Novel contrast agent for use in nuclear magnetic resonance imaging

Abstract

The present invention relates to a novel class of compounds of general formula (I), 3+ The present invention relates to chelate complexes, methods for preparing said compounds, and the use of said compounds as MRI contrast agents. JPEG2024512459000395.jpg52170

Description

[Technical Field]

[0001] The present invention relates to the items characterized by the claims, namely novel gadolinium chelate compounds, methods for preparing the compounds, the use of the compounds as MRI contrast agents, and their use in mammals. [Background technology]

[0002] 1. Introduction Magnetic resonance imaging (MRI) is a non-invasive technique that can provide information about the anatomical structure, function, and metabolism of tissues in vivo. Unenhanced MRI scans of tissue utilize hydrogen atoms in water to generate images. Apart from local differences in water content, the fundamental contrast of MR images is primarily due to regional differences in intrinsic relaxation times T(1) and T(2), each of which can be selected to dominate the image contrast. However, the intrinsic contrast provided by water T(1) and T(2), as well as the changes in their values ​​brought about by histopathology, are often too limited to enable highly sensitive and specific diagnoses. To overcome these limitations, the proton relaxation time can be influenced by the presence of paramagnetic ions. Commercially available gadolinium-based contrast agents (GBCAs) contain at least one paramagnetic ion (Gd) of the rare earth metal gadolinium. 3+ It contains ), which has the maximum number of unpaired electrons (7) for any stable ion, resulting in a high magnetic moment that is effective in enhancing proton relaxation.

[0003] Paramagnetic contrast agents indirectly enhance signal intensity by shortening the T1 (vertical) and T2 (transverse) relaxation times of surrounding water protons. The effectiveness of a drug in shortening relaxation times is called the degree of relaxation (r1 and r2), which is Gd 3+It depends on the ligands surrounding the ions and is influenced by exogenous factors including temperature, magnetic field strength, and the 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).

[0004] In addition to untargeted agents, two linear contrast agents (i.e., contrast agents in which gadolinium ions are bound to a linear ligand structure) are available for hepatic magnetic resonance imaging (MRI): Gd-BOPTA (gadobenic acid marketed as Multihance) and Gd-EOB-DTPA (gadoxetic acid marketed as Primovist in Europe and Eovist in the United States). Gd-EOB-DTPA (Bayer AG) and Gd-BOPTA (Bracco) are approved for the detection and differentiation of focal liver lesions at clinical doses of 0.025 mmol / kg body weight and 0.05 mmol / kg body weight, respectively. Both agents exhibit a dominant T1 effect in images, resulting in bright contrast. Both targeted agents are used in hepatic MRI for the detection of focal liver lesions in patients with known or suspected primary liver cancer (e.g., hepatocellular carcinoma HCC) or metastatic disease. These provide information regarding the distribution of lesional vessels in the arterial and venous phases, the presence of hepatocytes, and their function in the delayed hepatobiliary phase. Liver-specific contrast agents are taken up by healthy liver cells (hepatocytes), but not by malignant tumor tissue due to the lack of intact organic anion transport polypeptide (OATP) transporters. This improves the detection of focal liver lesions by increasing the contrast between lesions and the liver. Contrast-enhanced MRI (CE-MRI) provides important information for differential diagnosis. HCC does not express the respective uptake transporters and therefore does not accumulate liver-specific GBCA to the extent observed in healthy liver tissue.

[0005] Gd-BOPTA is secreted into the bile at a rate of 3-5%, and its administration allows for the capture of liver-specific phase images 1-2 hours later (Seale MK et al., Radiographics 2009;29:1725-1748).

[0006] In the early 2000s, research into novel contrast agents with improved tropism to hepatocytes led to the development of Gd-EOB-DTPA. Gd-EOB-DTPA is excreted into the bile at a rate of approximately 50% of the administered dose. Gd-EOB-DTPA can be administered as a bolus, ensuring satisfactory evaluation of the interstitial phase, followed by evaluation of the hepatobiliary phase (10-20 minutes later). Literature reviews have confirmed that liver MRI using Gd-EOB-DTPA can detect and identify localized liver lesions with high specificity and sensitivity in both patients with healthy livers and patients with tumors / cirrhotic livers (Fidler J et al. Hepatology 2011;53(2):678-82; Park Y et al. Korean J Radiol 2010;11(4):433-40; Bluemke DA et al. Radiology 2005;237:89-98).

[0007] Gd-EOB-DTPA is primarily taken up by hepatocytes via organic anion transport polypeptides (OATP1B1, OATP1B3), and subsequently excreted into the bile ducts mainly via multidrug resistance-associated protein 2 (MRP2, synonym cMOAT: bile duct side multiselective organic anion transporter) (Ringe KI et al., American Journal of Roentgenology. 2010;195:13~28; Leonhardt M et al., Drug Metab Dispos. July 2010;38(7):1024-8).

[0008] The molecular structures of both commercially available products (Gd-EOB-DTPA and Gd-BOPTA) contain hydrophilic and lipophilic groups. The linear DTPA-like ligand for gadolinium complexing contains a hydrophilic group, while the benzene (e.g., ethyl-oxybenzyl, EOB) side chain is a lipophilic group. The lipophilic group not only contributes to significant bile efflux but also to some weak protein binding of approximately 10% (Weinmann HJ et al., Magn Reson Med, 1991;22:233~237). Compared to commercially available extracellular GBCA, Gd-EOB-DTPA and Gd-BOPTA exhibit higher r1 and r2 relaxation degrees (Rohrer M et al., Invest Radiol. 2005 Nov.;40(11):715-24). The high relaxation degree values ​​depend on the molecular affinity to plasma proteins through the lipophilic group, which also contributes to specific hepatocyte uptake.

[0009] Several recent reports have shown increased signal intensity (SI) in the dentate nucleus (DN) and globus pallidus (GP) brain regions on unenhanced T1-weighted (T1w) MR images in renally functioning patients who have received multiple doses of linear gadolinium contrast agents (GBCAs). The visible increase in SI is highly associated with linear GBCAs only. To date, this has not correlated with any clinical symptoms. However, in Europe, the European Medicines Agency (EMA) has proposed recalling linear GBCAs from the market, with the exception of the two liver-specific market products, Gd-BOPTA (when used only in the liver) and Gd-EOB-DTPA. In March 2016, the EMA's Drug Safety Monitoring and Risk Assessment Committee (PRAC) initiated a procedure to re-examine linear GBCAs, and in March 2017, recommended the suspension of marketing authorizations for all multipurpose linear GBCAs in the European Union (EU), while supporting the continued use of macrocyclic GBCAs (i.e., contrast agents in which the gadolinium ion is bound to a macrocyclic ligand structure). Following this decision, the GBCA market has moved significantly away from linear gadolinium-based drugs. As of early 2022, no alternative liver-specific macrocyclic GBCAs are commercially available, so liver-specific GBCAs (Gd-EOB-DTPA and Gd-BOPTA) remain acceptable. Increased signal intensity observed in the dentate nucleus was also seen after repeated administration of linear Gd-EOB-DTPA (Kahn J et al., Radiology, 2017;282(3):708~716). Macrocyclic GBCAs are known to be more stable against Gd release (Frenzel et al. Invest Radiol. 2008 December;43(12):817-28). Therefore, there is a growing medical need for novel macrocyclic liver-specific contrast agents.

[0010] 2. Description of prior art, the problems to be solved, and the solutions. International Publication No. 199532741 describes bile acid conjugates that are claimed to be useful for imaging the liver and bile ducts.

[0011] International Publication No. 2001082795 describes an MRI agent having a covalently bound therapeutic blocking moiety, which induces a change in the signal intensity of the agent when it interacts with its intended target.

[0012] International Publication No. 2007009638 discloses metal complexes containing perfluoroalkyl groups that can be used as MRI and X-ray contrast agents, particularly for lymphangiography.

[0013] International Publication No. 2004006965 discloses a perfluoroalkyl-containing MRI contrast agent that exhibits micelle formation resulting in a high degree of r1 relaxation to represent intravascular thrombosis.

[0014] International Publication No. 1997032862 describes a class of polychelates bonded to alkene crosslinked amino groups for diagnostic imaging.

[0015] International Publication No. 1999005145 details the preparation method for tetraazama macrocycles. International Publication No. 1996016677 describes metal complexes for use as X-ray contrast agents for imaging of the liver and bile ducts.

[0016] International Publication No. 1995028392 clarifies the use of amphiphilic chelates and their use for hepatobiliary imaging.

[0017] International Publication No. 2013083535 describes the preparation of hyperpolarizing contrast agents for MR diagnostic analysis.

[0018] The medical need for CE-MRI of the liver is high, and because macrocyclic GBCA is not available, linear GBCA is still used, for example, for the differential diagnosis of focal liver lesions or the detection of small liver lesions. However, currently, there are no commercially available products containing macrocyclic GBCA with hepatic uptake that exhibit the desirable attributes of macrocyclic GBCA, which has the essential attributes of a liver contrast agent. Among the various desirable properties of a compound suitable as an MRI contrast agent are, for example, high water solubility, high degree of relaxation, complete and intact elimination, good tolerability, and a good safety profile.

[0019] European Patent No. 405704, in particular, describes the combination of Gd with derivatives of diethylenetriaminopentaacetic acid (DTPA), such as Gd-EOB-DTPA. 3+ This concerns complexes and their use as contrast agents in magnetic resonance imaging of the liver. However, as mentioned above, these linear compounds and complexes have been under increased scrutiny from health authorities in recent years and are still used in clinical settings due to the lack of suitable alternatives.

[0020] Therefore, there is an unmet medical need to provide macrocyclic GBCAs for magnetic resonance imaging, particularly for hepatic magnetic resonance imaging, that combine the beneficial properties of linear liver-specific drugs with macrocyclic GBCAs. Specifically, there is an unmet medical need to provide liver-specific GBCAs that demonstrate as many of the following criteria as possible: - Exhibits high water solubility, -Chemically stable, - Stable against metal release from chelates, - Showing a high degree of relaxation, - Human transfected OATP1B1 shows high in vitro uptake into HEK cells. - Shows high in vitro uptake of human transfected OATP1B3 into HEK cells. - Low protein binding, - Exhibits a favorable pharmacokinetic profile and dual elimination pathway, - Quickly and completely discharged, - Does not show long-term retention of Gd in both tissues and organs, 3+ - Is stable against metabolic degradation, - Has good tolerance, - Is suitable for liver imaging, - Is suitable for bile duct imaging, - Is suitable for imaging of liver diseases - May show high in vitro uptake (e.g., into rat hepatocytes).

[0021] The above prior art does not disclose the compounds of general formula (I) of the present invention as defined herein, or their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts or mixtures thereof as described and defined herein. The prior art does not disclose the compounds of general formula (I) of the present invention in the form of complexes with Gd 3+ <00​​​​​​​​​​​​​​​​​​​3+ The contained compounds exhibit advantageous stability of macrocyclic GBCA and high uptake into the liver. Furthermore, the Gd of the present invention 3+ The contained compounds exhibit high tolerability, improved mildness, excellent water solubility, and rapid and complete excretion, making them well-suited for magnetic resonance imaging, particularly hepatic magnetic resonance imaging. [Prior art documents] [Patent Documents]

[0024] [Patent Document 1] International Publication No. 199532741 pamphlet [Patent Document 2] International Publication No. 2001082795 [Patent Document 3] International Publication No. 2007009638 Pamphlet [Patent Document 4] International Publication No. 2004006965 [Patent Document 5] International Publication No. 1997032862 [Patent Document 6] International Publication No. 1999005145 [Patent Document 7] International Publication No. 1996016677 Pamphlet [Patent Document 8] International Publication No. 1995028392 Pamphlet [Patent Document 9] International Publication No. 2013083535 [Non-patent literature]

[0025] [Non-Patent Document 1] 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 [Non-Patent Document 2] Caravan P et al., Gadolinium(III) chelates as MRI contrast agents:structure, dynamics, and applications.Chem Rev.1999;99(9):2293-352 [Non-Patent Document 3] Seale MK et al., Radiographics 2009;29:1725~1748 [Non-Patent Document 4] Fidler J et al Hepatology 2011;53(2):678-82 [Non-Patent Document 5] Park Y et al. Korean J Radiol 2010;11(4):433-40 [Non-Patent Document 6] Bluemke DA et al. Radiology 2005;237:89~98 [Non-Patent Document 7] Ringe KI et al. American Journal of Roentgenology.2010;195:13~28 [Non-Patent Document 8] Leonhardt M et al., Drug Metab Dispos. July 2010;38(7):1024-8 [Non-Patent Document 9] Weinmann HJ et al. Magn Reson Med, 1991;22:233~237 [Non-Patent Document 10] Rohrer M et al., Invest Radiol. November 2005; 40(11):715-24. [Non-Patent Document 11] Kahn J et al., Radiology, 2017;282(3):708~716 [Non-Patent Document 12] Frenzel et al. Invest Radiol. December 2008; 43(12):817-28 [Overview of the project] [Means for solving the problem]

[0026] This invention describes a novel class of liver-specific (non-linear) gadolinium chelate complexes, a method for preparing them, and their use as MRI contrast agents.

[0027] Description of the Invention According to the first aspect, the present invention relates to a compound of general formula (I), [ka] (In the formula, Ar is [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X is CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 Each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 teeth, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The aforementioned C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 is a hydrogen atom or C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, R 6 is a hydrogen atom or C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- (Represents a base selected from) This includes stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, as well as mixtures thereof.

[0028] According to a second aspect, the present invention relates to Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with, as well as their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0029] Therefore, according to the second aspect described above, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2-# , (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 However, hydrogen atoms or C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, R 6 However, hydrogen atoms or C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with, as well as their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0030] definition The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by those selected from the indicated group, provided that the valency does not exceed the normal valency of the specified atom in the context in which it exists. Combinations of substituents and / or variables are permitted.

[0031] The term "optionally substituted" means that the number of substituents may be equal to or different from zero.

[0032] When a group in a compound according to the present invention is substituted, unless otherwise specified, the group may be monosubstituted or polysubstituted with one or more substituents. Within the scope of the present invention, the meaning of all repeating groups is independent of one another. A group in a compound according to the present invention may be substituted with one, two, or three identical or different substituents, in particular one substituent.

[0033] In the case of a composite substituent composed of two or more parts, for example (C1~C3-alkoxy)-(C2~C6-alkyl)-, the position of a given part can be any suitable position on the composite substituent, i.e., the C1~C3-alkoxy part can be bonded to any carbon atom of the C2~C6-alkyl part of the (C1~C3-alkoxy)-(C2~C6-alkyl)- group. The first or last hyphen of such a composite substituent indicates the bond site between the composite substituent and the rest of the molecule.

[0034] As used herein, the term "including" includes "consisting of" and "essentially consisting of."

[0035] If any item is referred to as “referred to herein” within the text, it means that it may be referred to anywhere in the text.

[0036] The terms used in this text have the following meanings:

[0037] The term "halogen atom" means fluorine, chlorine, bromine, or iodine atoms, and in particular fluorine, chlorine, or bromine atoms.

[0038] The term "C1-C6-alkyl" means a linear or branched saturated monovalent hydrocarbon group 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, neo-pentyl, 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, or 1,3-dimethylbutyl group, or their isomers or stereoisomers. In particular, the group is a group having 1, 2, 3, or 4 carbon atoms ("C1-C4-alkyl"), for example, a methyl, ethyl, propyl, isopropyl, butyl, sec-butylisobutyl, or tert-butyl group, and more particularly, a group having 1, 2, or 3 carbon atoms ("C1-C3-alkyl"), for example, a methyl, ethyl, n-propyl, or isopropyl group.

[0039] The term "C1-C3-haloalkyl" means a linear or branched saturated monovalent hydrocarbon group in which the term "C1-C3-alkyl" is as defined above, and one or more hydrogen atoms are replaced identically or differently by halogen atoms. In particular, the halogen atom is a fluorine atom. The C1-C3-haloalkyl group is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, 3,3,3-trifluoropropyl, or 1,3-difluoropropan-2-yl or other polyfluorosubstituted alkyl groups.

[0040] The term "C2-C6-hydroxyalkyl" means a linear or branched saturated monovalent hydrocarbon group in which one or more, preferably 1, 2, or 3 hydrogen atoms are replaced by a hydroxyl group, as defined above, such as 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl, 1-hydroxypropan-2-yl, 2,3-dihydroxypropyl, 1,3-dihydroxypropan-2-yl, 1,3-dihydroxy-2-(hydroxymethyl)propan-2-yl, 3-hydroxy-2-methylpropyl, and 2-hydroxy-2-methylpropyl groups.

[0041] The term "C1-C3-alkoxy" refers to a linear or branched saturated monovalent group of the formula (C1-C3-alkyl)-O-, as defined above, such as a methoxy, ethoxy, n-propoxy, or isopropoxy group.

[0042] The term "C3-C6-cycloalkyl" refers to a saturated monovalent monocyclic or bicyclic hydrocarbon ring ("C3-C6-cycloalkyl") containing 3, 4, 5, or 6 carbon atoms. The C3-C6-cycloalkyl group is, for example, a monocyclic hydrocarbon ring, such as a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0043] As used in this text, the term "C1-C6" refers to an alkyl group having a finite number of carbon atoms, i.e., 1 to 6 carbon atoms, in the context of the definition of "C1-C6-alkyl," for example.

[0044] Furthermore, as used herein, the term "C3-C6" as used in the text, for example, in the context of the definition of "C3-C6-cycloalkyl," means a cycloalkyl group having a finite number of carbon atoms, i.e., 3 to 6 carbon atoms, i.e., 3, 4, 5, or 6 carbon atoms.

[0045] Given a range of values, the range encompasses each value and subrange within that range.

[0046] for example: "C1~C6" means 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" encompasses C1, C2, C3, C4, C1~C4, C1~C3, C1~C2, C2~C4, C2~C3, and C3~C4; "C1~C3" encompasses C1, C2, C3, C1~C3, C1~C2, and C2~C3; "C2~C6" is C2, C3, C4, C5, C6, C2~C6, C2~C5, C2~C4, C2~C3, C3~C6, C3~C 5、 It includes C3-C4, C4-C6, C4-C5, and C5-C6; "C3~C6" is C3, C4, C5, C6, C3~C6, C3~C5, C3~C 4、 This includes C4-C6, C4-C5, and C5-C6.

[0047] The compounds of the present invention may contain one or more chiral centers, depending on the position and properties of various desired substituents. The chiral carbon atom may be present in (R) or (S) configuration, resulting in racemic mixtures, mixtures in which one enantiomer is present in greater quantities than the other, or, in the case of a single chiral center, a single enantiomer. In the case of multiple stereocenters, diastereomer mixtures, single diastereomers, or single enantiomers can be synthesized. In some cases, chirality may also be present by restricted rotation around a given bond, axial chirality, or coordination of a metallic center.

[0048] In the context of the present invention, the compound of formula (I), Gd 3+Compounds of formula (I), formula (II), formula (III) in the form of complexes, and any other compounds and / or intermediates described herein may contain an X group. The X group is, in particular, CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (The symbol indicates the bond point with the acetic acid moiety) and represents a group selected from the above. Those skilled in the art will know that the terms CH2, (CH2)2, (CH2)3 and (CH2)4 refer to linear alkyl groups, i.e. * CH2- # , * -(CH2)2- # , * -(CH2)3- # and * -(CH2)4- # group (in the formula, * This indicates the bonding point with Al, # You will recognize that this refers to the bond point with the acetic acid portion.

[0049] Preferred compounds are those that yield more desirable biological activity. Isolated, pure or partially purified isomers and stereoisomers or racemic or diastereomer mixtures of the compounds of the present invention are also within the scope of the present invention. Purification and separation of such materials can be achieved by standard techniques known in the art.

[0050] Optical isomers can be obtained by conventional methods of racemic mixture separation, for example, by the formation of diastereoisomer salts or covalent diastereomers using optically active acids or bases. Examples of suitable acids include tartaric acid, diacetyltartaric acid, ditoluyltartaric acid, and camphorsulfonic acid. Mixtures of diastereoisomers can be separated into individual diastereomers based on 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 liberated from the separated diastereomer salts. Another method of separating optical isomers involves the use of chiral chromatography (e.g., chiral HPLC columns), with or without conventional derivatization, which may be selected to maximize the separation of enantiomers. Suitable chiral HPLC columns are manufactured by Daicel, and examples include Chiracel OD and Chiracel OJ, among many others, all of which are routinely selectable. Enzymatic separation with or without derivatization is also useful. The optically active compounds of the present invention can also be obtained by chiral synthesis using optically active starting materials and / or reagents and catalysts.

[0051] To describe different isomers, refer to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).

[0052] The present invention comprises all possible stereoisomers of the compounds of the present invention as a single stereoisomer or as any mixture of the stereoisomers in any ratio, for example, R- or S-isomers or diastereomers. Isolation of a single stereoisomer of the compounds of the present invention, for example, a single enantiomer or a single diastereomer, can be achieved by any suitable prior art method described herein, for example, chromatography, in particular chiral chromatography.

[0053] Furthermore, the compounds of the present invention can exist as N-oxides, defined in that at least one nitrogen atom of the compound of the present invention is oxidized. The present invention encompasses all such possible N-oxides.

[0054] The present invention also relates to useful forms of the compounds disclosed herein, such as hydrates, solvates, salts, particularly pharmaceutically acceptable salts, and coprecipitations.

[0055] The compounds of the present invention can exist as hydrates or solvates, and for example, the compounds of the present invention contain polar solvents, particularly water, methanol, or ethanol, as structural elements of the crystal lattice of the compound. The amount of polar solvent, particularly water, may be present in stoichiometric or non-stoichiometric ratios. In the case of stoichiometric solvates, for example, hydrates, semi-, (semi-), mono-, sesqui-, di-, tri-, tetra-, penta-, etc., solvates, or hydrates are possible, respectively. The present invention encompasses all such hydrates or solvates.

[0056] Furthermore, the compounds of the present invention may exist in the form of salts. The salts may be either inorganic or organic addition salts, in particular any pharmaceutically acceptable inorganic or organic addition salt commonly used in pharmaceutical formulations.

[0057] Furthermore, in the context of the present invention, Gd, as described throughout this specification, 3+ Compounds of general formula (I) in the form of complexes with Gd 3+ The complex is a salt of the form of formula (Ia). [ka] (In the formula, Ar, X, and R 1 ~R 6 This refers to Gd, which is described throughout this specification. 3+ Compounds of general formula (I) in the form of complexes with Gd 3+ The group shown in different aspects, embodiments, examples, and any other descriptions and / or depictions of the complex is Y. +(This represents a hydrogen atom or a positively charged organic or inorganic pair ion.) It may exist as Gd, as described throughout this specification. In a particularly preferred embodiment, Gd 3+ Compounds of general formula (I) in the form of complexes with Gd 3+ The complex is formed as a salt of an alkali metal (Group 1 element), such as a sodium salt, i.e., as shown in formula (Ia) above (where Y + It may exist as a salt in the form of an alkali metal (Group 1 element) cation, for example, representing a positively charged sodium cation of an alkali metal (Group 1 element). In a particularly preferred embodiment, as described throughout this specification, Gd 3+ Compounds of general formula (I) in the form of complexes with Gd 3+ The complex is expressed as a sodium salt, i.e., as shown in the above formula (Ia) (where Y + It can exist as a salt in the form of a sodium cation (i.e., a positively charged sodium ion).

[0058] The term "pharmaceutically acceptable salt" refers to a relatively non-toxic inorganic or organic acid addition salt of the compound of the present invention. See, for example, SMBerge et al., "Pharmaceutical Salts," J. Pharm. Sci. 1977, 66, 1-19. The specific preparation of the neutral salt is described in U.S. Patent No. 5,560,903.

[0059] pharmaceutically acceptable salts of the compounds according to the present invention include salts with inorganic and / or organic bases or amino acids, particularly physiologically acceptable cations of inorganic and / or organic bases or amino acids, such as cations of primary, secondary, or tertiary amines. Examples, but not limited to, include salts of sodium, lithium, potassium, calcium, magnesium, arginine, lysine, ammonia, creatinine, diethanolamine, ethanolamine, morpholine, glucamine, N,N-dimethylglucamine, N-methylglucamine, ornithine, histidine, imidazole, tromethamine, and meglumine. Particularly preferred pharmaceutically acceptable salts of the compounds according to the present invention are their corresponding sodium salts.

[0060] Those skilled in the art will further recognize that a salt of the claimed compound can be prepared by the reaction of the compound with a suitable inorganic or organic base via one of several known methods.

[0061] The present invention comprises all possible salts of the compounds of the present invention, either as a single salt or as any mixture of the salts in any ratio.

[0062] In this text, particularly in the experimental section, when a compound is referred to as a salt form with a corresponding base or acid in relation to the synthesis of intermediates and examples of the present invention, the exact stoichiometric composition of the salt form obtained by each preparation and / or purification step is, in most cases, unknown.

[0063] This also applies when synthetic intermediates, example compounds, or salts thereof are obtained by preparation and / or purification steps as solvates, such as hydrates, of an unknown stoichiometric composition (if defined).

