Novel contrast agents for diagnostic imaging

Abstract

The present invention relates to novel manganese (Mn2 +) chelate compounds, to a method for preparing said compounds, to the use of said compounds as contrast agents in diagnostic imaging, such as magnetic resonance imaging (MRI), and to their use in mammalian bodies.

Description

[0001] This application is a divisional application of the invention patent application filed on May 15, 2024, with application number 202480032411.0 and invention title "Novel Contrast Agent for Diagnostic Imaging". Technical Field

[0002] This invention relates to the subject matter described in the claims, namely, novel manganese (Mn) 2+ Chelates, methods for preparing the compounds, the use of the compounds as contrast agents in diagnostic imaging such as magnetic resonance imaging (MRI), and their use in mammalian bodies. Background Technology

[0003] 1. Overview Magnetic resonance imaging (MRI) is a non-invasive technique that provides information about the anatomy, function, and metabolism of tissues in the body. Non-contrast MRI scans of tissue anatomy and function utilize hydrogen atoms in water to generate images. Aside from local differences in water content, the fundamental contrast of MR images is primarily due to regional differences in intrinsic relaxation times T1 and T2, both of which can be selected to dominate image contrast. However, the intrinsic contrast provided by water T1 and T2, as well as their numerical variations due to tissue lesions, is often too limited to achieve sensitive and specific diagnosis. To overcome these limitations, proton relaxation time can be affected by the presence of paramagnetic ions. Commercially available gadolinium-based contrast agents (GBCAs) contain at least one rare-earth metal, gadolinium (Gd). 3+ Paramagnetic ions, which have the most unpaired electrons (7) of any stable ion, produce a high magnetic moment and effectively enhance proton relaxation.

[0004] Paramagnetic contrast agents shorten the T1 (longitudinal) and T2 (transverse) relaxation times of surrounding water protons to indirectly produce a signal enhancement effect. The efficiency with which contrast agents shorten relaxation time is called the relaxation rate (r1 and r2), which depends on the ligands around the paramagnetic ion and is affected by external factors including temperature, magnetic field strength, and matrix (water, solid tissue, or blood). (Lauffer RB et al., Paramagnetic metal complexes as water proton relaxation agents for NMR imaging: theory and design. Chem Rev. 1987;87(5):901-27; Caravan P et al., Gadolinium(III) chelates as MRI contrast agents: structure, dynamics, and applications. Chem Rev. 1999;99(9):2293-352).

[0005] Due to unchelated Gd 3+ Ions are toxic; extracellular GBCA requires ligands to chelate Gd. 3+ Gd-DTPA (gadolinium pentanoate, trade name Magnevist, Bayer), Gd-DTPA-BMA (gadolinium diamine, trade name Omniscan, GeHealthcare), and Gd-BOPTA (gadolinium meglumine, trade name MultiHance, Bracco) are classified as linear GBCAs based on chain ligand structures. Gd-DOTA (gadolinium diglumine, e.g., trade name Dotarem, Guerbet), Gd-HP-DO3A (gadolinium tertrol, trade name ProHance, Bracco), and Gd-DO3A-butrol (gadolinium buttrol, e.g., trade name Gadovist, Bayer) contain cage-like ligands and are classified as macrocyclic contrast agents. Compared to linear contrast agents, macrocyclic contrast agents have better dissociation and Gd... 3+ Release more stable (Frenzel et al., Invest Radiol, Dec 2008; 43(12): 817-828).

[0006] In 2014, the first study showed that patients with normal renal function who received multiple injections of straight-chain gadolinium-based contrast agents (GBCAs) had increased signal intensity (SI) in the dentate nucleus (DN) and globus pallidus (GP) brain regions on unenhanced T1-weighted (T1w) MR imaging (Kanda et al., Radiology, March 2014; 270(3):834-41). This led to a comprehensive assessment of the safety of GBCAs, including regulatory activities and in-depth studies on Gd retention in organs after GBCA use. In March 2017, the European Union (EU) suspended marketing authorization for all multi-purpose straight-chain GBCAs while supporting the continued use of macrocyclic GBCAs.

[0007] Following this decision, the MRI market abandoned linear gadolinium-based contrast agents and intensified its efforts and strategies to reduce or replace Gd. Nevertheless, a novel high-relaxation-rate GBCA (gadolinium piperidinol, trade names Elucirem, Guerbet, and VUEWAY, Bracco) received US marketing approval in 2022, making it possible to reduce the dose while maintaining diagnostic efficacy. Other attempts include artificial intelligence methods that generate virtual enhanced images comparable to full-dose images to further reduce gadolinium dosage.

[0008] Therefore, there has long been a desire to abandon GBCA and replace it with alternative contrast agents, but this has not yet been achieved. In particular, there is a growing long-term medical need for novel non-Gd contrast agents for MRI. Endogenous paramagnetic elements have been considered as non-Gd alternatives for MRI. Manganese, an endogenous paramagnetic element, is an essential trace element for many enzymes in the human body, and its divalent state has five unpaired electrons.

[0009] To date, there are no commercially available multipurpose contrast agents based on endogenous manganese. Only one liver-specific Mn complex has been approved as a contrast agent for MRI: Mn-DPDP (manganese floccopyr, trade name TeslaScan). Mn-DPDP (GE Healthcare) was approved for liver imaging at a clinical dose of 0.005 mmol / kg, but was withdrawn from the US and EU markets by its manufacturer in 2003 and 2012, respectively. Mn-DPDP is metabolized in plasma and rapidly releases Mn ions through dephosphorylation and metal transfer with zinc. The released Mn ions are cleared by bile excretion, producing liver image contrast and detecting focal liver lesions (Toft KG et al., Metabolism and pharmacokinetics of MnDPDP in man. Acta Radiol, July 1997; 38(4 Pt 2):677-89). Therefore, the only approved non-Gd-based contrast agent to date has limited practicality due to its liver specificity and has been withdrawn from the market for over a decade. Currently, no suitable alternative to intravenous injection has been found.

[0010] Therefore, there is an increasing medical need for novel contrast agents for radiographic imaging. In particular, there is a growing need for novel contrast agents based on endogenous elements that can replace gadolinium. Given the low coordination stability of manganese (see Mn-DPDP above) and the clinically observed side effects, manganese-based contrast agents are challenged as a suitable and stable alternative to multipurpose GBCA; instead, research and development efforts have focused on other paramagnetic metal ions, such as iron. Superparamagnetic iron oxide nanoparticles (SPIONS) have been investigated for use as MRI contrast agents, but with very limited success: two examples are Ferumoxytol nanoparticles (trade name Feraheme, approved only for the treatment of iron deficiency, not for imaging use) and Ferucarbotran (trade name Resovist, Bayer AG, discontinued in 2009). SPIONS have different pharmacokinetic clearance and biodistribution than GBCA, so they cannot be fully compared (Jin et al., Superparamagnetic iron oxide nanoparticles for MR imaging and therapy: design considerations and clinical applications. Curr Opin Pharmacol, Oct 2014; 18:18-27). Iron chelates are still in the very early stages of development as alternatives (Boehm-Sturm et al., Low-Molecular-Weight Iron Chelates May Be an Alternative to Gadolinium-based Contrast Agents for T1-weighted Contrast-enhanced MR Imaging; Radiology, Feb 2018; 286(2):537. Snyder et al., A Class of FeIII Macrocyclic Complexes with Alcohol Donor Groups as Effective T1 MRI Contrast Agents. Angew Chem Int Ed Engl, Feb 3, 2020; 59(6):2414-2419). Therefore, there has been a growing medical demand for Gd-free, multi-purpose contrast agents.

[0011] 2. Description of existing technology, problems to be solved and their solutions WO2021 / 043926 A1 describes Mn-based chelates, their stereoisomers and their properties, including their potential use as MRI contrast agents. In particular, WO2021 / 043926 A1 describes specific diastereomers of Mn-based chelates, and one specific diastereomer ( R,S ) is alleged to exhibit excellent stability.

[0012] The medical need to provide new contrast agents for radiological imaging is clearly unmet, especially for magnetic resonance imaging contrast agents not based on the use of gadolinium. For a long time, there has been a desire to abandon GBCAs and replace them with alternative contrast agents, but this has not been achieved to date. In particular, the long-term medical need for new non-Gd contrast agents for magnetic resonance imaging has increased. In addition, the long-term medical need for new non-Gd contrast agents has increased, and their applicability is not limited to specific uses (such as liver imaging), i.e., multi-purpose applications. Specifically, the medical need to provide new contrast agents for radiological imaging is unmet, which is not based on the use of gadolinium, but preferably exhibits as many of the criteria listed below as possible: Having high water solubility, Being physically and chemically stable, Being sufficiently stable against the release of metal from the chelate, Having a high relaxation rate, Having a low protein binding rate, Excreting rapidly and completely, Having no long-term retention of Mn in tissues and organs, Being stable against metabolic degradation, Being well tolerated, Being capable of being produced in large quantities.

[0013] The above prior art does not disclose the compounds of general formula (I) as defined herein, or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, as described and defined herein. The prior art also does not disclose the compounds of general formula (I) in the form of metal complexes with Mn 2+ , and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof. The compounds of general formula (I) of the present invention and the compounds of general formula (I) in the form of metal complexes with Mn 2+ , and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, are hereinafter collectively or separately referred to as "the compounds of the present invention". The compounds of general formula (I) in the form of complexes with Mn 2+ , and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, may also be referred to as "the Mn 2+ -containing compounds of the present invention".

[0014] It has been discovered, and this forms the basis of the present invention, that the compounds of the present invention possess unexpected and advantageous properties.

[0015] In particular, compounds of general formula (I) of the present invention can be prepared with Mn 2+ The complex, that is, correspondingly with Mn 2+ The invention relates to compounds of general formula (I) in the form of metal complexes, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof. In particular, the invention contains Mn. 2+ The compounds exhibited good stability of macrocyclic GBCAs without many of the drawbacks associated with the use of gadolinium. This invention contains Mn. 2+ The stability of the compounds can be determined through numerous physical and chemical tests, including but not limited to heat, oxidation, pH, and light. Surprisingly, it was found that the stability of the compounds with Mn... 2+ The present invention comprises compounds of general formula (I) in the form of coordination compounds, which include a chiral center on a carbon atom of an α to tertiary nitrogen atom in a 12-membered macrocycle, and thus are capable of having diastereomers exhibiting little or no difference in the advantageous properties of different diastereomers, thereby eliminating the need for tedious, inefficient, and wasteful synthesis and / or isolation of a particular diastereomer. Furthermore, the present invention contains Mn 2+ The compounds exhibit high tolerance, ample relaxation rate, excellent water solubility, and rapid and complete excretion, making them ideal for diagnostic imaging, particularly magnetic resonance imaging. This invention contains Mn. 2+ Increased tolerability of the compound, as shown by cytotoxicity assays, is particularly beneficial, as toxicity has always been a major concern for radiologists and patients. Ongoing assessments of the safety of GBCA have raised public awareness of the potential toxicity and tolerability issues of contrast agents and increased demand for safer, more tolerable products. Summary of the Invention

[0016] According to a first aspect, the present invention includes compounds of general formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0017] in: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is an integer from 1 to 3, and n is an integer from 0 to 5; R 2 R 3 and R 4Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0018] According to the second aspect, the present invention includes Mn 2+ The compounds of the above general formula (I) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0019] As described in this invention, with Mn 2+ Compounds of general formula (I) in the form of complexes, namely those containing Mn in this invention. 2+ The compounds refer to those described below:

[0020] Therefore, according to the second aspect, the present invention includes [the use of] Mn 2+ Compounds of general formula (I) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, in: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group, Where m is an integer from 1 to 3, and n is an integer from 0 to 5; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0021] According to a third aspect, the present invention includes compounds of general formula (II) and compounds with Mn 2+ Compounds of general formula (II) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof,

[0022] in: R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups, where m is an integer from 1 to 3.

[0023] definition The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by a selected specified group, provided that the substitution does not exceed the normal valence of the specified atom under existing conditions. Combinations of substituents and / or variables are permitted.

[0024] The term "optionally substituted" means that the number of substituents can be zero or different from zero.

[0025] Unless otherwise stated, when a group in a compound according to the invention is substituted, the group may be mono- or poly-substituted by a substituent. Within the scope of the invention, the meaning of all repeated groups is independent of each other. A group in a compound according to the invention may be substituted by one, two, or three identical or different substituents, particularly by one substituent.

[0026] If a complex substituent consists of more than one part, such as (C1-C3 alkoxy)-(C2-C6 alkyl)-, then the position of a given part can be at any suitable position on the complex substituent; that is, the C1-C3-alkoxy moiety can be attached to any carbon atom of the C2-C6 alkyl moiety of the (C1-C3 alkoxy)-(C2-C6 alkyl)- group. A hyphen at the beginning or end of such a complex substituent indicates the point of connection between the complex substituent and the rest of the molecule.

