 (A) and reference compound 1 (B). The strong signal enhancement is visible, for example, in the vascular system (vessels) and in the muscles of the extremities.

[0188] Figure 7 Improvements in the MRI signal for different regions of the body.

[0189] Signal increase over time after administration of Example 3 and reference compound 1 (Gadovist®) to tongue, muscle, liver, spleen, aorta and extremity muscle. No differences were observed in the time course of signal changes between Example 3 and reference compound 1. This demonstrates identical pharmacokinetic properties and indicates the potential of Example 3 for imaging different regions of the body. As expected from the approximately 2-fold greater relativity (see example A), the contrast improvements observed in Example 3 were greater compared to reference compound 1 (Gadovist®). Vertical bars represent standard deviation.

[0190] Figure 8 Correlation of tissue gadolinium concentration and MRI signal enhancement.

[0191] Gadolinium concentration was measured in tissue samples from the brain, tongue, liver, spleen, blood and extremity muscle (muscle) and respective MRI signal changes determined in vivo, after administration of Example 3 and of reference compound 1. Vertical and horizontal error bars represent standard deviation. The dotted lines represent the linear regression between gadolinium concentration and MR signal change.

[0192] Figure 9 Diffusion of different contrast agents through semipermeable membranes (20 kDa).

[0193] Dynamic CT measurements were performed to show the ability of different contrast agents to diffuse through a semipermeable membrane. (A) CT images of Example 1, 2, 3, 4, 5 and 6 compared to reference compound 1 (Gadovist®) and 4 (Gadomer). A representative measurement region for evaluating the signal over time is indicated in image A1.

[0194] Figure 10 Signal analysis of the dynamic CT diffusion phantom study over time. Signal in Hounsfield units (HU) over time of the dialysis cassette in fetal bovine solution for Example 1-6 and reference compounds 1 and 4 demonstrate that, contrary to reference compound 4 (Gadomer), all investigated compound can pass through the semipermeable membrane (20 kDa).

[0195] Figure 11 Contrast-enhanced MRI images of GS9L brain tumors in mice (marked with white arrows). (A) Intraindividual comparison of reference compound 1 (Gadovist®) and Example 3 at the same dose of 0.1 mmol Gd/kg body weight (bw). Example 3 showed greater lesion contrast in the brain and excellent demarcation of the tumor border. (B) Comparison of reference compound 1 (Gadovist®) at 0.3 mmol Gd/kg bw and Example 3 at 0.1 mmol Gd/kw bw. Example 3 showed similar brain lesion contrast at one-third the dose of reference compound 1. EXPERIMENTAL SECTION Abbreviations

Materials and instrumentation

[0196] The chemicals used for the synthetic work were of reagent grade quality and were used as obtained.

[0197] All reagents, for which the synthesis is not described in the experimental section, are commercially available or are known compounds or can be created from known compounds by methods known to one skilled in the art.

[0198] 1H-NMR spectra were measured in CDCl3, D2O or DMSO-d6, respectively (room temperature, Bruker Avance 400 spectrometer, resonance frequency: 400.20 MHz for 1H or Bruker Avance 300 spectrometer, resonance frequency: 300.13 MHz for 1H. Chemical shifts are given in ppm relative to sodium (trimethylsilyl)propionate-d4 (D2O) or tetramethylsilane (DMSO-d6) as external standards (d = 0 ppm).

[0199] Compounds and intermediates produced according to the methods of the invention may require purification. The purification of organic compounds is well known to those skilled in the art and there may be several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, compounds can be purified by crystallization. In some cases, impurities can be agitated using a suitable solvent. In some cases, compounds can be purified by chromatography, particularly flash column chromatography using, for example, pre-packaged silica gel cartridges, e.g. Biotage SNAP KP-Sil® or KP-NH® cartridges in combination with a Biotage autopurification system (SP4® or Isolera Four®) and eluents, such as hexane/ethyl acetate or DCM/methanol gradients. In some cases, compounds can be purified by preparatory HPLC using, for example, a Waters autopurifier equipped with a diode array detector and/or electrospray ionization mass spectrometer in conjunction with a pre-reverse phase column. - packaged and eluents, for example water and acetonitrile gradients that may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.

[0200] The examples were analyzed and characterized by the following HPLC-based analytical methods to determine the characteristic retention time and mass spectrum:

[0201] Method 1: UPLC (ACN-HCOOH): Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 µm, 50x2.1mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 mL/min; temperature: 60°C; injection: 2 µl; DAD scan: 210-400 nm; ELSD.

[0202] Method 2: UPLC (polar ACN-HCOOH): Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 µm, 50x2.1mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 0-1.7 min 1-45% B, 1.7-2.0 min 45-99% B; flow 0.8 mL/min; temperature: 60°C; injection: 2 µl; DAD scan: 210-400 nm; ELSD.

[0203] Method 3: UPLC (ACN-HCOOH long run): Instrument: Waters Acquity UPLC-MS SQD 3001; column: Acquity UPLC BEH C18 1.7 µm, 50x2.1mm; eluent A: water + 0.1% formic acid, eluent B: acetonitrile; gradient: 0-4.5 min 0-10% B; flow 0.8 mL/min; temperature: 60°C; injection: 2 µl; DAD scan: 210-400 nm; ELSD.

[0204] Method 4: UPLC (ACN-NH3): Instrument: Waters Acquity UPLC-MS ZQ2000; column: Acquity UPLC BEH C18 1.7 µm, 50x2.1 mm; Eluent A: water + 0.2% ammonia, eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.62.0 min 99% B; flow rate 0.8 mL/min; temperature: 60°C; injection: 1 µL; DAD scan: 210-400 nm; ELSD.

[0205] Method 5: LC-MS: Instrument: Agilent 1290 UHPLCMS Tof; column: BEH C 18 (Waters) 1.7 µm, 50x2.1 mm, eluent A: water + 0.05 vol-% formic acid (99%), eluent B: acetonitrile + 0.05% formic acid; gradient: 0-1.7 min 98-10% A, 1.7-2.0 min 10% A, 2.0-2.5 min 10-98% A, flow 1.2 mL/min; temperature: 60°C; DAD scan: 210-400 nm. Example compounds Example 1

[0206] Pentagadolinium [4,10-bis (carboxylatomethyl)-7-{3,6,10,18,22,25-hexaoxo-26- [4,7,10-tris (carboxylatomethyl)-1,4,7 ,10- tetra-azacyclododecan-1-yl]-14- [({2- [4,7,10-tris(carboxylatomethyl)-1,4,7,10- tetraazacyclododecan-1-yl] propanoyl} amino)acetyl ]-9,19-bis({ [({2- [4,7,10- tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl] propanoyl}amino)acetyl]amino} methyl)-4,7,11,14,17,21,24-heptaazaheptacosan-2-yl}-1,4,7,10-tetraazacyclododecan-1-yl]acetate Di-tert-butyl (2-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}propane-1,3-diyl)biscarbamate

[0207] 3.60 g (11.3 mmol, 1 eq.) 3- [(tert-butoxycarbonyl)amino]-2- { [(tert-butoxycarbonyl)amino]methyl}propanoic acid (see WO 2006/136460 A2 ) and 1.43 g (12.4 mmol, 1.1 eq.) 1-hydroxypyrrolidine-2,5-dione were dissolved in 120 mL of THF. To the reaction mixture was added dropwise a solution of 2.57 g (12.4 mmol, 1.1 eq) N,N'-dicyclohexylcarbodiimide in 60 mL of THF. After stirring for 3 hours at room temperature, the resulting suspension was cooled to 0°C and the precipitated urea was filtered. The clear solution was evaporated to dryness, yielding 5.50 g (13.24 mmol, 117%) of the title compound. UPLC (ACN-HCOOH): Rt. = 1.15 min. MS (ES+): m/z = 416.3 (M + H)+. Example 1b Tert-butyl (7,17-bis{[(tert-butoxycarbonyl)amino]methyl}-2,2-dimethyl-4,8,16-trioxo-3-oxa-5,9,12,15-tetra -azaoctadecane-18-yl) carbamate

[0208] 4.70 g (11.3 mmol, 2.22 eq.) Di-tert-butyl (2-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}propane-1 was dissolved ,3-diyl)biscarbamate (example 1a) in 120 mL of THF. To the reaction mixture was added dropwise a solution of 0.53 g (5.10 mmol, 1 eq) N-(2-aminoethyl)ethane-1,2-diamine and 1.14 g (11.3 mmol, 2.22 eq.) triethylamine in 40 mL of THF. After stirring for 3 hours at room temperature, the resulting suspension was diluted with dichloromethane. The organic solution was washed with aqueous sodium hydroxide (0.1 M), water and dried over sodium sulfate. The crude product was isolated by evaporation under reduced pressure and purified by silica gel chromatography yielding 2.81 g (3.99 mmol, 78%) of the title compound.

[0209] 1H-NMR (400 MHz, DMSO-d6): d = 1.36 (s, 36 H), 2.39 - 2.47 (m, 3 H), 2.52 - 2.58 (m , 4 H), 2.95 - 3.20 (m, 12 H), 6.64 (t, 4 H), 7.72 (t, 2 H) ppm. UPLC (ACN-HCOOH): Rt. = 1.06 min. MS (ES+): m/z = 704.6 (M+ + H). Example 1c N,N'-(Iminodiethane-2,1-diyl)bis[3-amino-2-(aminomethyl)propanamide] pentahydrochloride

[0210] 600 mg (0.85 mmol) of Tert-butyl (7,17-bis{ [(tert-butoxycarbonyl)amino]methyl}-2,2-dimethyl-4,8,16-trioxo-3-oxa -5,9,12,15-tetraazaoctadecan-18-yl)carbamate (example 1b) were dissolved in 9.6 mL of methanol and 2.85 mL of aqueous hydrochloric acid (37%). The reaction mixture was heated under stirring for 2 hours at 50°C. For isolation the suspension was evaporated to dryness yielding 423 mg (0.87 mmol, 102%) of the title compound.

[0211] 1H-NMR (400 MHz, D2O): d = 3.04 - 3.15 (m, 2 H), 3.17 - 3.27 (m, 8 H), 3.29 - 3.38 (m, 4 H), 3.55 (t, 4 H) ppm. UPLC (ACN-HCOOH): Rt. = 0.19 min. MS (ES+): m/z = 304.2 (M + H)+, free base.

Example 1

[0212] Pentagadolinium [4,10-bis (carboxylatomethyl)-7-{3,6,10,18,22,25-hexaoxo-26- [4,7,10-tris (carboxylatomethyl)-1,4,7 ,10- tetra-azacyclododecan-1-yl]-14- [({2- [4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan-1-yl] propanoyl} amino )acetyl]-9,19-bis({ [({2- [4,7,10- tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan-1-yl] propanoyl}amino) acetyl]amino}methyl)-4,7,11,14,17,21,24-heptaazaheptacosan-2-yl}-1,4,7,10-tetra-azacyclododecan-1-yl]acetate

[0213] 150 mg (309 µmol, 1 eq.) N,N'- (Iminodiethane-2,1-diyl) bis [3-amino-2-(aminomethyl) -propanamide] pentahydrochloride was dissolved (example 1c) in 60 mL of DMSO. After addition of 499 mg (3.86 mmol, 12.5 eq.) N,N-diisopropylethylamine and 4.06 g (5.40 mmol, 17.5 eq.) of gadolinium 2,2',2'' - [10-(1-{ [2-(4-nitrophenoxy)-2- oxoethyl] amino}-1-oxopropan-2-yl)-1,4,7,10-tetra-azacyclododecane- 1,4,7 -triyl]triacetate (see WO 2001051095 A2) and the resulting reaction mixture were stirred and heated for 8 hours at 50°C. The cooled solution was concentrated under reduced pressure to a final volume of 15-20 ml. The concentrate was poured under stirring into 400 ml of ethyl acetate, the precipitate formed was removed by filtration and dried in vacuo. The solid was dissolved in water, the resulting solution was ultrafiltered with water using a 1 kDa membrane and the final concentrate was lyophilized. The crude product was purified by RP chromatography, yielding 668 mg (64%, 199 µmol) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.46 min. MS (ES-): m/z (z = 2) = 1680.5 (M - 2H)2-; (ES+): m/z (z =3) = 1121.3 (M + H)3+, m/z (z = 4) = 841.4 [(M + H)4+.

Example 2

[0214] Hexagadolinium [4,10-bis(carboxylatomethyl)-7-{3,6,10,15,19,22-hexaoxo-23- [4,7,10-tris(carboxylatomethyl)-1,4,7 ,10-tetraazacyclododecane-1-yl]-9,16-bis({ [({2- [4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl } amino)acetyl]amino}methyl)-11-(2-{ [3-{ [({2- [4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1- yl]propanoyl}amino)acetyl] amino}-2-({ [({2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclodode can-1-yl] propanoyl } amino) acetyl] amino} methyl) propanoyl] amino} ethyl) - 4,7,11,14,18,21-hexa-azatetracosan-2-yl} -1,4,7,10-tetra-azacyclododecan -1 -il] acetate Example 2a (Tert-butyl (12-{2- [(3- [(tert-butoxycarbonyl)amino]-2-{ [(tert-butoxycarbonyl )amino]-methyl}propanoyl)amino] ethyl}-7,14- bis{ [(tert-butoxycarbonyl)amino] methyl}-2,2-dimethyl-4,8,13-trioxo-3-oxa-5,9,12-triazapentadocan-15-yl) carbamate

[0215] 890 mg (2.80 mmol, 3 eq.) 3- [(tert-butoxycarbonyl) amino]-2- { [(tert-butoxycarbonyl) amino] -methyl} propanoic acid (see WO 2006/136460 A2) were dissolved in 22 mL of DMF. To the solution were added 434 mg (3.36 mmol, 3.6 eq.) N,N-diisopropylethylamine and 1.28 g (3.36 mmol, 3.6 eq.) HATU. The resulting reaction mixture was stirred for 2 hours at room temperature. After dropwise addition of a solution of 96.1 mg (0.93 mmol, 1 eq.) N-(2-aminoethyl) ethane-1,2-diamine and 434 mg (3.36 mmol, 3.6 eq) N,N-diisopropylethylamine in 9 mL of DMF, the resulting reaction mixture was heated under stirring for 3 hours at 70°C. After cooling and diluting with dichloromethane, the solution was washed with aqueous sodium hydroxide (0.1 M), aqueous citric acid (1%) and water and dried over sodium sulfate. The crude product was isolated by evaporation under reduced pressure and purified by silica gel chromatography yielding 451 mg (0.45 mmol, 48%) of the title compound.

[0216] 1H-NMR (400 MHz, DMSO-d6): d = 1.37 (s, 54 H), 2.36 - 2.49 (m, 3 H), 2.81 - 3.30 (m , 17 H), 3.36 - 3.70 (m, 3 H), 6.16 - 6.92 (m, 6 H), 7.77 - 8.35 (m, 2 H) ppm. UPLC (ACN-HCOOH): Rt. = 1.49 min. MS (ES+): m/z = 1004.6 (M + H)+.