[0064] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0065] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0066] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [Chemical formula] (wherein, # represents the bonding point with X) represents a group selected from X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 each independently represent a hydrogen atom or a group selected from C1-C3 alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3, R 4 is C2-C5 alkoxy, (C1-C3 alkoxy)-(CH2)2-O-, (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O- and (C1-C3 alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- represents a group selected from the C1-C3 alkoxy group and the C2-C5 alkoxy group are optionally substituted 1, 2, 3 or 4 times with a fluorine atom, R 5 represents a hydrogen atom, R 6 represents a hydrogen atom, covering the compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0067] According to a further embodiment of the first aspect, the present invention Ar is [Chemical formula] and [Chemical formula] (wherein, # represents the bonding point with X) represents a group selected from X represents a group selected from CH2 and (CH2)3, R 1and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 2 However, this represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0068] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0069] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 This represents a hydrogen atom or a -CH2OH group. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0070] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents the -(CH2)2OH group, R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0071] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents a -CH2OCH3 group, R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0072] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, #(This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents a group selected from C1-C3 alkyl groups. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0073] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, #(This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C4-alkoxy, (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0074] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0075] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0076] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 2 However, this represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0077] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0078] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 This represents a hydrogen atom or a -CH2OH group. R 4This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0079] According to a further embodiment of the first aspect, the present invention is Ar [ka] (In the formula, # (This indicates the connection point with X.) This represents, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 This represents the -CH2OH group, R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0080] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents the -(CH2)2OH group, R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0081] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents a -CH2OCH3 group, R 4This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0082] According to a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents a group selected from C1-C3 alkyl groups. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. This includes compounds of the above general formula (I) and their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0083] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0084] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0085] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0086] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 2 However, this represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0087] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, #(This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0088] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 This represents a hydrogen atom or a -CH2OH group. R 4but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0089] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents the -(CH2)2OH group, R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0090] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents a -CH2OCH3 group, R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0091] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents a group selected from C1-C3 alkyl groups. R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0092] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 but, C2~C4-alkoxy, (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0093] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0094] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0095] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 2 However, this represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. R 4This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0096] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0097] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 This represents a hydrogen atom or a -CH2OH group. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0098] According to a further embodiment of the second aspect, the present invention is Ar [ka] (In the formula, # (This indicates the connection point with X.) This represents, X represents a group selected from CH2 and (CH2)3, R 1 , R 2 and R 3 This represents the -CH2OH group, R4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0099] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents the -(CH2)2OH group, R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0100] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R 1 and R 3 This represents a hydrogen atom, R 2 This represents a -CH2OCH3 group, R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0101] According to a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # (This indicates the connection point with X.) Represents a base selected from, X represents a group selected from CH2 and (CH2)3, R1 and R 3 This represents a hydrogen atom, R 2 This represents a group selected from C1-C3 alkyl groups. R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. Gd 3+ This includes compounds of the above general formula (I) in the form of complexes with the above compound, as well as their stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0102] According to a further embodiment of the second aspect, the present invention relates to Ar, X, R 1 , R 2 , R 3 , R 4 , R 5 and R 6 Gd is defined as described in any of the embodiments above. 3+ Sodium (Na) complex with + This includes compounds of the above general formula (I) in salt form, and their stereoisomers, tautomers, hydrates or solvates, or mixtures thereof. In a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # indicates a connection point with X) Represents a base selected from, This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0103] In a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # indicates a connection point with X) Represents a base selected from, This invention relates to the compound of formula (I) and its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof. In a further embodiment of the first aspect, the present invention is Ar [ka] and [ka] (In the formula, # indicates a connection point with X) Represents a base selected from, R 5 and R 6 This represents a hydrogen atom. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0104] In a further embodiment of the first aspect, the present invention is Ar is the base [ka] (In the formula, # indicates a connection point with X) This represents, R 5 This represents a hydrogen atom. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0105] In a further embodiment of the first aspect, the present invention is X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0106] In a further embodiment of the first aspect, the present invention is X represents a group selected from CH2 and (CH2)3. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0107] In a further embodiment of the first aspect, the present invention is X represents (CH2)3. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0108] In a further embodiment of the first aspect, the present invention is R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0109] In a further embodiment of the first aspect, the present invention is R 1 and R 3However, each occurrence independently represents either a hydrogen atom or a -CH2OCH3 group. R 2 However, it represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0110] In a further embodiment of the first aspect, the present invention is R 1 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 2 However, it represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0111] In a further embodiment of the first aspect, the present invention is R 1 , R 2 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0112] In a further embodiment of the first aspect, the present invention is R 1 , R 2 and R 3 This represents a hydrogen atom or a -CH2OH group. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0113] In a further embodiment of the first aspect, the present invention is R 1 , R 2 and R 3 This represents the -CH2OH group. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0114] In a further embodiment of the first aspect, the present invention is R 1 and R 3 This represents a hydrogen atom, R 2 This represents the -CH2OH group. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0115] In a further embodiment of the first aspect, the present invention is R 1 and R 3 This represents a hydrogen atom, R 2 This represents the -CH2OCH3 group. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0116] In a further embodiment of the first aspect, the present invention is R 1 and R 3 This represents a hydrogen atom, R 2 This represents a C1-C3 alkyl group. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0117] In a further embodiment of the first aspect, the present invention is R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0118] In a further embodiment of the first aspect, the present invention is R 4 but, C2~C4-alkoxy, (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C2-C4 alkoxy group is optionally substituted with a fluorine atom one, two, three, or four times. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0119] In a further embodiment of the first aspect, the present invention is R 4 but, C2~C4-alkoxy, (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0120] In a further embodiment of the first aspect, the present invention is R 4 This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0121] In a further embodiment of the first aspect, the present invention is R 4 This represents (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- This invention relates to the compound of formula (I) and its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

[0122] In a further embodiment of the first aspect, the present invention is R 5 However, hydrogen atoms or C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, This invention relates to the compound of formula (I) and its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0123] In a further embodiment of the first aspect, the present invention is R 5 This represents a hydrogen atom. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0124] In a further embodiment of the first aspect, the present invention is R 6However, hydrogen atoms or C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, This invention relates to the compound of formula (I) and its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0125] In a further embodiment of the first aspect, the present invention is R 6 This represents a hydrogen atom. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0126] In a further embodiment of the first aspect, the present invention is R 5 and R 6 This represents a hydrogen atom. This invention relates to the compound of formula (I) and its stereoisomers, tautomers, hydrates, solvates, or salts, or mixtures thereof.

[0127] It should also be understood that the present invention relates to any combination of the above embodiments.

[0128] In the context of the present invention, the compound of formula (I) may contain one or more chiral centers. 1 =R 2 =R 3 When =H, the carbon atom bonded to X can be in the (R) or (S) configuration. Therefore, the present invention is R 1 =R 2 =R 3 This includes the (R) and (S) enantiomers of the compound of formula (I) when =H, or mixtures thereof.

[0129] Furthermore, R 1 , R 2 and / or R3 If one or more of them are different from hydrogen atoms, R 1 , R 2 and / or R 3 The carbon atom bonded to it can be in (R) or (S) configuration. Therefore, the present invention is R 1 , R 2 and / or R 3 This includes all possible stereoisomers of the compound of formula (I) or mixtures thereof, where one or more of the atoms differ from the hydrogen atom. 1 , R 2 or R 3 If one of them is different from a hydrogen atom, this includes the RR, SS, RS, SR stereoisomers of the compound of formula (I), or mixtures thereof. 1 , R 2 or R 3 If the two are different from hydrogen atoms, this includes the RRR, SSS, RRS, SSR, SRR, RSS, RSR and SRS stereoisomers of the compound of formula (I), or mixtures thereof. 1 , R 2 and R 3 If the atom is different from a hydrogen atom, this includes the stereoisomers of the compound of formula (I), RRRR, SRRR, RSRR, RRSR, RRRS, SSRR, SRSR, SRRS, RSSR, RSRS, RRSS, RSSS, SRSS, SSRS, SSSR, SSSS, or mixtures thereof.

[0130] Another embodiment of the first aspect is: 3-[2-(4-ethoxyphenyl)ethoxy]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, (2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, (2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 2-[7-(1-carboxyethyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanoic acid, 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoic acid, (2S)-6-(4-butoxyphenyl)-2-{4,7,10-tris[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}hexanoic acid, 3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, (2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, (2R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-methoxypropanoic acid, 3-(4-butoxyphenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, (2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid, 3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(1-carboxy-2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane-1-yl]pentanoic acid, (2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid, (2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(1R)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid, (2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(1R)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid, (2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(1-carboxy-2-hydroxyethyl)-1,4,7,10-tetraazacyclododecane-1-yl]pentanoic acid, 2,2',2”-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoic acid), 3-{5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-yl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 4-(4-propoxyphenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoic acid, 5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]pentanoic acid, (2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]pentanoic acid, (2S)-6-(4-ethoxyphenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]hexanoic acid, 5-(4-ethoxyphenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]pentanoic acid, 2-{7-[1-carboxy-2-(4-ethoxyphenyl)ethyl]-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid, (2S)-5-(4-butoxyphenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]pentanoic acid, 3-[4-(2-ethoxyethoxy)phenyl]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, (2S)-2-[4,10-bis(carboxymethyl)-7-{1-carboxy-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1-yl]-3-hydroxypropanoic acid, (2S)-5-(3-butoxyphenyl)-2-{4,7,10-tris[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid, (2S)-2-{7-[(1R)-1-carboxy-2-hydroxyethyl]-4,10-bis[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}pentanoic acid, (2S)-2-{7-[1-carboxy-3-hydroxypropyl]-4,10-bis[1-carboxy-3-hydroxypropyl]-1,4,7,10-tetraazacyclododecane-1-yl}-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}pentanoic acid, 2,2',2”-[10-(1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl]tris(4-hydroxybutanoic acid), 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-methoxypropanoic acid, 3-{3,5-bis[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 3-(2,4-bis{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 2-[7-(1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-hydroxypropanoic acid, 2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-hydroxypropanoic acid, 2-[7-(1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl)-4,10-bis(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoic acid, 3-(4-butoxyphenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 2-[4,10-bis(carboxymethyl)-7-{1-carboxy-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1-yl]-3-methoxypropanoic acid, 3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 3-[4-(2,2,2-trifluoroethoxy)phenyl]-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, 3-(4-propoxyphenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid, (2S)-2-{4,7-bis[(1R)-1-carboxy-2-hydroxyethyl]-10-[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}pentanoic acid and (2S)-2-{4-[(1R)-1-carboxy-2-hydroxyethyl]-7,10-bis[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}pentanoic acid A compound of formula (I) selected from the group consisting of the following, and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0131] In a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # indicates a connection point with X) Represents a base selected from, Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0132] In a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # indicates a connection point with X) Represents a base selected from, Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0133] In a further embodiment of the second aspect, the present invention is Ar [ka] and [ka] (In the formula, # indicates a connection point with X) Represents a base selected from, R 5 and R 6 This represents a hydrogen atom. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0134] In a further embodiment of the second aspect, the present invention is Ar [ka] (In the formula, # indicates a connection point with X) This represents, R 5 This represents a hydrogen atom. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0135] In a further embodiment of the second aspect, the present invention is X CH2, (CH2)2, (CH2)3, (CH2)4 and * -(CH2)2-O-CH2- # (In the formula, * This indicates the bonding point with Al, # (This indicates the bond point with the acetic acid portion.) Represents a base selected from, Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0136] In a further embodiment of the second aspect, the present invention is X represents a group selected from CH2 and (CH2)3. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0137] In a further embodiment of the second aspect, the present invention is X represents (CH2)3. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0138] In a further embodiment of the second aspect, the present invention is R 1 , R 2 and R 3 However, each occurrence independently represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH, and -CH2OCH3. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0139] In a further embodiment of the second aspect, the present invention is R 1 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OCH3 group. R 2 However, it represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0140] In a further embodiment of the second aspect, the present invention is R 1 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. R 2 However, it represents a hydrogen atom or a group selected from C1-C3-alkyl, -CH2OH, -(CH2)2OH and -CH2OCH3. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0141] In a further embodiment of the second aspect, the present invention is R 1 , R 2 and R 3 However, each occurrence independently represents either a hydrogen atom or a -CH2OH group. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0142] In a further embodiment of the second aspect, the present invention is R 1 , R 2 and R 3 This represents a hydrogen atom or a -CH2OH group. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0143] In a further embodiment of the second aspect, the present invention is R 1 , R 2 and R 3 This represents the -CH2OH group. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0144] In a further embodiment of the second aspect, the present invention is R 1 and R 3 This represents a hydrogen atom, R 2 This represents the -CH2OH group. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0145] In a further embodiment of the second aspect, the present invention is R 1 and R 3 This represents a hydrogen atom, R 2 This represents the -CH2OCH3 group. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0146] In a further embodiment of the second aspect, the present invention is R 1 and R 3 This represents a hydrogen atom, R 2 This represents a C1-C3 alkyl group. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0147] In a further embodiment of the second aspect, the present invention is R 4 but, C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C1-C3 alkoxy groups and C2-C5 alkoxy groups are optionally substituted with fluorine atoms one, two, three, or four times. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0148] In a further embodiment of the second aspect, the present invention is R 4 but, C2~C4-alkoxy, (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, The C2-C4 alkoxy group is optionally substituted with a fluorine atom one, two, three, or four times. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0149] In a further embodiment of the second aspect, the present invention is R 4 but, C2~C4-alkoxy, (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0150] In a further embodiment of the second aspect, the present invention is R 4This represents a group selected from (H3C-CH2)-O-(CH2)2-O-, (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-, and (H3C-CH2)-O-(CH2)2-O-(CH2)2-O-(CH2)2-O-. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0151] In a further embodiment of the second aspect, the present invention is R 4 This represents (H3C-CH2)-O-(CH2)2-O-(CH2)2-O- Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0152] In a further embodiment of the second aspect, the present invention is R 5 However, hydrogen atoms or C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0153] In a further embodiment of the second aspect, the present invention is R 5 This represents a hydrogen atom. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0154] In a further embodiment of the second aspect, the present invention is R 6 However, hydrogen atoms or C2~C5-alkoxy, (C1~C3-alkoxy)-(CH2)2-O-, (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C1~C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O- Represents a base selected from, Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0155] In a further embodiment of the second aspect, the present invention is R 6 This represents a hydrogen atom. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0156] In a further embodiment of the second aspect, the present invention is R 5 and R 6 This represents a hydrogen atom. Gd 3+ This invention relates to compounds of formula (I) in the form of complexes with and their stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof.

[0157] It should also be understood that the present invention relates to any combination of the above embodiments.

[0158] In the context of the present invention, Gd 3+ The compound of formula (I) in the form of a complex with R may contain one or more chiral centers. 1 =R 2 =R 3 When =H, the carbon atom bonded to X can be in the (R) or (S) configuration. Therefore, the present invention is R 1 =R 2 =R3 Gd when =H 3+ The compound comprises (R) and (S) enantiomers of the compound of formula (I) in the form of a complex with, or mixtures thereof.

[0159] Furthermore, R 1 , R 2 and / or R 3 If one or more of them are different from hydrogen atoms, R 1 , R 2 and / or R 3 The carbon atom bonded to it can be in (R) or (S) configuration. Therefore, the present invention is R 1 , R 2 and / or R 3 Gd when one or more of them are different from hydrogen atoms 3+ This includes all possible stereoisomers of the compound of formula (I) in the form of a complex with, or mixtures thereof. 1 , R 2 or R 3 If one of them is different from a hydrogen atom, then this is Gd 3+ The compound of formula (I) in the form of a complex with RR, SS, RS, SR stereoisomers, or mixtures thereof. 1 , R 2 or R 3 If these two are different from hydrogen atoms, then this is Gd 3+ The compound of formula (I) in the form of a complex with RRR, SSS, RRS, SSR, SRR, RSS, RSR and SRS stereoisomers, or mixtures thereof. 1 , R 2 and R 3 If it is different from a hydrogen atom, then this is Gd 3+ The compound of formula (I) in the form of a complex with RRRR, RRRS, RSRR, RSSR, RSRS, RRSS, RRSR, RSSS, SSSS, SSSR, SRSS, SRRS, SRSR, SSRR, SSRS, SRRR stereoisomers, or mixtures thereof.

[0160] According to a further embodiment of the second aspect, the present invention relates to Ar, X, R 1 , R 2 , R 3 , R4 , R 5 and R 6 Gd is defined as described in any of the embodiments above. 3+ Sodium (Na) complex with + This includes compounds of the above general formula (I) in salt form, and their stereoisomers, tautomers, hydrates or solvates, or mixtures thereof.

[0161] Another embodiment of the second aspect is, Gadolinium 2,2',2”-(10-{1-carboxy-2-[2-(4-ethoxyphenyl)ethoxy]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1R)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-[7-(1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl)-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate, Gadolinium 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoate, Gadolinium (2S,2'S,2”S)-2,2',2”-{10-[(1S)-5-(4-butoxyphenyl)-1-carboxypentyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2”-{10-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1R)-1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-methoxypropanoate, Gadolinium 2,2',2”-{10-[2-(4-butoxyphenyl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium (2S,2'S,2”S)-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2”-{10-[1-carboxy-2-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2,2',2”-{10-[1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2S,2'S,2”S)-2,2',2”-{10-[(1R)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2R,2'R,2”R)-2,2',2”-{10-[(1R)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2R,2'R,2”R)-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2”-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2”-{10-[1-carboxy-2-{5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-yl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-3-(4-propoxyphenyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-5-(4-ethoxyphenyl)pentyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-4-(4-ethoxyphenyl)butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-{7-[1-carboxy-2-(4-ethoxyphenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}pentanoate, Gadolinium 2,2',2”-{10-[(1S)-4-(4-butoxyphenyl)-1-carboxybutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-(10-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium(2S)-2-[4,10-bis(carboxylatomethyl)-7-{1-carboxy-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1-yl]-3-hydroxypropanoate, Gadolinium (2S,2'S,2”S)-2,2',2”-{10-[(1S)-4-(3-butoxyphenyl)-1-carboxybutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2S,2'S)-2,2'-{4-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1R)-1-carboxylat-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(3-hydroxypropanoate), Gadolinium-2,2'-{4-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[1-carboxylat-3-hydroxypropyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(4-hydroxybutanoate), Gadolinium-2,2'-{4-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-10-[1-carboxylat-3-hydroxypropyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(4-hydroxybutanoate), Gadolinium 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-methoxypropanoate, Gadolinium 2,2',2”-{10-[2-{3,5-bis[2-(2-ethoxyethoxy)ethoxy]phenyl}-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-2-(2,4-bis{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2-{7-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-hydroxypropanoate, Gadolinium-2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-hydroxypropanoate, Gadolinium-2-{4,10-bis(carboxylatomethyl)-7-[1-carboxypropyl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanoate, Gadolinium 2,2',2”-{10-[2-(5-butoxypyridine-2-yl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2-{4,10-bis(carboxylatomethyl)-7-[1-carboxy-2-methoxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]propanoate, Gadolinium 2,2',2”-(10-{1-carboxy-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium 2,2',2”-(10-{(1R)-1-carboxy-2-[4-(2,2,2-trifluoroethoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-2-(4-propoxyphenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium (2R,2'R)-2,2'-{7-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1S)-1-carboxylat-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,4-diyl}bis(3-hydroxypropanoate) and Gadolinium(2S,2'S)-2,2'-{7-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1R)-1-carboxylat-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,4-diyl}bis(3-hydroxypropanoate) Gd selected from the group consisting of 3+ The compound of formula (I) in the form of a complex with the compound, and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

[0162] Another embodiment of the second aspect is, Gadolinium 2,2',2”-(10-{1-carboxy-2-[2-(4-ethoxyphenyl)ethoxy]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1R)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-[7-(1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl)-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate, Gadolinium 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoate, Gadolinium (2S,2'S,2”S)-2,2',2”-{10-[(1S)-5-(4-butoxyphenyl)-1-carboxypentyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2”-{10-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1R)-1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-methoxypropanoate, Gadolinium 2,2',2”-{10-[2-(4-butoxyphenyl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium (2S,2'S,2”S)-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2”-{10-[1-carboxy-2-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2,2',2”-{10-[1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2S,2'S,2”S)-2,2',2”-{10-[(1R)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2R,2'R,2”R)-2,2',2”-{10-[(1R)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2R,2'R,2”R)-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2”-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2”-{10-[1-carboxy-2-{5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-yl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-3-(4-propoxyphenyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-5-(4-ethoxyphenyl)pentyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-4-(4-ethoxyphenyl)butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-{7-[1-carboxy-2-(4-ethoxyphenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}pentanoate, Gadolinium 2,2',2”-{10-[(1S)-4-(4-butoxyphenyl)-1-carboxybutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-(10-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium(2S)-2-[4,10-bis(carboxylatomethyl)-7-{1-carboxy-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1-yl]-3-hydroxypropanoate, Gadolinium (2S,2'S,2”S)-2,2',2”-{10-[(1S)-4-(3-butoxyphenyl)-1-carboxybutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2S,2'S)-2,2'-{4-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1R)-1-carboxylat-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(3-hydroxypropanoate), Gadolinium-2,2'-{4-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[1-carboxylat-3-hydroxypropyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(4-hydroxybutanoate), Gadolinium-2,2'-{4-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-10-[1-carboxylat-3-hydroxypropyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(4-hydroxybutanoate), Gadolinium 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-methoxypropanoate, Gadolinium 2,2',2”-{10-[2-{3,5-bis[2-(2-ethoxyethoxy)ethoxy]phenyl}-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2”-{10-[(1S)-2-(2,4-bis{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2-{7-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-hydroxypropanoate, Gadolinium-2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-hydroxypropanoate, Gadolinium-2-{4,10-bis(carboxylatomethyl)-7-[1-carboxypropyl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanoate, Gadolinium 2,2',2”-{10-[2-(5-butoxypyridine-2-yl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2-{4,10-bis(carboxylatomethyl)-7-[1-carboxy-2-methoxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]propanoate, Gadolinium 2,2',2”-(10-{1-carboxy-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium 2,2',2”-(10-{(1R)-1-carboxy-2-[4-(2,2,2-trifluoroethoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium 2,2',2”-{10-[1-carboxy-2-(4-propoxyphenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium (2R,2'R)-2,2'-{7-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1S)-1-carboxylat-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,4-diyl}bis(3-hydroxypropanoate) and Gadolinium(2S,2'S)-2,2'-{7-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1R)-1-carboxylat-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,4-diyl}bis(3-hydroxypropanoate) Gd selected from the group consisting of 3+ Sodium (Na) complex with +) A compound of formula (I) in the form of a salt, and its stereoisomers, tautomers, N-oxides, hydrates or solvates, or mixtures thereof.

[0163] In another aspect, the present invention encompasses methods for preparing the compounds of the present invention, including the steps described in the experimental section of this specification.

[0164] In a further aspect, the present invention relates to the preparation of compounds of general formula (I), particularly the above-mentioned Gd 3+ This document covers intermediate compounds useful for preparing compounds of general formula (I) in the form of complexes with [specific compound].

[0165] In particular, the present invention relates to intermediate compounds of general formula (II). [ka] and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof (wherein the formula is Ar, X, R 1 , R 2 and R 3 R is defined as above for compounds of general formula (I), and 7 This encompasses all groups (where C1-C4 alkyl and benzyl groups are selected).

[0166] In particular, the present invention relates to intermediate compounds of general formula (III). [ka] and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof (wherein Ar and X are defined as for the compound of general formula (I) above, R 7 R represents a group selected from C1-C4 alkyl and benzyl groups, 8 , R 9 and R 10 Each occurrence is independent of the others. -CH2O-C(CH3)3, -(CH2)2O-C(CH3)3, -CH2O-CH2Ph ​​and -((CH2)2O-CH2)Ph It covers all bases selected from the given list.

[0167] In particular, the present invention relates to intermediate compounds of general formula (IV). [ka] and its stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof (wherein R 7 R represents a group selected from C1-C4 alkyl and benzyl groups, 8 , R 9 and R 10 Each occurrence is independent of the others. -CH2O-C(CH3)3, -(CH2)2O-C(CH3)3, -CH2O-CH2Ph ​​and -((CH2)2O-CH2)Ph It covers all bases selected from the given list.

[0168] In particular, the present invention relates to intermediate compounds of general formula (IV). [ka] and its stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof (wherein R 7 R represents a group selected from C1-C4 alkyl and benzyl groups, 8 , R 9 and R 10 Each occurrence is independent of the others. C1-C3-alkyl, -CH2O(CH3), -CH2O-C(CH3)3, -(CH2)2O-C(CH3)3, -CH2O-CH2Ph ​​and -((CH2)2O-CH2)Ph It covers all bases selected from the given list.

[0169] In a further aspect, the present invention relates to the Gd defined above. 3+ This covers the use of the above-described intermediate compounds for preparing compounds of general formula (I) in the form of complexes with the other compounds.

[0170] In a further aspect, the present invention relates to the Gd defined above. 3+ For preparing a compound of general formula (I) in the form of a complex with, the compound of general formula (I) [ka] and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof (wherein the formula is Ar, X, R 1 , R 2 and R 3 (This is defined as for compounds of the general formula (I) above.) This covers all uses of [the subject].

[0171] In a further aspect, the present invention relates to the Gd defined above. 3+ A compound of general formula (II) for preparing a compound of general formula (I) in the form of a complex with [ka] and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof (wherein the formula is Ar, X, R 1 , R 2 and R 3 This is defined as for compounds of the above general formula (I), and R 7 (This represents a group selected from C1-C4 alkyl and benzyl groups.) This covers all uses of [the subject].

[0172] In a further aspect, the present invention relates to the Gd defined above. 3+ For preparing a compound of general formula (I) in the form of a complex with, an intermediate compound of general formula (III) [ka] and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof (wherein Ar and X are defined as for the compound of general formula (I) above, R 7R represents a group selected from C1-C4 alkyl and benzyl groups, 8 , R 9 and R 10 Each occurrence is independent of the others. -CH2O-C(CH3)3, -(CH2)2O-C(CH3)3, -CH2O-CH2Ph ​​and -((CH2)2O-CH2)Ph (Represents a base selected from) This covers all uses of [the subject].

[0173] In a further aspect, the present invention relates to the Gd defined above. 3+ For preparing a compound of general formula (I) in the form of a complex with, an intermediate compound of general formula (III) [ka] and its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof (wherein Ar and X are defined as for the compound of general formula (I) above, R 7 R represents a group selected from C1-C4 alkyl and benzyl groups, 8 , R 9 and R 10 Each occurrence is independent of the others. C1-C3 alkyl, -CH2O(CH3), -CH2O-C(CH3)3, -(CH2)2O-C(CH3)3, -CH2O-CH2Ph ​​and -((CH2)2O-CH2)Ph (Represents a base selected from) This covers all uses of [the subject].

[0174] In a further aspect, the present invention relates to the Gd defined above. 3+ Intermediate compound of general formula (IV) for preparing a compound of general formula (I) in the form of a complex with [ka] and its stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof (wherein R 7R represents a group selected from C1-C4 alkyl and benzyl groups, 8 , R 9 and R 10 Each occurrence is independent of the others. -CH2O-C(CH3)3, -(CH2)2O-C(CH3)3, -CH2O-CH2Ph ​​and -((CH2)2O-CH2)Ph (Represents a base selected from) This covers all uses of [the subject].

[0175] In a further aspect, the present invention relates to the Gd defined above. 3+ Intermediate compound of general formula (IV) for preparing a compound of general formula (I) in the form of a complex with [ka] and its stereoisomers, tautomers, hydrates, solvates or salts, or mixtures thereof (wherein R 7 R represents a group selected from C1-C4 alkyl and benzyl groups, 8 , R 9 and R 10 Each occurrence is independent of the others. C1-C3 alkyl, -CH2O(CH3), -CH2O-C(CH3)3, -(CH2)2O-C(CH3)3, -CH2O-CH2Ph ​​and -((CH2)2O-CH2)Ph (Represents a base selected from) This covers all uses of [the subject].

[0176] Furthermore, the present invention encompasses the intermediate compounds disclosed in the experimental section of the following text.

[0177] Gd 3+ Compounds of general formula (I) in the form of a complex, i.e., Gd of the compound of general formula (I) of the present invention 3+ The complex exhibited valuable complex stability, solubility, uptake into hepatocytes, relaxation, and valuable tolerability and pharmacokinetic profiles, which were unpredictable. The Gd of general formula (I) of the present invention 3+The compounds contained have been found to be effectively taken up by hepatocytes and to provide a high degree of relaxation while maintaining pharmacokinetics, a good safety and tolerability profile. Therefore, the compounds can be used for contrast-enhanced MRI (CE-MRI), preferably for multipurpose MRI and liver MRI, more preferably for the detection of liver diseases such as hepatic fibrosis, cirrhosis, and metastasis in humans and animals, as well as for the differential diagnosis and functional imaging of localized liver lesions.

[0178] A further aspect of the present invention is the use of the compound of general formula (I) described above for diagnostic imaging.

[0179] Those skilled in the art will know that the compound of general formula (I) of the present invention is Gd 3+ It will be noted that these can be used in combination with other MR-active metal ions instead, and such compounds are also included in the present invention.

[0180] A further aspect of the present invention is Gd for diagnostic imaging. 3+ This involves the use of the above general formula (I) compound in the form of a complex with [the other compound].

[0181] A further aspect of the present invention relates to the Gd compound of the above general formula (I) for diagnostic imaging. 3+ This involves the use of complexes.

[0182] Preferably, the compounds of the present invention in the diagnosis, i.e., the compounds of general formula (I) and / or Gd 3+ Compounds of the above general formula (I) in the form of complexes with and / or Gd of the above general formula (I) 3+ The use of the complex is performed using magnetic resonance imaging (MRI).

[0183] A further aspect of the present invention is the use of the compound of general formula (I) described above for magnetic resonance imaging, preferably of blood vessels, kidneys, or hepatobiliary tract or gastrointestinal tract, more preferably of liver magnetic resonance imaging.

[0184] Further aspects of the present invention relate to magnetic resonance imaging, preferably of blood vessels, kidneys or hepatobiliary tract or gastrointestinal tract, and more preferably of liver magnetic resonance imaging, Gd 3+ This involves the use of the above general formula (I) compound in the form of a complex with [the other compound].

[0185] A further aspect of the present invention relates to magnetic resonance imaging, preferably of blood vessels, kidneys, or hepatobiliary tract or gastrointestinal tract, and more preferably of liver, the Gd compound of the above general formula (I). 3+ This involves the use of complexes.

[0186] A further aspect of the present invention is a compound of general formula (I) for use in medical imaging.

[0187] A further aspect of the present invention is Gd for use in diagnostic imaging. 3+ It is a compound of general formula (I) in the form of a complex with [another compound].

[0188] A further aspect of the present invention is the use of the above-mentioned compound of general formula (I) Gd 3+ It is a complex.