[0027] For example, in the context of this invention, a compound of formula (I) may contain a group R. 1 It is -(CH2). m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group, where m is an integer from 1 to 3 and n is an integer from 0 to 5. In R 1 The hyphen at the beginning of the definition indicates that this is the group R. 1 The connection point with the rest of the molecule is via the methylene group "(CH2)" shown below. m "Group:"

[0028] When used in the instruction manual, the term "comprising" includes both "consisting of" and "mainly composed of".

[0029] If any term is referred to as “as described herein” in this document, it means that it may be used anywhere in this document.

[0030] The terms used in this article have the following meanings: The term "halogen atom" refers to a fluorine, chlorine, bromine, or iodine atom, especially a fluorine, chlorine, or bromine atom.

[0031] The term "C1-C6 alkyl" refers to a saturated monovalent hydrocarbon group with a straight or branched chain having 1, 2, 3, 4, 5, or 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 2,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, or its isomers or stereoisomers. In particular, the group has 1, 2, 3 or 4 carbon atoms (“C1-C4-alkyl”), such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl or tert-butyl, and more particularly has 1, 2 or 3 carbon atoms (“C1-C3-alkyl”), such as methyl, ethyl, n-propyl or isopropyl.

[0032] The term "C1-C3-haloalkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the term "C1-C3-alkyl" is as defined above, and wherein one or more hydrogen atoms are substituted with halogen atoms in the same or different ways. In particular, the halogen atom is a fluorine atom. The C1-C3-haloalkyl is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, or 1,3-difluoropropyl-2-yl or other polyfluorosubstituted alkyl groups.

[0033] The term "C2-C6-hydroxyalkyl" refers to a straight-chain or branched saturated monovalent hydrocarbon group, wherein the term "C2-C6-alkyl" is as defined above, and wherein one or more, preferably 1, 2 or 3 hydrogen atoms are substituted with hydroxyl groups, such as 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropyl-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropyl-2-yl, 1,3-dihydroxy-2-(hydroxymethyl)propyl-2-yl, 3-hydroxy-2-methylpropyl, and 2-hydroxy-2-methylpropyl.

[0034] The term “C1-C3-alkoxy” refers to a straight-chain or branched saturated monovalent group of the formula (C1-C3-alkyl)-O-, wherein the term “C1-C3-alkyl” is as defined above, such as methoxy, ethoxy, n-propoxy, or isopropoxy.

[0035] The term "C3-C6 cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing 3, 4, 5, or 6 carbon atoms ("C3-C6 cycloalkyl"). The C3-C6 cycloalkyl is, for example, a monocyclic hydrocarbon ring such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0036] As used herein, the term “C1-C6”, for example in the context of the definition of “C1-C6-alkyl”, refers to an alkyl group having a finite number of carbon atoms, i.e., 1, 2, 3, 4, 5 or 6 carbon atoms.

[0037] Furthermore, as used herein, the term “C3-C6”, for example in the context of the definition of “C3-C6-cycloalkyl”, refers to a cycloalkyl group having a finite number of carbon atoms, i.e., 3, 4, 5 or 6 carbon atoms.

[0038] When a range of values ​​is given, the range includes every value within that range and subranges.

[0039] For example: "C1-C6" includes C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5 and C5-C6; "C1-C4" includes C1, C2, C3, C4, C1-C4, C1-C3, C1-C2, C2-C4, C2-C3 and C3-C4; “C1-C3” includes C1, C2, C3, C1-C3, C1-C2, and C2-C3; "C2-C6" includes C2, C3, C4, C5, C6, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6; and "C3-C6" includes C3, C4, C5, C6, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6.

[0040] The compounds of this invention may contain one or more asymmetric centers, depending on the position and nature of the various substituents desired. The asymmetric carbon atom may exist in an (R) or (S) configuration, which can produce racemic mixtures in which one enantiomer is present in greater quantity than the other, or, in the case of a single asymmetric center, a single enantiomer. In the case of multiple stereocenters, diastereomeric mixtures, single diastereomeric compounds, or single enantiomers can be synthesized. In some cases, asymmetry may also exist due to hindered rotation around a given bond, axial chirality, or coordination of a metallic center.

[0041] Preferred compounds are those that produce more desirable biological activities. Isolation, purification, or partial purification of isomers and stereoisomers, racemic mixtures, or diastereomeric mixtures of the compounds of this invention are also included within the scope of this invention. The purification and isolation of these materials can be accomplished using standard techniques known in the art.

[0042] Optical isomers can be obtained by decomposing racemic mixtures using conventional methods, for example, by forming diastereomer salts or covalent diastereomers using optically active acids or bases. Examples of suitable acids are tartaric acid, diacetyltartaric acid, benzoyltartaric acid, and camphorsulfonic acid. Mixtures of diastereomers can be separated into their individual diastereomers according to their physical and / or chemical differences by methods known in the art, such as chromatography or fractional crystallization. The optically active base or acid is then released from the separated diastereomer salt. Another method for separating optical isomers involves using chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, the optimal choice to maximize enantiomer separation. Suitable chiral HPLC columns are manufactured by Daicel, such as Chiracel OD and Chiracel OJ, which are conventionally optional. Enzymatic separation, with or without derivatization, is also possible. The optically active compounds of the present invention can also be obtained via chiral synthesis using optically active raw materials and / or reagents and catalysts.

[0043] To describe the different types of isomers, refer to Section E of the IUPAC rule (Pure Appl Chem 45, 11-30, 1976).

[0044] This invention includes all possible stereoisomers of the compounds of this invention, as a single stereoisomer, or as any mixture of said stereoisomers, such as R- or S-isomers in any proportion, or diastereomers. The separation of a single stereoisomer of the compounds of this invention, such as a single enantiomer or a single diastereomer, can be achieved by any suitable prior art method as described herein, such as chromatography, particularly chiral chromatography.

[0045] In particular, as described throughout this article, compounds of general formula (I) and those with Mn 2+ The complex form of the general formula (I) compound, that is, the Mn of the general formula (I) compound. 2+ Complexes, including their salts as described below, can exist in different stereoconfigurations (i.e., as different stereoisomers). Therefore, the present invention includes complexes with Mn. 2+ All possible stereoisomers of the general formula (I) compound in its complex form, i.e., Mn of the general formula (I) compound. 2+ All stereoisomers of the complex, either as a single stereoisomer or as a mixture of two or more of the stereoisomers in any proportion.

[0046] In particular, as described throughout this article, compounds of general formula (I) and those with Mn 2+ The complex form of the general formula (I) compound, that is, the Mn of the general formula (I) compound. 2+ Complexes, including their salts as described below, exhibit a chiral center on a carbon atom located at an α to tertiary nitrogen atom in a 12-membered macrocycle, as shown below*:

[0047] These carbon atoms can be in (R) or (S) configuration. Therefore, as described throughout this document, the invention includes all compounds of general formula (I) and those related to Mn. 2+ The complex form of the general formula (I) compound, that is, the Mn of the general formula (I) compound. 2+ Complexes, including their salts as described below, wherein the carbon atoms are in (R) or (S) configuration. Depending on their configuration, different diastereomers and / or enantiomers may exist. This invention includes RR, SS, RS, and SR stereoisomers of compounds of formula (I), and those with Mn 2+ The complex form of the general formula (I) compound, that is, the Mn of the general formula (I) compound. 2+ The complexes, including the RR, SS, RS, and SR stereoisomers, are described in full in this paper.

[0048] In particular, as described throughout this article, compounds of general formula (II) and those with Mn 2+ The complex form of general formula (II) compounds, that is, Mn of general formula (II) compounds. 2+ Complexes, including their salts as described below, exhibit a chiral center on a carbon atom located at an α to tertiary nitrogen atom in a 12-membered macrocycle, as shown below*:

[0049] These carbon atoms can be in (R) or (S) configuration. Therefore, as described throughout this document, the invention includes all compounds of general formula (II) and those related to Mn. 2+ The complex form of general formula (II) compounds, that is, Mn of general formula (II) compounds. 2+ Complexes, including their salts as described below, wherein the carbon atoms are in (R) or (S) configuration. Depending on their configuration, different diastereomers and / or enantiomers may exist. This invention includes RR, SS, RS, and SR stereoisomers of compounds of formula (II), and those with Mn 2+ The complex form of general formula (II) compounds, that is, Mn of general formula (II) compounds. 2+ The complexes, including the RR, SS, RS, and SR stereoisomers, are described in full in this paper.

[0050] Given the chiral nature of chelating agents, it is important that the stereochemical centers remain stable under the diverse chemical and / or physical conditions that may arise during the development, production, transportation, and / or administration of any drug that may contain them. However, if any, i.e., if one or more, the chiral centers undergo conformational changes, it is crucial not to form diastereomers with undesirable or even harmful properties. For example, in the critical step of preparing sterile solutions of contrast agents under high temperature and / or high pressure—autoclaving—it is important not to form compounds with undesirable or even harmful properties—whether byproducts or other diastereomers.

[0051] Furthermore, the compounds of the present invention can exist as N-oxides, which are defined as compounds of the present invention in which at least one nitrogen atom is oxidized. The present invention includes all such possible N-oxides.

[0052] The present invention also relates to available forms of the compounds disclosed herein, such as hydrates, solvates, salts, and in particular pharmaceutically acceptable salts and coprecipitates.

[0053] The compounds of the present invention can exist as hydrates or solvates, wherein the compounds of the present invention contain a polar solvent, particularly water, methanol, or ethanol, for example as a structural element of the compound lattice. The amount of the polar solvent, particularly water, can be present in stoichiometric or non-stoichiometric proportions. Regarding stoichiometric solvates, such as hydrates, they can be hemi-, semi-, mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates or hydrates. The present invention includes all such hydrates or solvates.

[0054] Furthermore, the compounds of the present invention can be based on the substituent R 1 R 2 R 3 and R 4 The property is that it exists in the form of a salt. The salt can be an inorganic or organic addition salt, particularly any pharmaceutically acceptable inorganic or organic addition salt commonly used in pharmaceutical preparations.

[0055] The term "pharmaceuticalally acceptable salt" refers to a relatively non-toxic, inorganic or organic acid addition salt of the compounds of the present invention. See, for example, SM Berge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. Production of neutral salts, in particular, is described in U.S. Patent No. 5,560,903.

[0056] Pharmaceutically acceptable salts of the compounds of the present invention include salts containing inorganic and / or organic bases or amino acids, particularly physiologically tolerable inorganic and / or organic bases or amino acid cations, for example, especially primary, secondary, or tertiary amine cations. Examples may be, but are not limited to, salts of sodium, lithium, potassium, calcium, magnesium, arginine, lysine, ammonia, creatine, diethanolamine, ethanolamine, morpholine, glucosamine, N,N-dimethylglucosamine, N-methylglucosamine, ornithine, histidine, imidazole, tromethamine, meglumine, etc. Particularly preferred pharmaceutically acceptable salts of the compounds of the present invention are their corresponding sodium salts.

[0057] Those skilled in the art will further recognize that the salt of the claimed compound can be prepared by any of many known methods, through the reaction of the compound with a suitable inorganic or organic base.

[0058] This invention includes all possible salts of the compounds of this invention, as a single salt, or as any mixture of said salts in any proportion.

[0059] In this document, particularly in the experimental section, for the synthesis of intermediates and embodiments of the invention, when the compounds are described as salts of the corresponding bases or acids, the exact stoichiometric composition of the salt forms obtained by the corresponding preparation and / or purification methods is unknown in most cases.

[0060] This similarly applies to situations where synthetic intermediates or example compounds or their salts are obtained as solvates by the preparation and / or purification methods described above, such as hydrates having (if defined) unknown stoichiometric compositions.

[0061] Further embodiments of the present invention According to a further embodiment of the first aspect, the present invention includes compounds of the above general formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is an integer from 1 to 2, and n is an integer from 1 to 4; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0062] According to a further embodiment of the first aspect, the present invention includes compounds of the above general formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH- group Where m is 2 and n is an integer from 2 to 4; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0063] According to a further embodiment of the first aspect, the present invention includes compounds of the above general formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is an integer from 2 to 4; R 2 R 3 and R 4 Each is an independent hydrogen atom.

[0064] According to a further embodiment of the first aspect, the present invention includes compounds of the above general formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is 4; R 2 R 3 and R 4 Each is an independent hydrogen atom.

[0065] According to a further embodiment of the second aspect, the present invention includes [the following] with Mn 2+ The compounds of general formula (I) above in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1-(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is an integer from 1 to 2, and n is an integer from 1 to 4; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0066] According to a further embodiment of the second aspect, the present invention includes [the following] with Mn 2+ The compounds of general formula (I) above in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is an integer from 2 to 4; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0067] According to a further embodiment of the second aspect, the present invention includes [the following] with Mn 2+ The compounds of general formula (I) above in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is an integer from 2 to 4; R 2 R 3 and R 4 Each is an independent hydrogen atom.