Example 2b

[0217] 3-Amino-N,N-bis(2-{[3-amino-2-(aminomethyl)propanoyl]amino}ethyl)-2-(aminomethyl)-propanamide hexahydrochloride

[0218] 581 mg (0.58 mmol) tert-butyl (12-{2- [(3- [(tert-butoxycarbonyl) amino]-2-{ [(tert-butoxycarbonyl) amino] methyl} propanoyl) amino ]ethyl}-7,14-bis{[(tert-butoxycarbonyl)amino]methyl}-2,2-dimethyl-4,8,13-trioxo-3-oxa-5,9,12-triazapentadecan-15-yl ) carbamate (example 2a) were dissolved in 9.3 mL of methanol and 2.9 mL of aqueous hydrochloric acid (37%). The reaction mixture was heated under stirring for 2 hours at 50°C. For isolation, the suspension was evaporated until dry, producing 376 mg (0.60 mmol, 103%) of the title compound.

[0219] 1H-NMR (400 MHz, D2O): d = 3.13 - 3.27 (m, 2 H), 3.28 - 3.85 (m, 21 H) ppm. UPLC (ACN-HCOOH): Rt. = 0.19 min. MS (ES+): m/z = 404.3 (M + H)+, free base.

Example 2

[0220] Hexagadolinium [4,10-bis(carboxylatomethyl)-7-{3,6,10,15,19,22-hexaoxo-23- [4,7,10-tris(carboxylatomethyl)-1,4,7 ,10-tetraazacyclododecane- 1-yl]-9,16-bis({ [({2- [4,7,10-tris(carboxylatomethyl)-1,4,7,10- tetraazacyclododecan-1-yl]propanoyl} amino)acetyl]amino}methyl)-11-(2-{ [3- { [({2- [4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetraazacyclododecan-1-yl] propanoyl}amino)acetyl]amino}-2-({ [({2- [4,7,10-tris(carboxylatomethyl) - 1,4,7,10-tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) propanoyl] amino} ethyl) -4,7,11,14,18,21-hexa-azatetracosan-2-yl} - 1,4,7,10-tetra-azacyclododecan-1-yl] acetate

[0221] 150 mg (241 µmol, 1 eq.) was dissolved in 3-Amino-N, N-bis(2-{ [3-amino-2-(aminomethyl)propanoyl]amino}-ethyl)-2- ( aminomethyl)propanamide hexahydrochloride (example 2b) in 60 mL of DMSO. After addition of 467 mg (3.62 mmol, 15 eq.) N,N-diisopropylethylamine and 3.80 g (5.06 mmol, 21 eq.) gadolinium 2,2',2''-[10-( 1- { [2-(4-nitrophenoxy)-2-oxoethyl] amino}-1-oxopropan-2-yl)-1,4,7,10-tetra-azacyclododecane-1,4,7-triyl] triacetate ( see WO 2001051095 A2), the resulting reaction mixture was stirred and heated for 8 hours at 50°C. The cooled solution was concentrated under reduced pressure to a final volume of 15-20 ml. The concentrate was poured with stirring into 400 ml of ethyl acetate, the precipitate formed was removed by filtration and dried in vacuo. The solid was dissolved in water, the resulting solution was ultrafiltered with water using a 1 kDa membrane and the final concentrate was lyophilized. The crude product was purified by RP chromatography, yielding 677 mg (166 µmol, 69%) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.44 min. MS (ES+): m/z (z = 3) = 1357.4 (M + 3H)3+, m/z (z = 4) = 1018.8 (M + 4H)4+], m/z ( z = 5) = 815.7 (M + 5H)5+.

Example 3

[0222] Tetragadolinium [4,10-bis (carboxylatomethyl) -7- {3,6,12,15-tetraoxo-16- [4,7,10-tris (carboxylatomethyl) -1,4,7,10- tetra-azacyclododecan-1-yl]-9,9-bis({[({2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan-1-yl] propanoyl } amino) acetyl] amino} methyl) -4,7,11,14- tetra-azaheptadecan-2-yl} -1,4,7,10-tetra-azacyclododecan-1-yl] acetate

[0223] 225 mg (1.65 mmol, 1 eq.) 2,2-Bis (aminomethyl) propane-1,3-diamine (see W. Hayes et al., Tetrahedron 59 (2003), 79837996) was dissolved in 240 mL of DMSO. After addition of 1.71 g (13.2 mmol, 8 eq.) N,N-diisopropylethylamine and 14.9 g (19.85 mmol, 12 eq.) of gadolinium 2,2',2''-[ 10-(1-{[2-(4-nitrophenoxy)-2-oxoethyl]amino}-1-oxopropan-2-yl)-1,4,7,10-tetra-azacyclododecane-1,4,7-triyl ] triacetate (see WO 2001051095 A2), the resulting reaction mixture was stirred and heated for 8 hours at 50°C. The cooled solution was concentrated under reduced pressure to a final volume of 40 - 50 mL. The concentrate was poured under stirring into 600 ml of ethyl acetate, the precipitate formed was removed by filtration and dried in vacuo. The solid was dissolved in water, the resulting solution was ultrafiltered with water using a 1 kDa membrane and the final retentate was lyophilized. The crude product was purified by RP chromatography, yielding 3.42 g (80%, 1.33 mmol) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.42 min. MS (ES+): m/z (z = 2) = 1290.4 (M + H)2+, m/z (z = 3) = 860.7 (M + H)3+.

[0224] Example 3 comprises a mixture of stereoisomers that exhibit the following absolute configurations: all-R, all-S, RRRS, SSSR, RRSS.

Example 3-1

[0225] Tetragadolinium {4,10-bis (carboxylatomethyl) -7 - [(2R, 16R) - 3,6,12,15-tetraoxo-16- [4,7,10-tris (carboxylatomethyl) -1,4 ,7,10-tetra-azacyclododecan-1-yl]-9,9-bis({[({(2R)-2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10- tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azheptadecan-2-yl] -1,4,7,10-tetra-azacyclododecan-1- il} acetate Tert-butyl {10,10-bis [({ [(tert-butoxycarbonyl)amino]acetyl}amino)methyl]- 2,2-dimethyl-4,7,13-trioxo-3-oxa-5,8,12 -triazatetradecan-14-yl}carbamate

[0226] A mixture of 2,2-bis (aminomethyl) propane-1,3-diamine tetrahydrochloride (851 mg, 3.06 mmol, 1 eq.; see W. Hayes et al., Tetrahedron 59 (2003) , 7983-7996) in dichloromethane (50 mL) was treated with N,N-diisopropylethylamine (6.00 eq., 3.20 mL, 18.4 mmol) and 2,5-dioxopyrrolidin-1-yl N-(tert -butoxycarbonyl)glycinate (CAS no. [3392-07-2]; 6.00 eq., 5.00 g, 18.4 mmol) and stirred at room temperature for 2.5 days. The reaction mixture was diluted with water, the precipitate formed was removed by filtration and washed with water and dichloromethane. The precipitated material was subjected to silica gel chromatography (dichloromethane/methanol) to yield the title compound (800 mg, 34%).

[0227] 1H-NMR (400 MHz, DMSO-d6): d = 1.36 (s, br, 36H), 2.74 - 2.76 (m, 8H), 3.48 - 3.50 (m , 8H), 6.96 (s, br, 0.4H*), 7.40 - 7.42 (m, 3.6H*), 7.91 - 8.00 (m, 4H) ppm. LC-MS (ES+): m/z = 761.4 (M + H)+; Rt. = 1.16 min. Example 3-1b 2-Amino-N-(3- [(aminoacetyl)amino]-2,2- bis{ [(aminoacetyl)amino]methyl}propyl)acetamide tetrahydrochloride

[0228] A suspension of {10,10-bis [({ [(tert-butoxycarbonyl) amino] acetyl}amino)methyl]-2,2-dimethyl-4,7,13-trioxo-3-oxa-5, 8,12-triazatetradecan-14-yl} carbamate (1.00 eq., 800 mg, 1.05 mmol) of example 11a in CPME (10 mL) was cooled to 0°C and treated dropwise with HCl in CPME ( 10 eq., 3.5 mL of a 3 M, 10.5 mmol solution). The reaction mixture was stirred at 0°C for 1 h and at room temperature overnight after which dioxane (4 mL) and another amount of HCl in CPME (30 eq., 11 mL of a 3 M solution, 32 mmol) and stirring at room temperature continued for 2 days. The resulting suspension was concentrated in vacuo to yield the title compound (575 mg, quant.) which was not further purified.

[0229] 1H-NMR (400 MHz, DMSO-d6): d = 3.17 - 3.18 (m, 8H), 3.59 - 3.61 (m, 8H), 8.21 (s, br , 12H), 8.55 (t, 4H) ppm. LC-MS (ES+): m/z = 361.2 (M - 3HCl - Cl-)+; Rt. = 0.10 min. Example 3-1c Benzyl (2S)-2-{ [(trifluoromethyl)sulfonyl]oxy}propanoate

[0230] Prepared according to HCJ Ottenheim et al., Tetrahe dron 44 (1988), 5583 - 5595: A solution of (S)-(-)-lactic acid benzyl ester (CAS No. [56777-24-3] ; 1.00 eq., 5.00 g, 27.7 mmol) in dry dichloromethane (95 mL) was cooled to 0°C and treated with trifluoromethanesulfonic anhydride (CAS No. [358-23-6] , 1.1 eq., 5.2 mL, 8.6 g, 31 mmol). After stirring for 5 minutes, 2,6-dimethylpyridine (1.15 eq., 3.72 mL, 3.42 g) was added and stirring was continued for an additional 5 min. The reaction mixture obtained was used directly in the next step. Example 3-1d Benzyl (2R)-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoate

[0231] A solution of tri-tert-butyl 2,2',2''-(1,4,7,10-tetra-azacyclododecane-1,4,7-triyl) (CAS No. [122555-91- 3]; 1.00 eq., 9.52 g, 18.5 mmol) in dry dichloromethane (75 mL) was cooled to 0°C and treated with the reaction mixture of benzyl (2S)-2- { [( trifluoromethyl)sulfonyl]oxy}propanoate in dichloromethane prepared in example 3-1c; and N,N-diisopropylethylamine (3.0 eq, 9.7 mL, 55 mmol). The resulting solution was stirred at room temperature for 6 days, after which it was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic layer was dried with sodium sulfate and concentrated under reduced pressure. The material obtained was purified by amino phase silica gel chromatography (KP-NH®, hexane/ethyl acetate in dichloromethane/methanol) to yield the title compound (1.92 g, 14%).

[0232] 1H-NMR (400 MHz, DMSO-d6): d = 1.20 (d, 3H), 1.37 - 1.45 (m, 27H), 1.98 - 2.01 (m, 3H ), 2.08 - 2.24 (m, 5H), 2.57 - 2.84 (m, 7H), 2.94 - 3.11 (m, 4H), 3.38 - 3.48 (m , 3H), 3.75 (q, 1H), 5.07 - 5.17 (m, 2H), 7.32 - 7.40 (m, 5H) ppm. LC-MS (ES+): m/z = 677.5 (M + H)+, m/z (z =2) = 339.2 (M + H)2+; Rt. = 1.06 min. Example 3-1e (2R)-2-[4,7,10-Tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]propanoic acid

[0233] A solution of benzyl (2R)-2-[4,7,10-tris (2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecane-1-yl]propanoate (example 3-1d, 1.92 g, 2.84 mmol) in methanol (17.5 mL) was treated with Pd/C (10wt%, 0.050 eq., 151 mg, 0.14 mmol) and stirred under a hydrogen atmosphere at room temperature for 20 hours. The reaction mixture was filtered through Celite, washed with methanol and the filtrate was concentrated in vacuo to yield the title compound (1.51 g, 88%) which was not yet purified.

[0234] 1H-NMR (400 MHz, DMSO-d6): d = 1.11 (s, br, 3H), 1.42 - 1.43 (m, 27H), 1.97 - 2.13 (m , 5H), 2.56 - 2.82 (m, 7H), 2.97 - 3.07 (m, 4H), 3.34 - 3.53 (m, 7H), 12.8 (s, br , 1H) ppm. UPLC (ACN-NH3): Rt. = 1.31 min. MS (ES+): m/z = 587 (M + H)+. LC-MS (ES+): m/z = 587 (M + H)+, m/z (z =2) = 294.2 (M + H)2+; Rt. = 0.79 min. Example 3-1f Tert-butyl {4,10-bis(2-tert-butoxy-2-oxoethyl)-7- [(2R,16R)-3,6,12,15- tetraoxo-16- [4,7 ,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10- tetraazacyclododecan-1-yl]-9,9-bis({ [({(2R)-2- [4, 7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14- tetraazaheptadecan-2-yl]-1,4,7,10-tetraazacyclododecan-1-yl}acetate

[0235] A mixture of (2R) -2- [4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecane-1-yl] propanoic acid (example 3-1e, 12.0 eq., 1.50 g, 2.56 mmol) in N,N-dimethylacetamide (15 mL) with HATU (14.4 eq., 1.17 g, 3.07 mmol ) and N,N-diisopropylethylamine (14.4 eq, 534 µL, 3.07 mmol) and stirred at room temperature for 20 minutes. A suspension of 2-amino-N-(3-[(aminoacetyl)amino]-2,2-bis{[(aminoacetyl)amino] methyl}propyl)acetamide tetrahydrochloride (Example 3-1b; 1.00 eq. ., 108 mg, 213 µmol) in N,N-dimethylacetamide (6 mL) and the resulting mixture was stirred at 50°C overnight. The reaction mixture was concentrated under reduced pressure and the residue obtained was subjected to chromatography on amino phase silica gel (KP-NH®, ethyl acetate to ethyl acetate/methanol) to yield the title compound (260 mg, 42 %).

[0236] 1H-NMR (400 MHz, DMSO-d6): d = 1.03 (s, br, 5H), 1.28 (s, br, 7H), 1.36 - 1.43 (m, 108H ), 1.87 - 2.24 (m, 23H), 2.42 (s, br, 4H), 2.53 - 2.84 (m, 41H), 2.97 - 3.18 (m, 17H ), 3.28 (s, br, 5H), 3.39 - 3.46 (m, 6H), 3.58 (s, br, 7H), 3.76 (s, br, 2H), 4, 01 (s, br, 3H), 7.81 (s, br, 5H), 8.33 (s, br, 2H), 9.27 (s, br, 1H) ppm. UPLC (ACN-NH3): Rt. = 1.23 min. MS (ES+): m/z (z =4) = 660 (M + H)4+. LC-MS (ES+): m/z (z =2) = 1318 (M + H)2+, m/z (z =3) = 879 (M + H)3+, m/z (z =4 ) = 660 (M + H)4+; Rt. = 0.94 min. Example 3-1g {4,10-Bis(carboxymethyl)-7- [(2R,16R)-3,6,12,15-tetraoxo-16- [4,7,10- tris(carboxymethyl)-1,4 ,7,10-tetraazacyclododecan-1-yl]-9,9-bis({ [({(2R)-2- [4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan- 1- yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2- yl]-1,4,7,10-tetraazacyclododecan-1-yl}acetic acid

[0237] Tert-butyl {4,10-bis(2-tert-butoxy-2-oxoethyl)-7- [(2R,16R)- 3,6,12,15-tetraoxo-16- [4,7, 10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]-9,9-bis({ [({(2R)-2- [4 ,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11 ,14-tetra-azaheptadecan-2-yl]-1,4,7,10-tetra-azacyclododecan-1-yl}acetate (example 3-1f; 260 mg, 0.099 mmol) was treated with TFA (25 mL) under Stir at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue obtained was mixed with water (20 mL) and lyophilized. The raw product was used without additional characterization in the next chemical step.