[0189] A further aspect of the present invention is a compound of general formula (I) for use in magnetic resonance imaging (MRI), preferably of blood vessels, kidneys, or hepatobiliary tract or gastrointestinal tract, more preferably of liver magnetic resonance imaging.

[0190] A further aspect of the present invention is Gd for use in magnetic resonance imaging (MRI), preferably of blood vessels, kidneys or hepatobiliary tract or gastrointestinal tract, more preferably of liver magnetic resonance imaging. 3+ It is a compound of general formula (I) in the form of a complex with [another compound].

[0191] A further aspect of the present invention relates to the Gd compound of the above general formula (I) for use in magnetic resonance imaging (MRI), preferably of blood vessels, kidneys, or hepatobiliary tract or gastrointestinal tract, more preferably of liver magnetic resonance imaging. 3+ It is a complex.

[0192] The present invention also includes compounds of general formula (I) for the manufacture of diagnostic agents.

[0193] The present invention also provides for manufacturing diagnostic agents, Gd 3+ This also includes compounds of general formula (I) in the form of complexes with [the other compound].

[0194] A further aspect of the present invention is the use of a compound of general formula (I) or a mixture thereof for the manufacture of a diagnostic agent.

[0195] A further aspect of the present invention is Gd for manufacturing a diagnostic agent. 3+ This involves the use of a compound of general formula (I) or a mixture thereof in the form of a complex with [another compound].

[0196] A further aspect of the present invention is the use of a compound of general formula (I) or a mixture thereof for the manufacture of a diagnostic agent for magnetic resonance imaging (MRI).

[0197] A further aspect of the present invention relates to a method for manufacturing diagnostic agents for magnetic resonance imaging (MRI), Gd 3+ This involves the use of a compound of general formula (I) or a mixture thereof in the form of a complex with [another compound].

[0198] A further aspect of the present invention is the use of compounds of general formula (I) or mixtures thereof for producing diagnostic agents for magnetic resonance imaging (MRI) of blood vessels, kidneys, or hepatobiliary tract or gastrointestinal tract, preferably magnetic resonance imaging of the liver.

[0199] A further aspect of the present invention relates to the production of a diagnostic agent for magnetic resonance imaging (MRI) of blood vessels, kidneys, or hepatobiliary system or gastrointestinal tract, preferably for magnetic resonance imaging of the liver, Gd 3+ This involves the use of a compound of general formula (I) or a mixture thereof in the form of a complex with [another compound].

[0200] A further aspect of the present invention relates to the production of a diagnostic agent for magnetic resonance imaging (MRI) of the blood vessels, kidneys, or hepatobiliary system or gastrointestinal tract, preferably for magnetic resonance imaging of the liver, using the above-mentioned compound Gd 3+ This involves the use of a complex or a mixture thereof.

[0201] A further aspect of the present invention is a method for imaging a patient's body tissue, comprising one or more effective amounts of a patient-tolerable carrier containing one or more Gd 3+ The method comprises the steps of administering a compound of general formula (I) in the form of a complex with and subjecting the patient to NMR tomography.

[0202] A further aspect of the present invention is a method for imaging a patient's body tissue, comprising a patient-tolerable carrier containing an effective amount of one or more compounds of general formula (I) Gd 3+ The method comprises the steps of administering a complex and subjecting the patient to NMR tomography.

[0203] For manufacturing diagnostic agents, for example, for administration to humans or animals, Gd 3+ Compounds of general formula (I) in the form of complexes with Gd 3+ The complex or mixture may be conveniently formulated together with a pharmaceutical carrier or excipient. The contrast agent of the present invention may conveniently contain pharmaceutical formulation aids, such as stabilizers, antioxidants, pH adjusters, metal scavengers, electrolytes (e.g., sodium chloride), flavoring agents, etc. The diagnostic agent of the present invention may be formulated for parenteral or enteral administration or for direct administration into body cavities. For example, a parenteral formulation may contain a sterile solution or suspension of a dose of the compound of formula (I) according to the present invention in a concentration of 0.0001 to 5 mmol gadolinium / kg body weight, preferably 0.001 to 0.5 mmol gadolinium / kg body weight, more preferably 0.005 to 0.1 mmol gadolinium / kg body weight. Thus, the agent of the present invention may be a conventional pharmaceutical formulation such as a solution, suspension, dispersion, syrup, etc., in a physiologically acceptable carrier medium, 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.

[0204] In a further embodiment, the present invention relates to a method for diagnosing and monitoring the health of a patient. The method comprises the steps of: a) administering a compound of the present invention to a person requiring such diagnosis for detection of the compound in a person as described above and herein; and b) measuring the signal resulting from the administration of the compound to the person, preferably by magnetic resonance imaging (MRI).

[0205] In a further embodiment, the present invention relates to a method for diagnosing and monitoring the health of a patient. This method involves a) providing a person requiring such diagnosis with the compounds of the present invention for detection in a person as described above and herein, namely Gd 3+ The procedure includes the steps of: a) administering a compound of general formula (I) in the form of a complex with; and b) measuring the signal resulting from the administration of the compound to a human, preferably by magnetic resonance imaging (MRI).

[0206] In a further embodiment, the present invention relates to a method for diagnosing and monitoring the health of a patient. The method involves a) providing a person requiring such diagnosis with the compounds of the present invention, namely the compounds of general formula (I), for detection in a person as described above and herein, i.e., Gd 3+ The procedure includes the steps of: a) administering the complex; and b) preferably measuring the signal resulting from the administration of the compound to a human by magnetic resonance imaging (MRI).

[0207] general synthesis Gd 3+ Compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with , can be prepared using the following general procedures shown in schemes 1 to 9 below. Unless otherwise specified, the R shown herein 1 ~R 10 The base has the meaning described above. 1 , R 2 and / or R 3 If a protecting group chemistry is required for the introduction of one or more groups, R 8 , R 9 and / or R10 The group can be used. Therefore, if protecting group chemistry is not required, R 8 , R 9 and R 10 The base is R 1 , R 2 and R 3 Equivalent to the base. Generally, but not limited to, the following bases are R 7 =methyl, ethyl, or tert-butyl, R 11 =methyl, trifluoromethyl or para-nitrophenyl, and R 12 = Selected from benzyl.

[0208] For example, especially R 1 =R 2 =R 3 =Gd when it is hydrogen 3+ Compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with , can be prepared by the procedure shown in Scheme 1. [ka] Scheme 1.

[0209] Or, especially R 1 =R 2 =R 3 =Gd when it is hydrogen 3+ The compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with , can be prepared by following the procedure shown in Scheme 2, in which cyclone (1,4,7,10-tetraazacyclododecane) is first trialkylated, followed by alkylation of the remaining secondary nitrogen. [ka] Scheme 2.

[0210] Furthermore, especially R 1 =R 2 =R 3 =Gd when it is hydrogen 3+Compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with chloroacetic acid, can be prepared according to the procedure shown in Scheme 3, in which the acetic acid side chain can be directly introduced using chloroacetic acid. [ka] Scheme 3

[0211] In general, Scheme 4 is Gd 3+ The present invention provides a preparation route for compounds of general formula (I) described in this invention, including compounds of general formula (I) in the form of complexes with . This route starts, for example, with the known 1,7-bis-tert-butyldiacetatecyclene, Cas number [162148-48-3], in particular R 2 R 1 and R 3 It is particularly suitable for the preparation of 1,7-disubstituted compounds in cases different from those described above. [ka] Scheme 4.

[0212] Alternatively, the sequence shown in Scheme 5 starts with the known 1,7-bis-Cbz protected siklen, Cas number [162148-45-0], in particular R 2 R 1 and R 3 Gd in cases where it is different from 3+ It can be used to prepare compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with . [ka] Scheme 5.

[0213] Alternatively, the order shown in Scheme 6 is, in particular, R 1 =R 2 =R 3 = Gd when it is hydroxymethyl 3+ It can be used to prepare compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with . [ka] Scheme 6

[0214] Furthermore, Gd 3+ To prepare compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with R, the incorporation of an alkene side chain is particularly involved. 1 =R 2 =R 3 = can be used as a point for further derivatization as shown in Scheme 7 when it is hydroxymethyl. [ka] Scheme 7 (n=0, 1, 2).

[0215] In general, the order shown in Scheme 8 is, in particular, R 1 =R 2 =R 3 = Gd when hydroxyethyl 3+ It can be used to prepare compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with . [ka] Scheme 8.

[0216] Finally, the order shown in Scheme 9 starts from the known 1,4-bis-benzyl protected cyclene Cas number [216101-03-0], in particular R 1 R 2 and R 3 Gd when it is desirable for it to be different from 3+ It can be used to prepare compounds of general formula (I) described in the present invention, including compounds of general formula (I) in the form of complexes with . [ka] Scheme 9.

[0217] The above scheme and procedure illustrate, but are not intended to be limiting, the synthetic route to the compound of general formula (I) of the present invention. It will be apparent to those skilled in the art that the order of transformations illustrated in the scheme can be modified in various ways. Therefore, the order of transformations illustrated in the scheme is not intended to be limiting. Suitable protective groups and their introduction and cleavage are well known to those skilled in the art (see, for example, Protective Groups in Organic Synthesis, 3rd edition, Wiley 1999, by TW Greene and PGMWuts). Specific examples are described in the following paragraphs.

[0218] The contents of the references cited herein are incorporated herein by reference.

[0219] According to one embodiment, the present invention also defines Gd as defined above. 3+ Compounds of general formula (I) in the form of complexes with Gd 3+ A method for preparing a complex, comprising a compound of general formula (I): [ka] (In the formula, Ar, X, R 1 , R 2 and R 3 (As defined for the compound of general formula (I) above), react with a gadolinium(III) salt, Therefore, Gd 3+ Compounds of general formula (I) in the form of complexes with (wherein Ar, X, R) 1 , R 2 and R 3 (As defined above for compounds of general formula (I)), that is, Gd of compounds of general formula (I) 3+ The present invention relates to a method that includes the step of obtaining a salt solution.

[0220] According to further embodiments, the present invention also includes the Gd defined above. 3+ Compounds of general formula (I) in the form of complexes with Gd 3+A method for preparing a complex, comprising a compound of general formula (I): [ka] (In the formula, Ar, X, R 1 , R 2 and R 3 Gd is defined as above for compounds of general formula (I), and is reacted with a gadolinium(III) salt, such as gadolinium oxide, gadolinium chloride, gadolinium acetate, or gadolinium carbonate, thereby producing Gd 3+ Compounds of general formula (I) in the form of complexes with (wherein Ar, X, R) 1 , R 2 and R 3 (As defined above for compounds of general formula (I)), that is, Gd of compounds of general formula (I) 3+ The present invention relates to a method that includes the step of obtaining a salt solution.

[0221] According to further embodiments, the present invention also includes the Gd defined above. 3+ Compounds of general formula (I) in the form of complexes with Gd 3+ A method for preparing a complex, comprising a compound of general formula (I): [ka] (In the formula, Ar, X, R 1 , R 2 and R 3 (As defined for the compound of general formula (I) above), react with gadolinium(III) oxide, Therefore, Gd 3+ Compounds of general formula (I) in the form of complexes with (wherein Ar, X, R) 1 , R 2 and R 3 (As defined above for compounds of general formula (I)), that is, Gd of compounds of general formula (I) 3+ The present invention relates to a method that includes the step of obtaining a salt solution. [Brief explanation of the drawing]

[0222] [Figure 1] This figure shows the chemical stability of selected examples during heat sterilization. Normalized HPLC-ICP-MS (Gd157) signals are shown time-dependently before and after 1, 2, and 3 autoclave treatments (1 bar, 121°C for 20 minutes). All compounds were investigated at a concentration of 1 mmol / L in 10 mM Tris-HCl buffer at pH 7.4. [Figure 2] This figure shows the no-observed-adverse-effect levels (NOAELs) in mice for exemplary compounds with respect to lipophilicity (partition coefficient log P (butanol / water, pH 7.4)). The observed NOAEL (mmol Gd / kg body weight) indicates the exposure level at which no adverse effects were observed. The NOAELs for reference compounds 1 (RC1, Gd-EOB-DTPA) and 2 (RC2, Gd-BOPTA) are shown at 2.5 mmol Gd / kg body weight for illustrative purposes only (in reality, these are greater than 2.5 mmol Gd / kg body weight). [Figure 3] This figure shows contrast-enhanced liver MRI in healthy mice before and after contrast agent administration (approximately 10 minutes) compared to reference compound 1 (RC1, dose: 0.025 mmol / kg body weight, Gd-EOB-DTPA) and reference compound 2 (RC2, dose: 0.050 mmol / kg body weight, Gd-BOPTA). The tests were performed using a 4.7T preclinical MRI scanner equipped with a dedicated transmit / receive mouse body volume coil, employing a T1-weighted FLASH (fast low-angle shot) sequence with retrospective respiratory gating. [Figure 4]This figure shows contrast-enhanced liver MRI in tumor-carrying rabbits before intravenous contrast agent injection and 7 seconds, 5 minutes, 20 minutes, and 40 minutes after injection. The study was performed on a 1.5T MR system using a T1-weighted fat-saturated 3D gradient echo sequence (volume interpolation breath-hold test, VIBE) covering the entire liver in 36 slices of 2 mm thickness. Immediately after detection of contrast enhancement in the pulmonary artery, five consecutive axial dynamic scans were obtained (6 seconds each), with the first and second phases corresponding to the early and late arterial phases. The 7-second image shows high signal intensity in the aorta (white star). Exemplary tumor sections (black arrow: VX2 tumor) are shown as an example of Example 15 and as part of an intra-individual comparison (three-way crossover study) of reference compound 1 (RC1, dose: 0.025 mmol / kg body weight, Gd-EOB-DTPA) and reference compound 2 (RC2, dose: 0.050 mmol / kg body weight, Gd-BOPTA). [Figure 5] This figure shows an intra-individual comparison of bile excretion in pigs at 0.025 mmol Gd / kg body weight for Example 15 and reference compound 1 (RC1, Gd-EOB-DTPA). The study was performed with breath-hold on a 1.5T MR clinical system using gradient echo (VIBE) sequencing (A) MRI of the dynamic and late hepatobiliary phase (B) in the liver after contrast agent application. Exemplary maximum intensity projection (MIPS 2cm) is shown to visualize contrast agent excretion into bile (white arrow: common bile duct). [Modes for carrying out the invention]

[0223] Experimental Section

[0224] [Table 1A] [Table 1B]

[0225] Materials and instrumentation The chemicals used in the synthesis process were reagent-grade and used as obtained.

[0226] All reagents whose synthesis is not described in the Experimental Section are either commercially available, known compounds, or can be formed from known compounds by methods known to those skilled in the art.

[0227] 1 1H-NMR spectra were measured in CDCl3, D2O, or DMSO-d6, respectively (room temperature, Bruker Avance 400 spectrometer, resonance frequencies: 1 For H, 400.20 MHz, or Bruker Avance 300 spectrometer, resonance frequency: 1 (300.13 MHz for H). Chemical shifts are shown in ppm relative to sodium (trimethylsilyl)propionate-d4 (D2O) or tetramethylsilane (DMSO-d6) as external standards (δ=0 ppm).

[0228] Compounds and intermediates produced by the method of the present invention may require purification. The purification of organic compounds is well known to those skilled in the art, and several methods for purifying such compounds may exist. In some cases, purification may not be necessary. In some cases, compounds can be purified by crystallization. In some cases, impurities can be stirred with a suitable solvent. In some cases, compounds can be purified by chromatography, particularly flash column chromatography, using, for example, a pre-packed silica gel cartridge, e.g., Biotage SNAP cartridge KP-Sil® or KP-NH®, in combination with a Biotage automated purification system (SP4® or Isolera Four®) and an eluent (such as a hexane / ethyl acetate or DCM / methanol gradient). In some cases, the use of a (preparative) reverse-phase C18 column combined with an acetonitrile / water or methanol / water mixture, which may be modified with an acid or base as needed, is particularly advantageous. In some cases, for example, a Waters automated purification system equipped with a diode array detector and / or an online electrospray ionization mass spectrometer can be used in combination with a suitable pre-packed reversed-phase column and eluent, such as a water and acetonitrile gradient which may contain additives such as trifluoroacetic acid, formic acid, or aqueous ammonia, to purify the compound by preparative HPLC.

[0229] The compounds were analyzed and characterized using the following HPLC-based analytical methods, and characteristic retention times and mass spectra were measured:

[0230] Example Compounds Method 1: Equipment: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μm, 50x2.1mm; Eluent A: Water + 0.1 vol% formic acid (99%), Eluent B: MeCN; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate: 0.8 ml / min; Temperature: 60℃; DAD scan: 210-400 nm.

[0231] Method 2: Equipment: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μm, 50x2.1mm; Eluent A: Water + 0.1 vol% formic acid (99%), Eluent B: MeCN; Gradient: 0-1.7 min 1-45% B, 1.7-1.72 min 45-99% B, 1.72-2.0 min 99% B; Flow rate 0.8 ml / min; Temperature: 60℃; ELSD.

[0232] Method 3: Equipment: Agilent 1290 UPLCMS 6230 TOF; Column: BEH C 18 1.7 μm, 50 x 2.1 mm; Eluent A: Water + 0.05% Formic Acid (99%); Eluent B: MeCN + 0.05% Formic Acid (99%); Gradient: 0~1.7 2~90%B, 1.7~2.0 90%B; Flow rate: 1.2 ml / min; Temperature: 60℃; DAD scan: 190~400 nm.

[0233] Method 4: Equipment: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μm, 50x2.1mm; Eluent A: Water + 0.2 vol% aqueous ammonia (32%), Eluent B: MeCN; Gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; Flow rate: 0.8 ml / min; Temperature: 60℃; DAD scan: 210-400 nm.

[0234] Method 5: Equipment: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μm, 50x2.1mm; Eluent A: Water + 0.1 vol% formic acid (99%), Eluent B: MeCN; Gradient: 0-1.7 min 1-45% B, 1.7-1.72 min 45-99% B, 1.72-2.0 min 99% B; Flow rate 0.8 ml / min; Temperature: 60℃; ELSD.

[0235] Method 6: Equipment: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7μm, 50x2.1mm; Eluent A: Water + 0.2 vol% aqueous ammonia (32%), Eluent B: MeCN; Gradient: 0-1.7 min 1-45% B, 1.7-1.72 min 45-99% B, 1.72-2.0 min 99% B; Flow rate 0.8 ml / min; Temperature: 60℃; ELSD.

[0236] Method 7: HPLC instrument type: SHIMADZU LC-20AD; Column: Kinetex C18 LC column 4.6 × 50 mm, 5 μm; Mobile phase A: 0.0375% TFA (v / v) in water, B: 0.01875% TFA (v / v) in MeCN; Gradient: 0.0 min 0% B → 4.2 min 60% B → 5.3 min 60% B → 5.31 min 0% B → 6.0 min 0% B; Flow rate: 1.5 mL / min; Oven temperature: 50°C; UV detection: 220 nm, 254 nm, and 215 nm.

[0237] Method 8: MS equipment type: SHIMADZU LCMS-2020;Kinetex EVO C18 2.1X30mm, 5μm; Mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in MeCN (v / v); Gradient: 0.0 min 5% B → 0.8 min 95%B → 1.2 min 95%B → 1.21 min 5%B → 1.55 min 5%B; flow rate: 1.5 mL / min; oven temperature: 50 °C; UV detection: 220 nm and 254 nm.

[0238] Method 9: MS instrument type: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 2.1X30mm, 5μm; Mobile phase A: 0.025% NH3·H2O in water (v / v), B: MeCN; Gradient: 0.0 min 5% B → 0.8 min 95% B → 1.2 min 95% B → 1.21 min 5% B → 1.55 min 5% B; Flow rate: 1.5 mL / min; Oven temperature: 40 °C; UV detection: 220 nm and 254 nm.

[0239] Method 10: MS instrument type: SHIMADZU LC-20AB; Column: Kinetex EVO C18 2.1X30mm, 5μm; Mobile phase A: 0.0375% TFA (v / v) in water, B: 0.01875% TFA (v / v) in MeCN; Gradient: 0.0 min 5% B → 0.8 min 95% B → 1.20 min 95% B → 1.21 min 5% B → 1.55 min 5% B; Flow rate: 1.5 mL / min; Oven temperature: 50℃; UV detection: 220 nm and 254 nm.

[0240] Method 11: MS instrument type: SHIMADZU LCMS-2020;Kinetex EVO C18 2.1X30mm, 5μm; Mobile phase A: 0.0375% TFA in water (v / v), B: 0.01875% TFA in MeCN (v / v); Gradient: 0.0 min 5% B → 0.8 min 95%B → 1.2 min 95%B → 1.21 min 5%B → 1.55 min 5%B; flow rate: 1.5 mL / min; oven temperature: 50 °C; UV detection: 220 nm and 254 nm.

[0241] Method 12: MS instrument type: SHIMADZU LCMS-2020; Column: Kinetex EVO C18 2.1X30mm, 5μm; Mobile phase A: 0.025% NH3·H2O in water (v / v), B: MeCN; Gradient: 0.0 min 5% B → 0.8 min 95% B → 1.2 min 95% B → 1.21 min 5% B → 1.5 min 5% B; Flow rate: 1.5 mL / min; Oven temperature: 40 °C; UV detection: 220 nm and 254 nm.

[0242] Method 13: Equipment: SHIMADZU LCMS-2020 SingleQuad; Column: Chromolith@Flash RP-18E 25-2 MM; Eluent A: Water + 0.0375 vol% TFA, Eluent B: MeCN + 0.01875 vol% TFA; Gradient: 0-0.8 min, 5-95% B, 0.8-1.2 min, 95% B; Flow rate: 1.5 ml / min; Temperature: 50℃; DAD: 220 nm and 254 nm.

[0243] Intermediate 1 Methyl 3-[2-(4-ethoxyphenyl)ethoxy]-2-hydroxypropanoate [ka] 2-(4-ethoxyphenyl)ethane-1-ol (2.99 g, 18.0 mmol; [702-23-8]) was added to a 5 ml reaction flask, followed by methyloxirane-2-carboxylate (1.8 ml, 22 mmol; [4538-50-5]), and then magnesium perchlorate (1.11 g, 4.99 mmol; [10034-81-8]). The flask was sealed and stirred at 50°C for 4 days. Then, DCM was added, the mixture was washed twice with NaCl (saturated aqueous solution), the organic phase was dried over Na2SO4, the mixture was filtered, and concentrated under reduced pressure to obtain the marked compound as oil (intermediate 1, 4.11 g, yield 85%). LC-MS (Method 2):R t =1.01 min;MS(ESIpos):m / z=286[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.30(t,J=6.97 Hz,3H),2.70(t,J=6.97 Hz,2H),3.51-3.64(m,7H),3.97(q,J=6.84 Hz,3H),4.14-4.25(m,1H),5.54(d,J=6.08 Hz,1H),6.76-6.87(m,2H),7.02-7.15(m,2H).

[0244] Intermediate 2 Step 1 tert-butyl(2SR,3RS)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}oxirane-2-carboxylate [ka] In a three-necked flask equipped with a mechanical stirrer and thermometer, 4-[2-(2-ethoxyethoxy)ethoxy]benzaldehyde (30.0 g, 126 mmol, [117420-31-2]) was dissolved in THF (670 ml). The mixture was cooled to 0°C and sodium hydride (6.55 g, 60% in mineral oil, 164 mmol) was added (Note: strong foaming occurred!). After 10 minutes, the dropwise addition of tert-butylchloroacetate (24 ml, 97% purity, 160 mmol; [107-59-5]) in THF (60 ml) was started. After the addition was complete, the mixture was heated to RT and stirred overnight. The reaction was quenched by carefully adding water and extracted with siRNA. The organic phase was dried and concentrated under reduced pressure, yielding 50.4 g of the indicated compound (over 100%, containing mineral oil) as an orange oil. This substance was used directly in the next step. LC-MS (Method 1):R t =1.35min;MS(ESIpos):m / z=353.4[M+H] + .

[0245] The samples from the previous experiment were characterized: 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.25-7.31(m,2H),6.90-6.97(m,2H),4.06-4.11(m,2H),4.02(d,J=2.0 Hz,1H),3.70-3.75(m,2H),3.67(d,J=2.0 Hz,1H),3.54-3.59(m,2H),3.47-3.51(m,2H),3.42(q,J=7.1 Hz,2H),1.46(s,8H),1.09(t,J=7.0 Hz,3H).

[0246] Step 2 tert-butyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate [ka] 50.4 g, 143 mmol of tert-butyl(2SR,3RS)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}oxirane-2-carboxylate was dissolved in 1000 ml of SiO2, and 6.01 g, 10% C, 5.65 mmol; [7440-05-3] was added. The mixture was hydrogenated at RT and ambient pressure for 4 hours, after which 23.06 l (0.96 equivalents) of H2 was consumed. The solvent was removed under reduced pressure, and the residue was dissolved in the minimum amount of DCM. When subjected to chromatography (SiO2, 750g SNAP-ULTRA, 250ml / min, 254nm, A=n-hexane, B=siRNA, 0%B 20 CV, 0%~50%B at 8 CV, 50%B 1.7 CV, 50%~100%B at 1 CV, 100%B 2.5 CV), the indicated compound intermediate 2 (32.9g, yield 65%) was obtained as a pale yellow oil. LC-MS (Method 1):R t =1.24 min;MS(ESIpos):m / z=372.5[M+NH4] + . 1 H NMR (CDCl3,400 MHz): δ(ppm)7.13-7.18(m,2H),6.82-6.87(m,2H),4.28(td,J=6.1,4.8 Hz,1H),4.09-4.14(m,2H),3.83-3.89(m,2H),3.70-3.74(m,2H),3.60-3.64(m,2H),3.54(q,J=7.1 Hz,2H),3.02(dd,J=14.2,4.8 Hz,1H),2.88(dd,J=14.2,6.3 Hz,1H),2.82(d,J=5.8 Hz,1H),1.44(s,9H),1.22(t,J=7.0 Hz,3H).

[0247] The preparation was repeated several times using the same method, and similar results were obtained.

[0248] Racemic tert-butyl 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate, intermediate 2, 39.0 g (dissolved in 5 ml of CHCl3) was subjected to chiral-phase chromatography (PrepCon Labomatic HPLC-1; Chiralpak IG 5 μ, 250 × 50; A = MTBE; 100% A; 100 mL / min; 25°C; 280 nm) (37 × 5 ml injection) to obtain enantiomer 1 and enantiomer 2.

[0249] Intermediate 3 tert-butyl(2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate [ka] Enantiomer 1 (Intermediate 2 - Step 2): 18.2 g (47%), tert-butyl(2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate (Intermediate 3). LCMS (Chiralpak IG 3μ, 100×4.6; MTBE+0.1vol%DEA; 1.4ml / min; 25℃; 280nm):R t = 2.20 minutes (98.5%).ee > 99%. Specific rotation:α D 20 =+8.38°+ / -0.28°(c=1, MeOH). 1 H NMR (CDCl3,400 MHz): δ(ppm)7.12-7.17(m,2H),6.82-6.86(m,2H),4.27(td,J=6.1,4.8 Hz,1H),4.09-4.13(m,2H),3.82-3.87(m,2H),3.70-3.74(m,2H),3.59-3.63(m,2H),3.54(q,J=6.9 Hz,2H),3.02(dd,J=14.1,4.7 Hz,1H),2.87(dd,J=13.9,6.3 Hz,1H),2.80(d,J=5.8 Hz,1H),1.44(s,9H),1.21(t,J=7.1 Hz,3H).

[0250] By comparing with numerous literature examples, we assigned R-stereochemistry to enantiomers with positive optical rotation.