[0068] According to a further embodiment of the second aspect, the present invention includes [the following] with Mn 2+ The compounds of general formula (I) above in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m-(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is 4; R 2 R 3 and R 4 Each is an independent hydrogen atom.

[0069] According to a further embodiment of the third aspect, the present invention includes compounds of the above general formula (II), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: m is an integer from 1 to 2; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0070] According to a further embodiment of the third aspect, the present invention includes compounds of the above general formula (II), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: m is an integer from 1 to 2; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms and C1-C3 alkyl groups.

[0071] According to a further embodiment of the third aspect, the present invention includes compounds of the above general formula (II), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: m is 2; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms and C1-C3 alkyl groups.

[0072] According to a further embodiment of the third aspect, the present invention includes compounds of the above general formula (II), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: m is 2; R 2 R 3 and R 4 Each is an independent hydrogen atom.

[0073] According to a further embodiment of the third aspect, the present invention includes Mn 2+The compounds of general formula (II) above in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: m is an integer from 1 to 2; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0074] According to a further embodiment of the third aspect, the present invention includes Mn 2+ The compounds of general formula (II) above in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: m is an integer from 1 to 2; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms and C1-C3 alkyl groups.

[0075] According to a further embodiment of the third aspect, the present invention includes Mn 2+ The compounds of general formula (II) above in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: m is 2; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms and C1-C3 alkyl groups.

[0076] According to a further embodiment of the third aspect, the present invention includes Mn 2+ Compounds of general formula (II) above in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: m is 2; R 2 R 3 and R 4 Each is an independent hydrogen atom.

[0077] In a further embodiment of the first aspect, the present invention relates to compounds of formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n-CH2OH group Where m is an integer from 1 to 3, and n is an integer from 1 to 4.

[0078] R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is an integer from 1 to 2, and n is an integer from 1 to 4. And its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0079] In a further embodiment of the first aspect, the present invention relates to compounds of formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is an integer from 2 to 4.

[0080] In a further embodiment of the first aspect, the present invention relates to compounds of formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is 4.

[0081] In a further embodiment of the first aspect, the present invention relates to compounds of formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0082] In a further embodiment of the first aspect, the present invention relates to compounds of formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 2 R 3 and R 4Each is independently selected from hydrogen atoms and C1-C3 alkyl groups.

[0083] In a further embodiment of the first aspect, the present invention relates to compounds of formula (I), and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 2 R 3 and R 4 Each is an independent hydrogen atom.

[0084] It should be understood that the present invention also relates to any combination of the above embodiments.

[0085] Another embodiment of the first aspect is a compound of formula (II), which is 2-[9-(1,3-dicarboxypropyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl]glutaric acid and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0086] Another embodiment of the third aspect is a compound of formula (II), selected from 2-[9-(1,3-dicarboxypropyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3-yl]glutaric acid, (2 R ,2' R )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentanoic acid, (2 S ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentadiic acid and (2 R ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentanoic acid And its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0087] In a further embodiment of the second aspect, the present invention relates to Mn 2+ Compounds of formula (I) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is an integer from 1 to 3, and n is an integer from 1 to 4.

[0088] R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is an integer from 1 to 2, and n is an integer from 1 to 4; And its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0089] In a further embodiment of the second aspect, the present invention relates to Mn 2+ Compounds of formula (I) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is an integer from 2 to 4.

[0090] In a further embodiment of the second aspect, the present invention relates to Mn 2+ Compounds of formula (I) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group Where m is 2 and n is 4.

[0091] In a further embodiment of the second aspect, the present invention relates to Mn 2+ Compounds of formula (I) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

[0092] In a further embodiment of the second aspect, the present invention relates to Mn 2+ Compounds of formula (I) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 2 R 3 and R 4 Each is independently selected from hydrogen atoms and C1-C3 alkyl groups.

[0093] In a further embodiment of the second aspect, the present invention relates to Mn 2+ Compounds of formula (I) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein: R 2 R 3 and R 4 Each is an independent hydrogen atom.

[0094] It should be understood that the present invention also relates to any combination of the above embodiments.

[0095] Another implementation plan in the second aspect is with Mn 2+ The complex form of the compound of formula (I) is selected from 4-carboxy-2-[9-(3-carboxy-1-carboxypropyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3-yl]manganese butyrate(2+), 2-[9-(1-carboxypropyl-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl]-5-oxo-5-{[(2 S ,3 R 4 R 5 R Manganese (2+)-2,3,4,5,6-pentahydroxyhexyl]aminovalerate, and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0096] Another implementation plan in the second aspect is with Mn 2+ Compounds of formula (I) in the form of coordination compounds, selected from... 2-[9-(1-carboxylate-4-oxo-4-{[(2 S ,3R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl]-5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+), (2 R ,2' R )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]bis(5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+), (2 S ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]bis(5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+), (2 R )-2-{9-[(1 S )-1-carboxylate-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl}-5-oxo-5-{[(2 S ,3 R 4 R 5 R Manganese (2+)-2,3,4,5,6-pentahydroxyhexyl]aminovalerate (a mixture of stereoisomers) [(2 R )-2-{(3 R 9 S )-9-[(1S )-1-(carboxyl-κO)-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl-κ 4 N 3 , N 9 , N 15 , O 6}-5-Oxy-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}valerate (2-)-κO]manganese (isomer 1 ( RS ))and [(2 S )-2-{(3 R 9 S )-9-[(1 R )-1-(carboxyl-κO)-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl-κ 4 N 3 , N 9 , N 15 , O 6}-5-Oxy-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}valerate (2-)-κO]manganese (isomer 2 ( SR )) And its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0097] Another implementation plan in the third aspect is with Mn 2+Compounds of formula (II) in the form of coordination compounds, selected from 4-Carboxy-2-[9-(3-carboxy-1-carboxypropyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl]manganese butyrate(2+), Manganese(2+) Sodium(2) R ,2' R )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentadiate (1 / 2 / 1), Manganese(2+) Sodium(2) S ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentadiate (1 / 2 / 1) and Manganese(2+) Sodium(2) R )-2-{9-[(1 S [-1,3-dicarboxylic acid propyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1 (15),11,13-trien-3-yl}glutarate (1 / 2 / 1) And its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0098] According to another aspect, the present invention includes a method for preparing the compounds of the present invention, the method comprising the steps described in the experimental section herein.

[0099] According to a further aspect, the present invention includes intermediate compounds suitable for preparing compounds of general formula (I), particularly suitable for preparing the above-mentioned compounds with Mn 2+ Compounds of general formula (I) in the form of coordination compounds.

[0100] More specifically, the present invention includes the intermediate compounds disclosed in the Experimental Section below.

[0101] In particular, the present invention relates to Mn 2+ The compound of formula (I) in its complex form can be used as a contrast agent in contrast-enhanced MRI (CE-MRI), preferably for multipurpose MRI.

[0102] A further aspect of the invention is the use of the compounds of the above general formula (I) for diagnostic imaging.

[0103] Those skilled in the art will recognize that the compounds of general formula (I) of the present invention can be used with alternatives to Mn. 2+Other MR active metal ions are used in combination, and these compounds are also included in this invention.

[0104] A further aspect of the invention is with Mn 2+ The compounds of the above general formula (I) in the form of coordination compounds are used for diagnostic imaging.

[0105] A further aspect of the present invention is the Mn of the compound of the above general formula (I). 2+ The use of complexes in diagnostic imaging.

[0106] Preferably, the compound of the present invention, i.e., the compound of the above general formula (I) and / or with Mn 2+ The compounds of the above general formula (I) in the form of coordination compounds and / or the Mn of the above general formula (I) compounds 2+ The complex is used for diagnostic purposes, which are performed using magnetic resonance imaging (MRI).

[0107] Preferably, the compound of the present invention, i.e., the compound of the above general formula (I) and / or with Mn 2+ The compounds of the above general formula (I) in the form of coordination compounds and / or the Mn of the above general formula (I) compounds 2+ The complex is used for diagnostic purposes, which are performed using magnetic resonance imaging (MRI).

[0108] A further aspect of the invention is a compound of general formula (I) for diagnostic imaging.

[0109] A further aspect of the invention is for diagnostic imaging with Mn 2+ Compounds of general formula (I) in the form of coordination compounds.

[0110] A further aspect of the invention is the Mn of the above-described general formula (I) compound for diagnostic imaging. 2+ Coordination compounds.

[0111] Those skilled in the art will recognize that the compounds of general formula (I) of the present invention can be used with alternatives to Mn. 2+ Other MR active metal ions are used in combination, and these compounds are also included in this invention.

[0112] The present invention also includes compounds of general formula (I) for use in the manufacture of diagnostic agents.

[0113] The present invention also includes a method for manufacturing diagnostic reagents using Mn. 2+ Compounds of general formula (I) in the form of coordination compounds.

[0114] A further aspect of the invention is the use of compounds of general formula (I) or mixtures thereof in the manufacture of diagnostic agents.

[0115] A further aspect of the invention is with Mn 2+The use of compounds of general formula (I) or mixtures thereof in the form of coordination compounds for the manufacture of diagnostic reagents.

[0116] A further aspect of the invention is the use of compounds of general formula (I) or mixtures thereof in the manufacture of diagnostic agents for magnetic resonance imaging (MRI).

[0117] A further aspect of the invention is with Mn 2+ The use of compounds of general formula (I) or mixtures thereof in the form of complexes for the manufacture of diagnostic agents for magnetic resonance imaging (MRI).

[0118] A further aspect of the invention is a method for imaging a patient's body tissues, comprising the steps of: administering to the patient an effective amount of one or more pharmaceutically acceptable carriers mixed with Mn 2+ The compound of general formula (I) in the form of a complex was then subjected to NMR tomography on the patient.

[0119] A further aspect of the invention is a method for imaging a patient's body tissues, 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. 2+ The complex was then used, and the patient underwent NMR tomography.

[0120] For the manufacture of diagnostic agents, such as those administered to human or animal subjects, with Mn 2+ The complex form of the general formula (I) compound, that is, the Mn of the general formula (I) compound. 2+ The complex or mixture will be suitably formulated with a drug carrier or excipient. The contrast agents of the present invention may suitably contain pharmaceutical formulation adjuvants, such as stabilizers, antioxidants, pH adjusters, metal scavengers, electrolytes (e.g., sodium chloride), flavoring agents, etc. The diagnostic agents of the present invention can be formulated for parenteral or enteral administration or for direct administration into body cavities. For example, in compounds of general formula (I), Mn 2+ In the case of a complex, the parenteral formulation comprises a sterile solution or suspension at a dose of 0.0001-5 mmol manganese / kg body weight, preferably 0.001-0.5 mmol manganese / kg body weight, more preferably 0.005-0.1 mmol manganese / kg body weight of the compound of formula (I) of the present invention. Therefore, the contrast agent of the present invention can be in conventional pharmaceutical formulations, such as solutions, suspensions, dispersions, syrups, etc., in physiologically acceptable carrier media, preferably in water for injection. When the contrast agent is formulated for parenteral administration, it is preferably isotonic or hypertonic and close to pH 7.4.

[0121] In a further aspect, the present invention relates to a method for diagnosing and monitoring the health of a patient. The method comprises a) administering the compound of the invention to a person requiring such a diagnosis to detect the compound in the body, as described above and herein, and b) measuring the signal generated by the administration of the compound to the person, preferably by magnetic resonance imaging (MRI).

[0122] In a further aspect, the present invention relates to a method for diagnosing and monitoring the health of patients. The method comprises a) administering the compound of the invention, i.e., with Mn, to a person requiring such diagnosis. 2+ The compound of general formula (I) in the form of a complex is used to detect the compound in the human body, as described above and herein, and b) to measure the signal generated by the administration of the compound to a human body, preferably by magnetic resonance imaging (MRI).

[0123] In a further aspect, the present invention relates to a method for diagnosing and monitoring the health of a patient. The method comprises a) administering to a person requiring such a diagnosis the compound of the present invention, namely, Mn of the compound of general formula (I). 2+ The compound is used to detect compounds in the human body, as described above and herein, and b) to measure the signal produced by administering the compound to a human, preferably by magnetic resonance imaging (MRI).

[0124] Universal synthesis With Mn 2+ Compounds of general formula (I) in their complex form can be produced using the general process described in Scheme 1 below. Unless otherwise stated, R shown therein... 1 To R 4 The m group has the meaning given in the above specification. If the introduction of YCHCOOH requires protecting group chemistry, R can be used. 5 Group. Therefore, if protecting group chemistry is not required, R 5 The group is equal to H, usually, but not only, R. 5 Selected from methyl, ethyl or tert-butyl.