Example 3-1

[0238] Tetragadolinium {4,10-bis (carboxylatomethyl) -7 - [(2R, 16R) - 3,6,12,15-tetraoxo-16- [4,7,10-tris (carboxylatomethyl) -1,4 ,7,10-tetra-azacyclododecan-1-yl]-9,9-bis({[({(2R)-2-[4,7,10-tris(carboxylatomethyl)-1,4,7,10- tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azheptadecan-2-yl] -1,4,7,10-tetra-azacyclododecan-1- il} acetate

[0239] The raw material {4,10-bis (carboxymethyl)-7- [(2R, 16R) - 3,6,12,15-tetraoxo-16- [4,7,10-tris (carboxymethyl) -1 ,4,7,10-tetra-azacyclododecane-1-yl] -9,9-bis ({ [({(2R) -2- [4,7,10-tris (carboxymethyl) - 1,4,7, 10-tetra-azacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetra-azaheptadecan-2-yl]-1,4,7,10-tetra-azacyclododecan- 1-yl}acetic acid from example 3-1g was dissolved in water (20 mL). Gadolinium Tris(acetate-kappaO)tetrahydrate (298 mg, 0.734 mmol) was added and the reaction mixture was stirred at 70°C for 2 h. The pH value of the resulting solution was adjusted to 4.5 by adding aqueous sodium hydroxide solution (2N) and stirring at 70°C was continued for 2 days. The resulting solution was ultrafiltered with water (7x100 mL) using a 1 kDa membrane and the final concentrate was lyophilized yielding the title compound (70 mg, 27% in two steps). UPLC (ACN-HCOOH): Rt. = 0.39 min. MS (ES+): m/z (z = 2) = 1290.1 (M + H)2+, m/z (z = 3) = 860.3 (M + H)3+. LC-MS (ES+): m/z (z = 2) = 1290.3 (M + H)2+, m/z (z = 3) = 860.9 (M + H)3+, m/z (z = 4) = 645.6 (M + H)4+; Rt. = 0.25 min.

Example 3-2

[0240] Tetragadolinium {4,10-bis (carboxylatomethyl) -7 - [(2S, 16S) - 3,6,12,15-tetraoxo-16- [4,7,10-tris (carboxylatomethyl) -1,4 ,7,10-tetra-azacyclododecan-1-yl] -9,9-bis ({ [({(2S) -2- [4,7,10-tris(carboxylatomethyl) -1,4,7,10- tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azheptadecan-2-yl] -1,4,7,10-tetra-azacyclododecan-1- il} acetate Example 3-2a Benzyl (2R)-2-{ [(trifluoromethyl)sulfonyl]oxy}propanoate

[0241] Prepared in analogy to the corresponding S-isomer (example 3-1c) from (R)-(+)-lactic acid benzyl ester (CAS No. [74094-05-6], 8.00 g, 44.4 mmol) in dichloromethane. The reaction mixture obtained was used directly in the next step. Example 3-2b Benzyl (2S)-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]propanoate

[0242] Prepared in analogy to the corresponding R isomer (example 3-1d) from tri-tert-butyl 2,2',2''-(1,4,7,10-tetra-azacyclododecane-1,4, 7-triyl)triacetate (CAS No. [122555-91-3], 1.00 eq., 15.2 g, 29.6 mmol) and the reaction mixture of benzyl(2R)-2-{[(trifluoromethyl )sulfonyl]oxy}propanoate in dichloromethane prepared in example 3-2a. LC-MS (ES+): m/z = 677.4 (M + H)+, m/z (z =2) = 339.2 (M + H)2+; Rt. = 0.94 min. Example 3-2c (2S)-2-[4,7,10-Tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoic acid

[0243] Prepared in analogy to the corresponding R isomer (example 3-1e) from benzyl (2S)-2- [4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4, 7,10-tetra-azacyclododecane-1-yl] propanoate (example 3-2b). UPLC (ACN-NH3): Rt. = 1.31 min. MS (ES+): m/z = 587 (M + H)+. LC-MS (ES+): m/z = 587.4 (M + H)+, m/z (z =2) = 294.2 (M + H)2+; Rt. = 0.82 min.

Example 3-2d

[0244] Tert-butyl {4,10-bis(2-tert-butoxy-2-oxoethyl)-7- [(2S,16S)- 3,6,12,15-tetraoxo-16- [4,7, 10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra azacyclododecan-1-yl]-9,9-bis({ [({(2S)-2- [4, 7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14 -tetraazaheptadecan-2-yl]-1,4,7,10-tetraazacyclode decan-1-yl}acetate

[0245] Prepared in analogy to the corresponding R isomer (example 3-1f) from (2S)-2- [4,7,10-tris(2-tert-butoxy-2-oxoethyl)- 1,4,7 ,10-tetra-azacyclododecan-1-yl]propanoic acid (example 3-2c) and 2-amino-N-(3-[(aminoacetyl)amino]-2,2-bis{[(aminoacetyl)amino] me- til} propyl) acetamide tetrahydrochloride (example 3-1b).

[0246] LC-MS (ES+): m/z (z =2) = 1318 (M + H)2+, m/z (z =3) = 879 (M + H)3+, m/z ( z =4) = 660 (M + H)4+; Rt. = 0.95 min. Example 3-2e {4,10-Bis(carboxymethyl)-7- [(2S,16S)-3,6,12,15-tetraoxo-16- [4,7,10- tris(carboxymethyl)-1,4 ,7,10-tetraazacyclododecan-1-yl]-9,9-bis({ [({(2S)-2- [4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan- 1- yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetraazaheptadecan-2- yl]-1,4,7,10-tetraazacyclododecan-1-yl}acetic acid

[0247] Prepared in analogy to the R isomer (example 3-1g) from tert-butyl {4,10-bis(2-tert-butoxy-2-oxoethyl)-7- [(2S,16S)-3, 6,12,15- tetraoxo-16- [4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]-9,9 -bis({ [({(2S)-2- [4,7,10-tris(2-tert-butoxy-2-oxoethyl)- 1,4,7,10-tetra-azacyclododecan-1-yl]propanoyl }amino)acetyl]amino}methyl)-4,7,11,14-tetra-azaheptadecan-2-yl]-1,4,7,10-tetraazacyclododecan-1-yl}acetate (example 3-2d). The raw product was used without additional characterization in the next chemical step.

Example 3-2

[0248] Tetragadolinium {4,10-bis (carboxylatomethyl) -7 - [(2S, 16S) - 3,6,12,15-tetraoxo-16- [4,7,10-tris (carboxylatomethyl) -1,4 ,7,10-tetra-azacyclododecan-1-yl] -9,9-bis ({ [({(2S) -2- [4,7,10-tris (carboxylatomethyl) - 1,4,7,10- tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2-yl] -1,4,7,10-tetra-azacyclododecan-1- il} acetate

[0249] Prepared in analogy to the corresponding R isomer (example 3-1) from {4,10-bis(carboxymethyl)-7- [(2S, 16S)-3,6,12,15- tetraoxo-16- [4,7,10-tris(carboxymethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]-9,9-bis({ [({(2S)-2- [4,7, 10-tris(carboxymethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetra-azaheptadecan-2-yl] -1,4,7,10-tetra-azacyclododecane-1-yl} acetic acid (example 3-2e) and gadolinium tris(acetate-kappaO)tetrahydrate at pH 4.5. The resulting reaction solution was ultrafiltered with water (8x100 mL) using a 1 kDa membrane and the final concentrate was lyophilized and purified by preparative HPLC. UPLC (ACN-HCOOH): Rt. = 0.41 min. MS (ES+): m/z (z = 2) = 1290 (M + H)2+, m/z (z = 3) = 861 (M + H)3+. LC-MS (ES+): m/z (z = 2) = 1290 (M + H)2+, m/z (z = 3) = 860 (M + H)3+, m/z (z = 4 ) = 645.6 (M + H)4+; Rt. = 0.23 min. Example 4 Pentatriadinol [4-(1-{ [2-(bis {2- [({1,4-bis [({2- [4,7,10-tris (carboxylatomethyl)- 1,4,7,10 -tetra-azacyclododecane-1-yl]propanoyl}amino)acetyl]-1,4-diazepan-6-yl}carbonyl)amino]ethyl}amino)-2-oxoethyl]amino}-1-oxopropan-2-yl) -7,10-bis(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecane-1-yl] acetate Example 4a 6-(Methoxycarbonyl)-1,4-diazepanediium dichloride

[0250] 6.00 g (17.7 mmol) Methyl 1,4-dibenzyl-1,4-diazepane-6-carboxylate [see US 5,866,562] was dissolved in 30 mL of methanol. After adding 6 mL of aqueous hydrochloric acid (37%), 6 mL of water and 600 mg of palladium on charcoal (10%), the reaction mixture was hydrogenated (1 atm) for 17 hours at 40°C. The catalyst was removed by filtration and the solution was evaporated under reduced pressure, obtaining 4.1 g (17.7 mmol, 100%) of the title compound.

[0251] 1H-NMR (400 MHz, D2O): d = 3.62 - 3.84 (m, 9 H), 3.87 (s, 3 H) ppm. UPLC (ACN-HCOOH): Rt. = 0.20 min. MS (ES+): m/z = 159.1 (M + H)+, free base. Example 4b 1,4-di-tert-butyl-6-methyl 1,4-diazepane-1,4,6-tricarboxylate

[0252] 4.00 g (17.3 mmol, 1 eq.) 6-(Methoxycarbonyl)-1,4-diazepanediium dichloride (example 4a) were dissolved in 80 mL of DMF. After adding 7.71 g (76.2 mmol, 4.4 eq.) of trimethyl amine and 8.31 g (38.1 mmol, 2.2 eq.) di-tert-butyl dicarbonate, the mixture of resulting reaction was stirred overnight at room temperature. The suspension was filtered, the filtrate was evaporated under reduced pressure and diluted with ethyl acetate. The resulting solution was washed with aqueous citric acid solution (pH = 3-4), semi-saturated aqueous sodium bicarbonate, dried over sodium sulfate and evaporated under reduced pressure, yielding 4.92 g (13.7 mmol, 79% ) of the title compound. 1H-NMR (300 MHz, DMSO-d6): d = 1.36 (s, 18 H), 2.69 - 3.27 (m, 4 H), 3.35 - 4.00 (m, 5 H ), 3.62 (s, 3 H) ppm. UPLC (ACN-HCOOH): Rt. = 1.32 min. MS (ES+): m/z = 359.2 (M + H)+. Example 4c 1,4-Bis(tert-butoxycarbonyl)-1,4-diazepane-6-carboxylic acid

[0253] 4.86 g (13.66 mmol) of 1,4-di-tert-butyl-6-methyl 1,4-diazepane-1,4,6-tricarboxylate (example 4b) were dissolved in 82 mL of THF. After adding 27 mL of aqueous sodium hydroxide (2 M), the resulting reaction mixture was stirred for 20 hours at room temperature, diluted with water and acidified (pH = 3-4) by the addition of citric acid. . The crude product was extracted with dichloromethane, the organic layer was washed with brine, dried over sodium sulfate and evaporated to dryness yielding 4.67 g (12.4 mmol, 91%) of the title compound.

[0254] 1H-NMR (400 MHz, DMSO-d6): d = 1.38 (s, 18 H), 2.58 - 2.86 (m, 1 H), 2.94 - 4.00 (m , 8 H), 12.50 (s, br, 1 H) ppm. UPLC (ACN-HCOOH): Rt. = 1.12 min. MS (ES+): m/z = 345.2 (M + H)+. Example 4d Di-tert-butyl 6-{[(2,5-dioxopyrrolidin-1-yl)oxy]carbonyl}-1,4-diazepane-1,4-dicarboxylate

[0255] 1.76 g (5.11 mmol, 1 eq.) 1,4-bis (tert-butoxycarbonyl)-1,4-diazepane-6-carboxylic acid (example 4c) and 0.65 g (5, 62 mmol, 1.1 eq) of 1-hydroxypyrrolidine-2,5-dione were dissolved in 50 mL of THF. A solution of 1.16 g (5.62 mmol, 1.1 eq.) N,N'-dicyclohexylcarbodiimide in 30 mL of THF was added and the resulting reaction mixture was refluxed for 5 hours. The suspension was cooled to 0°C and the precipitated urea was filtered. The final activated ester solution was used directly for the next chemical step. UPLC (ACN-HCOOH): Rt. = 1.24 min. MS (ES+): m/z = 442.3 (M + H)+. Example 4e Tetra-tert-butyl 6,6'- [iminobis(ethane-2,1-diylcarbamoyl)]bis(1,4-diazepane-1,4-dicarboxylate)

[0256] For the solution of the activated ester (5.11 mmol, 2.2 eq.) di-tert-butyl 6-{ [(2,5-dioxopyrrolidin-1-yl) oxy] carbonyl}-1,4- diazepan-1,4-dicarboxylate from example 4d were added 517 mg (5.11 mmol, 2.2 eq.) triethylamine and 240 mg (2.32 mmol, 1 eq.) N-(2-aminoethyl)ethane- 1,2-diamine. The resulting reaction mixture was stirred for 20 hours at room temperature and was diluted with dichloromethane. The solution was washed with aqueous sodium hydroxide (0.1 M), water and dried over sodium sulfate. The crude product was isolated by evaporation and purified by silica gel chromatography yielding 1.20 g (1.59 mmol, 68%) of the title compound.

[0257] 1H-NMR (400 MHz, DMSO-d6): d = 1.37 (s, 36 H), 2.51 - 2.70 (m, 7 H), 2.85 - 3.28 (m , 12 H), 3.45 - 4.10 (m, 8 H), 7.69 - 8.27 (m, 2 H) ppm. UPLC (ACN-HCOOH): Rt. = 1.20 min. MS (ES+): m/z = 756.7 (M + H)+. Example 4f N,N'-(Iminodiethane-2,1-diyl)bis(1,4-diazepane-6-carboxamide) hydrochloride-

[0258] 385 mg (0.51 mmol) of tetra-tert-butyl 6,6'- [iminobis (ethane-2,1-diylcarbamoyl)]bis(1,4-diazepane-1,4-dicarboxylate) (example 4e) were dissolved in 5.7 mL of methanol and 1.7 mL of aqueous hydrochloric acid (37%). The reaction mixture was heated under stirring for 2 hours at 50°C. For isolation the suspension was evaporated to dryness yielding 277 mg (0.51 mmol, 100%) of the title compound.