[0251] Intermediate 4 tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate [ka] Enantiomer 2 (Intermediate 2-Step 2): 16.9 g (43%), tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate (Intermediate 4). LCMS (Chiralpak IG 3μ, 100×4.6; MTBE+0.1vol%DEA; 1.4ml / min; 25℃; 280nm):R t =3.86 minutes (98.8%).ee=99%. Specific rotation:α D 20 =-9.08°+ / -0.11°(c=1, MeOH). 1 H NMR (CDCl3,400 MHz): δ(ppm)7.13-7.18(m,2H),6.83-6.87(m,2H),4.28(td,J=6.1,4.8 Hz,1H),4.10-4.14(m,2H),3.83-3.89(m,2H),3.70-3.74(m,2H),3.60-3.64(m,2H),3.55(q,J=7.0 Hz,2H),3.03(dd,J=14.2,4.8 Hz,1H),2.88(dd,J=14.2,6.3 Hz,1H),2.82(d,J=5.8 Hz,1H),1.45(s,9H),1.22(t,J=7.0 Hz,3H).

[0252] By comparing with numerous examples from the literature, we assigned the S-stereochemistry to enantiomers with negative optical rotation.

[0253] Intermediate 5 Step 1 Ethyl(2SR,3RS)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}oxirane-2-carboxylate [ka] Sodium hydride (2.4 g, 60% purity, 60 mmol; [7646-69-7]) was cooled to 0°C in 200 ml of THF, and ethyl chloroethyl acetate (6.4 ml, 60 mmol, [105-36-2]) was added dropwise under N2. 4-[2-(2-ethoxyethoxy)ethoxy]benzaldehyde (9.55 g, 40.1 mmol, [117420-31-2]) dissolved in 60 ml of THF was added, and the reaction mixture was heated overnight in RT. The mixture was then added to an ice water mixture, the aqueous phase was extracted three times with SiO2, the organic phase was washed with water, and the mixture was dried over Na2SO4. The product was purified using chromatography (SiO2, Biotage 100g SNAP Ultra cartridge, gradient elution (A=hexane, B=siRNA, 0%B~50%, over 20CV)) to obtain the indicated racemic compound (4g, yield 30%). LC-MS (Method 3):R t =1.06min;MS(ESIpos):m / z=325.2[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.27-7.31(m,2H),6.92-6.97(m,2H),4.16-4.22(m,2H),4.07-4.12(m,3H),3.81(d,J=2.0 Hz,1H),3.69-3.76(m,2H),3.54-3.59(m,2H),3.47-3.50(m,2H),3.42(q,J=6.8 Hz,2H),1.24(t,J=7.1 Hz,3H),1.09(t,J=7.0 Hz,3H).

[0254] Step 2 Ethyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate [ka] Ethyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}oxirane-2-carboxylate (4.07 g, 12.5 mmol) was dissolved in EtOH (100 ml), and Pd / C (500 mg, 10% purity, 470 μmol; [7440-05-3]) was added. The mixture was circulated three times between vacuum and N2. The mixture was then hydrogenated using H2 at 1 atm. After 4 hours, an additional Pd / C (300 mg, 10% purity, 282 μmol) was added, and the mixture was stirred again overnight under H2. The mixture was then filtered through a glass fiber filter and concentrated under reduced pressure. The product was purified by chromatography (SiO2, Biotage, 50 g SNAP Ultra cartridge, A=hexane, B=siRNA, 0%B~100%B) to obtain the marked compound (intermediate 5, 2.44 g, 60% yield). LC-MS (Method 4):R t =1.02min;MS(ESIpos):m / z=327.3[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,J=6.97 Hz,3H),1.13(t,J=7.10 Hz,3H),2.72-2.79(m,1H),2.82-2.88(m,1H),3.43(q,J=7.01 Hz,2H),3.47-3.50(m,2H),3.55-3.58(m,2H),3.68-3.73(m,2H),4.00-4.08(m,3H),5.48(d,J=6.08 Hz,1H),6.80-6.85(m,2H),7.08-7.13(m,2H).

[0255] Intermediate 6 Step 1 4-(2-ethoxyethoxy)benzaldehyde [ka] 4-Fluorobenzaldehyde (5.00 g, 40.3 mmol; [459-57-4]), 2-Ethoxyethane-1-ol (12 ml, 120 mmol; [110-80-5]), and cesium carbonate (15.8 g, 48.3 mmol; [534-17-8]) were added to a reaction flask containing DMF (100 ml), and the mixture was stirred at 70°C until the 4-fluorobenzaldehyde starting material was consumed (by monitoring with LC-MS). Water was added, the aqueous phase was extracted with MTBE, the organic phase was washed with NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. N-heptane was added to the crude product, then removed under reduced pressure, and subsequently chromatographic chromatography (SiO2, Biotage 100g Ultra column, A=hexane, B=¼, 0%B~50%B) was performed to obtain the marked compound as a pale yellow crystalline solid (6.83g, yield 83%). LC-MS (Method 4):R t =0.95min;MS(ESIpos):m / z=195[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)9.87(s,1H),7.83-7.88(m,2H),7.11-7.17(m,2H),4.19-4.23(m,2H),3.70-3.74(m,2H),3.50(q,J=7.1 Hz,2H),1.12(t,J=7.1 Hz,3H).

[0256] Step 2 Ethyl-3-[4-(2-ethoxyethoxy)phenyl]oxirane-2-carboxylate [ka] Sodium hydride (2.1 g, 60% in mineral oil, 52 mmol) was added to THF (200 ml), and ethyl chloroethyl acetate (5.6 ml, 53 mmol) was added dropwise under N2. Then, 4-(2-ethoxyethoxy)benzaldehyde (6.83 g, 35.2 mmol) was added to THF (30 ml), and the reaction mixture was heated in RT and stirred for 3 days. The mixture was then added to an ice water mixture, and the aqueous layer was extracted three times with ethyl acetate. The product was then purified by chromatography (SiO2, Biotage, Ultra 100 g column, A=hexane, B=ethyl acetate, 0%B~50%B) to obtain the racemic labeled compound (6.60 g, yield 64%). LC-MS (Method 4):R t =1.14min;MS(ESIpos):m / z=281.3[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.27-7.31(m,2H),6.92-6.97(m,2H),4.15-4.24(m,2H),4.06-4.10(m,3H),3.81(d,J=2.0 Hz,1H),3.65-3.71(m,2H),3.49(q,J=7.0 Hz,2H),1.24(t,J=7.1 Hz,3H),1.12(t,J=7.1 Hz,3H).

[0257] Step 3 Ethyl 3-[4-(2-ethoxyethoxy)phenyl]-2-hydroxypropanoate [ka] Ethyl-3-[4-(2-ethoxyethoxy)phenyl]oxirane-2-carboxylate (6.60 g, 23.5 mmol) was dissolved in ethanol (110 ml), palladium (607 mg, 10% on carbon, 571 μmol) was added, and the mixture was hydrogenated overnight with H2 at 1 atm. The mixture was then filtered through a glass fiber filter and concentrated to dryness under reduced pressure. Purification by chromatography (SiO2, Biotage Ultra: 50 g column, A=hexane, B=siRNA, 0%B~50%B) yielded the marked compound, intermediate 6, as a racemic mixture (5.39 g, yield 77%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 0.94-1.23(m,7H),2.72-2.88(m,2H),3.46-3.52(m,2H),3.64-3.70(m,2H),3.95-4.18(m,5H),5.48(d,J=6.08 Hz,1H),6.81-6.91(m,2H),7.08-7.13(m,2H).

[0258] Intermediate 7 Step 1 4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}benzaldehyde [ka] 4-Fluorobenzaldehyde (9.2 ml, 85 mmol; [459-57-4]), 2-[2-(2-ethoxyethoxy)ethoxy]ethane-1-ol (24 ml, 140 mmol, [111-90-0]), and cesium carbonate (33.4 g, 102 mmol; [534-17-8]) were heated overnight at 70°C. The mixture was then added to water, the aqueous layer was extracted three times with MTBE, and the combined organic layers were washed with water and dried over Na2SO4 to obtain 20.7 g of the labeled compound (86% yield). LC-MS (Method 6):R t =0.99min;MS(ESIpos):m / z=283.2[M+H] + . 1H NMR(400 MHz,DMSO-d6)δ ppm 1.08(t,J=7.10 Hz,3H),3.38-3.60(m,11H),3.72-3.83(m,2H),4.17-4.26(m,2H),7.11-7.18(m,2H),7.83-7.89(m,2H),9.87(s,1H).

[0259] Step 2 Ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)oxirane-2-carboxylate [ka] Sodium hydride (2.4 g, 60% in mineral oil, 60 mmol) was added to THF (270 ml), the mixture was cooled to 0°C, and ethyl chloroethyl (6.3 ml, 60 mmol) was added dropwise. The solution was heated to 15°C, and 4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}benzaldehyde (11.3 g, 40.0 mmol) was added dropwise to a small amount of THF. The mixture was heated in RT and stirred overnight, then added to an ice / water mixture, the aqueous phase was extracted three times with MTBE, the organic phase was washed with NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and evaporated to dryness. Purification by chromatography (SiO2, Biotage, Ultra 100 g column, A=hexane, B=siRNA, 0%B~50%B) yielded the racemic labeled compound (3.79 g, yield 24%). LC-MS (Method 4):R t =1.18 min;MS(ESIpos):m / z=369.1[M+H] + . 1H NMR (DMSO-d6,400 MHz): δ(ppm)7.26-7.31(m,2H),6.92-6.97(m,2H),4.14-4.23(m,2H),4.05-4.11(m,3H),3.80(d,J=2.0 Hz,1H),3.70-3.75(m,2H),3.55-3.59(m,2H),3.47-3.55(m,4H),3.38-3.47(m,2H),3.41(q,J=7.0 Hz,2H),1.24(t,J=7.1 Hz,3H),1.08(t,J=7.0 Hz,3H).

[0260] Step 3 Ethyl 3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-hydroxypropanoate [ka] Ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)oxirane-2-carboxylate (3.79 g, 10.3 mmol) was dissolved in ethanol (49 ml), and palladium (381 mg, 10% on carbon, 358 μmol; [7440-05-3]) was added. The mixture was hydrogenated overnight at RT and ambient pressure. The reaction mixture was then filtered through a glass fiber filter and concentrated to dryness. Purification by chromatography (SiO2, Biotage Ultra: 50 g / A=hexane, B= Depositphotos, 0%B~50%B) yielded the marked compound, intermediate 7 (2.34 g, yield 58%). LC-MS (Method 4):R t =1.04min;MS(ESIpos):m / z=371.4[M+H] + . 1H NMR (DMSO-d6,400 MHz): δ(ppm)7.10(d,J=7.5 Hz,2H),6.80-6.87(m,2H),5.48(d,J=6.1 Hz,1H),4.15(dt,J=7.9,5.7 Hz,1H),4.00-4.07(m,4H),3.69-3.74(m,2H),3.56-3.59(m,2H),3.49-3.55(m,4H),3.44-3.48(m,2H),3.41(q,J=7.1 Hz,2H),2.85(dd,J=13.7,5.3 Hz,1H),2.75(dd,J=13.7,7.6 Hz,1H),1.13(t,J=7.1 Hz, 3H), 1.09(t, J=7.0 Hz, 3H).

[0261] Intermediate 8 Step 1 tert-butyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)oxirane-2-carboxylate [ka] 4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}benzaldehyde (intermediate 7-step 1, 7.50 g, 26.6 mmol) was added to a flask, followed by the addition of THF (300 ml) and sodium hydride (1.49 g, 60% in mineral oil, 37.2 mmol; [7646-69-7]) under N2. The mixture was stirred at RT for 5 minutes, then neat tert-butyl chloroacetate (5.0 ml, 35 mmol) was added at RT at 50 μl / min, and the reaction was stirred overnight at 250 rpm. Water (20 ml) was carefully added, and the mixture was extracted with MTBE (2 × 50 ml). The organic phase was dried over Na2SO4, and the solvent was removed under reduced pressure to obtain a racemic compound (11.1 g, yield 105% - containing mineral oil). LC-MS (Method 4):R t =1.33min;MS(ESIpos):m / z=419.3[M+Na] + . 1H NMR (DMSO-d6,400 MHz): δ(ppm)7.25-7.32(m,2H),6.91-6.97(m,2H),4.05-4.12(m,2H),4.02(d,J=1.8 Hz,1H),3.71-3.75(m,2H),3.67(d,J=1.8 Hz,1H),3.55-3.59(m,2H),3.48-3.55(m,4H),3.44-3.47(m,2H),3.41(q,J=7.0 Hz,2H),1.46(s,9H),1.08(t,J=7.1 Hz,3H).

[0262] The trans stereochemistry was assigned according to previous literature (e.g., Tetrahedron 2006, 62, 10255-10270; Chemical & Pharmaceutical Bulletin (1995), 43(10), 1821-3), and the coupling constant (1.7-2.0 Hz) for the epoxydoproton was observed.

[0263] Step 2 tert-butyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)oxirane-2-carboxylate (2.6 g dissolved in 10 mL of DCM / MeOH, injected into 20 × 0.5 ml) was separated into its enantiomer components via chiral HPLC (PrepCon Labomatic HPLC-3; YMC Cellulose SC 5 μ, 250 × 50; A = hexane + 0.1 vol. % DEA; B = ethanol + 0.1 vol. % DEA; 20% B; 120 ml / min; 25℃; 254 nm).

[0264] The enantiomer purity was determined using the following method (Waters Alliance 2695; YMC Cellulose SC 3μ, 100x4.6; A = hexane + 0.1 vol. %DEA; B = ethanol; 20% B; 1.4 ml / min; 25℃; 254 nm): Enantiomer 1:R t = 2.68 minutes, Enantiomer 2:R t =3.29 minutes.

[0265] The combined product fraction was concentrated, and the solvent was removed under reduced pressure to obtain both enantiomers. tert-butyl(2R,3S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)oxirane-2-carboxylate [ka] Enantiomer 1 (930 mg, 100% ee). HPLC:R t =2.68 minutes. Specific optical rotation: +124° (c=1, MeOH, 20°C, 589nm). 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.08(t,3H),1.46(s,8H),3.38-3.55(m,8H),3.55-3.59(m,2H),3.67(d,1H),3.71- 3.75(m,2H),4.02(d,1H),4.07-4.11(m,2H),6.87-7.01(m,2H),7.25-7.31(m,2H). tert-butyl(2S,3R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)oxirane-2-carboxylate [ka] Enantiomer 2 (1040 mg, 100% ee). LC-MS:R t =3.29 minutes. Specific optical rotation: -110° (c=1, MeOH, 20°C, 589nm). 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.08(t,3H),1.46(s,8H),3.38-3.55(m,8H),3.55-3.59(m,2H),3.67(d,1H),3.7 1-3.75(m,2H),4.02(d,1H),4.07-4.11(m,2H),6.87-7.01(m,2H),7.25-7.31(m,2 H).

[0266] Step 3 tert-butyl(2R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-hydroxypropanoate [ka] Dissolve tert-butyl(2R,3S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)oxirane-2-carboxylate (enantiomer 1, step 2, 930 mg, 2.35 mmol) in SiO2 (11 ml), add palladium (87.0 mg, 10% on carbon, 81.7 μmol; [7440-05-3]), circulate the mixture three times between vacuum and N2, and then dissolve the mixture in H2. 2( The mixture was left overnight under an atmosphere of 1 atm. The mixture was filtered through a glass fiber filter and concentrated to dryness under reduced pressure to obtain the marked compound, intermediate 8,812 mg (87%). The stereochemistry of the alcohol is assigned as (R) based on its positive optical rotation, with reference to a series of closely related literature examples. Specific optical rotation: +7.5° (c=1, MeOH, 20℃, 589nm). LC-MS (Method 4):R t =1.20min;MS(ESIpos):m / z=416.2[M+NH4] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,3H),1.34(s,9H),2.70-2.85(m,2H),3.39-3.59(m,10H),3.68-3.7 5(m,2H),4.01-4.07(m,3H),5.31(d,1H),6.81-6.85(m,2H),7.09-7.14(m,2 H).

[0267] Intermediate 9 Step 1 tert-butyl(2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-hydroxypropanoate [ka] tert-butyl(2S,3R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)oxirane-2-carboxylate, enantiomer 2, step 2 of intermediate 8) (1.04 g, 2.62 mmol) was dissolved in SiO2 (13 ml), palladium (97.2 mg, 10% on carbon, 91.4 μmol; [7440-05-3]) was added, and the mixture was circulated three times between N2 and vacuum, and then the mixture was hydrogenated overnight under H2 at 1 atm. The mixture was filtered through a glass fiber filter and concentrated to dryness under reduced pressure to obtain the marked compound (intermediate 9, 749 mg, 72%). The stereochemistry of the alcohol is assigned as (S) based on its negative optical rotation, with reference to a series of closely related literature examples. Specific optical rotation: -6.8° (c=1, MeOH, 20°C, 589nm). LC-MS (Method 4):R t =1.20min;MS(ESIpos):m / z=416.2[M+NH4] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,3H),1.17(s,1H),1.34(s,9H),2.52-2.55(m,1H),2.70-2.85(m,2H),3.39-3.59(m, 10H),3.68-3.75(m,2H),4.00-4.07(m,3H),5.31(d,1H),6.80-6.86(m,2H),7.09-7.14(m,2 H).

[0268] Intermediate 10 Step 1 Methyl-3-(4-butoxyphenyl)oxiran-2-carboxylate [ka] Sodium hydride (5.05 g, 60% purity, 126.2 mmol) was added to THF (190 ml), and the mixture was cooled to 0°C under N2. Methyl chloroacetate (3.7 ml, 42 mmol) was added, and the mixture was stirred for 10 minutes, after which 4-butoxybenzaldehyde (4.8 ml, 28 mmol [123-11-5]) was added. After reacting overnight, the mixture was brought to 0°C, HCl (0.5 M, aqueous solution) was added, and subsequently the mixture was extracted with MTBE. The organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the racemic labeled compound (9.80 g), which was used in the next step without further purification. LC-MS (Method 4):R t =1.33min;MS(ESIpos):m / z=251.2[M+H] + .

[0269] Step 2 Methyl 3-(4-butoxyphenyl)-2-hydroxypropanoate [ka] Methyl-3-(4-butoxyphenyl)oxirane-2-carboxylate (9.80 g, 27.4 mmol) was dissolved in ethanol (130 ml), palladium (714 mg, 10% on carbon, 671 μmol) was added, and the mixture was circulated three times between N2 and vacuum. The mixture was then hydrogenated overnight under H2 at 1 atm. The mixture was filtered through a glass fiber filter, concentrated under reduced pressure, and purified using chromatography (SiO2, Biotage, Ultra 100 g column, A=hexane, B=siRNA, 0%B~100%B) to obtain the marked compound (intermediate 10, 1.20 g, calculated yield 17% from step 1). LC-MS (Method 4):R t =1.18 min;MS(ESIpos):m / z=270.2[M+NH4] + . 1H NMR (DMSO-d6,400 MHz): δ(ppm)7.05-7.12(m,2H),6.78-6.84(m,2H),5.51(d,J=6.1 Hz,1H),4.17(ddd,J=7.9,6.1,5.1 Hz,1H),3.91(t,J=6.5 Hz,2H),3.59(s,3H),2.86(dd,J=13.7,5.1 Hz,1H),2.74(dd,J=13.7,7.9 Hz,1H),1.63-1.71(m,2H),1.36-1.48(m,2H),0.92(t,J=7.4 Hz,3H).

[0270] Intermediate 11 Step 1 6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-carbaldehyde [ka] 6-Bromopyridine-3-carbaldehyde (7.00 g, 37.6 mmol; [149806-06-4]), 2-(2-ethoxyethoxy)ethanol (10 ml, 75 mmol; [111-90-0]), and cesium carbonate (14.7 g, 45.2 mmol; [534-17-8]) were added to a reaction flask, and the mixture was stirred overnight at 70°C. The mixture was added to water and extracted with MTBE (3 times). The combined organic phase was washed once with water, dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, Biotage, Ultra 100 g column / A=hexane, B=siRNA, 0%B~100%B) yielded the marked compound (6.17 g, yield 69%). 1 H NMR (DMSO-d6,400 MHz): δ(ppm)9.96(s,1H),8.75(dd,J=2.4,0.6 Hz,1H),8.12(dd,J=8.7,2.4 Hz,1H),7.01(d,J=8.9 Hz,1H),4.47-4.52(m,2H),3.74-3.79(m,2H),3.55-3.58(m,2H),3.38-3.49(m,6H),1.08(t,J=7.0 Hz,3H).

[0271] Step 2 tert-butyl-3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}oxiran-2-carboxylate [ka] 6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-carbaldehyde (6.17 g, 25.8 mmol) was dissolved in THF (290 ml), and sodium hydride (1.44 g, 60% purity, 36.1 mmol; [7646-69-7]) was added gradually under N2 RT. The mixture was stirred for 5 minutes, and then tert-butyl chloroacetate (4.8 ml, 34 mmol) was added dropwise. The reaction mixture was stirred overnight, and then added to an ice water mixture. The aqueous phase was extracted with SiO2 (3 times), the organic phase was washed with NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure. Purification by chromatography (SiO2, Biotage, Ultra 100g column / A=hexane, B=¼, 0%B~100%B) yielded the racemic labeled compound (2.35g, 23%). LC-MS (Method 4):R t =1.25min;MS(ESIpos):m / z=354.3[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)8.25(d,J=2.3 Hz,1H),7.62(dd,J=8.6,2.5 Hz,1H),6.83(d,J=8.9 Hz,1H),4.35-4.38(m,2H),4.11(d,J=1.8 Hz,1H),3.82(d,J=2.0 Hz,1H),3.72(dd,J=5.4,3.9 Hz,2H),3.54-3.57(m,2H),3.46-3.49(m,2H),3.41(q,J=6.9 Hz,2H),1.46(s,9H),1.08(t,J=7.1 Hz,3H).

[0272] Step 3 tert-butyl3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-hydroxypropanoate [ka] tert-butyl 3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}oxirane-2-carboxylate (2.35 g, 6.65 mmol) was dissolved in siRNA (32 ml), and palladium (247 mg, 10% on carbon, 232 μmol; [7440-05-3]) was added. The mixture was circulated three times between N2 and vacuum, and then hydrogenated overnight under 1 atm H2. The mixture was filtered through a glass fiber filter and concentrated to dryness under reduced pressure to obtain the marked compound (intermediate 11, 2.13 g, 90%) with a purity of approximately 80% (H-NMR). LC-MS (Method 4):R t =1.11 min;MS(ESIpos):m / z=356.2[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.95(d,J=1.8 Hz,1H),7.58(dd,J=8.5,2.4 Hz,1H),6.74(d,J=8.4 Hz,1H),4.29-4.34(m,2H),4.08(dd,J=7.2,5.7 Hz,1H),3.71(dd,J=5.3,4.1 Hz,2H),3.38-3.57(m,6H),2.83(dd,J=13.9,5.3 Hz,1H),2.75(dd,J=13.9,7.4 Hz,1H),1.35(s,9H),1.09(t,J=7.0 Hz,3H).

[0273] Intermediate 12 Step 1 (5R)-2,2-dimethyl-5-(propa-2-en-1-yl)-1,3-dioxolan-4-one [ka] (2R)-2-hydroxypenta-4-enoic acid (35.0 g, 301 mmol, [413622-10-3]) was dissolved in acetone (700 ml) to which pyridinium p-toluenesulfonate (37.9 g, 151 mmol) and 2,2-dimethoxypropane (251 g, 2.41 mol) were added at room temperature. The mixture was stirred at 60°C for 3 hours. The mixture was concentrated to obtain a residue. This was combined with the residue (35 g) from the same experiment. The combined residue was diluted with siRNA and filtered through a Celite pad. The filtrate was concentrated to obtain a residue. The residue was purified by column chromatography (SiO2, 1000 mesh, petroleum ether:siRNA = 1:0, then 20:1) to obtain (5R)-5-allyl-2,2-dimethyl-1,3-dioxolan-4-one (51.0 g, 327 mmol, 54%) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6):δ[ppm]=5.84-5.67(m,1H),5.21-5.08(m,2H),4.73-4.67(m,1H),2.60-2.51(m,1H),2.46-2.34(m,1H),1.54(s,3H),1.52(s,3H).

[0274] Step 2 (5R)-5-[(2E)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}prop-2-en-1-yl]-2,2-dimethyl-1,3-dioxolan-4-one [ka] A mixture of (5R)-2,2-dimethyl-5-(propa-2-en-1-yl)-1,3-dioxolan-4-one (25.0 g, 160 mmol), 1-[2-(2-ethoxyethoxy)ethoxy]-4-iodobenzene (53.8 g, 160 mmol, [2305345-75-7]), palladium(II) acetate (3.59 g, 16.0 mmol), tri-2-tolylphosphine (4.87 g, 16.0 mmol), and DIPEA (70 ml, 400 mmol) in MeCN (500 ml) was stirred at 80°C for 12 hours. The mixture was concentrated to obtain a residue. This was combined with the residues (25 g and 3 g) from two identical experiments. The combined residue was diluted with siRNA and washed with NH4Cl (saturated aqueous solution). The organic phase was washed with NaCl (saturated aqueous solution), dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography (SiO2, petroleum ether: SiO2 = 1:0 to 10:1, then 10:1) to obtain (5R)-5-[(2E)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}prop-2-en-1-yl]-2,2-dimethyl-1,3-dioxolan-4-one (64.0 g, 176 mmol, 73%) as a yellow oil. LC-MS (Method 13):R t =0.951 min;MS(ESIpos):m / z=365.2[M+H] + . 1 H NMR(400 MHz,DMSO-d6):δ[ppm]=7.32(d,J=8.8 Hz,2H),6.90(d,J=8.8 Hz,2H),6.46(d,J=16 Hz,1H),6.12-5.99(m,1H),4.81-4.73(m,1H),4.13-4.05(m,2H),3.79-3.69(m,2H),3.63-3.55(m,2H),3.53-3.47(m,2H).3.43(q,J=6.8 Hz,2H).2.78-2.65(m,1H),2.60-2.52(m,1H),1.55(s,3H),1.55(s,3H),1.10(t,J=7.2 Hz, 3H).

[0275] Step 3 (5R)-5-(3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propyl)-2,2-dimethyl-1,3-dioxolan-4-one [ka] (5R)-5-[(2E)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}prop-2-en-1-yl]-2,2-dimethyl-1,3-dioxolan-4-one (59.0 g, 162 mmol) was dissolved in THF (1.2 l) and palladium (2.9 g, 10% on carbon, 5.54 mmol) was added at RT. The mixture was stirred at RT under an H2 atmosphere (15 psi) for 12 hours. The mixture was filtered, and the filtrate was concentrated to obtain the marked compound (60.0 g) as a yellow oil. LC-MS (Method 13):R t =0.987min;MS(ESIpos):m / z=367.1[M+H] + .

[0276] Step 4 Methyl(2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate [ka] (5R)-5-(3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propyl)-2,2-dimethyl-1,3-dioxolan-4-one (60.0 g, 164 mmol) was dissolved in MeOH (600 ml), to which 4-toluenesulfonic acid (2.82 g, 16.4 mmol) was added at RT. The mixture was stirred at RT for 12 hours. The mixture was combined with the previous experiment (5.2 g), concentrated, and diluted with ELISA. The organic phase was dissolved in NaHCO₃⁻. 3( The organic phase was washed with saturated aqueous solution and NaCl (saturated aqueous solution). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was filtered using a reversed-phase column (Agela HP1000; Welch Ultimate XB_C18 100). *400mm 20~40μm; 200ml / min; A=water (0.1% acid), B=MeCN; B%: 35 minutes, 10%B~45B%, 50%B 20 minutes; RT; UV 220 / 254nm) was refined and the labeled compound (intermediate 12, 48.4g, 142mmol, 80%) was produced as a yellow oil. LC-MS (Method 13): R t =0.630 points; MS(ESIpos): m / z=341.3[M+H] + . LC-MS (Method 3): R t =1.00 points (91%DAD);MS(ESIpos):m / z=341[M+H] + . キラルHPLC (Thermo Fisher UltiMate 3000; YMC Cellulose SB 3μ, 100×4.6; A=ヘキサン+0.1 volume%DEA; B=エタノール; 10%B; 1.4ml / min; 25℃; 280nm): R t =2.85 points (4.94%), R t =3.57 points (85.21%). ee=89%. Specific rotation: α D 20 =-7.46°+ / -0.58°(c=1, CHCl3). 1 H NMR (CDCL3, 400 MHz): δ (ppm) 7.05-7.10 (m, 2H), 6.82-6.86 (m, 2H), 4.20 (ddd, J = 7.0, 5.7, 4.1 Hz, 1H), 4.12 (dd, J = 5.6, 4.3 Hz,2H),3.86(dd,J=5.1,4.1 Hz,2H),3.77(s,3H),3.71-3.74(m,2H),3.60-3.64(m,2H),3.54(q,J=7.1 Hz,2H),2.74(d,J=5.6 Hz,1H),2.53-2.64(m,2H),1.74-1.86(m,2H),1.61-1.73(m,2H),1.22(t,J=7.1 Hz,3H). 13C NMR(101MHz,CDCL3)δ=175.67,156.96,134.13,129.21(2C),114.49(2C),70 .87,70.30,69.85,69.80,67.42,66.69,52.53,34.53,33.84,26.68,15.15.