[0125]

[0126] Option 1 For example, commercially available bis-(2-aminoethyl)-ethers can be nosylated or nitrosulfonated with the corresponding bromide or chloride in the presence of a base such as potassium carbonate or sodium carbonate. Cyclolation with active pyridines such as 2,6-bis(chloromethyl)pyridine (CAS 3099-28-3) or 2,6-bis(bromomethyl)pyridine (CAS 7703-74-4) can be carried out in the presence of a base such as potassium carbonate or sodium carbonate. Removal of the p-toluenesulfonyl group using concentrated sulfuric acid or treatment of bis-nitrosulfonates with thiophenol and a base releases the free diamine. Alkylation with α-halo- or α-sulfonyl-bis-carboxylic esters or nitriles can be carried out in the presence of a base such as potassium carbonate or sodium carbonate. After deprotection, complexation can be carried out in aqueous solutions at 50°C to 110°C and pH 5 to 12 using MnCl2. Activation of non-manganese-bound carboxylates with peptide reagents such as EDCl and / or HOBT allows for coupling with a suitable amine to yield the desired compound of formula I. Literature on the synthetic process shown in Scheme 1 can be found in (see, for example, WO 2017 / 089849, WO 2019 / 122255, J. Henig, E. Toth, J. Engelmann, S. Gottschalk, H. Mayer, H. Inorganic Chemistry 2010, 49(13), 6124-38, EP2457914 B1).

[0127] The above schemes and processes illustrate the synthetic route of the compounds of general formula (I) of the present invention and are not intended to be limiting. It will be apparent to those skilled in the art that the transformation sequence exemplified in the schemes can be modified in various ways. Therefore, the transformation sequence exemplified in the schemes is not intended to be limiting. Suitable protecting groups and their introduction and dissociation are well known to those skilled in the art (see, for example, TW Greene and PGM Wuts in...). Protective Groups in Organic Synthesis (3rd edition, Wiley 1999). Specific embodiments are described in subsequent paragraphs. Attached Figure Description

[0128] Figure 1 Chemical stability of the selected examples during heat sterilization. HPLC-ESI-MS chromatograms of Examples 8 and 9 and Reference Compound 3 before and after autoclaving (1 bar, 121°C, 20 min). All compounds were studied at a concentration of 1 mmol / L in 10 mM Tris-HCl buffer at pH 7.4.

[0129] Figure 2 Using 18 equivalents of Zn 2+ After adding ZnCl2, Examples 4, 6, 8 and 9 ( Figure 2 A) and reference compounds 1-4 ( Figure 2 B) Complex stability. The percentage of intact Mn chelates was measured over 24 hours. Measurements were performed using 100 mM BIS-TRIS at pH 7.

[0130] Figure 3 The stability of the Mn chelate complex in human plasma in Example 2 was described as the change in relaxation time measured over 24 hours. Figure 3 A) and the percentage of intact Mn chelates ( Figure 3 B). The test items were studied in human plasma containing heparin anticoagulants at a concentration of 100 µmol / L.

[0131] Figure 4 In vitro cytotoxicity of SH-SY5Y cells. Percentage of viable cells after incubation with the Mn chelate of Example 2 or the reference compound (a mixture of RC1-4). All compounds were tested at concentrations of 1 mmol / L and 5 mmol / L for 24 hours.

[0132] Figure 5 The change in plasma manganese levels over time after rats were injected with a dose of 0.1 mmol Mn / kg of the Mn chelate (Example 4).

[0133] Experimental Section Chemical names are generated using ACD / Labs' ACD / Name software. In some cases, the generally accepted name of a commercially available reagent is used instead of the name generated by ACD / Name.

[0134] Table 1 below lists the abbreviations used in this paragraph and the Examples section, which are not explained in the text. Other abbreviations have their own meanings as commonly known to those skilled in the art.

[0135] Table 1: Abbreviations

[0136]

[0137]

[0138]

[0139]

[0140] The various aspects of the present invention described in this application are illustrated by the following embodiments, which are not intended to limit the invention in any way.

[0141] The examples and experiments described herein are for illustrative purposes only, and the invention is not limited to the examples given.

[0142] Experimental Section - General Section All reagents not described in the experimental section are commercially available, or are known compounds, or can be formed by those skilled in the art from known compounds using known methods.

[0143] The compounds and intermediates produced by the method according to the invention may require purification. Those skilled in the art are familiar with the purification of organic compounds, and there are various methods for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, impurities can be removed by using a suitable solvent. In some cases, the compound can be purified by chromatography, particularly rapid column chromatography, using, for example, a pre-packed silica column, such as the Biotage SNAP column KP-Sil. ® or KP-NH ® With Biotage Automated Purification System (SP4) ® Or IsoleraFour ® The eluent and eluent can be a gradient of hexane / ethyl acetate or DCM / methanol. In rapid column chromatography, unmodified (“conventional”) silica gel as well as amino-phase functionalized silica gel can be used. Conventional silica gel is used if the experimental section mentions rapid column chromatography or rapid chromatography without specifying a stationary phase.

[0144] In some cases, compounds can be purified by preparative HPLC using, for example, a Waters automated purifier equipped with a diode array detector and / or an online electrospray ionization mass spectrometer, with a suitable pre-packed reversed-phase column and an eluent, such as a gradient of water and acetonitrile, which may contain additives such as trifluoroacetic acid, formic acid, or ammonia.

[0145] In some cases, the purification methods described above can provide the compounds of the present invention in salt form with sufficient basic or acidic functionality, for example, if the compounds of the present invention are sufficiently basic, such as trifluoroacetate or formate, or if the compounds of the present invention are sufficiently acidic, such as ammonium or sodium salts. Salts of this type can be converted to their free basic or free acidic forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent bioassays. It should be understood that the specific forms (e.g., salts, free acids, etc.) of the compounds of the present invention as described and isolated herein are not necessarily the only forms in which the compounds can be used for physicochemical or bioassays to characterize their properties.

[0146] Analytical LC-MS methods Method 1 Instruments: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7µm, 50×2.1 mm; Eluent A: Water + 0.2 vol. % ammonia (32%), Eluent B: Acetonitrile; Gradient: 0–1.6 min 1–99% B, 1.6–2.0 min 99% B; Flow rate: 0.8 mL / min; Temperature: 60℃; Injection: 2 µL; DAD scan: 210–400 nm; ELSD.

[0147] Method 2 Instruments: Waters Acquity UPLC-MS SQD 3001; Column: Acquity UPLC BEH C18 1.7µm, 50×2.1 mm; Eluent A: Water + 0.1 vol. % formic acid (99%), Eluent B: Acetonitrile; Gradient: 0–1.6 min 1–99% B, 1.6–2.0 min 99% B; Flow rate: 0.8 mL / min; Temperature: 60℃; Injection: 2 µL; DAD scan: 210–400 nm; ELSD.

[0148] Method 3 Instrument: SHIMADZU LCMS-2020; Column: Kinetex EVO C18, 5 µm, 30×2.1 mm; Mobile phase A: water + 0.0375 vol% TFA, B: acetonitrile + 0.01875 vol% TFA; Gradient: 0.01 min 5.00% B → 0.80 min 95.0% B → 1.20 min 95.0% B → 1.21 min 5.00% B → 1.55 min 5.00% B; Flow rate: 1.5 mL / min; Column temperature: 50℃; UV detection: PAD (220 nm and 254 nm).

[0149] Method 4 Instrument: SHIMADZU LCMS-2020, LabSolution Version 5.99 SP2; Column: HALO C 18 3.0 × 30 mm, 5 μm mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in acetonitrile (v / v); column oven temperature: 50℃; flow rate (1.5 mL / min), B: 0-0.50 min: 0-60%, 0.50-0.80 min: 60-60%, 0.80-0.81 min: 0%, 0.81-1.05 min: 0-0%.

[0150] Method 5 Instrument: SHIMADZU LCMS-2020, LabSolution Version 5.99 SP2; Column: HALO C 18 3.0 × 30 mm, 5 μm; Mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in acetonitrile (v / v); Column oven temperature: 50℃; Flow rate (1.5 mL / min), B: 0-0.50 min: 5-95%, 0.50-0.80 min: 95-95%, 0.80-0.81 min: 95-5%, 0.81-1.05 min: 5-5%.

[0151] Ion chromatography - quantification Quantitative analysis of cations and anions was performed using the external standard method; Instrument: Thermo Scientific ICS 5000+; Capillary ion chromatography columns: IonPac AS11-HC and IonPac CS16; Eluent: Gradient eluent water [H] + [OH] - Detector: Conductivity Detection Experimental Section - Intermediates Intermediate 1 2-[9-(4-methoxy-1-methoxycarbonyl-4-oxo-butyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(14),11(15),12-trien-3-yl]dimethyl glutarate

[0152] Potassium carbonate (55.3 g, 400 mmol) and dimethyl 2-bromoglutarate (33.5 g, 140 mmol) were added to a MeCN (600 mL) solution of 6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (CAS RN2098905-67-8, as a 3HBr salt, 30.0 g, 66.7 mmol). The mixture was stirred at 25 °C for 12 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (silica gel, dichloromethane / methanol 10 / 1) to give 21 g of the crude title compound as a yellow oil. Further purification by preparative HPLC (column: Phenomenex Luna C18 (250 × 80 mm, 15 μm); mobile phase: [water (TFA)-MeCN]; B%: 15%–45%, 20 min) yielded the TFA salt of the title compound as a yellow oil (18.0 g, 17.3 mmol, 33% yield, 83.0% purity, 3TFA).

[0153] LCMS (Method 3): R t = 0.631 min, m / z = 524.3 [M+H] + .

[0154] 1 H NMR: (400 MHz, CDCl3) δ 8.39-8.29 (m, 1H), 7.69-7.27 (m, 2H), 4.48-4.39 (m, 4H), 3.73-3.69 (m, 6H), 3.68-3.63 (m, 2H), 3.63-3.62 (m, 6H), 3.48-3.42 (m, 4H), 3.03-2.99 (m, 4H), 2.51-2.46 (m, 4H), 2.14-2.12 (m, 2H), 2.10-1.95 (m, 2H) ppm.

[0155] Intermediate 2 2-[9-(1,3-dicarboxypropyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl]glutaric acid

[0156] Dimethyl 2-[9-(4-methoxy-1-methoxycarbonyl-4-oxo-butyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(14),11(15),12-trien-3-yl]glutarate (intermediate 1, 18.0 g, 20.8 mmol, 3 TFA) was stirred in an aqueous HCl solution (6.00 M, 180 mL) at 80 °C for 5 h. The reaction mixture was lyophilized to give a yellow solid. The residue was purified by preparative HPLC (column: Phenomenex Luna C18, 10 µm, 250 × 80 mm; mobile phase: [water (HCl)-MeCN]; B%: 0%–20%, 20 min) to give 8.7 g of the HCl salt of the title compound (72% yield, 99% purity).

[0157] LC-MS (Method 3): R t = 0.49 min; MS (ESIpos): m / z = 468.2 [M+H] + .

[0158] Intermediate 3 (2 R Dimethyl 2-hydroxyglutarate

[0159] To (2) R HCl (12 M, 384 μL, 4.6 mmol) was added to a MeOH solution (240 mL) of 5-oxotetrahydrofuran-2-carboxylic acid (30.0 g, 230 mmol). The mixture was stirred at 65 °C for 12 h. NaHCO3 was added to the reaction mixture and the mixture was stirred at 20 °C for 2 h. After adding silica gel powder, the mixture was concentrated under reduced pressure to give the residue. The crude product was purified by column chromatography (silica gel, hexane / EtOAc, 0% to 50%) and concentrated under reduced pressure to give the title compound (37.8 g, 93% yield) as a pale yellow oil.

[0160] 1 H NMR: (400 MHz, CDCl3) δ 4.21-4.22 (m, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.03-3.04 (m, 1H), 2.42-2.49 (m, 2H), 2.10-2.19 (m, 1H), 1.85-1.97 (m,1H) ppm.

[0161] Intermediate 4 (2S Dimethyl 2-hydroxyglutarate

[0162] To (2) S HCl (12 M, 384 μL) was added to a MeOH (240 mL) solution of 30.0 g (230 mmol) of 5-oxotetrahydrofuran-2-carboxylic acid. The mixture was stirred at 65 °C for 12 h. NaHCO3 was added to the reaction mixture, and the resulting mixture was stirred at 20 °C for 2 h. Silica gel powder was added, and the mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by column chromatography (silica gel, hexane / EtOAc, 0% to 50%) to give 38.4 g of the title compound as a pale yellow oil (94.5% yield).