[0259] 1H-NMR (400 MHz, D2O): d = 3.18 (t, 4 H), 3.32 - 3.40 (m, 2 H), 3.51 (t, 4 H), 3 .57 - 3.69 (m, 16 H) ppm. UPLC (ACN-HCOOH): Rt. = 0.24 min. MS (ES+): m/z = 356.3 (M + H)+, free base. Example 4

[0260] Pentatriadinol [4-(1-{ [2-(bis {2- [({1,4-bis [({2- [4,7,10-tris (carboxylatomethyl)-1,4,7, 10-tetra-azacyclododecane-1-yl]propanoyl}amino)acetyl]-1,4-diazepan-6-yl}carbonyl)amino]ethyl}amino)-2-oxoethyl]amino}-1-oxopropan-2-yl )-7,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl] acetate

[0261] 150 mg (279 µmol, 1 eq.) N, N'-(Iminodiethane-2,1-diyl)bis(1,4-diazepane-6-carboxamide) pentahydrochloride (example 4f) were dissolved in 60 mL of DMSO. After addition of 451 mg (3.49 mmol, 12.5 eq.) N,N-diisopropylethylamine and 3.67 g (4.88 mmol, 17.5 eq.) of gadolinium 2,2',2'' - [10-(1-{ [2-(4-nitrophenoxy)-2-oxoethyl]amino}-1-oxopropan-2-yl)- 1,4,7,10-tetra-azacyclododecane-1,4,7 -triyl]triacetate (see WO 2001051095 A2), the resulting reaction mixture was stirred and heated for 8 hours at 50°C. The cooled solution was concentrated under reduced pressure to a final volume of 15-20 ml. The concentrate was poured under stirring into 400 ml of ethyl acetate, the precipitate formed was removed by filtration and dried in vacuo. The solid was dissolved in water, the resulting solution was ultrafiltered with water using a 1 kDa membrane and the final concentrate was lyophilized. The crude product was purified by RP chromatography, yielding 672 mg (197 µmol, 70%) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.43 min. MS (ES-): m/z (z = 2) = 1706.3 (M - 2H)2- m; (ES+): m/z (z = 4) = 854.5 (M + 4H)4+ . Example 5 Hexagadolinium 2,2',2'',2''',2'''',2''''',2'''''',2''''''',2'''''''',2''''''''',2'''''''''',2''''''''''',2'''''''''''',2''''''''''''',2'''''''',2''''''''''''''',2'''''''''''''''',2''''''''''''''''-{ethane-1,2-diylcarbamoyl-1,4-diazepane - 6,1,4-triyltris [(2-oxoethyl-2,1-diyl) imino (1-oxopropane-1,2-diyl) -1,4,7,10- tetra-azacyclododecane-10,1,4 ,7-tetrail]} octadeca-acetate, Example 5a Hexa-tert-butyl 6,6',6''-(ethane-1,2-diylcarbamoyl)tris(1,4-diazepane-1,4-dicarboxylate)

[0262] 1.20 g (3.48 mmol, 3 eq.) 1,4-bis (tert-butoxycarbonyl)-1,4-diazepane-6-carboxylic acid (example 4c), 540 mg (4.18 mmol , 3.6 eq.) of diisopropylethylamine and 1.59 g (4.18 mmol, 3.6 eq) HATU were dissolved in 30 mL of DMF and stirred for 2 hours at room temperature. After the dropwise addition of a solution of 120 mg (1.16 mmol, 1 eq.) N-(2-aminoethyl) ethane-1,2-diamine and 540 mg (4.18 mmol, 3.6 eq. ) N,N-diisopropylethylamine in 8 mL of DMF, the resulting reaction mixture was heated under stirring for 3 hours at 70°C. After cooling and diluting with dichloromethane, the solution was washed with aqueous sodium hydroxide (0.1 M), aqueous citric acid (1%), water and dried over sodium sulfate. The crude product was isolated by evaporation under reduced pressure and purified by silica gel chromatography yielding 660 mg (0.61 mmol, 52%) of the title compound.

[0263] 1H-NMR (400 MHz, DMSO-d6): d = 1.38 (s, 54 H), 2.55 - 4.06 (m, 35 H), 7.90 - 8.52 (m , 2 H) ppm. UPLC (ACN-HCOOH): Rt. = 1.64 min. MS (ES+): m/z = 1082.7 (M + H)+. Example 5b N,N-Bis{2-[(1,4-diazepan-6-ylcarbonyl)amino]ethyl}-1,4-diazepan-6-carboxamide hexahydrochloride

[0264] 654 mg (0.60 mmol) of Hexa-tert-butyl 6,6',6''-(ethane-1,2-diylcarbamoyl)tris(1,4-diazepane-1,4-dicarboxylate) ( example 5a) were dissolved in 6.8 mL of methanol and 3 mL of aqueous hydrochloric acid (37%). The reaction mixture was heated under stirring for 2.5 hours at 50°C. For isolation the suspension was evaporated to dryness yielding 441 mg (0.63 mmol, 105%) of the title compound.

[0265] 1H-NMR (400 MHz, DMSO-d6): d = 3.20 - 3.71 (m, 35 H), 8.50 - 8.80 ppm (m, 2 H), 9.76 ( s, br, 12 H). UPLC (ACN-HCOOH): Rt. = 0.19 min. MS (ES+): m/z = 482.3 (M + H)+, free base. Example 5 Hexagadolinium 2,2',2'',2''',2'''',2''''',2'''''',2''''''',2'' '''''',2''''''''',2'''''''''',2''''''''''',2'''''' '''''',2''''''''''''',2'''''''',2''''''''''''''',2 '''''''''''''''',2''''''''''''''''-{ethane-1,2-diylcarbamoyl-1,4-diazepane - 6,1,4-triyltris [(2-oxoethyl-2,1-diyl) imino (1-oxopropane-1,2-diyl) -1,4,7,10- tetra-azacyclododecane-10,1,4 ,7-tetrail]} octadeca-acetate,

[0266] 150 mg (214 µmol, 1 eq.) N,N-bis {2- [(1,4-diazepan-6-ylcarbonyl) amino]ethyl}-1,4-diazepane-6-carboxamide hexahydrochloride (example 5b) were dissolved in 60 mL of DMSO. After adding 0.42 g (3.21 mmol, 15 eq.) N,N-diisopropylethylamine and 3.38 g (4.50 mmol, 21 eq.) of gadolinium 2,2',2''- [ 10-(1-{[2-(4-nitrophenoxy)-2-oxoethyl]amino}-1-oxopropan-2-yl)-1,4,7,10-tetra-azacyclododecane-1,4,7-triyl ]triacetate (see WO 2001051095 A2), the resulting reaction mixture was stirred and heated for 8 hours at 50°C. The cooled solution was concentrated under reduced pressure to a final volume of 15-20 ml. The concentrate was poured under stirring into 400 ml of ethyl acetate, the precipitate formed was removed by filtration and dried in vacuo. The solid was dissolved in water, the resulting solution was ultrafiltered with water using a 1 kDa membrane and the final concentrate was lyophilized. The crude product was purified by RP chromatography, yielding 595 mg (143 µmol, 67%) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.41 min. MS (ES+): m/z (z = 3) = 1384.6 (M + H)3+, m/z (z = 4) = 1039.5 (M + H)4+, m/z (z = 5) = 831.6 (M + H)5+. Example 6 Hexagadolinium 2,2',2'',2''',2'''',2''''',2'''''',2''''''',2'''''''',2''''''''',2'''''''''',2''''''''''',2'''''''''''',2''''''''''''',2'''''''',2''''''''''''''',2'''''''''''''''',2''''''''''''''''-(1,4,7-triazonane-1,4,7 -triyltris{carbonyl-1,4-diazepane-6,1,4-triylbis[(2-oxoethyl-2,1-diyl)imino (1-oxopropane-1,2-diyl)-1,4,7,10 -tetra-azacyclododecane-10,1,4,7-tetrail]}) octadeca acetate Example 6a Hexa-tert-butyl 6,6',6''-(1,4,7-triazonane-1,4,7-triyltricarbonyl) tris (1,4-diazepane-1,4-dicarboxylate)

[0267] 800 mg (2.32 mmol, 3 eq.) 1,4-bis (tert-butoxycarbonyl)-1,4-diazepane-6-carboxylic acid (example 4c), 360 mg (2.79 mmol, 3 .6 eq.) of diisopropylethylamine and 1.06 g (2.79 mmol, 3.6 eq) HATU were dissolved in 20 mL of DMF and stirred for 2 hours at room temperature. After dropwise addition of a solution of 100 mg (774 µmol, 1 eq.) 1,4,7-triazonane trihydrochloride and 360 mg (2.79 mmol, 3.6 eq.) N,N-diisopropylethylamine in 5 mL of DMF, the resulting reaction mixture was heated under stirring for 3 hours at 70°C. After cooling and diluting with dichloromethane, the solution was washed with aqueous sodium hydroxide (0.1 M), aqueous citric acid (1%), water and dried over sodium sulfate. The crude product was isolated by evaporation under reduced pressure and purified by silica gel chromatography yielding 545 mg (492 µmol, 63%) of the title compound.

[0268] 1H-NMR (400 MHz, CDCl3): d = 1.47 (s, 54 H), 2.85 - 4.45 (m, 39 H) ppm. UPLC (ACN-HCOOH): Rt = 1.73 min. MS (ES+): m/z = 1108.8 (M + H)+. Example 6b 1,4,7-Triazonane-1,4,7-triyltris (1,4-diazepan-6-ylmethanone) hexahydrochloride

[0269] 380 mg (343 µmol) Hexa-tert-butyl 6,6',6''-(1,4,7-triazonane- 1,4,7-triyltricarbonyl)tris(1,4-diazepane-1, 4-dicarboxylate) (example 6a) were dissolved in 3.90 mL of methanol and 1.72 mL of aqueous hydrochloric acid (37%). The reaction mixture was heated under stirring for 2.5 hours at 50°C. For isolation, the suspension was evaporated to dryness yielding 257 mg (354 µmol, 103%) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.19 min. MS (ES+): m/z = 508.4 (M + H)+, free base. Example 6 Hexagadolinium 2,2',2'',2''',2'''',2''''',2'''''',2''''''',2'' '''''',2''''''''',2'''''''''',2''''''''''',2'''''' '''''',2''''''''''''',2'''''''''''''',2''' '''''''' '''',2'''''''''''''''',2'''''''''''''''''-(1,4,7-triazonane -1,4,7-triyltris{carbonyl-1,4-diazepane-6,1,4-triylbis[(2-oxoethyl-2,1-diyl) imino (1-oxopropane-1,2-diyl) - 1 ,4,7,10-tetra-azacyclododecane-10,1,4,7-tetrail]}) octadeca acetate

[0270] 175 mg (241 µmol, 1 eq.) 1,4,7-triazonane-1,4,7-triyltris (1,4-diazepan-6-ylmethanone) hexahydrochloride (example 6b) were dissolved in 60 mL of DMSO. After addition of 467 mg (3.61 mmol, 15 eq.) N,N- diisopropylethylamine and 3.80 g (5.06 mmol, 21 eq.) of gadolinium 2,2',2''-[10- (1-{[2-(4-nitrophenoxy)-2-oxoethyl]amino}-1-oxopropan-2-yl)-1,4,7,10-tetra-azacyclododecane-1,4,7-triyl]triacetate (see WO 2001051095 A2), the resulting reaction mixture was stirred and heated for 8 hours at 50°C. The cooled solution was concentrated under reduced pressure to a final volume of 15-20 ml. The concentrate was poured with stirring into 400 ml of ethyl acetate, the precipitate formed was removed by filtration and dried in vacuo. The solid was dissolved in water, the resulting solution was ultrafiltered with water using a 1 kDa membrane and the final concentrate was lyophilized. The crude product was purified by RP chromatography, yielding 590 mg (141 µmol, 58%) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.43 min. MS (ES+): m/z (z = 3) = 1393.1 (M + 3H)3+, m/z (z =4) = 1045.5 (M + 4H)4+, m/z (z = 5) = 837.0 [(M + 5H)5+. Example 7 Tetragadolinium 2,2',2'',2''',2'''',2''''',2'''''',2''''''',2'''''''',2''''''''',2''''''''',2'''''''''''- {1,4,7, 10-tetra-azacyclododecane-1,4,7,10-tetrailtetracis [(2-oxoethyl-2,1- diyl) imino (1-oxopropane-1,2-diyl) -1,4,7,10-tetra- azacyclododecane- 10,1, 4,7-tetrail]} dodeca-acetate

[0271] 35 mg (203 µmol, 1 eq.) 1,4,7,10-Tetra-azacyclododecane were dissolved in 60 mL of DMSO. After adding 2.14 g (2.84 mmol, 14 eq.) of gadolinium 2,2',2''- [10-(1-{ [2-(4-nitrophenoxy)-2-oxoethyl]amino }-1-oxopropan-2-yl)-1,4,7,10-tetra-azacyclododecane-1,4,7-triyl]triacetate (see WO 2001051095 A2), the resulting reaction mixture was stirred and heated for 8 hours at 50°C. The cooled solution was concentrated under reduced pressure to a final volume of 15-20 ml. The concentrate was poured under stirring into 400 ml of ethyl acetate, the precipitate formed was removed by filtration and dried in vacuo. The solid was dissolved in water, the resulting solution was ultrafiltered with water using a 1 kDa membrane and the final retentate was lyophilized. The crude product was purified by RP chromatography, yielding 28 mg (10.6 µmol, 5%) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.41 min. MS (ES+): m/z (z = 2) = 1311.7 (M + 2H)2+, m/z (z = 3) = 873.1 (M + 3H)3+. Example 8 Hexagadolinium 22'2''2'''2''''2'''''2''''''2'''''''2''''''''2'''''''''2''''''''''2'''''''''''2''''''''''''2'''''''''''''2''''''''''''''2''''''''''''''',2'''''''''''''''',2'''''''''''''''''- {3,7,10-triazatricycle [3.3.3.01,5] undecane-3,7,10- triyltris [carbonyl(3,6,11,14-tetraoxo-4,7,10,13-tetra-azahexadecane - 8,2,15-triyl)di-1,4,7,10-tetra-azacyclododecane-10,1 ,4,7-tetrail]}octadeca- acetate Example 8a Tetrahydro-1H, 4H-3a, 6a-(methaniminomethane) pyrrole [3,4-c] pyrrole

[0272] 4.0 g (6.5 mmol) of 2,5,8-Tris ((4-methylphenyl) sulfonyl) tetrahydro-1H, 4H-3a, 6a- (methaniminomethane) pyrrole [3,4- c] pyrrole (prepared by procedures described in J. Org. Chem. 1996, 61, 8897-8903) refluxed in 44 mL of aqueous hydrobromic acid (47%) and 24 mL of acetic acid for 18 hours. The solvent was removed under vacuum, the residue was dissolved in water and the aqueous phase was washed twice with dichloromethane. The aqueous phase was lyophilized and mixed in a small amount of water and passed through an anion exchange column (DOWEX 1X8) for elution with water. The basic fraction was collected and concentrated to yield 0.89 g of tetrahydro-1H, 4H-3a, 6a-(methaneiminomethane) pyrrole [3,4-c] pyrrole as the free base.

[0273] 1H-NMR (400 MHz, D2O): d = 2.74 (s, 12 H) ppm. Example 8b Tert-butyl-{1-[5,8-bis{2,3-bis[(tert-butoxycarbonyl)amino]propanoyl}dihydro-1H, 4H-3a, 6a-(methaniminomethane) pyrrole [3, 4-c]pyrrole-2(3H)-yl]-3-[(tert-butoxycarbonyl)amino]-1-oxopropan-2-yl}carbamate

[0274] A solution prepared from 431.5 mg (0.89 mmol, CAS [201472-68-6]) N-(tert-butoxycarbonyl)-3-[(tert-butoxycarbonyl) amino] alanine, N, N-dicyclohexylammonium salt, 0.44 mL (2.54 mmol) N,N-diisopropylethylamine and 386 mg (1.0 mmol) HATU in 4.3 mL DMF was added to 38.9 mg (254 µmol) of tetrahydro-1H, 4H-3a, 6a-(methaniminomethane)pyrrole[3,4-c]pyrrole in 2 mL of DMF. After stirring the combined mixture for 20 minutes at room temperature, the solvent was removed under vacuum and the residue was purified by amino phase silica gel chromatography (ethyl acetate in hexane, 0 to 100%) followed by HPLC. preparation (C18-Chromatorex 10 µm, acetonitrile in water + 0.1% formic acid, 65% to 100%) to produce 68.6 mg of tert-butyl-{1-[5,8-bis{ 2,3-bis[(tert-butoxycarbonyl)amino]propanoyl}dihydro-1H,4H-3a,6a-(methaniminomethane)pyrrole[3,4-c]pyrrol-2(3H)-yl] - 3 - [(tert-butoxycarbonyl)amino]-1-oxopropan-2-yl} carbamate.