[0277] Intermediate 13 Step 1 2-(2-ethoxyethoxy)ethylmethanesulfonate [ka] A solution of 2-(2-ethoxyethoxy)ethane-1-ol (10 ml, 75 mmol) in THF (200 ml) was treated with TEA (25 ml, 180 mmol), cooled to 0°C, and then MsCl (6.9 ml, 89 mmol) was added dropwise. The mixture was stirred at RT for 16 hours, then poured into an aqueous solution of NaHCO3, and subsequently extracted three times with siRNA. The organic layer was washed with NaCl (saturated aqueous solution), dried over Na2SO4, and concentrated under reduced pressure to obtain the marked compound (15.1 g, 95% yield). 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.10(t,J=6.97 Hz,3H),3.18(s,3H),3.43(q,J=7.01 Hz,2H),3.46-3.51(m,2H),3.53-3.58(m,2H),3.63-3.70(m,2H),4.28-4.33(m,2H).

[0278] Step 2 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propan-1-ol [ka] A solution of 4-(3-hydroxypropyl)phenol (2.80 g, 18.4 mmol; [10210-17-0]) and cesium carbonate (5.99 g, 18.4 mmol; [534-17-8]) in 40 ml of DMF was stirred at RT for 30 minutes. 2-(2-ethoxyethoxy)ethyl methanesulfonate (3.90 g, 18.4 mmol) was added to this mixture, and the mixture was stirred at 60°C for 16 hours. Water was added to the reaction mixture, and the mixture was extracted with MTBE (3 times). The organic layer was washed with saturated NaCl (aqueous solution), dried over Na2SO4, and concentrated under reduced pressure to obtain the labeled compound (4.90 g, (purity 92%), yield 99%). LC-MS (Method 1):R t =0.97min;MS(ESIpos):m / z=269.3[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,J=6.97 Hz,3H),1.61-1.70(m,2H),2.50-2.53(m,2H),3.35-3.45(m,4H),3.46-3.50(m ,2H),3.55-3.59(m,2H),3.69-3.75(m,2H),4.00-4.06(m,2H),4.44(t,J=5.20 Hz,1H),6.80-6.86(m,2H),7.05-7.11(m,2H).

[0279] Step 3 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanal [ka] A solution of 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propan-1-ol (4.90 g, 18.3 mmol) in DCM (120 ml) was sequentially treated with DMSO (32 ml), TEA (12 ml, 88 mmol), and pyridine sulfur trioxide complex (8.72 g, 54.8 mmol; [26412-87-3]), and the mixture was stirred at RT for 16 hours. The reaction mixture was poured into a mixture of saturated NH4Cl and ice, the aqueous layer was extracted with DCM (3 times), the organic layers were combined, washed with NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2, Biotage, Ultra 100 g column, A=hexane, B=siRNA, gradient) to obtain the marked compound (4.60 g, yield 95%). LC-MS (Method 1):R t =1.05min;MS(ESIpos):m / z=267.3[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,J=7.10 Hz,3H),2.68-2.74(m,2H),2.76-2.83(m,2H),3.42(q,J=7.10 Hz,2H),3.47-3.51(m,2H),3.53-3.59(m,2H),3.68-3.73(m,2H),3.99-4.09(m,2H),6.78-6.89(m,2H),7.08-7.19(m,2H),9.67-9.73(m,1 H).

[0280] Step 4 Ethyl(2EZ)-2-(acetyloxy)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}penta-2-enoate [ka] A solution of ethyl (acetyloxy)(diethoxyphosphoryl) acetate (7.47 g, 26.5 mmol, [162246-77-7]) in THF (30 ml) was added to lithium chloride (1.12 g, 26.5 mmol; [7447-41-8]). The mixture was stirred at RT for 1 hour. The mixture was cooled to 0°C in an ice bath, and 1,1,3,3-tetramethylguanidine (4.4 ml, 35 mmol; [80-70-6]) was added dropwise, and the mixture was stirred for 20 minutes. A solution of 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanal (4.70 g, 17.6 mmol) in THF (30 ml) was added, and the mixture was stirred for a further 10 minutes. The ice bath was removed, and the mixture was stirred at RT for a further 1 hour. The reaction mixture was quenched by adding saturated NH4Cl (aqueous solution), the layers were separated, and the aqueous layer was extracted by DCM (three times). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by chromatography (SiO2, Biotage, Ultra 50g column, eluents: A=hexane, B=siRNA, gradient elution) yielded the marked compound as an E:Z mixture (4.65g, yield 67%). LC-MS (Method 1):R t =1.30min;MS(ESIpos):m / z=395.4[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.08-7.14(m,2H),6.85(d,J=8.6 Hz,2H),6.50(t,J=7.6 Hz,0.3H),6.01(t,J=7.6 Hz,0.7H),4.09-4.16(m,2H),4.02-4.06(m,2H),3.69-3.74(m,2H),3.55-3.59(m,2H),3.47-3.50(m,2H),3.42(q,J=6.9 Hz,2H),2.71-2.81(m,1.4H),2.60-2.68(m,2H),2.38(q,J=7.6 Hz, 0.6H), 2.20 (s, 1H), 2.13 (s, 2H), 1.15-1.21 (m, 3H), 1.09 (t, J=7.0 Hz, 3H). The sample is a 7:3 mixture of E / Z isomers and contains ₹.

[0281] Step 5 Ethyl 5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-oxopentanoate [ka] Ethyl (2EZ)-2-(acetyloxy)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}penta-2-enoate (4.65 g, 11.8 mmol) was dissolved in ethanol (150 ml), and H2SO4 (concentrated, 5.0 ml, 94 mmol; [7664-93-9]) was added. The reaction mixture was stirred under reflux for 16 hours, then the mixture was concentrated under reduced pressure, and the residue was dissolved in ELISA and NaHCO3. 3( The sample was washed with a saturated aqueous solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the labeled compound (2.40 g, 58% yield). LC-MS (Method 1):R t =1.26 min;MS(ESIpos):m / z=370.4[M+H2O+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,J=7.10 Hz,3H),1.25(t,J=7.10 Hz,3H),1.76(quin,J=7.41 Hz,2H),1.72-1.72(m,1H),2.50-2.54(m,2H),2.79(t,J=7.35 Hz,2H),3.42(q,J=7.10 Hz,2H),3.46-3.50(m,2H),3.54-3.59(m,2H),3.67-3.74(m,2H),4.01-4.06(m,2H),4.20(q,J=7.10 Hz,2H),6.82-6.88(m,2H),7.06-7.11(m,2H).

[0282] Step 6 Ethyl-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate [ka] A solution of ethyl 5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-oxopentanoate (2.40 g, 6.81 mmol) in ethanol (100 ml) was treated with Pd / C (269 mg, purity 10%, 252 μmol; [7440-05-3]), followed by flow of N2 and three vacuum evacuations. The mixture was stirred under an H2 atmosphere at RT for 96 hours. The reaction mixture was filtered using a glass fiber filter and concentrated under reduced pressure to obtain the racemic compound (intermediate 13), 1.80 g (yield 75%). LC-MS (Method 1):R t =1.15min;MS(ESIpos):m / z=355.4[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,J=7.10 Hz,3H),1.17(t,J=7.10 Hz,3H),1.50-1.64(m,4H),2.46-2.53(m,2 H,coalescence with solvent signal)3.42(q,J=7.01 Hz,2H),3.47-3.50(m,2H),3.54-3.60(m,2H),3.69-3.74(m,2H),3.96-4.11(m,5H),5.32(d,J=6.08 Hz,1H),6.79-6.87(m,2H),7.04-7.10(m,2H).

[0283] Intermediate 14 Ethyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate [ka] Racemic ethyl-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate (intermediate 13, 3480 mg, dissolved in 25 ml of DCM) was separated into its two enantiomer components using the following method (PrepCon Labomatic HPLC-1; column: YMC Cellulose SB 10 μm, 250 × 50; A = hexane / 0.1 vol. % DEA; B = ethanol; 15% B; 100 mL / min; 280 nm; injection of 25 × 1 ml).

[0284] Analytical method for ee determination: (Thermo Fisher UltiMate 3000; YMC Cellulose SB 3μ, 100×4.6; A = hexane / 0.1 vol %DEA; B = ethanol; 10% B; 1.4 ml / min; 25℃, 280 nm). R t Enantiomer 1 = 3.03 min: R t Enantiomer 2 = 3.58 minutes.

[0285] Enantiomer 2: Ethyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate was obtained after combining the recovered fractions and concentrating them under reduced pressure at 45°C (intermediate 14, 1600 mg). The stereochemistry of the alcohol was determined by the correlation between the retention time via chiral HPLC and the compound produced from the chiral starting material. HPLC (analytical method described above): R t =3.58 minutes. Specific optical rotation: -1.6°±0.17 (CHCL3, 20℃, 589nm). LC-MS (Method 1):R t =1.15min;MS(ESIpos):m / z=355.4[M+H] + . 1H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,3H),1.17(t,3H),1.48-1.64(m,4H),1.91(s,2H),3.42(q,2H),3.46-3.50(m,2H),3. 54-3.59(m,2H),3.68-3.74(m,2H),3.97-4.11(m,5H),5.32(d,1H),6.84(d,2H),7.07(d,2H).

[0286] Intermediate 15 Ethyl(2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate [ka] Enantiomer 1 and intermediate 14: ethyl(2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate were obtained after combining the recovered fractions and concentrating them under reduced pressure at 45°C (intermediate 15, 1560 mg). The stereochemistry of the alcohol was assigned as (R) based on the correlation between the retention time via chiral HPLC and the compound produced from the chiral starting material. HPLC (analytical method described above): Rt = 3.03 mins. Specific optical rotation: 0.71°±0.4 (CHCL3, 20℃, 589nm). LC-MS (Method 1):R t =1.15min;MS(ESIpos):m / z=355.4[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,3H)1.17(t,3H)1.48-1.64(m,4H)1.91(s,2H)3.42(q,2H)3.46-3.50(m,2H)3.5 4-3.59(m,2H)3.68-3.74(m,2H)3.97-4.11(m,5H)5.32(d,1H)6.84(d,2H)7.07(d,2H).

[0287] Intermediate 16 Step 1 [2-phenyl-1,3-dioxan-4-yl]methanol [ka] Racemic ± butane-1,2,4-triol (9.3 ml, 100 mmol; [3068-00-6]) was dissolved in DMF (220 ml) under argon. Tetrafluoroboronic acid-diethyl ether complex (1.4 ml, 10 mmol; [67969-82-8]) was added to the stirred mixture, followed by the dropwise addition of (dimethoxymethyl)benzene (16 ml, 100 mmol; [1125-88-8]), and the mixture was stirred overnight at RT. The mixture was then dissolved in NaHCO₃⁻. 3( The mixture was neutralized with a solid and then concentrated under reduced pressure. The crude mixture was diluted with DCM, filtered through Celite, and the filtrate was concentrated under reduced pressure (24.5 g). Purification by chromatography (SiO2, Biotage; 340 g Ultra; A=hexane, B=siRNA, 0%B~100%B; 150 ml / min) yielded the marked compound as a mixture of diastereomers (16.0 g, yield 75%). LC-MS (Method 3):R t =0.67min;MS(ESIpos):m / z=195.2[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.48-1.55(m,1H)1.57-1.68(m,1H)3.36-3.52(m,2H)3.83-3.95(m,2H)4.13-4.21(m,1H)4.72-4.79(m,1H)5.52(s,1H)7.31-7.47(m,1H).

[0288] Step 2 tert-butyl 2-phenyl-1,3-dioxane-4-carboxylate [ka] Chromium(VI) oxide (12.0 g, 120 mmol; [1333-82-0]) was added to a mixture of DCM:DMF (400 ml, 4:1). Pyridine (26 ml) was added, and the mixture was stirred at RT for 30 minutes. 2-Methylpropan-2-ol (77 ml, 800 mmol) and acetic anhydride (30 ml, 320 mmol; [108-24-7]) were added. [2-phenyl-1,3-dioxan-4-yl]methanol (7.80 g, 40.2 mmol) dissolved in DCM:DMF (180 ml, 4:1) was added dropwise over 90 minutes, and the mixture was stirred overnight. The mixture was cooled to 0-5°C, and solid NaHCO₃⁻ was obtained. 3( 54.0 g (643 mmol) and ethanol (38 ml) were added, and the mixture was stirred for 30 minutes. Toluene was added, and the mixture was concentrated under reduced pressure. The mixture was then dissolved in HCl, filtered, and the filtration cake was washed with HCl. Purification by chromatography (SiO2, Biotage 120 g Ultra; A=hexane, B=HCl, C=MeOH, 100%A~100%B, followed by 0%C~15%C) yielded the marked compound as a mixture of diastereomers (5.53 g, yield 51%). LC-MS (Method 6):R t =1.25min;MS(ESIpos):m / z=282.3[M+NH4] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.43(s,9H)1.73-1.92(m,2H)3.91-4.05(m,1H)4.13-4.23(m,1H)4.50(dd,1H)5.56-5.62(s,1H)7.32-7.46(m,5H).

[0289] Step 3 tert-butyl-4-(benzyloxy)-2-hydroxybutanoate [ka] Triethylsilane (17 ml, 100 mmol, [617-86-7]) was added to DCM (110 ml), followed by racemic tert-butyl-2-phenyl-1,3-dioxane-4-carboxylate (5.53 g, 20.9 mmol). The mixture was cooled to -5°C, and TFA (8.1 ml, 100 mmol; [76-05-1]) was added dropwise. The mixture was then brought to RT and stirred for 90 minutes. A solution of NaHCO3 (saturated aqueous solution) was added until a basic pH was obtained, the layers were separated, and the organic phase was dried over Na2SO4. Purification by chromatography (SiO2, Biotage, 100 g Ultra; A=hexane, B=siRNA, 0%B~35%B, 120 ml / min) yielded the marked compound (2.16 g, yield 37%). LC-MS (Method 6):R t =1.18 min;MS(ESIpos):m / z=211.2[M+H-C4H8] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.39(s,9H)1.64-1.77(m,1H)1.90(m,1H)3.40-3.58(m,1H)3.99(m,1H)4.44(s,1H)5.23(d,2H)7.15-7.55(m,5H).

[0290] Step 4 tert-butyl(2R)-4-(benzyloxy)-2-[(methanesulfonyl)oxy]butanoate [ka] Racemic tert-butyl-4-(benzyloxy)-2-hydroxybutanoate (2.16 g, 8.11 mmol), TEA (2.3 ml, 16 mmol), and THF (110 ml) were stirred at 0-5°C. Under a N2 atmosphere, MsCl (690 μl, 8.9 mmol; [124-63-0]) was added, and the mixture was heated in RT and stirred overnight. The mixture was then dissolved in NaHCO₃⁻. 3(The mixture was added to a 50% saturated aqueous solution, extracted with MTBE (3 times), combined with the organic solution, washed with NaCl solution (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the marked compound (intermediate 16, 2.87 g, yield 92%). LC-MS (Method 6):R t =1.29min;MS(ESIpos):m / z=362.3[M+NH4] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.41(s,9H),1.93-2.20(m,2H),3.53(dd,2H),4.47(s,2H),4.98(dd,1H),7.24-7.40(m,5H).

[0291] Intermediate 17 Step 1 5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-carbaldehyde [ka] A mixture of 5-fluoropyridine-2-carbaldehyde (5.00 g, 40.0 mmol; [31181-88-1]) and 2-(2-ethoxyethoxy)ethane-1-ol (16 ml, 120 mmol) was treated with cesium carbonate (15.6 g, 48.0 mmol; [534-17-8]), and the mixture was stirred at 70°C for 18 hours. Water was added to the reaction mixture, and the mixture was extracted three times with MTBE. The organic layer was washed with NaCl solution (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography (SiO2, Biotage, Ultra 50 g column; eluents: A=hexane, B=siRNA; gradient elution) to obtain the labeled compound (1.99 g, yield 21%). LC-MS (Method 1):R t =0.85min;MS(ESIpos):m / z=240.1[M+H] + . 1H NMR(400 MHz,DMSO-d6)δ ppm 1.08(t,J=6.97 Hz,3H),3.42(q,J=6.93 Hz,2H),3.46-3.50(m,2H),3.56-3.61(m,2H),3.76-3.81(m,2H),4.29-4.33(m,2H),7.59-7.62(m,1H),7.93(d,J=8.62 Hz,1H),8.51(d,J=2.79 Hz,1H),9.89(s,1H).

[0292] Step 2 tert-butyl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-yl}oxiran-2-carboxylate [ka] A solution of 5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-carbaldehyde (2.00 g, 8.36 mmol) in THF (100 ml) was treated dropwise with sodium hydride (468 mg, 60% purity, 11.7 mmol; [7646-69-7]), the mixture was stirred for 5 minutes, then tert-butyl chloroacetate (1.6 ml, 11 mmol) was added dropwise, and the mixture was stirred at RT for 16 hours. The reaction mixture was poured into a mixture of ice and water, extracted three times with ELISA, the organic layer was washed with NaCl (saturated aqueous solution), dried over Na2SO4, and then concentrated under reduced pressure. The crude product was purified by chromatography (Biotage Sfar 50g column, eluent: A=hexane, B=siRNA, gradient elution) to obtain the cis and trans forms of the product of the identified compound (identified compound "trans" - 550 mg (19%) + identified compound "cis" - 1250 mg (42%)). The compound is labeled "trans". LC-MS (Method 4):R t =1.19min;MS(ESIpos):m / z=354.1[M+H] + . 1H NMR(DMSO-d6,500 MHz): δ(ppm)8.28(dd,J=2.5,1.0 Hz,1H),7.41-7.46(m,2H),4.17-4.21(m,2H),4.09(d,J=1.9 Hz,1H),3.82(d,J=1.9 Hz,1H),3.73-3.77(m,2H),3.56-3.59(m,2H),3.47-3.50(m,2H),3.42(q,J=7.0 Hz,2H),1.46(s,9H),1.09(t,J=7.0 Hz,3H). 13 C NMR (DMSO-d6, 126 MHz): δ (ppm) 166.8, 154.9, 145.2, 137.7, 122.6, 121.5, 82.0, 69.9, 69.1, 68.7, 67.6, 65.5, 56.8, 54.7, 27.5 (3C), 15.0. The compound is labeled "シス". LC-MS (Method 4): R t =1.13 points; MS(354.1): m / z=[M+H] + . 1 H NMR (DMSO-d6, 400 MHz): δ (ppm) 8.25 (d, J = 2.5 Hz, 1H), 7.43 ( dd, J = 8.6, 2.8 Hz, 1H), 7.28 ( d, J = 8.6 Hz, 1H), 4.28 ( d, J = 4.8 Hz,1H),4.14-4.18(m,2H),3.91(d,J=4.8 Hz,1H),3.71-3.75(m,2H),3.55-3.58(m,2H),3.46-3.50(m,2H),3.42(q,J=7.0 Hz,2H),1.19(s,9H),1.09(t,J=7.1 Hz,3H). 13 C NMR (DMSO-d6, 126 MHz): δ (ppm) 165.4, 154.5, 145.1, 137.1, 121.8, 121.0, 81.6, 70.0, 69.2, 68.8, 67.7, 65.6, 56.7, 55.2, 27.4 (3C), 15.1.

[0293] ステップ3 tert-butyl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-yl}-2-hydroxypropanoate [ka] A racemic solution of tert-butyl-3-{5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-yl}oxirane-2-carboxylate (1.25 g, 3.54 mmol) in SiO2 (15 ml) was treated with palladium / C (131 mg, purity 10%, 123 μmol; [7440-05-3]), and the mixture was circulated three times between N2 and vacuum. The mixture was stirred at RT under an H2 atmosphere (1 atm) for 72 hours. The reaction mixture was filtered using a glass fiber filter and concentrated under reduced pressure. Purification by chromatography (SiO2, Biotage ULTRA 25 g column, eluent: A=hexane, B=SiO2, gradient elution) yielded the racemic compound (intermediate 17, 1.05 g, yield 84%). LC-MS (Method 1):R t =0.84min;MS(ESIpos):m / z=356.2[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)8.18(d,J=2.8 Hz,1H),7.31(dd,J=8.6,3.0 Hz,1H),7.18(d,J=8.6 Hz,1H),5.36(d,J=6.3 Hz,1H),4.24(dt,J=8.0,5.9 Hz,1H),4.10-4.16(m,2H),3.71-3.76(m,2H),3.54-3.60(m,2H),3.47-3.50(m,2H),3.42(q,J=6.8 Hz,2H),2.97(dd,J=13.7,5.3 Hz,1H),2.87(dd,J=13.9,8.1 Hz,1H),1.35(s,9H),1.09(t,J=7.1 Hz,3H).

[0294] Intermediate 18 Step 1 (3E)2-oxo-4-(4-propoxyphenyl)buta-3-enoic acid [ka] Under an N2 atmosphere, 2-oxopropanoic acid (2.68 g, 30.4 mmol; [127-17-3]) was added to a mixture of 4-propoxybenzaldehyde (5.00 g, 30.4 mmol; [5736-85-6]) in MeOH (4 ml). To this mixture, a mixture of potassium hydroxide in MeOH (25 wt% solution, 45.7 mmol) was added while maintaining the reaction temperature below 15°C. A small amount of additional MeOH was added, and the mixture was heated in RT and stirred overnight. The mixture was concentrated under reduced pressure and added to a solution of HCl (1.5 M aqueous solution), and the aqueous mixture was extracted with ELISA. The organic phases were combined, washed with NaCl solution (saturated aqueous solution), dried over Na2SO4, and concentrated under reduced pressure to obtain the crude labeled compound (3.24 g, (purity 80%), yield 45%). The large J coupling value of the alkene signal suggests the assignment of the (E) configuration. LC-MS (Method 1):R t =1.06min;MS(ESIpos):m / z=235.1[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 0.98(t,J=7.48 Hz,3H),1.68-1.79(m,2H),3.97-4.04(m,2H),6.97-7.03(m,2H),7.13(d,J=16.22 Hz,1H),7.70(d,J=16.22 Hz,1H),7.74-7.80(m,2H).

[0295] Step 2 2-Hydroxy-4-(4-propoxyphenyl)butanoic acid [ka] (3E)2-oxo-4-(4-propoxyphenyl)buta-3-enoic acid (6.89 g, 29.4 mmol) was dissolved in ethanol (200 ml), and Pd / C (1.56 g, purity 10%, 1.47 mmol; [7440-05-3]) was added. The mixture was circulated three times between N2 and vacuum and hydrogenated overnight (1 atm H2). The mixture was filtered through a glass fiber filter, concentrated under reduced pressure, and then obtained the racemic labeled compound (6.50 g, yield 93%) by chromatography (SiO2, Biotage, Ultra 100 g column, A=hexane, B=siRNA, 0%B~100%B). LC-MS (Method 1):R t =1.01min;MS(ESIneg):m / z=237[MH] - . 1 H NMR(400 MHz,DMSO-d6)δ ppm 0.96(t,J=7.48 Hz,3H),1.64-1.92(m,4H),2.54-2.62(m,2H),2.58(t,J=7.86 Hz,2H),3.87(t,J=6.46 Hz,3H),5.20-5.27(br.s,1H),6.80-6.85(m,2H),7.05-7.11(m,2H),12.21-12.58(br.s,1H). Methyl-2-hydroxy-4-(4-propoxyphenyl)butanoate [ka]

[0296] Racemic 2-hydroxy-4-(4-propoxyphenyl)butanoic acid (6.50 g, 27.3 mmol) was dissolved in MeOH (50 ml), and the mixture was stirred overnight with one drop of concentrated H2SO4 and RT. The mixture was concentrated under reduced pressure and NaHCO3 was added. 3( A saturated aqueous solution was added, the mixture was extracted with toluene, dried over Na2SO4, and concentrated under reduced pressure to obtain the marked compound (intermediate 18, 3.85 g, yield 56%). LC-MS (Method 1):R t =1.14 min;MS(ESIpos):m / z=254[M+H] + . 1H-NMR (400MHz, DMSO-d6): δ[ppm]=0.96(t,3H),1.65-1.90(m,4H),2.52-2.60(m,2H),3.61 (s,3H),3.87(t,2H),3.94-4.04(m,1H),5.47(d,1H),6.79-6.86(m,2H),7.05-7.11(m,2H).

[0297] Intermediate 19 2-Oxooxolane-3-ylmethanesulfonate [ka] 3-Hydroxyoxolan-2-one (2.50 g, 24.5 mmol; [19444-84-9]), THF (82 ml), and TEA (7.5 ml, 54 mmol) were stirred under N2 at 0°C. MsCl (2.1 ml, 27 mmol; [124-63-0]) was added dropwise, and the mixture was stirred at 0°C for 30 minutes, followed by stirring overnight at RT. The mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain the marked compound (intermediate 19, 5.15 g, yield 82%), which also contained some TEA hydrochloride. 1 H NMR(400 MHz,DMSO-d6)δ ppm 2.39(m,1H),2.73(dddd,J=12.71,8.40,6.15,1.90 Hz,1H),3.33(s,3H),4.26(ddd,J=10.14,8.74,6.21 Hz,1H),4.43(td,J=8.93,1.90 Hz,1H),5.55(dd,J=9.76,8.49 Hz,1H).

[0298] Intermediate 20 Step 1 (2S)-2-(tert-butoxycarbonylamino)-5-(4-ethoxyphenyl)pentanoate [ka] To a solution of methyl(2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-pentenoate (60.0 g, 261 mmol, [89985-87-59]) in THF (600 mL), 9-BBN (0.50 M, 1.05 L, [280-64-8]) was added at 0°C for 30 minutes. The reaction mixture was stirred at 20°C for 1 hour. Then, K3PO4 was added. 4( 3.00 M aqueous solution (87.2 mL) was added to the reactant, followed by the addition of a mixture of 4-bromophenethole (57.8 g, 287 mmol, [588-96-5]), Pd(OAc)2 (2.94 g, 13.0 mmol, [3375-31-3]), and SPhos (10.7 g, 26.2 mmol, [657408-07-6]) in DMF (900 mL) at 20°C. The reaction mixture was stirred at 60°C for 12 hours, after which KCl (195 g, 2.62 mol) and saturated NaHCO3 were added. 3( 1000 mL was added and stirred at 20°C for 1 hour. TLC (PE:SiO=5:1) was performed on the starting material (R f =0.8) is consumed, and a large new spot (R f The detection of (=0.4) was indicated. The crude reaction mixture was work-treated together with the previously tested (74 g, 323 mmol) methyl(2S)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-pentenoate. The combined reaction mixture was poured into water (4.0 L) and extracted with SiO2 (1.0 × 3). The combined organic phase was washed with NaCl (1.0 L × 3 saturated aqueous solutions), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by chromatography (SiO2, A=PE, B=SiO2, A:B=30:1~20:1) to obtain the marked compound (162 g, 79%) as a yellow oil. LC-MS (Method 7):R t =0.824 min, m / z=252[M+H-C4H8-CO2] + . 1H NMR:(400 MHz CDCl3)δ 7.04-7.06(m,2H),6.80-6.82(m,2H),3.99(dd,J=14,14 Hz,2H),3.72(s,3H),2.55-2.57(m,2H),1.84-1.87(m,4H),1.63-1.66(m,7H),1.44(s,9H),1.38-1.42(m,3H).