[0163] 1 H NMR: (400 MHz, CDCl3) δ 4.22 - 4.25 (m, 1H), 3.79 (s, 3H), .3.67(s, 3H), 2.70 (s, 1H), 2.44-2.51 (m, 2H), 2.10-2.25 (m, 1H), 1.92-1.96 (m,1H) ppm.

[0164] Intermediate 5 (2 S )-2-{[(trifluoromethyl)sulfonyl]oxy}dimethyl glutarate

[0165] To (2) S TEA (35.9 g, 355 mmol, 49.5 mL) was added to a DCM (250 mL) solution of dimethyl 2-hydroxyglutarate (25.0 g, 141 mmol, intermediate 4). The mixture was cooled to -40 °C, and then Tf₂O (46.1 g, 163.64 mmol, 27.0 mL) was added dropwise at -40 °C. The mixture was stirred at -40 °C for 40 min. The color of the reaction mixture changed from pale yellow to deep red. The reaction mixture was used directly without purification.

[0166] Intermediate 6 (2 R )-2-{[(trifluoromethyl)sulfonyl]oxy}dimethyl glutarate

[0167] With (2) RThe title compound was prepared by analogy with intermediate 5, using dimethyl 2-hydroxyglutarate (intermediate 3) as the starting material.

[0168] Intermediate 7 (2 R )-2-{9-[(1 R [4-methoxy-1-methoxycarbonyl-4-oxo-butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(14),11(15),12-trien-3-yl]dimethyl glutarate

[0169] At -40℃, towards (2) S Dimethyl glutarate (44 g, 142 mmol, intermediate 5) was added to a mixture of 6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (CAS RN 2098905-67-8 as 3HBr salt, 20 g, 44.4 mmol) and triethylamine (67.6 g, 668 mmol, 93 mL) in DCM (600 mL). The mixture was heated to room temperature and stirred at 20 °C for 10 hours. The mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (1000 mL), and the aqueous phase was extracted with EtOAc (3 × 200 mL) and then extracted with DCM (3 × 300 mL). The combined organic phases were washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (silica gel, DCM / MeOH, 1% to 10%), followed by preparative reversed-phase HPLC (water + TFA / MeCN). The product containing the distillate was concentrated under reduced pressure to remove MeCN. NaHCO₃ aqueous solution was added to adjust the pH to 7.5. The mixture was then extracted with DCM (3 × 30 mL). The combined organic layers were washed with 50 mL brine, dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue (5.70 g, 10.8 mmol). The residue was purified by preparative-SFC (column: DAICL CHIRALPAK AS 250 mm × 30 mm, 10 µm; mobile phase: CO₂ / 10% EtOH (0.1% isopropylamine), isocratic elution mode) to give 4.3 g of the title compound as a yellow oil (18% yield).

[0170] LCMS (Method 5): R t= 0.427 min; MS (ESIpos): m / z = 524.3[M+H] + .

[0171] 1 H NMR: (400 MHz, CDCl3) δ 7.53 (s, 1H), 7.02-7.06 (m, 2H), 3.95-3.98(m, 2H), 3.75 (s, 7H), 3.63 (s, 6H), 3.51 (s, 2H), 3.25 (s, 3H), 3.02-3.09(m, 2H), 2.72-2.90 (m, 2H), 2.41-2.66 (m, 5H), 1.95-2.25 (m, 5H) ppm.

[0172] Intermediate 8 (2 S )-2-{9-[(1 S [4-methoxy-1-methoxycarbonyl-4-oxo-butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(14),11(15),12-trien-3-yl]dimethyl glutarate

[0173] At -40℃, towards (2) RDimethyl glutarate (44 g, 142 mmol, intermediate 5) was added to a mixture of 6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-triene (CAS RN 2098905-67-8 as a 3HBr salt, 20 g, 44.4 mmol) and triethylamine (67.6 g, 668 mmol, 93 mL) in DCM (600 mL). The mixture was heated to room temperature and stirred at 20 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to give a residue. Ethyl acetate (500 mL) was added to the residue, the resulting mixture was filtered, and the filtrate was concentrated under reduced pressure to give a residue. The residue was diluted with ethyl acetate (500 mL), washed with water (3 × 300 mL) and brine (500 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, DCM / MeOH, 0% to 5%). Subsequently, it was purified by SFC (column: DAICL CHIRALPAK AS 250 mm × 30 mm, 10 µm; mobile phase: CO₂ / 10% EtOH (0.1% diethylamine); isocratic elution mode) to give 9.2 g of the title compound as a brown oil (39% yield).

[0174] LC-MS (Method 5): R t = 0.418 min; MS (ESIpos): m / z = 524.3 [M+H] + .

[0175] 1 H NMR: (400 MHz, CDCl3) δ 7.52-7.72 (m, 3H), 4.10-4.46 (m, 1H), 4.97-4.09(m, 1H) 3.64 (s, 6H), 3.06 (m, 2H), 3.07-3.10 (m, 1H), 2.61-2.98 (m, 4H), 2.50-2.52 (m, 4H), 2.46-2.48 (m, 4H), 1.72-2.20 (m, 10H) ppm.

[0176] Intermediate 9 (2 R Dimethyl glutarate 2-(6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(14),11(15),12-trien-3-yl)glutarate

[0177] At -40 °C, 60 g (133 mmol) of 6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-triene (CAS RN 2098905-67-8 as a 3HBr salt, 60 g, 133 mmol) and TEA (202 g, 2.00 mol, 278 mL) in DCM (600 mL) solution were added (2 S A solution of dimethyl glutarate (41.1 g, 133 mmol, intermediate 5) in DCM (240 mL) was prepared and stirred at -40 °C for 1 h, followed by stirring for 4 h while the temperature was raised from -40 °C to 0 °C. The reaction mixture was quenched with MeOH (100 mL) and concentrated to give the residue. The residue was purified by column chromatography (silica gel, DCM / MeOH, 0% to 10%), followed by preparative HPLC (TFA conditions). The product containing the distillate was concentrated under reduced pressure to remove MeCN, and then extracted with DCM / i-PrOH, 3:1 (3 × 1.0 L). The organic phase was concentrated to give 21 g of the title compound as a yellow oil (43.1% yield).

[0178] LC-MS (Method 4): R t = 0.408 min; MS (ESIpos): m / z = 366.2 [M+H] + .

[0179] 1 H NMR: (400 MHz, CDCl3) δ 7.60 (t, 1H), 7.04-7.10 (m, 2H), 5.30-5.56(m, 1H), 4.23-4.24 (m, 1H), 4.02-4.18 (m, 2H), 3.90 (s, 1H), 3.80 - 3.84 (m,1H), 3.76 (br s, 3H), 3.60 (br s, 3H), 2.74 - 3.46 (m, 9H), 2.56 (dt, 1H),2.08 - 2.24 (m, 1H), 1.85 - 2.01 (m, 1H) ppm.

[0180] Intermediate 10 (2 R )-2-{9-[(1 S[4-methoxy-1-methoxycarbonyl-4-oxo-butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(14),11(15),12-trien-3-yl]dimethyl glutarate

[0181] At -40℃, (2) R A solution of 2-(6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(14),11(15),12-trien-3-yl)dimethyl glutarate (20 g, 54.7 mmol, intermediate 9) and TEA (11.1 g, 109 mmol, 15.2 mL) in DCM (210 mL) was added to (2 R In a DCM (150 mL) solution of dimethyl glutarate (25.3 g, 82.1 mmol, intermediate 6) of 2-{[(trifluoromethyl)sulfonyl]oxy}, the mixture was stirred for 1 hour while the temperature of the combined mixture was raised to 20 °C. Stirring was continued at 20 °C for 3 hours. The reaction mixture was concentrated to obtain a residue, which was dissolved in EtOAc (500 mL) and washed with water (3 × 300 mL). The organic phase was washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated to obtain the residue. The residue was purified by column chromatography (silica gel, DCM / MeOH, 0% to 5%), followed by purification by SFC (column: DAICEL CHIRALCEL OJ, 250 mm × 30 mm, 10 µm); mobile phase: (CO2 / 10% i-PrOH (0.1% NH3H2O), isocratic elution mode) to give 6.6 g of the title compound as a brown oil (61.7% yield).

[0182] LC-MS (Method 4): R t = 0.439 min; MS (ESIpos): m / z = 524.3 [M+H] + .

[0183] 1H NMR: (400 MHz, CDCl3) δ 8.22 - 8.43 (m, 1H), 7.55 - 7.80 (m, 2H), 4.44 (br s, 3H), 3.74 (s, 6H), 3.65 (s, 8H), 3.49 - 3.59 (m, 2H), 3.38 (d,2H), 3.03 (q, 6H), 2.44 - 2.59 (m, 4H), 2.09 - 2.18 (m, 2H), 1.91 - 2.02 (m,2H) ppm.

[0184] Intermediate 11 (2 R ,2' R )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentanoic acid

[0185] (2) R )-2-{9-[(1 R A solution of dimethyl 4-methoxy-1-methoxycarbonyl-4-oxo-butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(14),11(15),12-trien-3-yl}glutarate (4.3 g, 8.21 mmol, intermediate 7) in HCl (9 M, 43 mL, 387 mmol) was stirred at 100 °C for 12 h. The mixture was diluted with 100 mL H2O and lyophilized to give 4.7 g of the title compound as a grayish-white solid (99% yield, 99% purity, 3HCl).

[0186] LC-MS (Method 4): R t = 0.361 min MS (ESIpos): m / z = 468.1[M+H] + .

[0187] 1 H NMR: (400 MHz, DMSO- d6) δ 8.45 (t, 1H), 7.85 (d, 2H), 5.38-6.55 (m,5H), 4.41-4.55 (m, 4H), 3.50-3.57 (m, 2H), 3.25-3.48 (m, 4H), 2.82-3.14 (m,4H), 2.20-2.38 (m, 3H), 1.65-2.10 (m, 5H) ppm.

[0188] Optical rotation: [α] D = +1.569° (c = 1.12 mg / ml, water).

[0189] Intermediate 12 (2 S ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentanoic acid

[0190] (2) S )-2-{9-[(1 S A solution of dimethyl 4-methoxy-1-methoxycarbonyl-4-oxo-butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(14),11(15),12-trien-3-yl}glutarate (9.2 g, 17.5 mmol, intermediate 8) in HCl (9 M, 92 mL, 828 mmol) was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (HCl conditions) to give 7.5 g of the title compound as a pale yellow solid (74% yield, 99.5% purity, 3HCl).

[0191] LC-MS (Method 4): R t = 0.361 min MS (ESIpos): m / z = 468.1[M+H] + .

[0192] 1 H NMR: (400 MHz, DMSO- d6) δ 8.43 (s, 1 H), 7.85 (d, 2H), 4.41-4.55 (m, 4H), 3.45-3.75 (m, 4H), 3.34 (s, 5H), 3.02 (s, 2H), 2.18-2.40 (m, 3H),1.65-2.10 (m, 5H) ppm.

[0193] Optical rotation: [α] D = -1.427° (c = 1.01 mg / ml, water).

[0194] Intermediate 13 (2 R ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentanoic acid

[0195] (2) R )-2-{9-[(1 S A solution of dimethyl 4-methoxy-1-methoxycarbonyl-4-oxo-butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(14),11(15),12-trien-3-yl}glutarate (6.6 g, 12.6 mmol) in HCl (9 mol / L, 66.0 mL, 47.1 equivalents) was stirred at 100 °C for 12 h. The reaction mixture was diluted with H2O (200 mL), and the crude product was lyophilized to give 6.0 g of the title compound as a gray solid (81% yield, 98.4% purity, 3HCl).

[0196] LC-MS (Method 4): R t = 0.359 min MS (ESIpos): m / z = 468.2[M+H] + .

[0197] 1 H NMR: (400 MHz, D2O) δ 8.04-8.08 (m, 1H), 7.54 (d, 2H), 4.79-4.89(m, 4H), 4.20-4.23 (m, 2H), 3.16-3.57 (m, 8H), 2.71-2.77 (m, 4H), 2.26-2.33(m, 4H) ppm.

[0198] Example Example 1 4-Carboxy-2-[9-(3-carboxy-1-carboxypropyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl]manganese butyrate(2+)

[0199] The pH of 2-{9-[1,3-dicarboxypropyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadeca-1(15),11,13-trien-3-yl}glutaric acid hydrogen chloride (1 / 1) (4.00 g, 7.94 mmol) in water (40 mL) was adjusted to pH 7 by adding ammonium hydroxide aqueous solution (33%). Manganese(II) chloride tetrahydrate (1.57 g, 7.94 mmol) was added, and the mixture was stirred at 100 °C for 10 h and then at 120 °C for 1 h. Chelex was added to the cooled reaction solution. ® 100, stir the mixture for 120 minutes. The crude product is obtained by column chromatography (Biotage). ® Purified with Sfär C18 D (water / acetonitrile), the title compound was given as a mixture of stereoisomers (95% purity, 61% yield) in 4.0 g.