[0275] 1H-NMR (300 MHz, CDCl3): d = 1.43 s, br, 54H), 3.34 - 3.97 (m, 18H), 4.48 (s, br, 3H), 5 .01-5.67(m, 6H) ppm. UPLC (ACN-HCOOH): Rt. = 1.48 min. MS (ES+): m/z = 1012.6 (M + H)+. Example 8c 3,3',3''- [1H,4H-3a,6a-(methanoiminomethane)pyrrole [3,4-c]pyrrole- 2,5,8(3H,6H)-triyl]tris(3- oxopropane-1,2-diaminium) hexachloride

[0276] 65 mg (60 µmol) of tert-butyl-{1-[5,8-bis{2,3-bis[(tert-butoxycarbonyl)amino]propanoyl}dihydro-1H, 4H-3a, 6a - (methanoiminomethane)pyrrole[3,4-c]pyrrole-2(3H)-yl]-3[(tert-butoxycarbonyl)amino]-1-oxopropan-2-yl}carbamate (example 8b) were dissolved in 2, 0 mL of DMF and 0.48 mL of hydrochloric acid in dioxane (4 M, 0.19 mmol) were added. The reaction mixture was heated in microwave radiation for 10 min at 80°C while stirring. The solvent was removed in vacuo, the residue was mixed in a small amount of water and lyophilized to yield 38.9 mg of 3,3',3''- [1H, 4H-3a, 6a-(methaniminomethane) pyrrole [3 ,4 -c] pyrrole-2,5,8 (3H, 6H)-triyl] tris(3-oxopropane-1,2-diaminium) hexachloride. 1H-NMR (600 MHz, D2O): d = 3.40 - 3.50 (m, 3H), 3.52 - 3.56 (m, 3H), 3.79 - 4.19 (m, 12H) , 4.51 - 4.54 (m, 3H) ppm. UPLC (ACN-HCOOH): Rt. = 0.20 min. MS (ES+): m/z = 412.3( [M + H)+, free base. Example 8 Hexagadolinium '''''''''''',2'''''''''''''''',2''''''''''''''' ''- {3,7,10-triazatricycle [3.3.3.01,5] undecane-3,7,10- triyltris [carbonyl(3,6,11,14-tetraoxo-4,7,10,13-tetra- azahexadecane - 8,2,15-triyl)di-1,4,7,10-tetra-azacyclododecane-10,1,4,7-tetrail]}octadeca- acetate

[0277] 30 mg (48 umol) of 3,3',3''- [1H, 4H-3a, 6a-(methanoiminomethane) pyrrole [3,4-c] pyrrole-2,5,8 (3H, 6H)-triyl] tris(3-oxopropane-1,2-diaminium) hexachloride (example 8c) were dissolved in a mixture of 1.8 mL of DMSO, 1.8 mL of DMF and 116 µL of pyridine. At 60°C, 281 mg (0.38 mmol, WO 2001051095 A2) of gadolinium 2,2',2''- [10-(1-{ [2-(4-nitrophenoxy)-2-oxoethyl] amino} -1-oxopropan-2-yl)-1,4,7,10-tetraazacyclodo decane-1,4,7-triyl] triacetate were added followed by 44 µL of trimethylamine and the resulting reaction mixture was stirred. for 15 hours at 60°C at room temperature for two days. Another amount of gadolinium 2,2',2''- [10-(1-{ [2-(4-nitrophenoxy) -2-oxoethyl] amino}-1-oxopropan-2- yl)-1,4,7 ,10-tetra-azacyclododecane-1,4,7-triyl] triacetate (56 mg, 75 umol) and trimethylamine (5.4 µL) were added at 60°C and stirring at 60°C continued for 15 hours. The solvent was removed in vacuum, the residue was mixed in 200 mL of water and the resulting solution was ultrafiltered using a 1 kDa membrane. After diluting the concentrate twice with an additional 200 mL of deionized water and continuing ultrafiltration, the final concentrate was freeze-dried. The residue was dissolved in a mixture of 1.6 mL of DMSO, 1.6 mL of DMF and 105 µL of pyridine and the addition of 261 mg (0.35 mmol) of gadolinium 2,2',2''- [ 10-(1-{[2-(4-nitrophenoxy)-2-oxoethyl]amino}-1-oxopropan-2-yl)-1,4,7,10-tetra-azacyclode decane-1,4,7- triyl] triacetate and 48 µL of triethylamine at 60°C was repeated for the third time. After stirring for 18 hours at 60°C, the ultrafiltration procedure using a 1 kDa membrane was repeated and the concentrate after three filtrations of 200 mL was lyophilized. The crude product was purified by preparatory HPLC (XBrigde C18, 5 µm, acetonitrile in water + 0.1% formic acid, 0% to 7%) to yield 51 mg of the title compound. UPLC (ACN-HCOOH long run): Rt. = 2.95 min. MS (ES+): m/z (z =3) = 1360.4 (M + 3H)3+, m/z (z =4) = 1021.3 (M + 4H)4+, m/z (z = 5) = 817.5 (M + 5H)5+. Example 9 Tetragadolinium 2,2',2'',2''',2'''',2''''',2'''''',2''''''',2'''''''',2''''''''',2''''''''',2'''''''''''- (3,7,9- triazabicyclo[3.3.1]nonane-3,7-diylbis{carbonyl-1,4-diazepane-6,1,4-triylbis[(2-oxoethyl-2,1-diyl)-1,4,7,10- tetra-azacyclododecane- 10,1,4,7-tetrail]}) dodeca-acetate Example 9a 3,7,9-Triazabicyclo [3.3.1]nonane

[0278] 220 mg (0.49 mmol) of 3,9-Dibenzyl-7- (phenylsulfonyl) -3,7,9- triazabicyclo [3.3.1] nonane (prepared using the procedures described in Tetrahedron Letters, 2005, 46, 5577-5580) was refluxed in 3.4 mL of aqueous hydrobromic acid (47%) and 1.8 mL of acetic acid for 17 hours. The solvent was removed in vacuo, the residue was dissolved in water and the aqueous phase was washed twice with dichloromethane. The aqueous phase was lyophilized and mixed in a small amount of water and passed through an anion exchange column (DOWEX 1X8) for elution with water. The basic fraction was collected and concentrated to yield 29.6 mg of 3,7,9-triazabicyclo [3.3.1] nonane as the free base. 1H-NMR (400 MHz, D2O): d = 2.88 (t, 2H), 3.15 (d, 8H) ppm. Example 9b 6-(Methoxycarbonyl)-1,4-diazepanediium dichloride

[0279] To 8.3 g (24.5 mmol) of methyl 1,4-dibenzyl-1,4-diazepane-6-carboxylate (prepared in analogy to US005866562A, p.9) in 42 mL of methanol were added 8 .3 mL of concentrated hydrochloric acid, 2 mL of water and 830 mg of palladium on charcoal (10%). The suspension was stirred under a hydrogen atmosphere for 5 hours at 40°C and 17 hours at room temperature. The mixture was filtered through a celite pad and the filtrate was concentrated in vacuo after which toluene was added twice and removed in vacuo. The residue was dissolved in water and lyophilized to yield 5.65 g of 6-(methoxycarbonyl)-1,4-diazepanediium dichloride. 1H-NMR (400 MHz, D2O): d = 3.49 - 3.68 (m, 9H), 3.70 - 3.73 (m, 4H), 3.75 (s, 3H) ppm. Example 9c Methyl 1,4-bis {[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra- azacyclododecane-1-yl]acetyl}-1,4-diazepane-6-carboxylate

[0280] To 200 mg (0.78 mmol) of 6-(methoxycarbonyl)-1,4-diazepanediium dichloride in 10 mL of dichloromethane were added 10 mL (6.2 mmol) of N,N-diisopropylethylamine and the mixture was stirred for 5 minutes at room temperature. 1.04 g (1.56 mmol) tri-tert-butyl 2,2',2''-(10-{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl} - 1,4,7,10-tetra-azacyclododecane-1,4,7-triyl) triacetate (prepared in analogy with Cong Li et al., J. Am.Chem.Soc. 2006, 128, p.15072 15073; S3-5 and Galibert et al., Bioorg. Med. Chem. Letters 2010 (20), 5422-5425) was added and the mixture was stirred for 18 hours at room temperature. The solvent was removed under reduced pressure and the residue was purified by chromatography on amino-phase silica gel (ethyl acetate in hexane, 20 to 100%, then ethanol in ethyl acetate, 0 to 100%) to yield 210 mg of the compound holder. UPLC (ACN-HCOOH): Rt. = 0.94 min. MS (ES+): m/z = 1267.6 (M + 1H)+ Example 9d Dodeca-tert-butyl 2,2',2'',2''',2'''',2''''',2'''''',2''''''',2'''''''',2''''''''',2'''''''''',2'''''''''''- (3,7,9-triazabicyclo [3.3.1]nonane-3,7-diylbis{carbonyl-1,4-diazepane- 6,1,4- triylbis [(2-oxoethyl-2,1-diyl) -1,4,7,10-tetra-azacyclododecane- 10,1,4,7-tetrail]}) dodeca-acetate

[0281] 305 mg (0.24 mmol) of methyl 1,4-bis { [4,7,10-tris (2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra azaceclododecan- 1-yl]acetyl}-1,4-diazepane-6-carboxylate (example 9c) were dissolved in 3.9 mL of THF and a solution of 6.6 mg of lithium hydroxide in 0.87 mL of water was added . After stirring for 15 minutes, the solvent was removed under reduced pressure and 1,4-bis{[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra- Crude lithium azacyclododecan-1-yl]acetyl}-1,4-diazepane-6-carboxylate (300 mg) was dissolved in 2.0 mL of dichloromethane. 120 µL (0.71 mmol) of N,N-diisopropylethylamine, 112 mg (0.30 mmol) of HATU and 40 mg (0.30 mmol) of 3H- [1,2,3] triazole [4, 5-b] pyridin-3-ol and after stirring for 15 minutes, a solution of 15 mg (0.12 mmol) of 3,7,9-triazabicyclo [3.3.1]nonane in 1 mL of dichloromethane was added and the mixture was stirred for 3 days. An additional 170 mg of 1,4-bis{[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]acetyl} 1 Crude lithium ,4-diazepane-6-carboxylate in 1 mL of dichloromethane were added 67 mg (0.18 mmol) of HATU, 24 mg (0.18 mmol) of 3H-[1,2,3] triazole [4 ,5-b] pyridin-3-ol for 15 minutes and 50 µL of N,N-diisopropylethylamine. After stirring for 15 minutes, the freshly prepared HATU solution was added to the reaction mixture. After one day, the solvent was removed under reduced pressure, after which toluene was added six times and removed in vacuo. The residue was purified by amino phase silica gel chromatography (ethyl acetate in hexane, 0 to 100%, then ethanol in ethyl acetate, 0 to 40%) to yield 181 mg of the title compound. UPLC (ACN-HCOOH): Rt = 0.78-0.84 min. MS (ES-): m/z (z = 2) = 1298.7 (M - 2H)2- Example 9 Tetragadolinium 2,2',2'',2''',2'''',2' '''',2'''''',2''''''',2'''''''',2''''''''',2'''''' '''',2'''''''''''- (3,7,9-triazabicyclo [3.3.1]nonane-3,7-diylbis{carbonyl-1,4-diazepane- 6,1 ,4-triylbis [(2-oxoethyl-2,1-diyl) -1,4,7,10-tetra-azacyclododecane- 10,1,4,7-tetrail]}) dodeca-acetate

[0282] 390 mg (mmol) of Dodeca-tert-butyl 2,2',2'',2''',2'''',2''''',2'''''',2 ''''''',2'''''''',2''''''''',2'''''''''',2'''''''''''-(3,7,9-triazabicyclo[3.3.1]nonane-3,7-diylbis{carbonyl-1,4-diazepan-6,1,4-triylbis[(2-oxoethyl-2,1- diyl)-1,4,7,10-tetra-azacyclododecane-10,1,4,7-tetrail]}) do-decaacetate (example 9d) were dissolved in 10.8 mL of water and the solution was adjusted to pH 2.5 by adding aqueous hydrochloric acid (2M). 440 mg (1.25 mmol) of Gadolinium(III) oxide were added and the mixture was stirred at 80°C for 17 hours, while the pH of the suspension changed to pH 5. The mixture was diluted with water, sonicated and filtered. The filtrate was ultrafiltrated using a 1 kDa membrane. After diluting the concentrate twice with an additional 100 mL of deionized water and continuing ultrafiltration, the final concentrate was freeze-dried. The crude product was purified by preparatory HPLC (C18 YMC-ODS AQ, 10 µm, acetonitrile in water + 0.1% formic acid, 1% to 10%) to yield 14.5 mg of the title compound. UPLC (ACN-HCOOH): Rt. = 0.34 min. MS (ES+): m/z (z = 2) = 1272.9 (M + 2H)2+ Example 10 Tetragadolinium {4,10-bis (carboxylatomethyl) -7- [2-oxo-2 - ({3 - ({ [4,7,10- tris(carboxylatomethyl) -1,4,7,10-tetra-azacyclododecane-1- yl] acetyl} amino) -2,2-bis [({ [4,7,10- tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]acetyl}amino)methyl]propyl}amino)ethyl]-1,4,7,10-tetra-azacyclododecan-1-yl} acetate Example 10a {4,10-bis(2-tert-butoxy-2-oxoethyl)-7-[2-oxo-2-({3-({[4,7,10-tris(2-tert-butoxy- 2-oxoethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) - 2,2-bis [({ [4,7,10-tris (2-tert-butoxy-2 -oxoethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) methyl] propyl} amino) ethyl] -1,4,7,10- tetra-azacyclododecan-1-yl} acetate

[0283] 6.6 mg (49.8 µmol, 1 eq.) 2,2-Bis (aminomethyl) propane-1,3-diamine (see W. Hayes et al., Tetrahedron 59 (2003), 7983-7996 ) were dissolved in 7 mL of DMSO. After addition of 77 mg (0.6 mmol, 12 eq.) N,N-diisopropylethylamine and 400 mg (0.6 mmol, 12 eq.) of tri-tert-butyl 2,2',2''-( 10-{2-[(2,5-dioxopyrrolidin-1-yl)oxy]-2-oxoethyl}-1,4,7,10-tetra-azacyclododecane-1,4,7-triyl) triacetate (see M. Galibert et al., Bioorg. Med. Chem. Letters 2010 (20), 5422-5425 and J. Am.Chem.Soc. 2006, 128, p.15072-15073; S3-5), the reaction mixture resulting was stirred and heated overnight at 50°C. The cooled solution was concentrated under reduced pressure. The raw product was used without additional characterization for the next chemical step. Example 10b {4,10-bis(carboxymethyl)-7-[2-oxo-2-({3-({[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecan -1-yl] acetyl} amino) -2,2-bis [({ [4,7,10-tris(carboxymethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) methyl] propyl} amino) ethyl] -1,4,7,10-tetra-azacyclododecan-1-yl} acetic acid