[0299] Step 2 (2S)-2-amino-5-(4-ethoxyphenyl)pentanoate [ka] A solution of methyl(2S)-2-(tert-butoxycarbonylamino)-5-(4-ethoxyphenyl)pentanoate (95.0 g, 270 mmol) was mixed with HCl aqueous solution (6.00 M, 2.25 L) at 20°C. The reaction mixture was stirred at 100°C for 3 hours. When the reaction mixture was concentrated under reduced pressure, the labeled compound (128 g, over 100%) was obtained as a yellow solid. LC-MS: (Method 8):R t =0.513 min, MS=238[M+H] + . 1 H NMR:EW16671-49-P1B1,400 MHz MeOD)δ 7.08-7.11(m,2H),6.81-6.83(m,2H),3.94-4.02(m,3H),2.61-2.64(m,2H),1.72-1.94(m,4H),1.34-1.38(m,3H).

[0300] Step 3 (2S)-5-(4-ethoxyphenyl)-2-hydroxypentanoic acid [ka] (2S)-2-amino-5-(4-ethoxyphenyl)pentanoate (32.0 g, 117 mmol) is dissolved in H2SO4 (0.50 M aqueous solution, 320 mL) and THF (320 mL) with NaNO2. 2(23.4 g (338 mmol, 160 mL) was added at 0°C for 3 hours. The reaction mixture was stirred at 0°C for 2 hours and then at 20°C for 12 hours. The reaction mixture was combined with another identical preparation (30 g), and the combined reaction mixture was extracted with ELISA (1.0 L x 3). The combined organic phase was washed with saturated NaCl (500 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain (2S)-5-(4-ethoxyphenyl)-2-hydroxypentanoic acid (66.0 g, over 100%) as a yellow oil. LC-MS (Method 9):R t =0.178 minutes, =237[MH] - .

[0301] Step 4 Methyl(2S)-5-(4-ethoxyphenyl)-2-hydroxypentanoate [ka] (2S)-5-(4-ethoxyphenyl)-2-hydroxypentanoic acid (28.0 g, 117 mmol) is dissolved in DCM (60.0 mL) and MeOH (30.0 mL) with TMSCHN. 2( 2.00 M, 235 mL, [18107-18-1]) was added dropwise at 0°C for 30 minutes. The reaction mixture was stirred at 20°C for 2 hours. TLC (PE:HCl=3:1) was performed using the starting material (R f =0.25) is completely consumed, and a large new spot (R f The detection of (=0.6) was indicated. The reaction mixture was combined with the same reactant (10 g). CH3COOH (50 mL) was added dropwise to the combined reaction mixture. The mixture was quenched with 10% NaHCO3 aqueous solution (500 mL) and extracted with DCM (500 mL x 3). The combined organic phase was washed with saturated NaCl (500 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, A=PE, B=siRNA, A:B=30:1~20:1) to obtain the marked compound (intermediate 20, 19.0 g, 75.3 mmol, yield 47%) as a yellow oil. LC-MS: (Method 10):Rt = 0.850 minutes, = 253 [M+H] + . SFC: (Chiralpak AD-3 50×4.6 mm inner diameter, 3 μm, A = CO2, B = MeOH (0.05% DEA); 5% B~40% B; 3 mL / min; DAD; 35 °C; 100 Bar): R t = 1.10 minutes (100%). 1 H NMR: (400 MHz CDCl3) δ 7.07 - 7.09 (m, 2H), 6.81 - 6.84 (m, 2H), 4.20 - 4.21 (m, 1H), 3.99 - 4.04 (m, 2H), 3.77 (s, 3H), 2.74 (d, J = 6 Hz, 1H), 2.57 - 2.62 (m, 2H), 1.63 - 1.84 (m, 4H), 1.42 (t, J = 6.8 Hz, 3H).

[0302] Intermediate 21 Ethyl 3-(4-ethoxyphenyl)-2-hydroxypropanoate [Chemical Structure Diagram] Ethyl 2-hydroxy-3-(4-hydroxyphenyl)propanoate (2.50 g, 11.9 mmol, [62517-34-4]) was dissolved in DMF (86 ml), and cesium carbonate (4.26 g, 13.1 mmol; [534-17-8]) was added. The mixture was placed under N2 and cooled to 0 °C. Iodoethane (1.24 ml, 15.5 mmol; [75-03-6]) was added dropwise, and the reaction mixture was stirred overnight at RT. An NaCl (3.1 M, aqueous solution) solution was added, and the mixture was extracted with MTBE (3 times). The combined organic phases were washed with NaCl (saturated aqueous solution), dried over Na2SO4, and concentrated under reduced pressure. The resulting crude product was purified by chromatography (SiO2, A = hexane, B = EtOAc, 0% B~100% B) to obtain the title compound (Intermediate 21, 1.19 g, yield 40%). LC-MS (Method 4): R t = 1.04 minutes; MS (ESIpos): m / z = 239 [M+H] + . 1H NMR (DMSO-d6,400 MHz): δ(ppm)7.06-7.13(m,2H),6.73-6.88(m,2H),5.48(d,J=6.1 Hz,1H),4.15(dt,J=7.8,5.7 Hz,1H),4.04(q,J=7.1 Hz,2H),3.97(q,J=6.8 Hz,2H),2.85(dd,J=13.7,5.3 Hz,1H),2.75(dd,J=13.7,7.6 Hz,1H),1.30(t,J=7.0 Hz,3H),1.13(t,J=7.1 Hz,3H).

[0303] Intermediate 22 Step 1 Methyl(2R)-[5-[4-butoxy]phenyl]-2-[[(1,1-dimethylethoxy)carbonyl]amino]pentanoate [ka] To a solution of methyl(2R)-2-[[(1,1-dimethylethoxy)carbonyl]amino]-4-pentenoate (20.1 g, 88 mmol, [150652-96-3]) in THF (200 mL), 9-BBN (0.50 M, 349 mL) was added at 0°C. The reaction mixture was stirred at 16°C for 1 hour. Then, K3PO4 was added. 4( Add 3M (29.2 mL), followed by 1-bromo-4-butoxybenzene (20.0 g, 87.3 mmol, [39969-57-8]) and Pd(OAc) in DMF (500 mL). 2( 980 mg (4.37 mmol) was added to a mixture of SPhos (3.60 g, 8.77 mmol, [657408-07-6]). After stirring at 60°C for 18 hours under N2, 1.00 L of aqueous NaHCO3 and 651 g (8.73 mol) of potassium chloride were added to the reaction mixture and stirred at 16°C for 2 hours. The reaction mixture was poured into water (1.00 L) and extracted with SiO2 (500 mL x 3). The combined organic phase was washed with saturated aqueous NaCl (500 mL x 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the labeled compound (60.0 g, crude) as a yellow oil. LC-MS (Method 12):Rt = 1.177 minutes, MS: 379.24 [M+H] + .

[0304] Step 2 (2R)-2-Amino-[5-[4-butoxy]phenyl]pentanoic acid

Chemical formula

[0305] Step 3 (2R)-[5-[4-butoxy]phenyl]-2-hydroxypentanoic acid

Chemical formula

[0306] Step 4 Methyl(2R)-5-(4-butoxyphenyl)-2-hydroxypentanoate [ka] (2R)-[5-[4-butoxy]phenyl]-2-hydroxypentanoic acid (33.0 g, 124 mmol) was dissolved in DCM / MeOH (3 / 1, 440 mL), to which TMSCHN2 (55.0 g, 482 mmol, [18107-18-1]) was added at -10°C and the mixture was stirred at 20°C for 12 hours. TLC (PE:EA = 20:1) showed that the acid was completely consumed. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (Phenomenex Luna C18 250 × 80 mm × 10 μm; A = [water (0.05% HCl), B = MeCN, 45B%~75B at 19 min) to obtain the marked compound (intermediate 22, 7.00 g, 25.0 mmol, yield 20%) as a yellow oil. LC-MS (Method 7):R t =0.931 min, MS:281.1[M+H] + . SFC:(Chiralpak AD-3 50×4.6mm inner diameter, 3μm; A=CO2, B=MeOH(0.05%DEA); 5%B~40%B, 3mL / min; DAD; 35℃; 100Bar):R t =1.20 minutes (94%), R t =1.27 minutes (6%); ee=88%. Specific rotation:α D 20 =-5.4°+ / -0.24°(c=1, CHCl3). 1H NMR(400 MHz,CDCl3)δ 7.04-7.10(m,2H),6.78-6.84(m,2H),4.20(dd,J=4.06,7.10 Hz,1H),3.93(t,J=6.59 Hz,2H),3.77(s,3H),2.75(br,s,1H),2.51-2.64(m,2H),1.60-1.86(m,6H),1.48(qt,J=7.40,7.60 Hz,2H),0.97(t,J=7.48 Hz,3H). 13 C NMR(101 MHz,CDCL3)δ 175.7,157.3,133.7,129.2(2C),114.3(2C),70.3,67.7,52.5,34.5,33.9,31.4,26.7,19.3,13.9.

[0307] Intermediate 23 Step 1 Ethyl (2RS,3SR)-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]oxirane-2-carboxylate [ka] Sodium hydride (1.78 g, 60% in mineral oil, 44.5 mmol) was suspended in THF (190 ml), placed under N2, and cooled to 0°C. Ethyl chloroethyl acetate (4.7 ml, 44 mmol) was added dropwise, followed by the addition of 4-(2,2,3,3-tetrafluoropropoxy)benzaldehyde (7.00 g, 29.6 mmol, [103962-17-0]) in THF (10 ml). The reaction mixture was stirred overnight in RT. The reaction mixture was poured into ice water and extracted with SiO2 (3 times). The combined organic phase was washed with NaCl (saturated aqueous solution), dried over Na2SO4, and concentrated under reduced pressure. Chromatography (SiO2, SNAP Ultra 100 g, A=hexane, B=SiO2, 0%B to 50%B in 30 min, 80 ml / min) yielded 5.21 g (52%) of the labeled compound. LC-MS (Method 4):R t =1.23min;MS(ESIpos):m / z=323.1[M+H] + . 1H NMR (DMSO-d6,400 MHz): δ(ppm)7.32-7.37(m,2H),7.00-7.12(m,2H),6.68(tt, 2 J HF =51.7, 3 J HF =5.6 Hz, 1H), 4.60(t, 3 J HF =13.4 Hz,2H),4.15-4.24(m,2H),4.12(d,J=1.8 Hz,1H),3.82(d,J=1.8 Hz,1H),1.24(t,J=7.1 Hz,3H). 19 F NMR(DMSO-d6,377 MHz):δ(ppm)-125.27(tq,J=13.7,5.7 Hz,1F),-139.69(dt,J=52.4,5.3 Hz,2F). 13 C NMR(DMSO-d6,101 MHz):δ(ppm)167.9,157.8,128.4,128.0(2C),115.2(2C),115.0(tt, 1 J CF =248.8, 2 J CF =26.3 Hz), 109.3(tt, 1 J CF =247.8, 2 J CF =32.7 Hz), 64.7(t, 2 J CF =27.6 Hz),61.3,56.8,55.7,14.0.

[0308] Step 2 Ethyl 2-hydroxy-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]propanoate [ka] Ethyl 3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]oxirane-2-carboxylate (5.21 g, 16.2 mmol) was dissolved in ethanol (73 ml), and palladium (417 mg, 10% on carbon, 392 μmol) was added. The mixture was hydrogenated overnight at RT and ambient pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography (SiO2, SNAP Ultra 50 g, 40 min / min, A=n-hexane, B=siRNA, 0%B to 50%B at 30 min) to obtain the marked compound (intermediate 23, 4.42 g, 80%). 19 F NMR(DMSO-d6,377 MHz):δ(ppm)-125.32(ttd,J=13.8,5.7,5.4 Hz,2F),-139.78(dt,J=52.6,5.7 Hz,2F). 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.14-7.18(m,2H),6.92-6.97(m,2H),6.67(tt,J=52.0,5.6 Hz,1H),5.51(d,J=6.1 Hz,1H),4.53(t,J=13.4 Hz,2H),4.17(dt,J=7.8,5.6 Hz,1H),4.05(q,J=7.1 Hz,2H),2.88(dd,J=13.7,5.3 Hz,1H),2.78(dd,J=13.7,7.9 Hz,1H),1.14(t,J=7.1 Hz,3H). 13 C NMR(DMSO-d6,101 MHz):δ(ppm)173.5,155.9,131.1,130.5(2C),115.2(tt, 1 J CF =249.2, 2 J CF 26.3 Hz), 114.5 (2C), 109.3 (tt, 1 J CF =247.8, 2 J CF 32.8 Hz), 71.3, 64.7 (t, 2 J CF =27.6 Hz), 60.0, 39.2, 14.1.

[0309] Intermediate 24 Step 1 Methyl(2R)-2-hydroxypenta-4-enoate [ka] To a solution of copper(I) bromide dimethyl sulfide complex (20.1 g, 98.0 mmol; [54678-23-8]) in THF (400 ml), bromide (ethenyl)magnesium (240 ml, 240 mmol, 1 M in THF; [1826-67-1]) was added at -70°C. The mixture was stirred at -70°C for 0.5 hours. Next, a solution of methyl(2R)-oxirane-2-carboxylate (20.0 g, 196 mmol; [111058-32-3]) in THF (200 ml) was added to the above mixture at -70°C. The mixture was stirred at -70°C for 1 hour. The mixture was quenched with NH4Cl (saturated aqueous solution) and extracted with siRNA. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash column chromatography (SiO2, A=PE, B=SiO, 1:0~9:1, then 9:1 A:B) to obtain methyl(2R)-2-hydroxypenta-4-enoate (6.30 g, yield 25%) as a yellow oil. 1 H NMR(400 MHz,DMSO-d6)δ[ppm]=5.87-5.69(m,1H),5.54-5.43(m,1H),5.11-4.99(m,2H),4.15-4.06(m,1H),3.62(s,3H),2.45-2.25(m,2H).

[0310] Step 2 Methyl(2R,4E)-5-(3-butoxyphenyl)-2-hydroxypenta-4-enoate [ka] A mixture of 1-butoxy-3-iodobenzene (12.7 g, 46.1 mmol; [103030-54-2]), methyl(2R)-2-hydroxypenta-4-enoate (6.00 g, 46.1 mmol), palladium(II) diacetate (1.04 g, 4.61 mmol; [3375-31-3]), tri-2-tolylphosphine (1.40 g, 4.61 mmol; [6163-58-2]), and DIPEA (20 ml, 120 mmol; [7087-68-5]) in MeCN (150 ml) was stirred at 80°C for 12 hours. TLC (PE:SiO=2:1) ​​showed that the iodide was consumed and a new major spot was formed. The mixture was concentrated and diluted with SiO. The mixture was washed with NH4Cl (saturated aqueous solution) and NaCl (saturated aqueous solution). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the residue. The residue was purified by flash column chromatography (SiO2, PE:SiO5 = 10:1, ~4:1, then 4:1) to obtain the marked compound as a yellow oil. The substance was combined with the substance from the previous experiment: 6.80 g (50% yield). LCMS (Method 13):R t =1.001min;MS(ESIpos):m / z=279.2[M+H] + . 1 H-NMR(400 MHz,DMSO-d6)δ[ppm]=7.20(t,J=8.0 Hz,1H),6.95-6.88(m,2H),6.80-6.74(m,1H),6.44-6.36(m,1H),6.30-6.19(m,1H),5.57(d,J=6.0 Hz,1H),4.22-4.15(m,1H),3.95(t,J=6.4 Hz,2H),3.63(s,3H),2.60-2.52(m,1H),2.48-2.37(m,1H),1.75-1.61(m,2H),1.50-1.37(m,2H),0.93(t,J=7.6 Hz,3H).

[0311] Step 3 Methyl(2R)-5-(3-butoxyphenyl)-2-hydroxypentanoate [ka] To a solution of methyl(2R,4E)-5-(3-butoxyphenyl)-2-hydroxypenta-4-enoate (6.30 g, 22.6 mmol) in methanol, palladium (10% on carbon) was added at room temperature. The mixture was stirred under an H2 atmosphere (15 Psi) at room temperature for 5 hours. The mixture was filtered and combined with the results of a pilot experiment. When the combined filtrate was concentrated under reduced pressure, the marked compound (intermediate 24, 5.80 g, yield 82%) was obtained as a yellow oil. LCMS: (Method 9):R t =0.997min;MS(ESIpos):m / z=281.2[M+H] + . Specific rotation:α D 20 =-6.54°+ / -0.16°(c=1, CHCl3). 1 H NMR(CDCl3,400MHz):δ(ppm)7.15-7.20(m,1H),6.70-6.77(m,3H),4.21(dd,J=7.1,3.8 Hz,1H),3.95(t,J=6.6 Hz,2H),3.77(s,3H),2.55-2.68(m,2H),1.61-1.88(m,6H),1.44-1.55(m,2H),0.98(t,J=7.4 Hz,3H). 13 C NMR (CHLOROFORM-d, 101MHz): δ(ppm)175.6,159.2,143.4,129.2,120.6,114.8,111.6,70.3,67.5,52.5,35.5,33.9,31.4,26.4,19.3,13.9.

[0312] Intermediate 25 Step 1 Ethyl-2-hydroxy-3-methoxypropanoate [ka] Ethyl oxirane-2-carboxylate (2.5 g, 21.5 mmol; [4660-80-4]) was dissolved in MeOH (1 ml, 32 mmol) in a crimp-seal vial. Magnesium triflate (1.74 g, 5.38 mmol; [60871-83-2]) was added, the vial was crimped and closed, and the mixture was stirred at 40°C until the starting material was consumed (16 hours). The mixture was filtered and purified by chromatography (SiO2, A=hexane, B=siRNA, gradient elution) to obtain the marked compound (771 mg, yield 24%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.19(t,3H),3.25(s,3H),3.50(dd,2H),4.10(q,2H),4.17(dt,1H),5.51(d,1 H).

[0313] Step 2 Ethyl-2-[(methanesulfonyl)oxy]-3-methoxypropanoate [ka] Racemethyl-2-hydroxy-3-methoxypropanoate (771 mg, 5.20 mmol) and TEA (1.6 ml, 11 mmol) were added to THF solution (15 ml), and the mixture was cooled to 0-5°C. Under N2, MsCl (440 μl, 5.7 mmol; [124-63-0]) was added dropwise, and the mixture was heated to RT and stirred for 3 hours. The mixture was added to an aqueous solution of NaHCO3 (50% saturated at RT), followed by extraction with MTBE (3 times), the organic phases were combined, washed with NaCl (saturated aqueous solution) (2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the marked compound (intermediate 25, 780 mg, yield 63%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.21(t,J=7.10 Hz,3H),3.26(s,3H),3.29(s,3H),3.64-3.74(m,1H),3.75-3.82(m,1H),4.11-4.27(m,2H),5.26-5.34(m,1H).

[0314] Intermediate 26 Step 1 Methyl(2R)-3-tert-butoxy-2-hydroxypropanoate [ka] 2-methylpropan-2-ol (370 ml, 3.9 mol) was added to a three-necked round-bottom flask equipped with a mechanical stirrer, and magnesium trifluoromethanesulfonate (79.0 g, 245 mmol; [60871-83-2]) and toluene (370 ml) were added. The reaction mixture was placed under N2 and heated to 50°C (measured in the flask). Methyl(2R)-oxirane-2-carboxylate (21 ml, 240 mmol; [111058-32-3]) was then added dropwise, and the mixture was stirred at 60°C for 3.5 days. After cooling to RT, toluene was added. The reaction mixture was washed twice with NaCl (3.1 M aqueous solution), and the organic phase was concentrated under reduced pressure. The residue was codistilled three times with toluene to remove unreacted methyl glycidate. The crude product obtained was purified by chromatography (Isolera LS, Sfar 350g, A=hexane, B=DCM, C=toluene, A=3CV, 5CV for A to B, B=4CV, 6CV for B to 50% C). The target fraction was pooled, concentrated under reduced pressure, and co-distilled once with toluene to obtain 37.3g of the labeled compound (68) as a clear oil. 1 H NMR (CDCl3,400 MHz): δ(ppm)3.77(s,3H),3.60-3.66(m,2H),1.15(s,9H).

[0315] Step 2 Methyl(2R)-3-tert-butoxy-2-[(trifluoromethanesulfonyl)oxy]propanoate [ka] Methyl(2R)-3-tert-butoxy-2-hydroxypropanoate (5.00 g, 28.4 mmol) in DCM (4.0 ml) was cooled to -70°C under N2, and lutidine (4.0 ml, 34 mmol) was added. Trifluoromethanesulfonic anhydride (30 ml, 1.0 M in DCM, 30 mmol) was added dropwise, and the mixture was stirred at -70°C for 2.5 hours. The mixture was then warmed to -20°C and quenched with ice water. The phases were separated, and the aqueous phase was extracted with dichloromethane. The combined organic phase was filtered through a hydrophobic filter and concentrated under reduced pressure. The indicated compound intermediate 26 (9.45 g (over 100%)) was used without further purification. Specific rotation:α D 20 =+20.9°+ / -0.2°(c=1, CHCl3). 19 F NMR(CDCl3,471 MHz):δ(ppm)-75.86(s,1F). 1 H NMR (CDCl3,500 MHz): δ(ppm)5.22(dd,J=6.9,2.8 Hz,1H),3.86(s,3H),3.85(dd,J=11.0,2.8 Hz,1H),3.80(dd,J=11.0,6.9 Hz,1H),1.20(s,9H).

[0316] Residual lutidine triflate is easily quantified: δ(ppm) 8.04 (t, J=7.9Hz, 0.11H), 7.41 (d, J=7.9Hz, 0.21H), 2.82 (s, 0.66H); -79.62 (s, 0.1F).

[0317] Intermediate 27 Step 1 Ethyl-3-tert-butoxy-2-hydroxypropanoate [ka] Due to safety concerns, the reactants were divided into three equal portions: 2-methylpropan-2-ol (8.2 ml, 120 mmol, [75-65-0]), ethyl oxirane-2-carboxylate (15.6 g, 134 mmol, [4660-80-4]) and magnesium perchlorate (7.53 g, 33.7 mmol, [10034-81-8]) were placed in three crimp-sealed vials in equal amounts, sealed and stirred at 50 °C for 48 hours. The three batches were combined, diluted with DCM and then washed with NH4Cl (saturated aqueous solution) and subsequently with NaCl (saturated aqueous solution). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to give the title racemic compound (12.0 g, 52% yield). 1 1H NMR (400 MHz, DMSO-d6) δ ppm 1.09 (s, 9H), 1.19 (t, 3H), 3.46 (dd, 2H), 4.02 - 4.15 (m, 3H), 5.35 (d, 1H).

[0318] Step 2 Ethyl 3-tert-butoxy-2-[(trifluoromethanesulfonyl)oxy]propanoate

Chemical formula

[0319] Intermediate 28 Step 1 Methyl(2S)-3-tert-butoxy-2-hydroxypropanoate [ka] 2-Methylpropan-2-ol (2.1 ml, 22 mmol), methyl(2S)-oxirane-2-carboxylate (2.1 ml, 24 mmol, [118712-39-3]), and magnesium perchlorate (1.37 g, 6.1 mmol, [10034-81-8]) were added together and stirred at 50°C for 48 hours. The mixture was treated with DCM and then washed with NH4Cl (saturated aqueous solution) and NaCl (saturated aqueous solution). The organic layer was dried over Na2SO4 and concentrated under reduced pressure to obtain the marked compound (2.70 g, 70% yield). Specific optical rotation: 10.5° (CHCl3, 20℃, 589nm). 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(s,9H),3.46(d,J=5.07 Hz,2H),3.62(s,3H),4.10(dt,J=6.27,4.97 Hz,1H),5.40(d,J=6.59 Hz,1H).

[0320] Step 2 Methyl(2S)-3-tert-butoxy-2-[(trifluoromethanesulfonyl)oxy]propanoate [ka] A solution of methyl(2S)-3-tert-butoxy-2-hydroxypropanoate (2.70 g, 15.3 mmol) in DCM (54 ml) was cooled to -60°C, and then 2,6-dimethylpyridine (2.1 ml, 18.4 mmol, [108-48-5]) was added, and N2 was passed through the reaction vessel. Trifluoromethanesulfonic anhydride (1 M, 16.1 mmol, [358-23-6] in DCM) was added dropwise to the mixture under N2, and the mixture was stirred at -60°C for 3 hours. The mixture was warmed to 0°C, then extracted with water and HCl (1 M, aqueous solution), the organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain 3.66 g of the marked compound (28 intermediates, 77% yield). 1 H NMR (DMSO-d6,400 MHz): δ(ppm)4.10(t,J=4.9 Hz,1H),3.62(s,3H),3.46(d,J=5.1 Hz,2H),1.09(s,9H).

[0321] Example 1 Step 1 Methyl 3-[2-(4-ethoxyphenyl)ethoxy]-2-[(methanesulfonyl)oxy]propanoate [ka] Methyl-3-[2-(4-ethoxyphenyl)ethoxy]-2-hydroxypropanoate (intermediate 1, 1.61 g, 6.02 mmol) and TEA (2.1 ml, 15 mmol; [121-44-8]) in THF (40 ml) were cooled to 0-5°C under N2. MsCl (700 μl, 9.0 mmol; [124-63-0]) was added dropwise, and the mixture was heated on RT and stirred overnight. The mixture was then dissolved in NaHCO₃⁻. 3( The compound was added to a 50% saturated aqueous solution, extracted with dimethyl glycol (three times), the organic phase was washed with NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the labeled compound (1.79 g, yield 86%). LC-MS (Method 1):R t =1.17 min;MS(ESIpos):m / z=364[M+H] + . 1H-NMR (400MHz, DMSO-d6): δ[ppm]=1.30(t,3H),2.71(t,2H),3.22(s,3H),3.52-3.67(m,2H),3.6 9(s,3H),3.75-3.87(m,2H),3.97(q,2H),5.31-5.33(m,1H),6.80-6.82(m,2H)7.09-7.12(m,2H).

[0322] Step 2 Methyl 3-[2-(4-ethoxyphenyl)ethoxy]-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] Tri-tert-butyl 2,2',2”-(1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate (6.52g, 12.7mmol, [122555-91-3]), methyl 3-[2-(4-ethoxyphenyl)ethoxy]-2-[(methanesulfonyl)oxy]propanoate (6.58g, 19.0mmol), K2CO 3( 2.63 g (19.0 mmol) and MeCN (44 ml) were added to the reaction vessel and heated overnight at 80°C. The mixture was filtered, the solid was washed with MeCN, and the combined organic phase was concentrated under reduced pressure to obtain the crude product (12.57 g). LC-MS (Method 2):R t =1.18 min;MS(ESIpos):m / z=765.5[M+H] + .

[0323] Step 3 2,2',2”-(10-{3-[2-(4-ethoxyphenyl)ethoxy]-1-methoxy-1-oxopropan-2-yl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid [ka] Crude product methyl 3-[2-(4-ethoxyphenyl)ethoxy]-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate (15.1 g, 19.7 mmol) and formic acid (320 ml) were heated at 50°C for 2 hours, and then the temperature was raised to 70°C for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product (17.3 g). Purification by RP chromatography (two injections of the crude mixture into 50% MeOH water, Biotage C18 120 g, A=water / 1% formic acid, B=MeOH / 1% formic acid, 0%B~50% at 15 CV) yielded a product containing approximately 1 equivalent of formic acid (3.38 g, yield 29%). LC-MS (Method 2):R t =0.68min;MS(ESIpos):m / z=597.3[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.30(t,3H)2.67-2.73(m,4H)2.80-3.14(m,14H)3.41-3.54(m,8H)3.57(s,3H)3.73-3.81(m,3H)3.97(q,2H)6.80(dd,2H)7.11(dd,2H).