[0200] LC-MS (Method 2): R t = 0.48 min and 0.54 min; MS (ESIpos): m / z = 521 [M+H] + Example 2 2-[9-(1-carboxylate-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl]-5-oxo-5-{[(2 S ,3 R 4 R 5 R Manganese (2+)-2,3,4,5,6-pentahydroxyhexyl]aminovalerate

[0201] The pH of 1-amino-1-deoxy-D-glucanol (CAS-RN: 488-43-7, 1.16 g, 6.43 mmol) in water (14 mL) was adjusted to pH 7 by adding hydrochloric acid aqueous solution (1 M). Add 4-carboxy-2-[9-(3-carboxy-1-carboxypropyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3-yl]manganese butyrate (2+) (Example 1, 700 mg, 1.35 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS-RN: 25952-53-8, 609 mg, 3.17 mmol) and 1-hydroxybenzotriazole hydrate (CAS-RN: 123333-53-9, 86.5 mg, 565 μmol), and stir the mixture at room temperature for 16 hours. Additional 1-amino-1-deoxy-D-glucanol (260 mg, 1.43 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (304 mg, 1.59 mmol) were added, and the pH was adjusted to 6 by adding aqueous hydrochloric acid (1 M). After stirring at room temperature for 16 hours, the mixture was heated to 120 °C for 2 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was analyzed by column chromatography (Biotage). ® The crude title compound was purified by SfärC18 D (water / acetonitrile) to give 802 mg of crude compound. The crude product was purified by preparative HPLC (instrument: Labomatic HD-5000, pump head HDK-280, gradient module NDB-1000, manual injection valve Rheodyne 3725i038, fraction collector: Labomatic Labocol Vario 2000, Knauer Azura UV detector Azura UVD 2.1S, Prepcon 5 software; column: Chromatorex RP C18 10 μm, 120×30 mm; eluent A: water; eluent B: acetonitrile; gradient: 0–10 min 1%–3% B, 10–12 min 99% B; flow rate: 100 mL / min; temperature: 25 °C) to give 289 mg of the title compound as a mixture of stereoisomers (95% purity, 24% yield).

[0202] LC-MS (Method 1): R t = 0.40 min; MS (ESIpos): m / z = 847 [M+H] + , 424[M+2H] 2+ Example 3 Manganese(2+) Sodium(2) R ,2' R )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentadiate (1 / 2 / 1)

[0203] (2) R ,2' R )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-triene-3,9-diyl]diglutaric acid hydrogen chloride (1 / 2.5) (2.0 g, 3.6 mmol, intermediate 11) in water (42 mL) was adjusted to pH 7 by adding an aqueous solution of sodium hydroxide (2 M). Manganese(II) chloride tetrahydrate (714 mg, 3.61 mmol) was added, and the mixture was stirred at room temperature for 10 hours. Chelex was added to the reaction solution. ® 100, stir the mixture for 120 minutes. The crude product is obtained by column chromatography (Interchim PuriFlash). ® Purified with PF-15 C18 AQ F0330 (water / acetonitrile), yielded 2.02 g of the title compound (96% purity, 95% yield).

[0204] UPLC-MS (Method 1): R t = 0.18 min; MS (ESIpos): m / z = 521 [M+H] + , 1041 [2M+H] + MS (ESIneg) 519 [MH] HRMS (ESI, [M+H] + The calculated value of C21H28N3O9Mn is 521.1206; the measured value is 521.1207.

[0205] Ion chromatography (sodium): calculated value 8.1%; measured value 7.9%.

[0206] Optical rotation: [α] D = -5.76° + / -0.14° (c = 9 mg / ml, water).

[0207] Example 4 (2 R ,2' R)-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]bis(5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+))

[0208] The pH of 1-amino-1-deoxy-D-glucanol (CAS-RN: 488-43-7, 3.55 g, 19.6 mmol) in water (65 mL) was adjusted to pH 7 by adding hydrochloric acid aqueous solution (1 M). Sodium manganese(2+) (2...) was added to water (40 mL)... R ,2' R )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-triene-3,9-diyl]diglutarate (1 / 2 / 1) (Example 3, 2.04 g, 3.61 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS-RN: 25952-53-8, 1.77 g, 9.25 mmol) and 1-hydroxybenzotriazole hydrate (CAS-RN: 123333-53-9, 300 mg, 1.96 mmol) were mixed and stirred at room temperature for 16 hours. Additional 1-amino-1-deoxy-D-glucanol (1.07 g, 5.88 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.35 g, 7.06 mmol) were added, and the pH was adjusted to 6 by adding aqueous hydrochloric acid (1 M). Stirring was continued for 16 hours at room temperature. Amberlite ion exchange resin was then added. ® IRA 400 (chloride form, 30 mL) and Amberlite ® IRA 120 (sodium form, 150 mL) was added, and the mixture was stirred at room temperature for 2 hours. The ion exchange resin was removed by filtration, and the filtrate was concentrated under reduced pressure. Chelex was added to the concentrated aqueous solution. ® 100, stir the mixture for 1 hour. The crude product is obtained by column chromatography (InterchimpuriFlash). ® Purified with PF-15 C18 AQ F0330 (water / acetonitrile), 1.61 g of the title compound as a single stereoisomer was obtained (99% purity, 48% yield).

[0209] LC-MS (Method 1): Rt = 0.42 min; MS (ESIpos) m / z = 847.4 [M+H] + , 424.4[M+2H] 2+ .

[0210] HRMS (ESI, [M+H] + The calculated value of C33H54N5O17Mn is 847.2895; the measured value is 847.2904.

[0211] Ion chromatography: Sodium not detected.

[0212] Optical rotation: [α] D = -21.20° + / -0.17° (c = 8.3 mg / ml, water).

[0213] Example 5 Manganese(2+) Sodium(2) S ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentadiate (1 / 2 / 1)

[0214] (2) S ,2' S The pH of 2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]dipentanoic acid (4.13 g, 8.83 mmol, intermediate 12) and manganese(II) chloride tetrahydrate (1.75 g, 8.83 mmol) in water (100 mL) was adjusted to pH 7 by adding an aqueous solution of sodium hydroxide (2 M). The mixture was stirred at room temperature for 10 hours. Chelex was added to the reaction solution. ® 100, stir the mixture for 120 minutes. The crude product is obtained by column chromatography (Interchim PuriFlash). ® Purified with PF-15 C18 AQ F0330 (water / acetonitrile), 2.86 g of the title compound as a single stereoisomer was obtained (99% purity, 57% yield).

[0215] UPLC-MS (Method 1): R t = 0.22 min; MS (ESIpos): m / z = 521 [M+H] + .

[0216] HRMS (ESI, [M+H] + The calculated value of C21H28N3O9Mn is 521.1206; the measured value is 521.1201.

[0217] Optical rotation: [α] D = +6.80° + / -0.08° (c = 9.2 mg / ml, water).

[0218] Ion chromatography (sodium): calculated value 8.1%; measured value 9.6%.

[0219] Example 6 (2 S ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]bis(5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+))

[0220] The pH of 1-amino-1-deoxy-D-glucanol (CAS-RN: 488-43-7, 4.41 g, 24.4 mmol) in water (110 mL) was adjusted to pH 6 by adding hydrochloric acid aqueous solution (1 M). Sodium manganese(2+) was added (2... S ,2' S2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-triene-3,9-diyl]dipentadiate (1 / 2 / 1) (Example 5, 2.75 g, 4.87 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS-RN: 25952-53-8, 2.15 g, 11.2 mmol) and 1-hydroxybenzotriazole hydrate (CAS-RN: 123333-53-9, 373 mg, 2.44 mmol) were mixed and stirred at room temperature for 16 hours. The pH of the mixture was adjusted from pH 4 to pH 6 by adding an aqueous sodium hydroxide solution (1 M), and stirring was continued for 2 hours. Additional 1-amino-1-deoxy-D-glucanol (1.76 g, 9.74 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.68 g, 8.77 mmol) were added, and the pH was adjusted to 6 by adding aqueous hydrochloric acid (1 M). After stirring at room temperature for 16 hours, the mixture was concentrated under reduced pressure. The residue was analyzed by column chromatography (Interchim PuriFlash). ® Purified with PF-15 C18 AQ F0330 (water / acetonitrile), 1.89 g of the title compound as a single stereoisomer was obtained (98% purity, 45% yield).

[0221] LC-MS (Method 1): R t = 0.38 min; MS (ESIpos) m / z = 847.6 [M+H] + , 424.4[M+2H] 2+ .

[0222] HRMS (ESI, [M+H] + The calculated value of C33H54N5O17Mn is 847.2895; the measured value is 847.2914.

[0223] Ion chromatography: Sodium not detected.

[0224] Optical rotation: [α] D = +4.31° + / -0.22° (c = 8.5 mg / ml, water).

[0225] Example 7 Manganese(2+) Sodium(2) R )-2-{9-[(1 S[-1,3-dicarboxylic acid propyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3-yl}glutarate (1 / 2 / 1)

[0226] (2) R )-2-{9-[(1 S [1,3-Dicarboxypropyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3-yl}glutaric acid (3.0 g, 6.42 mmol, intermediate 13) and manganese(II) chloride tetrahydrate (1.27 g, 6.42 mmol) in water (70 mL) were mixed. The pH was adjusted to pH 7 by adding an aqueous solution of sodium hydroxide (2 M). The mixture was stirred at room temperature for 10 hours, followed by stirring at 50 °C for 8 hours. After cooling, Chelex was added to the reaction solution. ® 100, stir the mixture for 120 minutes. The crude product is obtained by column chromatography (Interchim PuriFlash). ® Purified with PF-15 C18 AQF0330 (water / acetonitrile), 2.04 g of the title compound (99% purity, 55% yield) was obtained.

[0227] UPLC-MS (Method 1): R t = 0.17 min; MS (ESIpos): m / z = 521.4 [M+H] + .

[0228] HRMS (ESI, [M+H] + The calculated value of C21H28N3O9Mn is 521.1206; the measured value is 521.1202.

[0229] Optical rotation: [α] D = + / -0.0° (c = 9.2 mg / ml, water).

[0230] Ion chromatography (sodium): calculated value 8.1%; measured value 8.9%.

[0231] Example 8 (2 R )-2-{9-[(1 S )-1-carboxylate-4-oxo-4-{[(2 S ,3 R 4 R 5 R)-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl}-5-oxo-5-{[(2 S ,3 R 4 R 5 R Manganese (2+)-2,3,4,5,6-pentahydroxyhexyl]aminovalerate (a mixture of stereoisomers)

[0232] The pH of 1-amino-1-deoxy-D-glucanol (CAS-RN: 488-43-7, 4.18 g, 23.1 mmol) in water (80 mL) was adjusted to pH 6 by adding hydrochloric acid aqueous solution (1 M). Sodium manganese(2+) (2...) was added to water (40 mL). R )-2-{9-[(1 S 1,3-dicarboxylic acid propyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecano-1(15),11,13-trien-3-yl}glutarate (1 / 2 / 1) (Example 7, 2.40 g, 4.61 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS-RN: 25952-53-8, 2.21 g, 11.5 mmol) and 1-hydroxybenzotriazole hydrate (CAS-RN: 123333-53-9, 353 mg, 2.31 mmol) were mixed and stirred at room temperature for 16 hours. Amberlite ion exchange resin was then added. ® IRA 400 (chloride form, 30 mL) and Amberlite ® IRA 120 (sodium form, 150 mL) was added, and the mixture was stirred at room temperature for 2 hours. The ion exchange resin was removed by filtration, and the filtrate was concentrated under reduced pressure. Chelex was added to the concentrated aqueous solution. ® 100, stir the mixture for 1 hour. The crude product is obtained by column chromatography (Interchim PuriFlash). ® Purified (PF-15 C18 AQ F0330, water / acetonitrile) to give 1.77 g of the title compound as a mixture of two diastereomers (99% purity, 49% yield).

[0233] LC-MS (Method 1): R t = 0.42 min; MS (ESIpos) m / z = 847.4 [M+H] + .

[0234] The calculated value of HR-ESI: C33H54N5O17Mn is 847.2895; the measured value is 847.2897.

[0235] Optical rotation: [α] D = -10.2° + / -0.12° (c = 8.5 mg / ml, water).

[0236] Example 9 [(2 R )-2-{(3 R 9 S )-9-[(1 S )-1-(carboxyl-κO)-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl-κ 4 N 3 , N 9 , N 15 , O 6}-5-Oxy-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}valerate (2-)-κO]manganese (isomer 1 ( RS ))

[0237] The title compound (2) from Example 8 was analyzed by preparative HPLC. R )-2-{9-[(1 S )-1-carboxy-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl}-5-oxo-5-{[(2 S ,3 R 4 R 5 RManganese (2+)-2,3,4,5,6-pentahydroxyhexyl]aminovalerate (210 mg) was isolated as its single stereoisomer, yielding the title compound (isomer 1, 26 mg, at R... t = 34.2 - 35.1 min) and isomer 2 (7 mg, in R t = 35.4 - 36.7 min (see Example 10).