[0284] O {4,10-bis (2-tert-butoxy-2-oxoethyl) -7- [2-oxo-2 - ({3 - ({ [4,7,10-tris (2-tert- butoxy-2-oxoethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) -2,2-bis [({ [4,7,10-tris (2-tert-butoxy - 2-oxoethyl) -1,4,7,10- tetra-azacyclododecan-1-yl] acetyl} amino) methyl] propyl} amino) ethyl] - 1,4,7,10-tetra-azacyclododecan-1-yl } crude acetate from example 10a was dissolved in 40 ml of TFA. The resulting solution was stirred overnight at room temperature and concentrated under reduced pressure. The raw product was used without additional characterization for the next chemical step. Example 10 Tetragadolinium {4,10-bis(carboxylatomethyl)-7-[2-oxo-2-({3-({[4,7,10- tris(carboxylatomethyl)-1,4,7,10-tetra- azacyclododecan-1- yl] acetyl} amino) -2,2-bis [({ [4,7,10-tris(carboxylatomethyl) -1,4,7,10-tetra- azacyclododecan-1-yl] acetyl} amino ) methyl] propyl} amino ) ethyl] -1,4,7,10- tetra-azacyclododecan-1-yl} acetate

[0285] O {4,10-bis (carboxymethyl) -7- [2-oxo-2 - ({3 - ({ [4,7,10-tris (carboxymethyl) -1,4,7,10-tetra -azacyclododecan-1 -yl] acetyl} amino) -2,2- bis [({ [4,7,10-tris(carboxymethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) methyl] propyl} amino) ethyl] -1,4,7,10-tetra-azacyclododecan-1-yl} crude acetic acid from example 10b was dissolved in 10 ml of water. After adding 326 mg of gadolinium tris(acetate-kappaO)tetrahydrate, the pH value of the resulting solution was adjusted to 3.5 to 4.5 by adding aqueous sodium hydroxide solution. The reaction mixture was heated under stirring overnight at 70°C. The resulting solution was ultrafiltered with water using a 1 kDa membrane and the final concentrate was lyophilized. The crude product was purified by RP chromatography, yielding 65 mg (28 µmol, 46%) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.40 min. MS (ES+): m/z (z = 2) = 1149.7 (M + 2H)2+, m/z (z =3) = 766.0 (M + 3H)3+. Example 11 Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra- azacyclododecan-1- yl] -8,8- bis ({ [({ [4,7,10-tris(carboxylatomethyl) -1,4,7,10-tetra-azacyclododecan-1- yl] acetyl} amino) acetyl ]amino} methyl) -3,6,10,13-tetra-azapentadec-1-yl}-1,4,7,10-tetra-azacyclododecan-1-yl] acetate Example 11a Tert-butyl[4,10-bis(2-tert-butoxy-2-oxoethyl)-7-{2,5,11,14-tetraoxo-15-[4,7,10-tris(2-tert -butoxy -2-oxoethyl) -1,4,7,10-tetra-azacyclododecan-1- yl] -8,8-bis ({ [({ [4,7,10-tris (2-tert-butoxy- 2-oxoethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) acetyl] amino} methyl) -3,6,10,13- tetra-azapentadec-1-yl} -1 ,4,7,10-tetra-azacyclododecane -1-yl] acetate

[0286] 2.99 g (4.75 mmol, 12 eq.) N-{ [4,7,10-tris (2-tert-butoxy-2-oxoethyl) -1,4,7,10-tetra- azacyclododecan-1-yl] acetyl} glycine (see M. Suchy et al., Org. Chem. 2010, 8, 2560 - 2566) and 732 mg (5.70 mmol, 14.4 eq.) of ethyldiisopropylamine were dissolved in 40 mL of N,N-dimethylformamide. After adding 2.17 g of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU; 5.70 mmol, 14, 4 eq.), the reaction mixture was stirred for 15 minutes at room temperature. 100.1 mg (396 µmol, 1 eq.) 2,2-bis(ammonomethyl)propane-1,3-diaminium tetrachloride (see W. Hayes et al., Tetrahedron 59 (2003), 7983-7996) and 982, 7 mg (7.60 mmol, 19.2 eq.) ethyl diisopropylamine was added and the resulting reaction mixture was stirred overnight at 50°C. The cooled solution was concentrated under reduced pressure. The raw product was used without additional characterization for the next chemical step. Example 11b [4,10-bis(carboxymethyl)-7-{2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetra -azacyclododecan-1-yl] -8,8-bis ({ [({ [4,7,10-tris(carboxymethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) acetyl]amino}methyl)-3,6,10,13-tetra-azapentadec-1-yl}-1,4,7,10-tetra-azacyclododecan-1-yl]acetic acid

[0287] Tert-butyl [4,10-bis (2-tert-butoxy-2-oxoethyl) -7- {2,5,11,14- tetraoxo-15- [4,7,10-tris (2 -tert-butyl -butoxy-2-oxoethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] -8,8-bis ({ [({ [4,7,10-tris (2- tert-butoxy-2- oxoethyl) - 1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) acetyl] amino} methyl) - 3,6,10,13-tetra-azapentadec-1- yl}-1,4,7,10-tetra-azacyclododecane-1-yl] crude acetate from example 11a was dissolved in 125 ml of TFA. The resulting solution was stirred for 2 hours at 70°C, overnight at room temperature and concentrated under reduced pressure. The oily product was dissolved in 200 mL of water, isolated by freeze-drying and used without further characterization for the next chemical step. Example 11 Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra- azacyclododecan-1- yl] -8,8- bis ({ [({ [4,7,10-tris(carboxylatomethyl) -1,4,7,10-tetra-azacyclododecan-1- yl] acetyl} amino) acetyl ]amino} methyl) - 3,6,10,13-tetra-azapentadec-1-yl} -1,4,7,10-tetra-azacyclododecan-1-yl] acetate

[0288] O [4,10-bis (carboxymethyl) -7- {2,5,11,14-tetraoxo-15- [4,7,10-tris (carboxymethyl) -1,4,7,10-tetra -azacyclododecan-1-yl] -8,8- bis ({ [(4,7,10-tris(carboxymethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) acetyl] amino} methyl) -3,6,10,13-tetra-azapentadec-1-yl} - 1,4,7,10-tetra-azacyclododecan-1-yl] crude acetic acid from example 11b was dissolved in 100 mL of water. After adding 2.89 g of gadolinium tris(acetate-kappaO)tetrahydrate, the pH value of the resulting solution was adjusted to 3.0 to 3.5 by adding aqueous sodium hydroxide solution. The reaction mixture was heated under stirring for 24 hours at 70°C. The resulting solution was ultrafiltered with water using a 1 kDa membrane and the final concentrate was lyophilized. The crude product was purified by RP chromatography, yielding 296 mg (120 µmol, 30%) of the title compound. UPLC (ACN-HCOOH): Rt. = 0.41 min. MS (ES+): m/z (z = 2) = 1262.8 (M + 2H)2+, m/z (z =3) = 841.5 (M + 3H)3+. Reference compound 1 Gadovist® (gadobutrol, Bayer AG, Leverkusen, Germany) Reference compound 2 Magnevist® (gadopentetate dimeglumine, Bayer AG, Leverkusen, Germany) Reference compound 3 Primovist® (gadoxetate disodium, Bayer AG, Leverkusen, Germany) Reference compound 4 Gadomer-17 was synthesized as described in EP0836485B1, Example 1k. In vitro and in vivo characterization of the Example compounds

[0289] The examples were tested in trials one or more times. When tested more than once, data are reported as average values or as intermediate values, in which • the average value, also referred to as arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and • the middle value represents the average number of the group of values when sorted in ascending or descending order. If the number of values in the data set is odd, the middle value is the middle value. If the number of values in the data set is even, the intermediate is the arithmetic mean of the two middle values.

[0290] The examples were summarized one or more times. When synthesized more than once, test data represent average values or intermediate values calculated using data sets obtained from testing one or more synthetic batches. Example A Relaxivity measurements at 1.4 T

[0291] Relaxivity measurements at 1.41 T were carried out using a MiniSpec mq60 spectrometer (Bruker Analytik, Karlsruhe, Germany), operating at a resonance frequency of 60 MHz and a temperature of 37°C. T1 attenuation times were determined by the standard inversion recovery (IR) method with a fixed attenuation delay of at least 5 x T1. The variable inversion time (TI) was automatically calculated by standard MiniSpec mq60 software (8 steps). T2 measurements were performed using a Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence, applying an attenuation delay of at least 5 x T1.

[0292] Each relaxivity measurement was performed using three different concentrations of Gd (3 concentrations between 0.05 and 2 mM). The T1 and T2 attenuation times of example compounds 1-10 were measured in different media, for example in water, fetal bovine serum (FBS, Sigma, F7524) and human plasma.

[0293] Preparation of human plasma: For each experiment, fresh blood was drawn from a volunteer using 10 ml citrate tubes (Sarstedt S-Monovette 02.1067.001, 10 ml, Citrate). The 10 ml citrate tubes were carefully inverted 10 times to mix blood and anticoagulant and centrifuged for 15 minutes at 1811 g at room temperature (Eppendorf, Centrifuge 5810R).

[0294] The relaxivities ri (where i = 1, 2) were calculated based on the measured attenuation rates Ri in water and plasma: Ri = Ri(0) + ri [CGd], where Ri (0) represents the rate attenuation of the respective solvent and CGd the concentration of the compound normalized for Gadolinium. Gadolinium concentrations of the investigated solutions were verified by inductively coupled plasma mass spectroscopy (ICP-MS Agilent 7500a, Waldbronn, Germany).

[0295] The determined relaxivity values are summarized in Table 1.

[0296] Table 1: Relaxivities of investigated compounds in water, fetal bovine serum (FBS) and human plasma at 1.41 T and relaxivities of reference compounds 1-4 (RC1-RC4) at 1.5 T in water and bovine plasma. All values were measured at 37°C, are normalized to Gd and produced in L mmol-1 s-1. * values represented in L mmol-1 s-1 A Relaxivities of reference compounds from Rohrer et. al. (Invest. Radiol. 2005; 40, 11: 715-724), bovine plasma (Kreaber GmbH, Phar-maceutical Raw Material, Ellerbek, Germany) Relaxivity measurements at 3.0 T

[0297] Relaxivity measurements at 3.0 T were performed with a 3.0 T MRI Scanner (Philips Intera, Philips Healthcare, Hamburg, Netherlands) using a knee coil (SENSE-Knee-8, Philips Healthcare, Hamburg, Netherlands). Sample tubes (CryoTubetm vials, Thermo Scientific 1.8 mL, Roskilde, Denmark) were positioned in 3 rows of 4 and 5 tubes in a plastic holder in a box filled with water. The temperature was adjusted to 37°C. For the MRI sequence, the shortest possible echo time (TE) was used at 7.46 milliseconds. The inversion times were chosen to optimize the sequence for measuring T1 values corresponding to the T1 range estimated from all attenuation times of solutions containing contrast medium. The following inversion times (TIs) were applied: 50, 100, 150, 200, 300, 500, 700, 1000, 1400, 2100, 3200 and 4500 milliseconds. The sequence was executed with a constant attenuation delay of 3.4 seconds after recording the last echo (variable TR in the range of 3450 to 7900 milliseconds). For details on the adjustment procedure, see Rohrer et.al. (Invest. Radiol. 2005; 40, 11: 715-724). The experimental matrix of the phantom measurement was 320 x 320.

[0298] Relaxivities were evaluated using three different concentrations of each compound (3 concentrations between 0.05 and 2 mM).

[0299] The T1 attenuation times of example compounds 16 were measured in water and human plasma. Preparation of human plasma: For each experiment, fresh blood was drawn from a volunteer using 10 ml citrate tubes (Sarstedt S-Monovette 02.1067.001, 10 ml, Citrate). The 10 ml citrate tubes were carefully inverted 10 times to mix blood and anticoagulant and centrifuged for 15 minutes at 1811 g at room temperature (Eppendorf, Centrifuge 5810R).

[0300] The relaxivities ri (where i = 1, 2) were calculated based on the measured attenuation rates Ri in water and plasma: Ri = Ri(0) + ri [CGd], where Ri (0) represents the rate of attenuation of the respective solvent and CGd the concentration of the compound normalized to Gadolinium (Table 2) Table 2: Relaxivities (normalized to Gd) in water and human plasma at 3.0 T and 37°C [L mmol-1 s -1] * Mean standard deviation ±, values represented in L mmol-1 s-1 Example B Pharmacokinetic parameters

[0301] The pharmacokinetic parameters of the compound of Example 3 were determined in male rats (Han-Wistar, 220-230 g, n=3). The compound was administered as a sterile aqueous solution (52.5 mmol Gd/L) as a bolus into the tail vein of the animals. The dose was 0.1 mmol Gd/kg. Blood samples were obtained at 1, 3, 5, 10, 15, 30, 60, 90, 120, 240, 360, 480 and 1440 min. after injection and Gd concentration was determined by inductively coupled plasma mass spectroscopy (ICP-MS Agilent 7500a, Waldbronn, Germany). The blood level was converted to plasma concentrations by dividing by 0.625 (rat blood plasma fraction, strictly assuming extracellular distribution). As a control, 3 animals were treated in the same way with Gadovist®, a low molecular weight contrast agent. Time courses of blood plasma levels are shown in Figure 1.

[0302] Fitting the data obtained to a three-compartment model (Phoenix - WinNonlin) produced the pharmacokinetic parameters that are shown in Table 3. Table 3: Time courses of blood plasma levels

Example C Excretion and residual concentration of gadolinium from organs after 5 days

[0303] The excretion and organ distribution of Example 3 was determined in male rats (Han-Wistar, 100-110 g, n = 3). The compound was administered as a sterile aqueous solution (54 mmol Gd/L) as a bolus into the tail vein of the animals. The dose was 0.1 mmol Gd/kg. Urine was collected at the following periods 0-1 h, 1-3 h, 3-6 h, 6-24 h, 1-2 of 2-5 d post-injection and feces 0-1 d, 1-2 of 2 -5 d post-injection. As a control, 3 animals were treated in the same way with Gadovist®, a low molecular weight contrast agent. On day 7, the animals were sacrificed and the following organs were excised: blood, liver, kidney, spleen, heart, lung, brain, mesenteric lymph nodes, muscle, skin, stomach, intestine, bone and bone marrow. The remaining carcass was freeze-dried and ground to a fine powder. Gd concentration in organs and carcass was determined by ICP-MS (ICP-MS Agilent 7500a, Waldbronn, Germany). The organ distribution results of Example 3 and reference compound 1 (Gadovist®) are summarized in Table 4. Example 3 is rapidly excreted via the kidneys. After 3 h, 95.8% ± 3.4% of the injected dose was found in the urine and 96.9% ± 3.7% after 5 days. About 1.4% ± 0.6% was excreted in feces. Less than 0.5% of the administered dose was present in the body 7 days after injection. Individual organs contained less than 0.03% of the injected dose, except the kidney which is the organ of excretion. Table 4: Excretion and organ distribution of Gadovist® and Example 3 in rats

Example D Chemical stability

[0304] Examples 1, 2, 3 and 6 were dissolved separately in 10 mM Tris-HCl buffer, pH 7.4 at a final concentration of 5 mmol Gd/L. An aliquot was removed and the remainder of the clear, colorless solution was autoclaved at 121°C for 20 min. After autoclaving, the solution was still clear and colorless. The aliquot removed before and after autoclaving was analyzed by HPLC-ICP-MS to determine compound integrity.