[0324] Step 4 Gadolinium 2,2',2”-(10-{1-carboxy-2-[2-(4-ethoxyphenyl)ethoxy]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate [ka] 2,2',2”-(10-{3-[2-(4-ethoxyphenyl)ethoxy]-1-methoxy-1-oxopropan-2-yl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (990 mg, 1.66 mmol) and Gd2O3 (259 mg, 713 μmol) were added to a reaction vessel, water (16 ml) was added, and the mixture was heated at 100°C for 18 hours. The pH of the mixture was adjusted to 5 using NaOH (1 M, aqueous solution), 2 g Chelex 100 (trademark) (sodium type, wash) was added, and the mixture was stirred at RT for 2 hours. A xylenol-orange test was performed, showing that the mixture did not contain uncomplexed gadolinium. The mixture was filtered and then RP chromatography (Biotage, SNAP Ultra C18) was performed. Purification by 120g, 50ml / min, A=water, B=MeCN, 15C (5%B~50%B) yielded the marked compound (1.41g, containing water, yield 115%). LC-MS (Method 2):R t =0.71 min;MS(ESIpos):m / z=738[M+H] + . LC-MS (Method 3):R t =0.69min;MS(ESIpos):m / z=369.7[M+2H] ++ ,738.3[M+H] + ,747.3[2M+2H+H2O] ++ The observed isotopic pattern is consistent with that of a gadolinium complex.

[0325] Example 2 Step 1 tert-butyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(methanesulfonyl)oxy]propanoate [ka] tert-butyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate (intermediate 2, 9.68 g, 27.3 mmol) was added to THF (91 ml) under N2 conditions, followed by the addition of TEA (8.4 ml, 60 mmol; [121-44-8]), and the mixture was cooled to 0-5°C. MsCl (2.3 ml, 30 mmol; [124-63-0]) was added dropwise, and the reaction mixture was then heated to RT and stirred for 3 hours. The mixture was added to NaHCO3 (50% saturated aqueous solution), the aqueous layer was extracted with SiO3 (3 times), the combined organic phase was washed with NaCl (saturated aqueous solution, 2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the marked compound (11.7 g, 94% yield). LC-MS (Method 1):R t =1.26min;MS(ESIpos):m / z=450.4[M+NH4] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.16-7.22(m,J=8.6 Hz,2H),6.84-6.92(m,2H),5.11(dd,J=7.4,5.8 Hz,1H),4.00-4.09(m,2H),3.69-3.74(m,2H),3.55-3.59(m,2H),3.47-3.50(m,2H),3.42(q,J=7.0 Hz,2H),3.02(s,3H),2.98-3.11(m,2H),1.36(s,9H),1.09(t,J=7.0 Hz,3H).

[0326] Step 2 tert-butyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate [ka] Racemic tert-butyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(methanesulfonyl)oxy]propanoate (38.5 g, 88.9 mmol), 1,4,7,10-tetraazacyclododecane (18.4 g, 107 mmol), and MeCN (220 ml) were heated overnight at 70°C under N2. The mixture was filtered, and the crude product (45.2 g) was used without further purification. LC-MS (Method 2):R t =0.63min;MS(ESIpos):m / z=509.4[M+H] + .

[0327] Step 3 tert-butyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] 45.0 g, 88.5 mmol of tert-butyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate was dissolved in 450 ml of MeCN under N2 conditions. 77 ml, 440 mmol; [7087-68-5] was added, followed by the dropwise addition of 46 ml, 310 mmol of tert-butyl bromoacetate dissolved in 15 ml of MeCN. The mixture was stirred at 60°C for 5 hours. The mixture was concentrated under reduced pressure, and the residue was dissolved in ELISA and NaHCO3. 3( The compound was washed with a 50% saturated aqueous solution, followed by NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and the solvent was removed under reduced pressure to obtain the crude labeled compound (88.5 g). LC-MS (Method 2):R t =1.17min;MS(ESIpos):m / z=851.4[M+H] + .

[0328] Step 4 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid [ka] Crude racemic tert-butyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate (88.5 g, 83.2 mmol) was stirred with formic acid (530 ml, 14 mol; [64-18-6]) at 70°C for 4 hours. The mixture was concentrated under reduced pressure and purified using RP chromatography (compound divided into two batches, Biotage C18 Ultra 400g, 70ml / min, A=water, B=MeCN, 0%B to 50%B at 30 mins, 100%B at 10 mins) to obtain the marked compound (24.8g, 48% yield over 4 steps) and a further fraction of the low-purity product (8.4g, maximum yield 16%). LC-MS (Method 2):R t =0.59min;MS(ESIpos):m / z=627.3[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,3H)2.67-3.1(m,15H)3.35-3.61(m,12H)3.64-3.79(m,2H)3.92-4.12(m,2H)6.79-6.83(m,2H)7.14-7.25(m,2H). 13 C NMR(DMSO-d6,101 MHz):δ(ppm)172.3,171.5(br),169.9(br,2C),157.2,130.8(2C),130.6,114.4(2C),70.2,69.5,69.3,67.2,65 .9,65.3(br),55.4(br),55.2(br,2C),52.0(br,2C),51.7(br,2C),49.3(br,2C),47.1(br,2C),33.1(br),15.4.

[0329] Step 5 Gadolinium 2,2',2”-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate [ka] Racemic 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid (24.8 g, 39.5 mmol), water (310 ml), and Gd2O 3( 6.45 g, 17.8 mmol ([12064-62-9]) was heated and stirred at 105°C for 4 hours. Chelex100 (trademark) (sodium type, washed, 10 g) was added, and the pH was adjusted to 5 using NaOH (aqueous solution, 1 M), and stirring was continued until the solution was tested to be gadolinium-free. The mixture was filtered and then purified by RP chromatography (mixture divided into two, C18 Biotage 120 g, 40 ml / min, A=water, B=MeCN, 0%B to 50%B at 25 mins, 100%B at 10 mins), and the corresponding product fractions were then combined to obtain the marked compound (16.0 g, yield 52%) and a second fraction of the low-purity product fraction (11 g, purity 84%, yield 29%). LC-MS (Method 3):R t =0.59min;MS(ESIpos):m / z=391.7[M+2H] ++ ,782.4[M+H] + The observed isotopic pattern is consistent with that of a gadolinium complex.

[0330] Example 3 Step 1 tert-butyl(2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(methanesulfonyl)oxy]propanoate [ka] Intermediate 3, (2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate (9.20 g, 26.0 mmol) was dissolved in 2-methyltetrahydrofuran, and DIPEA (14 ml, 78 mmol; [7087-68-5]) was added. The mixture was cooled to 10°C, and MsCl (6.0 ml, 78 mmol) was added dropwise. The reaction mixture was heated in RT and stirred overnight. MTBE (400 ml) was added, and the reaction mixture was dissolved in water (5 × 200 ml) and saturated NaHCO₃⁻. 3( Extraction was performed with 2 × 200 ml of NaCl (saturated aqueous solution, 200 ml), and the mixture was dried over Na2SO4. Upon removal of the solvent under reduced pressure, 11.5 g (over 100%) of the labeled compound was obtained as an orange oil, which was used directly in the next step. LC-MS (Method 2):R t =1.30min;MS(ESIpos):m / z=450.5[M+NH4] + . 1 H NMR (CDCl3,400 MHz): δ(ppm)7.13-7.17(m,2H),6.84-6.88(m,2H),4.99(dd,J=8.4,4.6 Hz,1H),4.11(dd,J=5.8,5.1 Hz,2H),3.85(dd,J=5.4,4.2 Hz,2H),3.68-3.73(m,2H),3.60-3.63(m,2H),3.53(q,J=7.0 Hz,2H),3.17(dd,J=14.4,4.3 Hz,1H),3.05(dd,J=14.4,8.4 Hz,1H),2.83(s,3H),1.44(s,9H),1.21(t,J=7.1 Hz, 3H).

[0331] Step 2 tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate [ka] 1,4,7,10-Tetraazacyclododecane (5.50 g, 31.9 mmol, 1.2 equivalents) was dissolved in MeCN, and cesium carbonate (8.66 g, 26.6 mmol) was added. The mixture was heated to 50°C, and a solution of tert-butyl(2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(methanesulfonyl)oxy]propanoate (11.5 g, 26.6 mmol) in MeCN (10 ml) was added. The mixture was then heated overnight at 70°C. LCMS (Method 1):R t A reaction time of 0.76 mins (74% ELSD, m / z 509) indicated that the reaction was complete. The solid was filtered off, washed with MeCN, and the combined filtrate was concentrated under reduced pressure. 13.3 g of tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate was obtained as an orange oil, which was used directly in the next step. LC-MS (Method 2):R t =0.76 min;MS(ESIpos):m / z=509.6[M+H + ] + .

[0332] Step 3 tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate (13.3 g, 26.1 mmol) was dissolved in MeCN (220 ml) and placed under N2. K2CO2 3(11.9 g (86.3 mmol) was added, and the mixture was heated to 50°C. 11.7 ml (15.6 mmol) of tert-butyl bromoacetate was added, and the mixture was stirred overnight at 50°C. The solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in DCM (500 ml) and extracted with water (1 × 200 ml). The organic phase was dried and concentrated under reduced pressure to obtain the marked compound (24.1 g) as an orange-brown oil, which was used directly in the next step. LC-MS (Method 2):R t =1.35min;MS(ESIpos):m / z=852.3[M+H] + .

[0333] Step 4 (2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid [ka] 24.1 g, 28.3 mmol of tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate was dissolved in formic acid (160 ml) and stirred at 70°C for 4 hours and overnight at RT. LC-MS (Method 2):R tA reaction time of 0.58 min (82% ELSD) indicated that the reaction was complete. Formic acid was removed under reduced pressure, and the residue was suspended in toluene, which was then removed under reduced pressure. The toluene procedure was repeated three times, during which the residue became more solid and was obtained as foam. 22.2 g of the crude substance thus obtained was dissolved in water / MeCN 98 / 2 (1.2 g remained as residue, which was filtered off) and purified by RP chromatography in 5 × 20 ml increments (SNAP C18 120 g, 50 ml / min, 205 nm. A = water / 0.1% TFA, B = MeCN, 0%~28% B, 48% B~100% B 1 CV, 100% B 1.2 CV at 6.8 CV). The fraction of interest was pooled and freeze-dried to obtain 4.9 g of the labeled compound.

[0334] Another batch (9.0 g) of intermediate 3 was obtained through steps 1-4 in the same manner. The resulting substance (5.6 g) was identical and was combined with the 4.9 g obtained above. After drying (10 mbar), 9.5 g (30%, calculated from step 1) of (2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid was obtained. LC-MS (Method 2):R t =0.58 min;MS(ESIpos):m / z=627.7[M+H] + .

[0335] Step 5 Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate [ka] (2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid (9.10 g, 14.5 mmol) was dissolved in water (120 ml), and Gd2O3 (2.37 g, 6.53 mmol, 0.9 equivalents) was added. The pH was adjusted to 4 (formic acid), and the mixture was stirred at 100°C for 8 hours. Chelex100 (trademark) (sodium type, approximately 10 g) was added, and the mixture was stirred overnight at RT. Subsequently, the xylenol-orange test showed that no free gadolinium was present. The pH was adjusted to 8 (25% ammonium hydroxide), and the entire mixture was packed into an empty Biotage cartridge and subjected to RP chromatography (SNAP C18 400 g, 100 ml / min, 220 nm). A=water, B=MeCN, 0%B 5CV, 4.4CV (0%~15% B), 15%B 0.3CV, 0.3CV (15%~16% B), 16%B 1.3CV, 10.2CV (16%B~50% B) were directly applied. The target fraction was pooled, freeze-dried, and dried at 50°C to obtain 7.44g (63%) of the marked compound as a white, fluffy substance. od 3):R t =0.60min(100% DAD);MS(ESIpos):m / z=391[M+2H] ++ , 782[M+H] + and some [2M+2H] ++ ,791[2M+H2O+2H] ++ The observed isotopic pattern is consistent with that of a gadolinium complex.

[0336] Example 4 Step 1 tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(methylsulfonyl)oxy]propanoate [ka] tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate (intermediate 4, 650 mg, 1.83 mmol) and TEA (560 μl, 4.0 mmol; [121-44-8]) were stirred in THF (6.1 ml) under an N2 atmosphere. The mixture was cooled to 0-5°C, and MsCl (160 μl, 2.0 mmol; [124-63-0]) was added dropwise. The mixture was heated to RT and stirred for 3 hours, then added to a solution of NaHCO3 (50% saturated aqueous solution), the mixture was extracted with MTBE (3 times), the combined organic phase was washed with a solution of NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the marked compound (831 mg, 100% yield). LC-MS (Method 4):R t =1.29min;MS(ESIpos):m / z=450.4[M+NH4 + ] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,J=6.97 Hz,3H)1.36(s,9H)2.97-3.10(m,5H)3.42(q,J=6.84 Hz,2H)3.46-3.50(m,2H)3.54-3.61(m,2H)3.67-3.82(m,2H)4.00-4.15(m,2H)5.04-5.15(m,1H)6.84-6.93(m,2H)7.14-7.25(m,2H).

[0337] Step 2 tert-butyl(2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate [ka] tert-butyl(2S)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(methanesulfonyl)oxy]propanoate (830 mg, 1.92 mmol) and 1,4,7,10-tetraazacyclododecane (397 mg, 2.31 mmol) were stirred overnight at 55°C in MeCN (17 ml). The temperature was then increased to 70°C and the reaction mixture was stirred for a further 18 hours. The mixture was then concentrated under reduced pressure to obtain the crude product (977 mg, 80% product by ELSD). LC-MS (Method 2):R t =0.66min;MS(ESIpos):m / z=509.2[M+H] + .

[0338] Step 3 tert-butyl(2R) * )-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] The crude product, (2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate (977 mg, 1.92 mmol), was stirred in MeCN (20 ml) under N2. DIPEA (1.7 ml, 9.6 mmol; [7087-68-5]) was added, followed by the dropwise addition of tert-butylbromoacetate (990 μl, 6.7 mmol) dissolved in MeCN (0.33 ml), and the mixture was heated at 60°C for 5 hours. The mixture was then concentrated under reduced pressure, the residue was dissolved in SiO2, washed with a solution of NaHCO3 (50% saturated aqueous solution), followed by washing with NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and the mixture was concentrated under reduced pressure to obtain the crude product (2.19 g). LC-MS (Method 2):R t =1.15min;MS(ESIpos):m / z=851.4[M+H] + .

[0339] Step 4 (2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid [ka] The crude product tert-butyl(2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate (2.19 g, 2.57 mmol) was heated with formic acid (33 ml) at 70°C for 4 hours. The mixture was then concentrated under reduced pressure and purified by RP chromatography (Biotage C18 60 g, 50 ml / min, A=water, B=MeCN, 0%B to 50%B at 30 min, 100%B at 10 min) to obtain the marked compound (286 mg, 18% yield over 4 steps). Specific optical rotation: 5.6° (MeOH, 20℃, 589nm). LC-MS (Method 2):R t =0.58min;MS(ESIpos):m / z=627.1[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.20(d,J=8.6 Hz,2H),6.82(d,J=8.6 Hz,2H),4.01-4.06(m,2H),3.69-3.73(m,2H),3.36-3.61(m,14H),2.63-3.10(m,17H),1.09(t,J=7.0 Hz,3H). 13C NMR(DMSO-d6,101 MHz):δ(ppm)171.8,170.9,169.4(br,2C),156.6,130.2(2C),130.1,113.8(2C),69.7,69.0,68.7,66.7,65.3 ,64.8(br),54.9(br),54.7(br,2C),51.4(br,2C),51.1(br,2C),48.8(br,2C),46.5(br,2C),32.5(br),14.9.

[0340] Step 5 Gadolinium 2,2',2”-{10-[(1R)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate [ka] (2R)-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid (286 mg, 456 μmol), Gd2O 3( 74.4 mg (205 μmol) and water (4.7 ml) were stirred overnight in a sealed vial at 105°C. The mixture was then heated to 120°C for a further 5 hours. Chelex100 (trademark) (approximately 5 g, sodium type, washed) was added, and the pH was adjusted to 5 using NaOH (1 M, aqueous solution). The mixture was stirred for 1 hour. The mixture was filtered, concentrated to dryness, and then purified by RP chromatography (Biotage C18 30 g, 25 ml / min, A=water, B=MeCN, 0%B to 50%B at 25 mins, 100%B at 10 mins) to obtain the marked compound (267 mg, yield 75%). Specific optical rotation: -14.1° (c=1, MeOH, 20℃, 589nm). LC-MS (Method 2):R t =0.66min;MS(ESIpos):m / z=782.3[M+H + ] + . LC-MS (Method 3):Rt =0.62min;MS(ESIpos):m / z=391.7[M+2H + ] +2 ,782.3[M+H + ] + ,790[2M+2H] + [+H2O] ++ .

[0341] Example 5 Step 1 Ethyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(methanesulfonyl)oxy]propanoate [ka] Ethyl-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypropanoate (intermediate 5, 2.44 g, 7.48 mmol) and TEA (2.3 ml, 16 mmol; [121-44-8]) were stirred in THF (25 ml) under N2 at 0-5°C. MsCl (640 μl, 8.2 mmol; [124-63-0]) was added dropwise to the mixture and stirring was continued for 3 hours. The mixture was then added to a solution of NaHCO3 (50% saturated aqueous solution), the aqueous layer was extracted with MTBE (3 times), the combined organic layers were washed with a solution of NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the marked compound (2.82 g, 93% yield). LC-MS (Method 4):R t =1.14 min;MS(ESIpos):m / z=422.3[M+NH4 + ] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,3H)1.16(t,3H)3.00-3.14(m,5H)3.38-3.51(m,4H)3.54-3.59(m,2H)3.69-3 .75(m,2H)4.05(dd,2H)4.13(q,2H)5.26(dd,1H)6.84-6.91(m,2H)7.12-7.21(m,2H).

[0342] Step 2 Ethyl-2-[4,10-bis(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanoate [ka] Di-tert-butyl 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetate (1.86g, 4.65mmol, [162148-48-3]), K2CO 3( 0.71 g, 5.1 mmol) of racemic 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(methanesulfonyl)oxy]propanoate (1.88 g, 4.65 mmol) and MeCN (22 ml) were stirred at 70°C for 3 days. The mixture was filtered, the solid was washed with MeCN, the filtrates were combined and concentrated under reduced pressure to obtain the crude product (3.30 g).

[0343] Step 3 Methyl-2-[(methanesulfonyl)oxy]propanoate [ka] Methyl-2-hydroxypropanoate (5.00 g, 48.0 mmol), TEA (15 ml, 110 mmol; [121-44-8]), and THF (50 ml) were stirred at 0-5°C. Under an N2 atmosphere, MsCl (4.1 ml, 53 mmol; [124-63-0]) was added dropwise, and the mixture was then brought to RT and stirred for 3 hours. The mixture was then added to a solution of NaHCO3 (50% saturated aqueous solution), extracted with MTBE (3 times), washed with NaCl (saturated aqueous solution 2 times), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the labeled compound (7.17 g, yield 82%). 1 H NMR (DMSO-d6,400 MHz): δ(ppm)5.21(q,J=6.9 Hz,1H),3.72(s,3H),3.25(s,3H),1.48(d,J=7.1 Hz,3H).

[0344] Step 4 Ethyl-2-{4,10-bis(2-tert-butoxy-2-oxoethyl)-7-[1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanoate [ka] Racemic ethyl-2-[4,10-bis(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanoate, Step 2 (1.10g, 1.55 mmol), Methyl-2-[(methanesulfonyl)oxy]propanoate (339mg, 1.86 mmol), K2CO2 in MeCN (2.8 ml) 3( 472 mg (3.41 mmol) was stirred together at 55°C overnight. The temperature was then raised to 80°C for a further 6 hours. The mixture was then filtered, the solid was washed with EtOH, the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain the crude product as a mixture of diastereomers (1.14 g). LC-MS (Method 2):R t =1.11~1.17 min;MS(ESIpos):m / z=795.9[M+H + ] + .

[0345] Step 5 2,2'-{4-[1-ethoxy-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-1-oxopropan-2-yl]-10-[1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}diacetic acid [ka] Ethyl-2-{4,10-bis(2-tert-butoxy-2-oxoethyl)-7-[1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanoate (1.14 g, 1.44 mmol) and formic acid (15 ml, 400 mmol; [64-18-6]) were stirred at 60°C overnight, followed by 6 hours at 70°C. The mixture was concentrated under reduced pressure. Purification by RP chromatography (Biotage C18 Ultra 60g, 50ml / min, A=water / 0.5% formic acid; B=EtOH / +0.5% formic acid; 5%B 1CV, 5%B~40 B 15CV) yielded the marked compound as a mixture of diastereomers (250mg, purity 95%, yield 24%). LC-MS (Method 2):R t =0.72min;MS(ESIpos):m / z=683.7[M+H + ] + . 1 H NMR(DMSO-d6,400 MHz):δ(ppm)7.12-7.27(m,2H),6.76-6.86(m,2H),3.91-4.08(m,4H),3.39-3.82(m,16H),2.55-3.27(m,18H),0.99-1.28(m,9H).

[0346] Step 6 Gadolinium 2-[7-(1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl)-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] 2,2'-{4-[1-ethoxy-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-1-oxopropan-2-yl]-10-[1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}diacetic acid (250 mg, 366 μmol), Gd2O in 5 ml of water. 3(59.7 mg (165 μmol) was stirred in a crimped-seal reaction vessel at 105°C for 18 hours, and then the temperature was increased to 120°C for a further 18 hours. The mixture was treated with Chelex100™ (sodium type, washed, approximately 5 g), stirred for 1 hour, then filtered, concentrated under reduced pressure, and purified by RP chromatography (Biotage SNAP Ultra C18 30 g, 25 ml / min, A=water, B=MeCN, 0%B to 50% at 25 mins, 100%B at 10 mins) to obtain two diastereomers: diastereomer 1 (40 mg, yield 13%) and diastereomer 2 (130 mg, yield 42%). Diastereomer 1: LC-MS (Method 3):R t =0.61 min;MS(ESIpos):m / z=398.6[M+2H] ++ ,796.4[M+H + ] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0347] Example 6 Gadolinium 2-[7-(1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl)-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] 2-130 mg of the diastereomer from Example 5 (95% purity). LC-MS (Method 3):R t =0.63min;MS(ESIpos):m / z=398.7[M+2H] ++ ,796.4[M+H + ] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0348] Example 7 Step 1 Ethyl-3-[4-(2-ethoxyethoxy)phenyl]-2-[(methanesulfonyl)oxy]propanoate [ka] Ethyl-3-[4-(2-ethoxyethoxy)phenyl]-2-hydroxypropanoate (5.39 g, 19.1 mmol, intermediate 6) and TEA (5.9 ml, 42 mmol; [121-44-8]) were stirred in THF (56 ml) under N2 at 0-5°C. MsCl (1.6 ml, 21 mmol; [124-63-0]) was added dropwise to the mixture and stirring was continued for 3 hours. The mixture was then added to a solution of NaHCO3 (50% saturated aqueous solution), the aqueous layer was extracted with MTBE (3 times), the combined organic layers were washed with a solution of NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the marked compound (6.96 g, purity 90%, yield 91%). LC-MS (Method 4):R t =1.15min;MS(ESIpos):m / z=378.3[M+NH4 + ] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09-1.18(m,6H)3.02(s,3H)3.04-3.10(m,2H)3.49(q,2H)3.64-3.70(m,2H)4 .02-4.07(m,2H)4.13(q,2H)5.26(dd,1H)6.85-6.90(m,2H)7.14-7.19(m,2H).

[0349] Step 2 Ethyl-2-[4,10-bis(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-[4-(2-ethoxyethoxy)phenyl]propanoate [ka] Di-tert-butyl 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl) diacetate (0.51g, 11.2mmol, [162148-48-3]), racemiethyl-3-[4-(2-ethoxyethoxy)phenyl]-2-[(methanesulfonyl)oxy]propanoate (4.46g, 12.4mmol) and K2CO2 in MeCN (31ml) 3( 3.42 g (24.8 mmol) was stirred at 80°C for 24 hours. The mixture was filtered, the solid was washed with EtOH, the organic phase was combined, and the mixture was concentrated under reduced pressure to obtain the crude labeled compound (8.40 g, 57% product as detected by ELSD). LC-MS (Method 2):R t =1.26min;MS(ESIpos):m / z=665.8[M+H + ] + .

[0350] Step 3 Ethyl-2-[(methanesulfonyl)oxy]butanoate [ka] Ethyl-2-hydroxybutanoate (5.00 g, 37.8 mmol; [52089-54-0]) and TEA (12 ml, 83 mmol; [121-44-8]) were stirred in THF (110 ml) under N2 at 0-5°C. MsCl (3.2 ml, 42 mmol; [124-63-0]) was added dropwise to the mixture and stirring was continued for 3 hours. The mixture was then added to a solution of NaHCO3 (50% saturated aqueous solution), the aqueous layer was extracted with MTBE (3 times), the combined organic layers were washed with NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the labeled compound (8.21 g, yield 103%). 1 H NMR(400 MHz,DMSO-d6)δ ppm 0.93(t,3H)1.22(t,3H)1.71-1.95(m,2H)3.25(s,3H)4.19(dtt,2H)5.05(dd,1H).

[0351] Step 4 Ethyl-2-[4,10-bis(2-tert-butoxy-2-oxoethyl)-7-{(2SR)-1-ethoxy-3-[4-(2-ethoxyethoxy)phenyl]-1-oxopropan-2-yl}-1,4,7,10-tetraazacyclododecane-1-yl]butanoate [ka] Ethyl-2-[4,10-bis(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-[4-(2-ethoxyethoxy)phenyl]propanoate, Step 2 (4.20 g, 6.32 mmol), ethyl-2-[(methanesulfonyl)oxy]butanoate (2.12 g, 10.1 mmol), and K2CO3 (1.75 g, 12.6 mmol) were stirred at 80°C for 24 hours. The mixture was then filtered, the solid was washed with EtOH, the organic phases were combined, and the mixture was concentrated under reduced pressure to obtain the crude labeled compound (6.50 g). LC-MS (Method 2):R t =1.28min;MS(ESIpos):m / z=779.9[M+H] + .

[0352] Step 5 2,2'-(4-{1-ethoxy-3-[4-(2-ethoxyethoxy)phenyl]-1-oxopropan-2-yl}-10-[(2SR)-1-ethoxy-1-oxobutan-2-yl]-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid [ka] Ethyl-2-[4,10-bis(2-tert-butoxy-2-oxoethyl)-7-{1-ethoxy-3-[4-(2-ethoxyethoxy)phenyl]-1-oxopropan-2-yl}-1,4,7,10-tetraazacyclododecane-1-yl]butanoate (6.50 g, 8.34 mmol) and formic acid (110 ml) were stirred together at 70°C overnight. The mixture was concentrated under reduced pressure and the marked compound was obtained as a mixture of diastereomers (1.21 g, purity 95%, yield 22% over 5 steps) by RP chromatography (Biotage SNAP Ultra C18 120 g, 50 ml / min, A=water, B=MeCN, 0%B to 50%B at 30 min, 100%B at 10 min). LC-MS (Method 2):R t =0.76min;MS(ESIpos):m / z=665.7[M+H] + . 1 H NMR (DMSO-d6,600 MHz): δ(ppm)7.17-7.24(m,2H),6.82(d,J=7.8 Hz,2H),4.07-4.13(m,2H),3.94-4.04(m,4H),3.74(dd,J=9.4,6.4 Hz,0.6H),3.66(t,J=4.7 Hz,2H),3.63(br dd,J=9.0,6.4 Hz,0.5H),3.48(q,J=6.9 Hz,2H),3.31-3.41(m,4H),2.58-3.28(m,19H),1.64-1.78(m,1H),1.53 -1.63(m,1H),1.18-1.23(m,3H),1.03-1.13(m,6H),0.81-0.89(m,3H). 13C NMR(DMSO-d6,151 MHz):δ(ppm)171.5 / 171.4,170.7 / 170.7,167.9 / 168.7(br.2C),156.7,130.3 / 13 0.2(2C),129.4 / 129.5,113.8 / 113.8(2C),68.1,66.7,65.4,65.3 / 65.2,64.1(br) ,59.7 / 59.7,59.6 / 59.7,55.3 / 54.4(2C),52.4 / 52.7(2C),52.0(br,2C),45.9 / 45 .7(2C),45.5(br,2C),33.5 / 33.3,21.5 / 21.3,14.8,14.0,13.9,13.8,10.7 / 10.7.