[0238] Preparative HPLC method: Instruments: Labomatic HD5000, Labocord-5000; Gilson GX-241, Labcol Vario 4000; Column: YMC-Actus ODS-AQ; 250×30 mm, 5 µm, 12 nm; Eluent A: 5 mM ammonium acetate in water, pH=5.0; Eluent B: Acetonitrile; Gradient: 0 - 10 min: 0%B; 10 - 22.5 min: 0 - 5%B; 22.5 – 50 min: 5%B; Flow rate: 30 mL / min; Temperature: 25℃; Detection: Maximum absorption wavelength UV; Injection volume: 50 mg per injection, dissolved in 2 mL of eluent A.

[0239] Analytical chiral HPLC method: Instruments: Agilent HPLC 1290 Infinity; Column: YMC-Actus ODS-AQ; 100 × 4.6 mm, 3 µm, 12 nm; Eluent A: 10 mM ammonium acetate in water, pH=5.0; Eluent B: Acetonitrile; Gradient: 0–2 min: 0% B; 2–5 min: 0–5% B; 5–7 min: 5% B; 7–8 min: 5–10% B; 8–9 min: 10–90% B; Flow rate: 1.2 mL / min; Temperature: 50℃; Detection: Maximum absorption wavelength UV. Analytical HPLC: R t = 7.45 min.

[0240] Example 10 [(2 S )-2-{(3 R 9 S )-9-[(1 R )-1-(carboxyl-κO)-4-oxo-4-{[(2 S ,3 R 4 R 5 R)-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl-κ 4 N 3 , N 9 , N 15 , O 6}-5-Oxy-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}valerate (2-)-κO]manganese (isomer 2 ( SR ))

[0241] For the preparation of the title compound in a mixture with another stereoisomer (Example 9), see Example 8. 7 mg of the title compound was obtained by preparative high-performance liquid chromatography (method as described in Example 9) (Rt = 35.4 - 36.7 min).

[0242] Analytical HPLC (see Example 9 for the method): R t = 7.69 min.

[0243] Reference compound Reference 1 (2 R ,2' R )-2,2'-[3,6,9,15-tetraazabicyclo[9.3.1]pentadecano-6-methyl-1(15),11,13-triene-3,9-diyl]bis(5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+))

[0244] Reference compound 1 was prepared according to the method described in Example 16 of WO 2021 / 043926. It was prepared by column chromatography (Interchim PuriFlash). ® The final purification was performed using PF-15 C18 AQ F0330 (water / acetonitrile) to obtain a purity of 99% ( R , R Reference 1.

[0245] LC-MS (Method 1): R t = 0.42 min; MS (ESIpos): m / z = 860.6 [M+H] + , 430.9 [M+2H] 2+ .

[0246] Reference 2 (2 S ,2' S )-2,2'-[6-methyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]bis(5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+))

[0247] Reference compound 2 was prepared according to the method described in Example 17 of WO 2021 / 043926. The preparation was performed by column chromatography (Biotage). ® The final purification process (using Sfär C18 D, water / acetonitrile) yielded a 99% purity ( ). S , S Reference 2.

[0248] LC-MS (Method 1): R t = 0.44 min; MS (ESIpos): m / z = 860.4 [M+H] + 430.8 [M+2H] 2+ .

[0249] Reference 3 [(2 R )-2-{(3 R 9 S )-9-[(1 S )-1-(carboxyl-κO)-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-methyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl-κ 4 N3 , N 9 , N 15 , O 6}-5-Oxy-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}valerate (2-)-κO]manganese ( RS -Isomer)

[0250] Reference compound 3 was prepared according to the method described in Example 18 of WO 2021 / 043926. It was prepared by column chromatography (Interchim PuriFlash). ® The final purification was performed using PF-15 C18 AQ F0330 (water / acetonitrile) to obtain a purity of 99% ( R , S (Refer to 3)

[0251] LC-MS (Method 1): R t = 0.44 min; MS (ESIpos): m / z = 860.6 [M+H] + , 430.9 [M+2H] 2+ .

[0252] Reference 4 [(2 S )-2-{(3 R 9 S )-9-[(1 R )-1-(carboxyl-κO)-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-methyl-3,6,9,15-tetraazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl-κ 4 N 3 , N 9 , N 15 , O 6}-5-Oxy-5-{[(2 S ,3 R 4R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}valerate (2-)-κO]manganese ( SR -Isomer)

[0253] Reference compound 4 was prepared according to the method described in Example 18 of WO 2021 / 043926 for use in the second separated product. It was prepared by column chromatography (Interchim-PuriFlash). ® The final purification and separation from reference 3 (PF-15 C18 AQ F0330, water / acetonitrile) yielded a purity of 96%. S , R (Ref. 4)

[0254] LC-MS (Method 1): R t = 0.42 min; MS (ESIpos): m / z = 860.8 [M+H] + , 431.0 [M+2H] 2+ .

[0255] Experimental Section - Physicochemical and Biological Assays In vitro and in vivo characterization of the compounds in the examples The examples involve one or more trials in selected measurements. When more than one trial is conducted, data are recorded as the mean or median, where... ●The mean, also known as the arithmetic mean, is the sum of the obtained values ​​divided by the number of trials. ● The median represents the middle value of a set of values ​​arranged in ascending or descending order. If the number of values ​​in the dataset is odd, the median is the middle value. If the number of values ​​in the dataset is even, the median is the arithmetic mean of the two middle values.

[0256] One or more synthesis examples may be performed. When more than one synthesis is performed, the measured data represent the mean or median, which is calculated using datasets obtained from experiments on one or more synthesis batches.

[0257] Example A - Water-soluble The water solubility of the compounds under investigation was determined at room temperature (20 °C) in a buffer solution (10 mM Tris-HCl, pH 7.4). Solid compounds were added incrementally to the buffer solution. More compounds were added after all suspended matter had dissolved, until equilibrium was reached between undissolved and dissolved substances. The suspension was mixed using a shaker (Heidolph Reax 2000) and treated in an ultrasonic bath (Bandelin, Sonorex Super RK255H) for 5 min. The manganese concentration of the test compounds in the clear solution was measured by ICP-MS. The results are summarized in Table 1.

[0258] Table 1: Solubility of selected compounds in pH 7.4 buffer solutions

[0259] Example B-1.4 Relaxation rate measurement at T T1 and T2 relaxation times were measured using a Bruker MQ60 micro-spectral contrast agent analyzer at 60 MHz (1.41 T) and 37°C. Manganese-containing chelates were dissolved in different media, and three different Mn concentrations were used for each relaxation rate measurement. The measurements of r1 and r2 relaxation rates were performed using Mn concentrations of 0, 0.25, 0.5, and 1 M in water and human plasma containing heparin as an anticoagulant. Relaxation rate r i (where i=1, 2) Based on the relaxation rate R measured in water and plasma i Calculated: r i = (R i - R i(0) ) / C Mn Where R i(0) C represents the relaxation rate of the corresponding solvent. Mn The values ​​represent the compound concentration normalized to manganese. The manganese concentration of the studied solution was verified by inductively coupled plasma mass spectrometry (ICP-MS Agilent 7500a, Waldbronn, Germany). The measured relaxation rate values ​​are summarized in Table 2.

[0260] Table 2: Relaxation rates of the studied compounds in water and human plasma at 1.41 T. All values ​​were measured at 37 °C and normalized to manganese, expressed in L mmol. -1 s -1 The unit is [unit missing]. Minor variations in recorded values ​​may be due to the presence of trace impurities.

[0261]

[0262] Example C - Chemical Stability (Physical Chemistry) The examples were dissolved in suitable media / buffer solutions.

[0263] The stability of Mn-chelates was tested under different conditions: a) Heating: Dissolve the Mn chelate in 10 M Tris-HCl buffer at pH 7.4 to a final concentration of 1 mmol Mn / L. Autoclave the solution three times at 1 bar and 121 °C for 20 min each time.

[0264] b) Oxidation: After adding oxidants such as H2O2 and O2, assess the stability of the test items.

[0265] c) pH: Evaluate the stability of the test item in solutions with different pH values. This evaluation can be carried out at different temperatures, such as 25°C and 121°C.

[0266] d) Light exposure: After exposing the test items to light, assess their stability.

[0267] During the experiment, equal portions of the Mn-chelate were taken out and frozen at -20°C for subsequent analysis by HPLC-ICP-MS or HPLC-ESI-MS to determine the integrity of the compound.

[0268] Example of HPLC method used: Agilent 1290 Infinity II LC, Agilent ICP-MS 7900, column: Waters BEH Acquity C18 UPLC, 1.7 µm, 2.1 × 50 mm. Solvent A: 50 mmol / L NH4HCO3, pH 8.0. Solvent B: MeOH. Gradient from 0% B to 0.7% B over 6.5 min, flow rate 0.8 mL / min. Detection by ICP-MS or ESI-MS. Chromatograms showing the intensity of detected Mn signal or UV signal intensity were compared.

[0269] The chemical stability and isomerization of isomers were compared: a) Heat sterilization is commonly used for parenteral solutions. After heat sterilization, Examples 9 (RS) and 10 (SR) undergo isomerization to produce Example 8 (RS / SR mixture), which has a fixed stoichiometric ratio of 2:1. Figure 1 ).

[0270] For reference compounds RC3 and RC4, tautomerism between the RS and SR isomers was also observed. Sterilization of the RS isomer RC3 by heat yielded an RS / SR mixture with a stoichiometric ratio of approximately 9:1. Figure 1 ).

[0271] Example D - Complex stability (metal transfer effect) The stability of the complex to other metals (such as Zn) was assessed using relaxation rate as a reading. The Mn chelate was dissolved in 100 mM BIS-TRIS buffer at pH 7. The T2 relaxation rate was measured at 37°C using a Bruker MQ60 micro-spectral contrast agent analyzer. The T2 relaxation rate was monitored periodically after adding ZnCl2 solution to achieve an Mn:Zn ratio of 1:18. If the test compound is unstable under these conditions, metal transfer during this test will affect the Zn content of the test compound. 2+ The formation of complexes, and Mn 2+ Released and used as [Mn(H2O)6] 2+ It exists in solution. (Due to [Mn(H₂O)₆]) 2+ The T2 relaxation time is affected by this continuous exchange reaction, which causes the T2 relaxation time of the solution to decrease over time (measured at 1.41 T).

[0272] Based on the measurement of the relaxation rate of the Mn-chelate, and with the known Mn concentration and [Mn(H2O)6] in the determination 2+ The known relaxation rate (r² = 57 mM) -1 s -1 The stability of Mn chelates was determined by calculating the known relaxation rates of the buffer system and the buffer solution system.

[0273] and

[0274] The metal transfer rates of Examples 4, 6, 9, and 10 were comparable after 24 hours, indicating that all isomers were sufficiently stable to decompose the Mn complex under these stress conditions and at the corresponding time points, as the Mn chelate was cleared from the body within 24 hours after injection. Unexpectedly, no significant difference was observed between the RS Mn chelate (Example 9) and the SR Mn chelate (Example 10), indicating no difference in stability as a function of chelate stereochemistry. This differs from the RS and SR stereoisomers of the reference compounds RC3 and RC4, where RC4 (the SR stereoisomer) exhibited significantly lower metal transfer stability at physiological pH. Figure 2 This shows how variations were made in embodiments 4, 6, 9, and 10 ( Figure 2 A) and reference compounds 1-4 ( Figure 2 B) The percentage of intact chelates as a function of time, measured by the relaxation rate T2. Values ​​in percentage form are summarized in Table 3.

[0275] Table 3: Metal transfer stability of Mn chelates over 168 hours [%] (18 equivalent zinc at pH 7.4)

[0276] Example E - Complex stability (plasma) Stability in human plasma was measured. A buffer solution of the Mn-chelate was added to human plasma containing heparin as an anticoagulant. The concentration of the Mn-chelate in the plasma sample was 100 µM Mn. The T2 relaxation rate was measured at 37 °C using a Bruker MQ60 micro-spectroscopy contrast agent analyzer. The T2 relaxation rate was monitored periodically. If the test compound is unstable under these conditions, dechelation during this test will result in the release of Mn. 2+ It binds to plasma proteins and / or low molecular weight substances in plasma samples. Mn 2+ Protein binding affects T2 relaxation time, and this continuous exchange reaction causes the T2 relaxation time of the solution to decrease over time (measured at 1.41 T).