[0305] HPLC: Column: Hypercarb 2.5 mm x 15 cm. Solvent A: 0.1% formic acid in water. Solvent B: acetonitrile. Gradient from 100% A to 5% A + 95% B in 10 min. Flow 1 mL/min. Detection by ICP-MS, set to 158Gd. The chromatograms, which displayed the detected Dd intensity, were compared visually. No changes were detected in the chromatograms before and after autoclaving. The compounds were stable during the autoclaving procedure. Example E Release of gadolinium after addition of zinc and phosphate

[0306] The proton relaxometric protocol for the assessment of transmetallation for determining the stability of MR contrast medium is described in Laurent S. et al. (Invest. Radiol. 2001; 36, 2:115-122). The technique is based on measuring the evolution of the paramagnetic longitudinal attenuation rate of the water proton in phosphate buffer (pH 7.00, 26 mmol/L, KH2PO4 Merck, Hessen, Germany) containing 2.5 mmol/L of complex of gadolinium and 2.5 mmol/L of ZnCl2 Sigma -Aldrich, Munich, Germany). 100 microliters of a 250 mmol/L ZnCl2 solution were added to 10 mL of a paramagnetic complex buffered solution (reference compounds 1-4 and Example 3). The mixture was shaken vigorously and 300 µL were extracted for the relaxometric study at 0 min, 60 min, 120 min, 3 h, 4 h, 5 h, 24 h, 48 h and 72 h. Measurements were performed on a MiniSpec mq60 spectrometer (Bruker Analytik, Karlsruhe, Germany) at 60 MHz and 37°C. The results of Example 3 compared to reference compound 1 (Gadovist®), reference compound 2 (Magnevist®) and reference compound 3 (Primovist®) are shown in Figure 2. If transmetalation of Gadolinium is triggered by Zn2+ ions in a phosphate buffered solution, then the free released Gd3+ reacts with the free PO43- ions to form GdPO4. Due to the low solubility of GdPO4, part of the Gadolinium precipitates are solid and have no further influence on the longitudinal attenuation rate of water. A decrease in proton attenuation rate would be observed for Gadolinium chelates with low stability [see linear contrast media in Figure 2: Reference compounds 2 (Magnevist®) and 3 (Primovist®)]. The stability of Example 3 is comparable to the high stability of reference compound 1 (Gadovist®). Example F Gd complex stabilities in human plasma at 37°C, 15 d

[0307] Examples 3 and 10 were dissolved separately in human plasma at 1 mmol Gd/L. As a reference for Gd3+ released 0.1 mmol/L, Gadolinium chloride (GdCl3) was dissolved in human plasma. Plasma samples were incubated for 15 days at 37°C under a 5% CO2 atmosphere to maintain the pH at 7.4. Aliquots were used at the beginning and end of incubation. The amount of Gd3+ released from the complexes was determined by HPLC-ICP-MS. Column: Sepharose chelator (HiTrap, 1mL). Solvent A: 10 mM BisTris-HCl pH 6.0. Solvent B: 15 mM HNO3. Gradient: 3 min at 100% A, 3 to 10 min at 100% B. Flow 1 mL/min. Detection by ICP-MS, set to 158Gd. The chromatograms, which display the intensity of detected Gd, were evaluated by peak area analysis. The size of the Gd3+ peak, eluting after changing solvent A to B, was recorded. For both compounds, the increase in this peak and, therefore, the release of Gd3+ was below the limit of quantification (<0.1% of the total amount of gadolinium injected). Both Gd complexes are stable under physiological conditions. Example G Solubility in water

[0308] The water solubility of the compounds was determined at room temperature (20°C) in 0.5 mL of buffer solution (10 mM Tris-HCl) in microcentrifuge tubes (Eppendorf, 2.0 mL safety caps) . The solid compound was gradually added to the buffer solution. The suspension was mixed using a stirrer (Heidolph Reax 2000) and treated for 5 min in an ultrasound bath (Bandelin, Sonorex Super RK255H). The suspension was stored at room temperature (20°C) overnight and the final Gadolinium concentration was determined by inductively coupled plasma mass spectroscopy (ICP-MS). The results are summarized in Table 5. Table 5: Solubilities of compounds in water at 20°C. Example H Contrast-enhanced magnetic resonance angiography (CEMRA)

[0309] The potential for a significant dose reduction was demonstrated by an intraindividual comparison of 100 µmol of gadolinium per kilogram of body weight [100 µmol Gd/kg b.w.], which is comparable to the standard human dose and a low dose protocol using 30 µmol of gadolinium per kilogram of body weight. Reference compound 1 (Gadovist®), as an approved representative of Gadolinium-based MR contrast agents, was used in both dose protocols (100 µmol Gd/kg bw and 30 µmol Gd/kg bw) and compared to Example 3 (30 µmol Gd/kg bw).

[0310] The contrast-enhanced magnetic resonance angiography study was performed on a 1.5 T clinical scanner (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany). For optimal signal exploration, a standard spine coil was used to obtain the data. The study was done using male New Zealand white rabbits (weight 2.5-2.9 kg, n = 6, Charles River Kisslegg). All animals were initially anesthetized using an intramuscular injection adjusted to body weight of a mixture (1+2) of xylazine hydrochloride (20 mg/mL, Rompun 2%, Bayer Vital GmbH, Leverkusen) and ketamine hydrochloride ( 100 mg/mL, Ketavet, Pfizer, Pharmacia GmbH, Berlin) using 1 mL/kg of body weight. Continuous anesthesia of intubated animals (endotracheal tube, Rueschelit Super Safe Clear, 3.0 mm cuff, Willy Ruesch AG, Kernen, Germany) was achieved by intravenous injection of 0.9 mg of propofol per kilogram per hour (10 mg /mL, Propofol-Lipuro 1%, B. Braun Melsungen AG, Melsungen, Germany). Continuous intravenous injection was performed using an MR infusion system (Continuous MR Infusion System, Medrad Europe B. V., AE Beek, The Netherlands). Tracheal breathing (SV 900C, Maquet, Rastatt, Germany) was performed with 55% oxygen, forty breaths per minute and a respiratory volume of 7 mL per kilogram of body weight per minute.

[0311] Based on a localizer sequence oriented in coronal, axial and sagittal directions, the anatomical course of the aorta was obtained. Time to peak was determined using a small intravenous test bolus (0.25 mL/2.5-2.7 kg or 0.3 mL/2.8-2.9 kg bw, reference compound 1) and a 3D FLASH sequence (test cake sequence: repetition time: 36.4 milliseconds, echo time 1.45 milliseconds, clearance angle: 30 degrees, spatial resolution: 1.0x0.8x17 mm) . The 3D FLASH angiography sequence was characterized by a repetition time of 3.24 milliseconds, an echo time of 1.17 milliseconds, a gap angle of 25 degrees, and a slice thickness of 0.94 mm. The 141x300 mm field of view was combined with a 150x320 matrix resulting in a spatial resolution of 0.9x0.9x0.9 mm and an integer acquisition time of 13 seconds per 3D tile. The 3D FLASH sequence was performed once before and immediately after contrast agent injection. The time interval for intraindividual comparison between different applications of the contrast agent was twenty to thirty minutes (n = 3 animals).

[0312] The magnetic resonance angiographies resulting from the intraindividual comparison in rabbits are represented in Figure 3: (A) 30 µmol of Gd/kg bw Reference compound 1 (Gadovist®); (B) 30 µmol Gd/kg bw Example 3 and (C) 100 µmol Gd/kg bw Reference compound 1. The contrast enhancement of the low dose protocol with Example 3 (B) is comparable to that of the standard dose of reference compound 1 (C). Furthermore, the image quality of the low dose protocol of Example 3 (B) is significantly better than the low dose protocol of reference compound 1 (A). The angiography study demonstrates the potential of Example 3 for significant dose reduction. Example J Full body image

[0313] Classic extracellular gadolinium-based contrast agents exhibit rapid passive extracellular distribution throughout the body and are excreted exclusively through the kidney. The rapid extracellular distribution throughout the body enables classic imaging possibilities, such as angiography and imaging of the central nervous system, extremities, heart, head/face/neck, abdomen and breast. The comparability of the pharmacokinetic and diagnostic behavior of reference compound 1 (Gadovist®) and other ECCMs has been demonstrated and forms the basis for surpassing the efficacy of all commonly imagined body parts in diagnosing a variety of diseases (Tombach B et al., Eur Radiol 2002;12(6):1550-1556). The contrast-enhanced MRI study compares the pharmacokinetic distribution and diagnostic performance of Example 3 with reference compound 1 (Gadovist®), as an approved representative of Gadolinium-based MR contrast agents.

[0314] To demonstrate that Example 3 has the same mode of action, MR signal intensity over time and Gd concentrations were determined in various tissues. The study was performed on a clinical whole body MRI equipped with body spine coil, flexible abdomen coil, neck coil (1.5 T Magnetom Avanto, Siemens Healthcare, Erlangen, Germany). The study was done using male New Zealand white rabbits (weight 2.3-3.0 kg, n = 8, Charles River Kisslegg). All animals were initially anesthetized using an intramuscular injection adjusted to body weight of a mixture (1+2) of xylazine hydrochloride (20 mg/mL, Rompun 2%, Bayer Vital GmbH, Leverkusen) and ketamine hydrochloride (100 mg/mL, Ketavet, Pfizer, Pharmacia GmbH, Berlin) using 1 mL/kg of body weight. Continuous anesthesia of intubated animals (endotracheal tube, Rueschelit Super Safe Clear, 3.0 mm cuff, Willy Ruesch AG, Kernen, Germany) was achieved by intravenous injection of 0.9 mg of propofol per kilogram per hour (10 mg /mL, Propofol-Lipuro 1%, B. Braun Melsungen AG, Melsungen, Germany). Continuous intravenous injection was performed using an MR infusion system (Continuous MR Infusion System, Medrad Europe B. V., AE Beek, The Netherlands). Tracheal breathing (SV 900C, Maquet, Rastatt, Germany) was performed with 55% oxygen, forty breaths per minute and a respiratory volume of 7 mL per kilogram of body weight per minute.

[0315] Dynamic MRI measurements up to 22 min post injection with subsequent quantitative signal analysis (Siemens Mean Curve software (SYNGO Task Card, Siemens Healthcare, Erlangen, Germany) were performed for three different head and neck regions (brain, tongue, cheek muscle, neck muscle), abdomen (spleen, liver, blood) and pelvis (extremity muscle).For the three different slice groups, a 3D T1-weighted Vibe sequence (TR = 4, 74 ms, TE = 2.38, slope = 10°, 1:29 min).The dynamic measurements of the three slice groups (head/neck: 1:29 min, Abdomen: 00:49 min, Pelvis: 1:16 min) were obtained up to 22 min after injection: 1. Head/Neck: baseline, 1.4, 5.2, 8.9, 12.8, 16.5, 20.4 min, 2. Abdomen: baseline, 0.5, 4.3, 8.1, 11.9, 15.7, 19.5 min and 3. Pelvis: baseline, 2.9, 6.7, 10.5, 14 .4, 18.1, 22.0 min. 30 min after injection, animals were sacrificed and Gd concentrations were measured using inductively coupled plasma mass spectroscopy (ICP-MS Agilent 7500a, Waldbronn, Germany) at the following tissue samples: blood, brain, tongue, liver and extremity muscle. A quantitative imaging assessment was performed for the 30-min time point p.i. due to the combination of quantitative Gadolinium ICP-MS concentrations and the analysis of the MRI region of interest.

[0316] Administration of the contrast agent leads to an increase in signal in the vascular system and in the extravascular, extracellular space of the body. Signal enhancement is based on the pharmacokinetic and physicochemical properties of contrast agents. Figure 4 shows representative images of the head and neck region before and 1.4 min after administration of Example 3 and reference compound 1. Figure 5 shows representative abdominal images before and 0.5 min after administration of Example 3 and reference compound 1. Figure 6 shows representative images of the pelvic region before and 0.5 min. after administration of Example 3 and reference compound 1. All images show clear signal enhancement, for example, in the heart, tongue, aorta, kidney, liver, spleen, entire vascular system and muscles.

[0317] The signal-time curves show the change in signal over time after administration of the contrast agent and represent the pharmacokinetics of the contrast agent in the respective tissue (Figure 7). In all tissues investigated, a rapid increase in signal intensity was observed after contrast agent injection, which was followed by a continuous decrease in signal. The degree of these contrast enhancements is tissue specific. However, no differences in the time course of contrast enhancements were observed between Example 3 and reference compound 1. This demonstrates identical pharmacokinetic properties and shows that Example 3 is suitable for different regions of the body (Figures 7). The amplitude of contrast enhancement depends on tissue characteristics, especially tissue perfusion, and physicochemical properties, especially relaxivity. As expected from the approximately 2-fold greater relaxivity (see example A), the contrast enhancement in Example 3 is greater compared to reference compound 1.

[0318] The relationship between Gadolinium concentration and MRI signal change was investigated by comparing the amount of Gadolinium in tissue 30 min p.i. with the signal change in the MRI measurement performed at 19.5 min p.i. (abdomen), 20.4 min p.i. (head and neck) and 22.0 min p.i. (pelvis). Respective data for Example 3 and reference compound 1 are shown in Figure 8. A linear correlation was observed between Gadolinium concentrations in various tissues and respective MR signal changes. This demonstrates that the effectiveness of Example 3 and reference compound 1 is independent of the region of the body or tissue investigated. A slight deviation from this correlation was observed for the spleen, which presents a greater increase in MR signal than would be expected from the tissue concentration of Gadolinium. This was observed for both contrast agents and relates to the significantly greater blood volume of the spleen compared to other organs and tissues. Consequently, the spleen loses a large part of its Gadolinium concentration through exsanguination, which in turn results in an incompatibility between in vivo imaging and ex vivo Gadolinium determination. The correlation between the signal change and the gadolinium concentration of all other tissues and organs, which represents the respective relaxivity, depends on the effectiveness of the contrast agent used. A greater slope was determined for Example 3 (1.9) than for the reference compound 1 (1.0), which is in agreement with the better known greater relaxivity of Example 3 (Figure 8, see also the relaxivity data described in Example A). Example K Dynamic CT Diffusion Phantom Study

[0319] As indicated in Example A, reference compound 4 has a relaxivity that is in a similar range to that of the compounds of the present invention. After intravenous injection, all small-monomer GBCA (gadopentetate dimeglumine, gadomeglumine terate, gadoteridol, gadodiamide, gadobutrol and gadoversetamide) are distributed into the blood and extravascular/extracellular space by passive distribution (Aime S et al., J Magn Reson Imaging. 2009;30, 1259-1267). Contrast agents with a high protein binding, for example, gadofosveset trisodium with a prolonged period in the blood vessels caused by reversible binding to HSA or large hydrodynamic sizes such as, for example, reference compound 4 are difficult to pass through the vessel wall. For good imaging results, rapid diffusion through the vessel walls is required due to rapid renal excretion of GBCAs.