[0277] As described in Example D, based on the measurement of the relaxation rate of Mn-chelates in plasma, and the known Mn concentration and unchelated Mn in plasma during the determination. 2+ The relaxation rate of (MnCl2) (r2 = 76 mM) -1 s -1 The stability of Mn chelates in plasma was determined by calculating the known relaxation rates of pure plasma samples and pure plasma samples. Figure 3 The changes in T2 relaxation time over 24 hours and the calculated percentage of intact chelating agent are shown.

[0278] Example F - Cytotoxicity (SH-SY5Y cells) Cell viability was measured after exposure to different concentrations of the test substance. Undifferentiated adherent SH-SY5Y cells were exposed to 1 and 5 mM Mn-chelates in cell culture medium for 24 h. Cell viability was measured using CellTiterGlo (Promega) according to the manufacturer's instructions. Luminescence intensity was measured using a spectrophotometer (Spectramax, Molecular Devices). Viability was determined as a percentage by comparing the luminescence intensity of the described Mn-chelate and gadolinium-based reference compound (Gadovist, Bayer AG). Figure 4 The percentage of activity of the Mn chelates is shown.

[0279] Example G-partition coefficient (logP butanol / buffer) The partition coefficient P (logP / butanol / buffer) was determined by mixing a buffer solution (10 µM compound in 0.5 mL of 50 mM butanol-saturated Tris-HCl, pH 7.4) and 1-butanol 1+1, and the mixture was shaken at room temperature for 2 hours (n=3). The Mn concentration C in each phase was measured by ICP-MS. 丁醇 and C 缓冲液 (The Chemistry of Contrast Agents in Medical Magnetic Resonance Imaging 2nd edition, Merbach AS, Helm L, Toth E, eds. Hoboken, NJ: Wiley 2013).

[0280] Table 4: Partition coefficient P (log P = log butanol / buffer, pH 7.4)

[0281] Example H-NOAEL The No Observed Adverse Effect Level (NOAEL) was tested in mice using a modified 4-step escalation method with increasing test item dose. The observed NOAEL represents the level of exposure at which no serious adverse effects were observed (Dorato et al., Regul Toxicol Pharmacol, August 2005; 42(3):265-74). The test item was administered via intravenous bolus injection into the mouse tail vein. The starting dose was 0.5 mmol / kg bw (5 times the clinical dose of Example 2), and if no adverse effect was observed in the animals, the next dose was increased to 1.0 mmol Mn / kg bw, and if any adverse effect was observed in the mice, the next dose was decreased. The next dose was 2.5 mmol Mn / kg bw. At the highest dose level of 5.0 mmol Mn / kg bw, three animals were injected. Symptoms were continuously monitored throughout the experiment (2 hours after contrast agent administration). Seven days after injection, surviving mice were euthanized under deep anesthesia (xeracil hydrochloride 20 mg / mL, lonephridine 2%, Bayer Vital GmbH, Leverkusen, and ketamine hydrochloride 100 mg / mL, ketazolam, Pfizer, Pharmacia GmbH, Berlin). Microscopic analysis was performed immediately after death of all mice. Blood was collected via vena cava puncture for analysis of ALT, AST, GGT, GLDH, creatinine, and BUN (300 µL serum). No adverse effects were observed at the maximum experimental dose (5 mmol Mn / kg body weight) of the Mn chelate in Example 4, with a NOAEL > 5 mmol Mn / kg body weight.

[0282] Example I - Plasma Protein Binding The binding of Example 2 to plasma proteins of different species (human, dog, monkey, rabbit, mouse and rat) was investigated in vitro by equilibration dialysis in a reusable 96-well microequilibration dialysis device (HT dialysis) (Banker MJ et al., J PharmSci, May 2003; 92(5): 967-74).

[0283] Example J - In vivo pharmacokinetics of rats after intravenous administration The pharmacokinetic parameters of Example 2 were determined in male rats (Han-Wistar, n=3). The compound was administered as a sterile aqueous solution via tail vein injection at a dose of 100 µmol Mn / kg body weight. Plasma samples were collected before administration and at 1, 3, 5, 10, 15, 30, 60, 120, 240, 360, and 1440 minutes after administration, and Mn concentrations were determined by inductively coupled plasma mass spectrometry (ICP-MS Agilent 7500a, Waldbronn, Germany). Samples were diluted with 1% nitric acid and digested under strongly acidic and high-temperature oxidative conditions to bring the samples within the quantitative range of the method. The lower limit of quantitation for all elements was 1 nmol / L, and the upper limit of quantitation for diluted samples was 1000 nmol / L.

[0284] The obtained data were fitted with a three-compartment model (Phoenix, WinNonlin 6.4, 3-compartment model) to obtain pharmacokinetic parameters.

[0285] Figure 5 The plasma manganese (Mn) level was measured after intravenous administration of Mn chelate 4. After 24 hours, plasma Mn levels returned to baseline endogenous Mn levels.

[0286] Example: Bile excretion in K-biliary cannulated (BDC) rats The bile excretion of the compounds was investigated in bile duct cannulation (BDC) rats (Burden N et al., Lab Anim, October 2017, 51(5): 457–464). All animals were initially anesthetized by intramuscular injection of a mixture of xylazine hydrochloride (20 mg / mL, Lompon 2%, Bayer Vital GmbH, Leverkusen) and ketamine hydrochloride (100 mg / mL, Ketazolam, Pfizer, Pharmacia GmbH, Berlin) at a dose adjusted to 1 ml / kg body weight (1+2). Continuous anesthesia of the animals was achieved by intravenous infusion of 1.5 mL / h via tail vein (Introcan, 24G, yellow) (Braun infusion device 1+2, 1:20 saline, xylazine hydrochloride 20 mg / mL, Lompon 2%, Bayer Vital GmbH, Leverkusen, and ketamine hydrochloride 100 mg / mL, Ketazolam, Pfizer, Pharmacia GmbH, Berlin). The animals were administered 0.1 mmol Mn / kg bw (50 mmol Mn / L formulation) via tail vein bolus injection. Bile and urine samples were collected at 0–0.5 h, 0.5 h, 1–2 h, 2–3 h, and 3–4 h post-injection. The manganese concentration in the bile components was determined by inductively coupled plasma mass spectrometry (ICP-MS Agilent 7500a, Waldbronn, Germany). Bile fractions (n=3 times, 10 µL each) were dried at 90 °C for 2 hours, then treated in a microwave oven (5 cycles: 5 min 40 W, 5 min 120 W, 10 min 200 W, 10 min 320 W, and 25 min 400 W, Fa VWR Chemicals, AnalaR NORMAPUR, #18J024022) with 50 µL 65% nitric acid (HNO3, Fa. Fisher, Optima Grade #1219010) and 30 µL 30% hydrogen peroxide (H2O2, Fa. CEM, Mars5 Xpress). After cooling to room temperature, the samples were diluted thoroughly with 920 µL ICP diluent (1% HNO3 + 0.01% Triton Tx100 and 50 µM Terbium internal standard), and the manganese concentration was measured by ICP-MS. No significant bile excretion was observed in Example 4 of the Mn chelate treatment. Four hours later, >96% of the administered dose was excreted through the kidneys.

[0287] Table 5: Bile excretion in cannulated rats shows the Mn levels measured in bile and urine collected at selected time points after injection of the Mn chelator.

[0288]

[0289] Example: L-rat excretion study (5 days) and residual manganese organ distribution (7 days) Excretion and organ distribution of the test items were determined in male rats (Han-Wistar, n=3). The compound was administered as a sterile aqueous solution to the tail vein of the animals at appropriate doses. Urine was collected at the following time points post-injection: 0–1 hour, 1–3 hours, 3–6 hours, 6–24 hours, 1–2 days, and 2–5 days; and feces were collected at the following time points post-injection: 0–1 hour, 1–3 hours, 3–6 hours, 6–24 hours, 1–2 days, and 2–5 days; and feces were collected at the following time points post-injection: 0–1 day, 1–2 days, and 2–5 days. As a control group, three animals were treated with saline in the same manner. Rats were sacrificed on day 7, and the following organs were subsequently removed: blood, liver, kidneys, spleen, heart, lungs, brain, muscles, skin, stomach, intestines, bones, and bone marrow. The remaining animal carcasses were freeze-dried and ground into a fine powder. Mn concentrations in organs and animal carcasses were determined by ICP-MS (Agilent 7500a, Waldbronn, Germany). Organ distribution results for the studied examples and the saline control group are summarized (mean ± standard deviation).

[0290] Table 6: Excretion in rats in Example 4

[0291] Table 7: Organ distribution of manganese in rats 7 days after injection of Example 4 or saline control group

Claims

1. A kind of Mn 2+ Compounds of general formula (I) in their coordination form, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, in: R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group, Where m is an integer from 1 to 3, and n is an integer from 0 to 5; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

2. The compound according to claim 1, and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein... R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group, Where m is an integer from 1 to 2, and n is an integer from 1 to 4; R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups.

3. The compound according to claim 1 or 2, and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein... R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group, Where m is 2 and n is an integer from 2 to 4; R 2 R 3 and R 4 Each is an independent hydrogen atom.

4. The compound according to any one of claims 1 to 3, and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein R 1 -(CH2) m -(C=O)(NH)-(CH2)-(CH(OH)) n -CH2OH group, Where m is 2 and n is 4; R 2 R 3 and R 4 Each is an independent hydrogen atom.

5. The compound according to any one of claims 1 to 4, and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, wherein the compound is selected from... 2-[9-(1-carboxylate-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl)-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl]-5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+), (2 R ,2' R )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]bis(5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+), (2 S ,2' S )-2,2'-[6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-triene-3,9-diyl]bis(5-oxo-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]aminovalerate manganese(2+), (2 R )-2-{9-[(1 S )-1-carboxylate-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl}-5-oxo-5-{[(2 S ,3 R 4 R 5 R Manganese (2+)-2,3,4,5,6-pentahydroxyhexyl]aminovalerate (a mixture of stereoisomers) [(2 R )-2-{(3 R 9 S )-9-[(1 S )-1-(carboxyl-κO)-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl-κ 4 N 3 , N 9 , N 15 , O 6 }-5-Oxy-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}valerate (2-)-κO]manganese (isomer 1 ( RS ))and [(2 S )-2-{(3 R 9 S )-9-[(1 R )-1-(carboxyl-κO)-4-oxo-4-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}butyl]-6-oxa-3,9,15-triazabicyclo[9.3.1]pentadecan-1(15),11,13-trien-3-yl-κ 4 N 3 , N 9 , N 15 , O 6 }-5-Oxy-5-{[(2 S ,3 R 4 R 5 R )-2,3,4,5,6-pentahydroxyhexyl]amino}valerate (2-)-κO]manganese (isomer 2 ( SR )).

6. A method for preparing Mn according to any one of claims 1 to 5 2+ A method for compounding a general formula (I) compound in the form of a coordination compound, the method comprising reacting Mn with... 2+ Compounds of general formula (II) in the form of coordination compounds, or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, with the formula (H2N)-(CH2)-(CH(OH)). n -CH2OH, where n is an integer from 2 to 4, represents the steps of the amine reaction. Where R 2 R 3 and R 4 With Mn as described in any one of claims 1 to 5 2+ The general formula (I) is defined in the form of a complex of compounds, where m is an integer from 1 to 3. Thus, we obtain Mn 2+ Compounds of general formula (I) in the form of coordination compounds, wherein R 1 R 2 R 3 and R 4 With Mn as described in any one of claims 1 to 5 2+ The general formula (I) is defined in the form of a coordination compound.

7. Use of the compound according to any one of claims 1 to 5 for diagnostic imaging, preferably for magnetic resonance imaging.

8. The compound according to any one of claims 1 to 5, for use in diagnostic imaging, preferably for magnetic resonance imaging.

9. Use of the compound or mixture thereof according to any one of claims 1 to 5 for the manufacture of diagnostic agents, preferably for the manufacture of contrast agents for magnetic resonance imaging.

10. A method for imaging a patient's body tissues, comprising the following steps: The patient is given an effective amount of one or more of the compounds of claim 5 in a pharmaceutically acceptable carrier, and then the patient is subjected to magnetic resonance imaging.

11. With Mn 2+ A compound of general formula (II) in the form of a coordination compound, or a stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt thereof, or a mixture thereof, is used to prepare any one of claims 1 to 5 with Mn 2+ Uses of compounds of general formula (I) in their coordination form, Where R 2 R 3 and R 4 With Mn as described in any one of claims 1 to 5 2+ The complex form of the compound is defined in the general formula (I) and m is an integer from 1 to 3.

12. Compounds of general formula (II) or those with Mn 2+ Compounds of general formula (II) in the form of coordination compounds, and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof, in: R 2 R 3 and R 4 Each is independently selected from hydrogen atoms, C1-C3 alkyl groups, and C1-C3 alkoxy groups, and m is an integer from 1 to 3.

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