[0320] The described dynamic CT diffusion study compares the ability of Examples 1, 2, 3, 4, 5, 6 and reference compounds 1 and 4 to pass through a semipermeable membrane (20 kDa). A 128-line clinical CT device (SOMATOM Definition, 128; Siemens Healthcare, Forchheim, Germany) was used to monitor diffusion through a semipermeable membrane at 100 kV and 104 mA. Single measurements were performed at 0 min, 1 min, 2 min, 3 min, 5 min, 10 min, 15 min, 20 min, 30 min, 45 min, 60 min, 2 h, 3 h, 5 h, 7 h , 22 h, 24 h, 30 h, 46 h and 48 h after placement of the filled dialysis cassette (Slide-A-Lyser, 20,000 MWCO, 0.1-0.5 mL capacity, Thermo Scientific, Roskilde, Denmark) with contrast agent in fetal bovine serum solution (FBS, Sigma, F7524). Images were reconstructed with a slice thickness of 2.4 mm and a B30 convolution kernel. The concentration used in the dialysis cassettes of Examples 1, 2, 3, 4, 5, 6 and reference compounds 1 and 4 was 20 mmol Gd/L.

[0321] The imaging results for all investigated Examples and reference compounds 1 and 4 for the time points 0 min and 48 h after placing the cassettes in the FBS solution are depicted in Figure 9. For analysis of images, regions of interest were manually drawn on a centrally located slice for each moment in time (a representative measurement region is indicated in Figure 9: Image 1A). The Hounsfield Units (HU) results of the analyzed regions over time are shown in Figure 10. The calculated diffusion half-lives of the Examples and reference compounds investigated are summarized in Table 6. Table 6: Diffusion half-lives through of a semipermeable membrane (20 kDa)

[0322] Figure 10 and the calculated half-life data show, similar to reference compound 1 (Gadovist®) and in contrast to reference compound 4, that examples 1-6 can pass the semipermeable membrane. Furthermore, the data from the compounds investigated show otherwise that other high relaxivity agents, which have high protein binding rates or very low rates (e.g., reference compound 4), that the compounds of the present invention have. hydrodynamic dimensions that can overcome barriers in a timely manner. These findings indicate the ability of the compounds of the invention to overcome barriers such as endothelial walls in the vascular system, which is a requirement for whole-body imaging. Example L Assessment of potential side effects

[0323] None of the investigated example compounds showed unwanted negative side effects in animals after application. Furthermore, the off-target activity of Example 3 was screened in commercial radioligand and enzyme binding assays (LeadProfilingScreen®, Eurofins Panlabs, Taipei, Taiwan) and did not reveal critical results. Example M Contrast-enhanced MRI of brain tumors in rats

[0324] The potential for a significant dose reduction was demonstrated by an intraindividual comparison of 0.3 mmol gadolinium per kilogram of body weight (300 µmol Gd/kg body weight) and a dose protocol low using 0.1 mmol of gadolinium per kilogram of body weight (100 µmol of Gd/kg of body weight). Reference compound 1 (Gadovist®), as an approved representative of Gadolinium-based MR contrast agents, was used in both dose protocols (0.3 mmol Gd/kg bw and 0.1 mmol Gd/kg bw ) and compared to Example 3 (0.1 mmol Gd/kg b.w.).

[0325] The GS9L cell line (European Collection of Cell Cultures, Cancer Res 1990; 50: 138-141; J Neurosurg 1971; 34: 335) was cultured in Dulbecco's modified Eagle's medium (DMEM, Gluta-MAXTM, Ref: 31966-021, Gibco) with 10% fetal bovine serum (FBS, Sigma F75249) and 1% penicillin-streptomycin (10,000 units/mL, Gibco). The study was done using male Fisher rats (F344, weight 170-240 g, n = 4, Charles River Kisslegg). Inoculation was performed under ketamine/xylazine anesthesia using an intramuscular injection adjusted to body weight of a mixture (1 + 2) of xylazine hydrochloride (20 mg/mL, Rompun 2%, Bayer Vital GmbH, Leverkusen) and ketamine hydrochloride (100 mg/mL, Ketavet, Pfizer, Pharmasa GmbH, Berlin) using 1 mL/kg of body weight. For orthotopic intracerebral implantation, anesthetized animals were fixed in a stereotaxic apparatus and 1.0E + 06 GS9L cells suspended in a volume of 5 µl of medium were slowly injected into the brain using a Hamilton syringe.

[0326] The contrast-enhanced MRI study was performed on a 1.5 T clinical scanner (Magnetom Avanto, Siemens Healthcare, Erlangen, Germany). A rat head coil (Rat Animal Coil and Holder, RAPID Biomedical GmbH) was used for data acquisition. The rats were anesthetized using a mixture of isoflurane (2.25%), oxygen gas (approximately 0.5 L/min) and nitrous oxide (flow approximately 1 L/min). MR imaging was performed using a 3D turborotation echo sequence (12 1 mm slices in a 3 D block, field of view: 80 mm (33% oversampling), repetition time: 500 milliseconds, echo time 19 milliseconds, spatial resolution: 0.3x0.3x1.0 mm). The animals were photographed on two consecutive days. On the first day, reference compound 1 (Gadovist®) and Example 3 were compared intraindividually at the same dose of 0.1 mmol Gd/kg b.w., which is comparable to the standard human dose. On the second day, reference compound 1 (Gadovist®) was compared at 0.3 mmol Gd/kg b.w., which is comparable to the triple human dose (clinically approved in certain CNS indications), with the standard dose of Example 3 (0.1 mmol Gd/kg bw). The resulting MR images of brain tumors from GS9L rats are depicted in Figure 11: (A) Intraindividual comparison of reference compound 1 (Gadovist®) and Example 3 at the same dose of 0.1 mmol Gd/kg of body weight (b.w.). Example 3 showed, at the same dose, greater contrast of the lesion in the brain and an excellent demarcation of the tumor border. (B) Comparison of reference compound 1 (Gadovist®) at 0.3 mmol Gd/kg bw (triple dose) and Example 3 at 0.1 mmol Gd/kw bw (standard dose). Example 3 showed similar brain lesion contrast at one-third the dose of reference compound 1.

Claims (16)

1. Compound, characterized by the fact that it presents the General Formula (I), in which represents a group the group * indicates the connection point of the group mentioned with R1; R1 represents a group R3; N represents an integer from 1 to 4; R2 represents a hydrogen atom R3 represents a group selected from: in which the groups * indicate the connection point of the mentioned group with the rest of the molecule; R4 represents a hydrogen atom; R5 represents a hydrogen atom or a methyl group; or a stereoisomer, a tautomer, a hydrate or a solvate thereof or a mixture thereof. 2. Compound according to claim 1, characterized by the fact that R5 represents a methyl group. 3. Compound according to claim 1 characterized by the fact that R3 represents a group: 4. Compound, according to claim 1 or 2 characterized by the fact that R3 represents a group: 5. Compound according to any one of claims 1 to 4, characterized in that it is selected from the group consisting of: Tetragadolinium [4,10-bis (carboxylatomethyl) -7- {3,6,12, 15-tetraoxo-16-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecane-1-yl]-9,9-bis ({ [({2-[4, 7,10-tris(carboxylatomethyl) - 1,4,7,10-tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2- yl}-1,4,7,10-tetra-azacyclododecan-1-yl] acetate; Tetragadolinium {4,10-bis(carboxylatomethyl)-7-[(2R,16R)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxylatomethyl)-1,4,7, 10-tetra-azacyclododecan-1-yl]-9,9-bis ({ [({(2R) -2- [4,7,10-tris(carboxylatomethyl) - 1,4,7,10-tetra-azacyclododecan -1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2-yl] -1,4,7,10-tetra-azacyclododecan-1-yl} acetate ; Tetragadolinium {4,10-bis(carboxylatomethyl)-7-[(2S,16S)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxylatomethyl)-1,4,7, 10-tetra-azacyclododecan-1-yl]-9,9-bis ({ [({(2S) -2- [4,7,10-tris(carboxylatomethyl) - 1,4,7,10-tetra-azacyclododecan -1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2-yl] -1,4,7,10-tetra-azacyclododecan-1-yl} acetate ; Tetragadolinium {4,10-bis(carboxylatomethyl)-7-[2-oxo-2-({3-({[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecane- 1- yl] acetyl} amino)-2,2-bis [({ [4,7,10-tris(carboxylatomethyl) -1,4,7,10-tetra- azacyclododecan-1-yl] acetyl} amino) methyl ] propyl} amino)ethyl] -1,4,7,10- tetra-azacyclododecan-1-yl} acetate; and Tetragadolinium [4,10-bis(carboxylatomethyl)-7-{2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan - 1- yl] -8,8-bis ({ [({ [4,7,10-tris(carboxylatomethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) acetyl] amino} methyl) - 3,6,10,13-tetra-azapentadec-1-yl} -1,4,7,10-tetra-azacyclododecan-1-yl] acetate, or a stereoisomer, a tautomer, a hydrate or a solvate thereof or a mixture thereof. 6. Compound according to any one of claims 1, 3 and 4 characterized by the fact that it is tetragadolinium [4,10-bis (carboxylatomethyl) -7- {3,6,12,15-tetraoxo-16- [4,7,10-tris(methyl carboxylate)-1,4,7,10-tetra-azacyclododecane-1-yl]-9,9-bis ({ [({2- [4,7,10- tris(carboxylatomethyl)-1,4,7,10-tetra-azacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetra-azaheptadecan-2-yl}-1 ,4,7,10- tetra-azacyclododecan-1-yl] acetate, or a stereoisomer, a tautomer, a hydrate or a solvent thereof or a mixture thereof. 7. Method for preparing a compound of General Formula (Id), as defined in any one of claims 1 to 6, characterized in that it comprises the step of leaving a compound of Formula 4, in which is a tetraamine as defined for compounds of General Formula (I), as defined in any one of claims 1 to 6, or its salt, reacting with a compound of General Formula (III): wherein R5 is as defined for compounds of General Formula (I) as defined in any one of claims 1 to 6, and LG represents an activating leaving group, such as, for example, 4-nitrophenol, thereby providing a compound of General Formula wherein R5 is as defined for the compounds of General Formula (I), as defined in any one of claims 1 to 4, and is a tetraamine as defined according to any one of claims 1 to 6. 8. Use of a compound as defined in any one of claims 1 to 6, characterized in that it is for generating magnetic resonance imaging (MRI). 9. Compounds according to any one of claims 1 to 6, characterized in that they are for use in generating magnetic resonance imaging (MRI). 10. Use of the compounds, or mixtures thereof, as defined in any one of claims 1 to 6, characterized by the fact that it is for the manufacture of diagnostic agents. 11. Use of the compounds, or mixtures thereof, as defined in any one of claims 1 to 6, characterized by the fact that it is for manufacturing contrast agents for generating magnetic resonance imaging. 12. Method for imaging body tissue in a patient, characterized in that it comprises the steps of: administering to the patient an effective amount of one or more compounds, as defined in any one of claims 1 to 6, in a vehicle pharmaceutically acceptable, and subject the patient to magnetic resonance imaging. 13. Use of a compound of General Formula (III), in which R5 is as defined for compounds of General Formula (I), as defined in any one of claims 1 to 6, and LG represents an activation leaving group, such as, for example, 4-nitrophenol, said use being characterized by the fact that it is for preparing a compound of General Formula (I), as defined in any one of claims 1 to 6. 14. Intermediate compound for preparing a compound, as defined in any one of claims 1 to 6, characterized by the fact that it has the General Formula (I): in equal represents a group in which the group * indicates the connection point of the group mentioned with R1; R1 represents a group R3; N represents an integer from 1 to 4; R2 represents a hydrogen atom R3 represents a group selected from: in which the groups * indicate the connection point of the mentioned group with the rest of the molecule; R4 represents a hydrogen atom; R5 represents a hydrogen atom or a methyl group; or a stereoisomer, a tautomer, a hydrate or a solvate thereof or a mixture thereof. 15. Intermediate compound according to claim 14, characterized in that it is selected from the group consisting of: [4,10-bis (carboxylatomethyl) -7- {3,6,12,15-tetraoxo-16- [ 4,7,10- tris (carboxylatomethyl) -1,4,7,10-tetra-azacyclododecane-1- yl] -9,9-bis ({ [({2- [4,7,10-tris (carboxylatomethyl) ) -1,4,7,10-tetra-azacyclododecan-1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azheptadecan-2-yl} - 1,4, 7,10-tetra-azacyclododecan-1-yl] acetic acid; {4,10-bis(carboxymethyl)-7-[(2R,16R)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10 -tetra-azacyclododecan-1-yl] -9,9-bis ({ [({(2R) -2- [4,7,10-tris(carboxymethyl) -1,4,7,10-tetra-azacyclododecan- 1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2- yl] -1,4,7,10-tetra-azacyclododecan-1-yl} acetic acid ; {4,10-bis(carboxymethyl)-7-[(2S,16S)-3,6,12,15-tetraoxo-16-[4,7,10-tris(carboxymethyl)-1,4,7,10 -tetra-azacyclododecan-1-yl] -9,9-bis ({ [({(2S) -2- [4,7,10-tris (carboxymethyl) -1,4,7,10-tetra-azacyclododecan- 1-yl] propanoyl} amino) acetyl] amino} methyl) -4,7,11,14-tetra-azaheptadecan-2- yl] -1,4,7,10-tetra-azacyclododecan-1-yl} acetic acid ; {4,10-bis(carboxymethyl)-7-[2-oxo-2-({3-({[4,7,10-tris(carboxymethyl)-1,4,7,10-tetra-azacyclododecane -1- yl] acetyl} amino) -2,2-bis [({ [4,7,10-tris(carboxymethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) methyl]propyl}amino)ethyl]-1,4,7,10-tetra-azacyclododecan-1-yl}acetic acid; and [4,10-bis(carboxymethyl)-7-{2,5,11,14-tetraoxo-15-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetra-azacyclododecan- 1- yl] -8,8-bis ({ [({ [4,7,10-tris(carboxymethyl) -1,4,7,10-tetra-azacyclododecan-1-yl] acetyl} amino) acetyl] amino } methyl) - 3,6,10,13-tetra-azapentadec-1-yl} -1,4,7,10-tetra-azacyclododecan-1-yl] acetic acid or a stereoisomer, a tautomer, a hydrate a solvate or its salt or a mixture thereof. 16. Intermediate compound according to claim 15, characterized by the fact that it is [4,10-bis (carboxylatomethyl) -7- {3,6,12,15-tetraoxo-16- [4,7,10- tris (carboxylatomethyl) -1,4,7,10-tetra-azacyclododecane-1- yl] -9,9-bis ({ [({2- [4,7,10-tris (carboxylatomethyl) - 1,4, 7,10-tetra-azacyclododecan-1-yl]propanoyl}amino)acetyl]amino}methyl)-4,7,11,14-tetra-azaheptadecan-2-yl}-1,4,7,10-tetra- azaciclododecan-1-yl] acetic acid, or a stereoisomer, a tautomer, a hydrate, a solvate or salt thereof or a mixture thereof.