[0353] Step 6 Gadolinium 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoate [ka] 2,2'-(4-{1-ethoxy-3-[4-(2-ethoxyethoxy)phenyl]-1-oxopropan-2-yl}-10-[1-ethoxy-1-oxobutan-2-yl]-1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetic acid (1.21g, 1.81mmol), Gd2O 3( 296 mg (817 μmol) and water were stirred together and heated in a crimped sealed container at 105°C for 24 hours, then the mixture was heated further at 120°C for 6 hours. The mixture was treated with Chelex100™ (sodium type, washed, approximately 5 g), stirred for 1 hour, then filtered, concentrated under reduced pressure, and purified by RP chromatography (Biotage SNAP Ultra C18 60 g, 50 ml / min, A=water, B=MeCN, 0%B to 50%B at 25 mins, 100%B at 10 mins) to obtain the marked compound as a diastereomer mixture. Fraction 1 (Example 7, 575 mg, yield 41%) and Fraction 2 (74 mg, yield 5%). Fraction 1 LC-MS (Method 3):Rt =0.58 min (24% DAD) and 0.63 min (74% DAD); MS (ESIpos): m / z = 383.7 [M + 2H] ++ ,766.4[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0354] Example 8 Gadolinium 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoate [ka] Fraction 2 - Step 6 Example 7 LC-MS (Method 3):R t =0.63min(100%DAD);MS(ESIpos):m / z=383.7[M+2H] ++ ,766.4[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0355] Example 9 Step 1 Methyl(2R)-2-hydroxyhexa-5-enoate [ka] A mixture of copper(I) bromide and dimethyl sulfide (16.8 g, 81.8 mmol; CAS registry number: [54678-23-8]) in THF (80 mL) was cooled to -70°C, and while maintaining the temperature between -70°C and -60°C, magnesium chloride (propa-2-en-1-yl) (150 mmol, 74 mL of 2.0 M solution in THF; CAS registry number: [2622-05-1]) was added dropwise. After stirring at -70°C for another 30 minutes, a solution of methyl(2R)-oxirane-2-carboxylate (16.7 g, 164 mmol; CAS registry number: [111058-32-3]) in THF (70 mL) was added dropwise, and stirring at -70°C was continued for 30 minutes. The reaction mixture was gradually heated to RT and quenched with NH4Cl (saturated aqueous solution). The reaction mixture was extracted with toluene, the organic layer was washed twice with water, and dried over Na2SO4. The mixture was filtered and carefully concentrated under reduced pressure (for volatile substances) to obtain the labeled compound (22.3 g, 100%). LC-MS (Method 3):R t =0.61 min;MS(ESIpos):m / z=145.1[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 2.05-2.11(m,2H),2.85(dd,1H),2.96(dd,1H),3.69(s,3H),4.01-4.07(m,1H),4.94-5.05(m,2H),5.41(d,1H),5.75-5.85(m,1H).

[0356] Step 2 Methyl(2R)-2-[(4-nitrobenzene-1-sulfonyl)oxy]hexa-5-enoate [ka] A solution of crude methyl(2R)-2-hydroxyhexa-5-enoate (16.3 g, 113 mmol) in anhydrous toluene (210 mL) was cooled to 0°C and treated with 4-nitrobenzene-1-sulfonyl chloride (27.6 g, 125 mmol) and TEA (32 mL, 227 mmol; [121-44-8]). The reaction mixture was heated in RT and stirred overnight. The mixture was concentrated under reduced pressure, the residue was dissolved with siRNA, the formed precipitate was filtered off (discarded), and washed with siRNA. The filtrate was washed with water, and the aqueous layer was extracted with siRNA. The combined organic layers were washed with saturated NaCl, dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude material was purified by Biotage Isolera™ chromatography (SNAP Si 340 g, eluted with hexane-siRNA 0:1~7:3) to obtain the marked compound (7.2 g, 18%). LC-MS (Method 3):R t =1.17min;MS(ESIpos):m / z=330.0[M+H] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.84-1.92(m,2H),1.95-2.02(m,2H),3.61(s,3H),4.89-4.96(m,2H), 5.11(t,1H),5.64-5.74(m,1H),8.20-8.24(m,2H),8.45-8.49(m,2H).

[0357] Step 3 Methyl(2S)-2-(1,4,7,10-tetraazacyclododecane-1-yl)hexa-5-enoate [ka] A solution of 1,4,7,10-tetraazacyclododecane (3.45 g, 20.0 mmol) in MeCN (25 mL) was mixed with RT, and a solution of methyl(2R)-2-[(4-nitrobenzene-1-sulfonyl)oxy]hexa-5-enoate (3.3 g, 10 mmol) in MeCN (15 mL) and K2CO2 were mixed. 3(The mixture was treated with 1.38 g (10.0 mmol). The reaction mixture was stirred at 60°C for 7 hours, then overnight in RT. The solid was filtered off, washed with MeCN, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved with dimethyl, washed with NaOH (0.1 M aqueous solution) and NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude labeled compound (2.6 g, 39%). Specific rotation: [α] D 20 =-46.6°+ / -0.24°(c=1, CHCl3). LC-MS (Method 3):R t =0.19min;MS(ESIpos):m / z=299.1[M+H] + ,150.1[M+2H] 2+ . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.57-1.75(m,2H),2.01-2.22(m,2H),2.26-2.35(m,5H),2.41-2.44(m,3H),2.54-2.57(m,2H),2.60- 2.65(m,4H),2.73-2.78(m,2H),3.35-3.37(m,1H),3.61(s,3H),4.96-5.07(m,2H),5.74-5.84(m,1H).

[0358] Step 4 Benzyl(2R)-3-(benzyloxy)-2-hydroxypropanoate [ka] A solution of (2R)-3-(benzyloxy)-2-hydroxypropanoic acid (2.00 g, 10.2 mmol; [130111-08-9]) in phenylmethanol (1.3 mL, 12 mmol; [100-51-6]) is converted to H2SO4 by RT. 4( After treating with 54 μL of concentrated solution (1.0 mmol), the mixture was heated to 50°C and stirred overnight. The reaction mixture was cooled to RT and diluted with DCM. The organic layer was NaHCO3 3(The crude product was washed with a saturated aqueous solution, concentrated under reduced pressure, and subjected to Biotage Isolera™ chromatography (elution with SNAP Si 100g, DCM-hexane 7:3, followed by DCM-MeOH 8:2) to obtain the marked compound (1.75g, 57%). Specific rotation: [α] D 20 =21.4°+ / -0.58°(c=1, CHCl3). LC-MS (Method 3):R t =1.10min;MS(ESIpos):m / z=304.1[M+H2O] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 3.65(dq,2H),4.30-4.33(m,1H),4.46(d,1H),4.52(d,1H),5.13(d,1H),5.17(d,1H),5.66(d,1H),7.26-7.35(m,10H).

[0359] Step 5 Benzyl(2R)-3-(benzyloxy)-2-[(trifluoromethanesulfonyl)oxy]propanoate [ka] A solution of benzyl(2R)-3-(benzyloxy)-2-hydroxypropanoate (870 mg, 3.04 mmol) in DCM (10 mL) was cooled to -70°C, and 2,6-dimethylpyridine (150 mmol, 410 μL; [108-48-5]) was added dropwise, followed by trifluoromethanesulfonic anhydride (570 μL, 3.3 mmol; [358-23-6]). The mixture was stirred at -70°C for 2 hours, then heated to -40°C and stirred for 2 hours, and finally heated to -20°C and stirred for 1 hour. The reaction mixture was diluted with MTBE at 0°C, the formed precipitate was filtered off (discarded), and the mixture was washed with MTBE. The filtrate was washed with water and 0.1 M aqueous HCl solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude labeled compound (1.3 g) was used in the next step without further purification. LC-MS (Method 3):Rt =1.46min;MS(ESIpos):m / z=436.2[M+H2O] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 3.95(dq,2H),4.46(d,1H),4.59(d,1H),5.27(d,1H),5.34(d,1H),5.55-5.57(m,1H),7.22-7.25(m,2H),7.31-7.39(m,8H). 19 F NMR(377 MHz,DMSO-d6)δ[ppm]:-78.12(s,3F).

[0360] Step 6 Methyl(2S)-2-{4,7,10-tris[(2S)-1,3-bis(benzyloxy)-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}hexa-5-enoate [ka] A suspension of 1-methyl(2S)-2-(1,4,7,10-tetraazacyclododecane-1-yl)hexa-5-enoate, Step 3 (206 mg, 690 μmol), in MeCN (5 mL) was treated with DIPEA (600 μL, 3.5 mmol; [7087-68-5]) at RT, and then treated dropwise with a solution of crude benzyl(2R)-3-(benzyloxy)-2-[(trifluoromethanesulfonyl)oxy]propanoate (1.3 g, 3.1 mmol) in MeCN (25 mL). The reaction mixture was stirred overnight at 70°C, cooled to RT, and diluted with water. The mixture was extracted with DCM (twice), and the combined organic layer was Na2CO2. 3( The compound was washed with a saturated aqueous solution, filtered through a hydrophobic filter, and concentrated under reduced pressure to obtain the crude labeled compound (1.08 g), which was used in the next step without further purification. LC-MS (Method 3):R t =1.40 / 1.46 min;MS(ESIpos):m / z=1103.8[M+H] + ,552.4[M+2H] 2+ .

[0361] Step 7 Methyl(2S,5E)-6-(4-butoxyphenyl)-2-{4,7,10-tris[(2S)-1,3-bis(benzyloxy)-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}hexa-5-enoate [ka] A mixture of crude methyl(2S)-2-{4,7,10-tris[(2S)-1,3-bis(benzyloxy)-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}hexa-5-enoate (1.00 g, 906 μmol) and 1-bromo-4-butoxybenzene (170 μL, 1.0 mmol; [39969-57-8]) in MeCN (90 mL) was degassed under reduced pressure and placed under argon. TEA (2.5 mL, 18 mol; [121-44-8]), tri-o-tolylphosphine (99 mg, 330 μmol; [6163-58-2]), and palladium(II) acetate (24 mg, 110 μmol; [3375-31-3]) were added, the mixture was degassed under reduced pressure, and the mixture was again placed under argon. The reaction mixture was stirred overnight at 80°C, then an additional amount of 1-bromo-4-butoxybenzene (77 μL, 0.45 mmol) and palladium(II) acetate (24 mg, 110 μmol) were added, and stirring was continued for a further 24 hours. The mixture was cooled to RT, filtered through Celite®, and the filtrate was washed with MeCN. The filtrate was concentrated under reduced pressure, the residue was dissolved in DCM, and washed with water. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude material was subjected to Biotage Isolera™ chromatography (SNAP Si-100g, DCM-hexane 1:1, followed by elution with DCM-MeOH 85:15) to obtain the marked compound (866 mg, 46%). LC-MS (Method 3):R t =1.57min;MS(ESIpos):m / z=626.5[M+2H] 2+ .

[0362] Step 8 (2S,2'S,2”S)-2,2',2”-{10-[(2S)-6-(4-butoxyphenyl)-1-methoxy-1-oxohexane-2-yl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoic acid) [ka] Methyl(2S,5E)-6-(4-butoxyphenyl)-2-{4,7,10-tris[(2S)-1,3-bis(benzyloxy)-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}hexa-5-enoate (850 mg, 679 μmol) was placed in a steel autoclave under an argon atmosphere and dissolved in a 3:1 mixture of MeOH and THF (28 mL). Pd charcoal (180 mg, 10% purity, 170 μmol, 0.25 equivalents; [7440-05-3]) was added, and the reaction mixture was heated at 80°C for 30 hours under an H2 pressure of 40 bar to obtain a maximum pressure of 42 bar. Since the conversion was not complete, an additional amount of Pd charcoal (180 mg, 10% purity, 170 μmol, 0.25 equivalents) was added, and the mixture was heated for a further 40 hours at 80°C under an H2 pressure of 40 bar. The autoclave was cooled to RT, the pressure was released, and the reaction mixture was filtered. The filtrate cake was washed with MeOH (20 mL) and THF (20 mL), and the filtrate was concentrated under reduced pressure to obtain the crude labeled compound (672 mg), which was used in the next step without further purification. LC-MS (Method 3):R t =0.92min;MS(ESIpos):):m / z=713.6[M+H] + ,357.3[M+2H] 2+ .

[0363] Step 9 (2S)-6-(4-butoxyphenyl)-2-{4,7,10-tris[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}hexanoic acid [ka] A solution of crude (2S,2'S,2”S)-2,2',2”-{10-[(2S)-6-(4-butoxyphenyl)-1-methoxy-1-oxohexane-2-yl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoic acid) (670 mg, 940 μmol) in THF (3 mL) was treated overnight with NaOH (5.0 equivalents, 2.4 mL, 4.7 mmol, 2 M aqueous solution) under RT. The reaction mixture was adjusted to pH 7 by adding HCl (2 M aqueous solution) and concentrated under reduced pressure. The resulting aqueous layer was washed twice with DCM, concentrated to a volume of 4 mL, and subjected to Biotage Isolera™ chromatography (SNAP Si-C18-60 g, eluted with water-MeCN 1:0 to 0:1) to obtain the indicated compound (7.3 mg). LC-MS (Method 3):R t =0.87min;MS(ESIpos):m / z=699.5[M+H] + ,350.4[M+2H] 2+ .

[0364] Step 10 Gadolinium(2S,2'S,2”S)-2,2',2”-{10-[(1S)-5-(4-butoxyphenyl)-1-carboxypentyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate) [ka] (2S)-6-(4-butoxyphenyl)-2-{4,7,10-tris[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}hexanoic acid (7.3 mg, 10 μmol) in water (1 mL) is dissolved in Gd2O 3(The mixture was treated with 0.49 equivalents, 1.9 mg, 5.1 μmol ([12064-62-9]) and stirred at 105°C for 44 hours. The reaction mixture was cooled to RT and treated with excess Chelex100™ (sodium type, washed) chelate resin (pH adjusted from 9 to 5 by adding formic acid). The resin was filtered off, and the filtrate was freeze-dried to obtain the marked compound (5.1 mg, 52%). LC-MS (Method 3):R t =0.96~0.99min;MS(ESIpos):m / z=854.4[M+H] + ,427.7[M+2H] 2+ .

[0365] Example 10 Step 1 Ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[(methanesulfonyl)oxy]propanoate [ka] Racemic ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-hydroxypropanoate (intermediate 7, 2.34 g, 6.32 mmol) and TEA (1.9 ml, 14 mmol; [121-44-8]) were stirred in THF (21 ml) under N2 at 0-5°C. MsCl (540 μl, 6.9 mmol; [124-63-0]) was added dropwise to the mixture and stirring was continued for 3 hours. The mixture was then added to a solution of NaHCO3 (50% saturated aqueous solution), the aqueous layer was extracted with MTBE (3 times), the combined organic layers were washed with a solution of NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude labeled compound (2.97 g, 99% yield). LC-MS (Method 4):R t =1.17min;MS(ESIpos):m / z=466.2[M+H] + . 1H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,3H)1.36(s,9H)3.00-3.08(m,4H)3.38-3.48(m,2H)3.44-3.47(m,2H)3.49-3.55(m,4H)3.56- 3.59(m,2H)3.69-3.77(m,2H)4.03-4.08(m,2H)5.05-5.16(m,1H)6.84-6.94(m,2H)7.14-7.25(m,2H).

[0366] Step 2 Ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate [ka] 1,4,7,10-Tetraazacyclododecane (384 mg, 2.23 mmol), Racemicethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[(methanesulfonyl)oxy]propanoate (1.00 g, 2.23 mmol), K2CO 3( 308 mg (2.2 mmol) and MeCN (6.2 ml) were stirred under N2 at 55°C for 24 hours. The mixture was filtered, the filter cake was washed with EtOH, and the organic filtrates were combined and concentrated under reduced pressure to obtain the crude labeled compound as a racemic mixture (1.46 g, 61% product by ELSD). LC-MS (Method 2):R t =0.55min;MS(ESIpos):m / z=525.3[M+H] + .

[0367] Step 3 Ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] Dissolve racemic ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate (1.40 g, 2.67 mmol) in MeCN (13 ml) and K2CO2 3( 3.13 g, 22.7 mmol; [584-08-7]) was added. Under an N2 atmosphere, tert-butylbromoacetate (1.4 ml, 9.3 mmol, [5292-43-3]) in MeCN (3.8 ml) was added dropwise, and the mixture was stirred overnight at RT. The mixture was filtered, the filter cake was washed with EtOH, and the combined organic phase was concentrated under reduced pressure to obtain the crude labeled compound (2.40 g, yield 104%). LC-MS (Method 2):R t =1.13min;MS(ESIpos):m / z=867[M+H] + .

[0368] Step 4 2,2',2”-{10-[1-ethoxy-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetic acid [ka] Racemic ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate (2.30 g, 2.65 mmol) was stirred overnight at 50°C in formic acid (15 ml, 400 mmol; [64-18-6]). The solvent was removed under reduced pressure, and the marked compound was purified by RP chromatography (Biotage SNAP Ultra C18 60 g, A=water, B=MeCN, 0%B~100%B at 12 CV, 50 ml / min) to obtain a racemic mixture (614 mg, 33% yield over 4 steps). LC-MS (Method 2):R t =0.67min;MS(ESIpos):m / z=700[M+H]+ . 1 H NMR(D2O,400 MHz):δ(ppm)7.31(br d,J=8.4 Hz,2H),6.95(d,J=8.4 Hz,2H),4.26(br dd,J=10.0,4.7 Hz,1H),4.15-4.22(m,2H),3.91-4.10(m,4H),3.81-3.89(m,4H),3.52-3.75(m,13H),2.74-3.51(m,17H),1.15(t,J=7.1 Hz,3H),1.03(t,J=7.1 Hz,3H). 13 C NMR(D2O,101 MHz):δ(ppm)174.7,173.0,170.1,169.5,156.9,130.8(2C),129.8,115.0(2C),69.8,69.7,69.6,69.1,69.0,67.3 ,66.7,62.0(2C),56.8,56.4,52.9,52.5,51.1(2C),49.9,49.0(br),46.7(br),45.8,44.2,34.2(br),14.1,13.4.

[0369] Step 5 Gadolinium 2,2',2”-{10-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate [ka] Racemic 2,2',2”-{10-[1-ethoxy-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetic acid (600 mg, 859 μmol), Gd2O3 (140 mg, 386 μmol), and water (8.8 ml) were stirred at 120°C for 24 hours. Chelex100 (trademark) was added (sodium type, washed, approximately 5 g), and the pH was adjusted to 5 using NaOH (1 M, aqueous solution), and the mixture was stirred for 1 hour. Filtration and RP C18 chromatography (Biotage SNAP Ultra C18 60 g, 50 ml / min, A=water, B=MeCN, 0%B~50%B, 100%B) were performed in 25 minutes. Purification using (10 minutes) yielded the racemic labeled compound (607 mg, purity 95%, yield 81%). LC-MS (Method 3):R t =0.62min;MS(ESIpos):m / z=413.6[M+2H] ++ ,826.3[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0370] Example 11 Step 1 tert-butyl(2R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[(methylsulfonyl)oxy]propanoate [ka] tert-butyl(2R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-hydroxypropanoate (intermediate 8, 811 mg, 2.04 mmol) and TEA (620 μl, 4.5 mmol; [121-44-8]) were stirred in THF (6.8 ml) under an N2 atmosphere at 0-5°C. MsCl (170 μl, 2.2 mmol; [124-63-0]) was added dropwise to the mixture, and stirring was continued for 3 hours. The mixture was then added to a solution of NaHCO3 (50% saturated aqueous solution), the aqueous layer was extracted with MTBE (3 times), the combined organic layer was washed with a solution of NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude labeled compound (1.02 g, purity 95%, yield 100%). LC-MS (Method 4):R t =1.27min;MS(ESIpos):m / z=494.2[M+NH4] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 1.09(t,3H)1.36(s,9H)2.97-3.11(m,5H)3.37-3.47(m,4H)3.48-3.55(m,4H)3.55-3.60(m,2 H)3.68-3.75(m,2H)4.03-4.08(m,2H)5.08-5.14(m,1H)6.84-6.92(m,2H)7.16-7.21(m,2H).

[0371] Step 2 tert-butyl(2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate [ka] tert-butyl(2R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[(methanesulfonyl)oxy]propanoate (1.02 g, 2.14 mmol) and 1,4,7,10-tetraazacyclododecane (402 mg, 2.33 mmol) were heated and stirred overnight at 55°C under N2 in MeCN (18 ml), followed by stirring at 65°C for 6 hours and then at 70°C for a further 18 hours. The mixture was then concentrated under reduced pressure to obtain the crude product (1.18 g, 67% product by ELSD). LC-MS (Method 5):R t =0.69min;MS(ESIpos):m / z=553.9[M+NH4] + .

[0372] Step 3 tert-butyl(2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] tert-butyl(2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate (1.18 g, 2.13 mmol) and MeCN (22 ml) were stirred under N2. DIPEA (1.9 ml, 11 mmol; [7087-68-5]) was added, followed by tert-butyl bromoacetate (1.1 ml, 7.5 mmol) in MeCN (370 μl), and the mixture was stirred at 60°C for 5 hours. The mixture was concentrated under reduced pressure. The residue was then dissolved in SiO2, the organic phase was washed with water, NaHCO3 (aqueous solution), and NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product (2.87 g, 41% product by ELSD). LC-MS (Method 2):R t =1.17min;MS(ESIpos):m / z=895.4[M+H]+ .

[0373] Step 4 (2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid [ka] tert-butyl(2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate (2.87 g, 3.21 mmol) was stirred in formic acid (41 ml) at 70°C for 4 hours. The mixture was then concentrated under reduced pressure and purified by RP chromatography (Biotage C18 / 60 g, 50 ml / min, A=water, B=MeCN, 0%B to 50%B at 30 min, 100%B at 10 min) to obtain the labeled compound (337 mg, purity 95%, yield 16%). Specific optical rotation: -2.4°±0.3 (C=1, MeOH, 20℃, 589nm). LC-MS (Method 2):R t =0.62min;MS(ESIpos):m / z=671.3[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.20(br d,J=8.4 Hz,2H),6.82(d,J=8.6 Hz,2H),3.99-4.07(m,2H),3.68-3.75(m,2H),3.25-3.64(m,18H),2.54-3.19(m,18H),1.09(t,J=7.0 Hz,3H). 13C NMR(DMSO-d6,101 MHz):δ(ppm)172.1,171.3,169.7(br,2C),156.9,130.5(2C),130.4,114.1(2C),69.9,69.9,69.8,69.2,69.0,67.0 ,65.6,65.1(br),55.2(br),54.9(br,2C),51.7(br,2C),51.5(br,2C),49.1(br,2C),46.8(br,2C),32.8(br),15.2.

[0374] Step 5 Gadolinium 2,2',2”-{10-[(1S)-1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate [ka] (2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid (339 mg, 505 μmol), Gd2O 3( 82.4 mg (227 μmol) and water (5.2 ml) were placed in a crimped-seal vial and stirred overnight at 105°C, followed by stirring at 120°C for a further 5 hours. Chelex100 (trademark) (sodium type, washed, approximately 5 g) was added, and the pH was adjusted to 5 using NaOH (1 M, aqueous solution), and the mixture was stirred for 1 hour. Purification by filtration and RP chromatography (Biotage C18 30 g, 25 ml / min, A=water, B=MeCN, 0% B to 50% B, 100% B in 25 mins, 100% B in 10 mins) yielded the marked compound (307 mg, purity 95%, yield 74%). Specific optical rotation: 14.9° (c=1, MeOH, 20°C, 589nm). LC-MS (Method 3):R t =0.64min;MS(ESIpos):m / z=m / z=413.6[M+2H] ++ ,826.4[M+H] +The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0375] Example 12 Step 1 (2R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid [ka] (2R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid was prepared from tert-butyl(2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-hydroxypropanoate (intermediate 9) in the same manner as (2S)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid (Example 11 - Step 4) to obtain the marked compound (310 mg, total yield 16% over 4 steps). Specific optical rotation: 1.7°±0.53 (c=1, MeOH, 20℃, 589nm). LC-MS (Method 2):R t =0.61 min;MS(ESIpos):m / z=671.3[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)7.11-7.23(m,2H),6.82(d,J=8.6 Hz,2H),3.99-4.07(m,2H),3.68-3.75(m,2H),3.36-3.62(m,17H),2.53-3.14(m,18H),1.09(t,J=7.0 Hz,3H). 13C NMR(DMSO-d6,101 MHz):δ(ppm)172.1(br),171.3(br),169.7(br,2C),156.9,130.5(2C),130.4,114.1(2C),69.9,69.9,69.8,69.2,69.0, 67.0,65.6,65.1(br),55.2(br),54.9(br,2C),51.7(br,2C),51.5(br,2C),49.1(br,2C),46.8(br,2C),32.8(br),15.2.

[0376] Step 2 Gadolinium 2,2',2”-{10-[(1R)-1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate [ka] (2R)-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid (305 mg, 455 μmol), Gd2O 3( 74.2 mg (205 μmol) and water (4.6 ml) were placed in a crimped-seal vial and stirred overnight at 105°C, followed by stirring at 120°C for a further 5 hours. Chelex100 (trademark) (sodium type, washed, approximately 5 g) was added, and the pH was adjusted to 5 using NaOH (1 M, aqueous solution), and the mixture was stirred for 1 hour. Purification by filtration and RP chromatography (Biotage C18 30 g, 25 ml / min, A=water, B=MeCN, 0% B to 50% B, 100% B in 25 mins, 100% B in 10 mins) yielded the marked compound (292 mg, 100% purity, 78% yield). Specific optical rotation: -13.7° (c=1, MeOH, 20℃, 589nm). LC-MS (Method 3):R t =0.64min;MS(ESIpos):m / z=413.7[M+2H] ++ ,826.4[M+H] +The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0377] Example 13 Step 1 Ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[(methanesulfonyl)oxy]propanoate [ka] Racemethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-hydroxypropanoate (intermediate 7, 2.34 g, 6.32 mmol) and TEA (1.9 ml, 14 mmol; [121-44-8]) were stirred in THF (21 ml) at 0-5°C. Under an N2 atmosphere, MsCl (540 μl, 6.9 mmol; [124-63-0]) was added dropwise, and the mixture was heated to RT and stirred for 3 hours. The mixture was then dissolved in NaHCO₃⁻. 3( The compound was added to a 50% saturated aqueous solution, followed by extraction with MTBE (3 times), the organic phase was combined, washed with NaCl solution (2 times in saturated aqueous solution), dried on Na2SO4, and concentrated under reduced pressure to obtain the labeled compound (2.97 g, purity 95%, quantitative). LC-MS (Method 4):R t =1.17min;MS(ESIpos):m / z=466.2[M+NH4] + .

[0378] Step 2 Ethyl 2-[4,10-bis(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)propanoate [ka] Racemic ethyl-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-2-[(methanesulfonyl)oxy]propanoate (2.79 g, 6.22 mmol), di-tert-butyl 2,2'-(1,4,7,10-tetraazacyclododecane-1,7-diyl)diacetate (2.27 g, 5.65 mmol, [162148-48-3]), K2CO3 (1.56 g, 11.3 mmol), and MeCN (51 ml) were stirred together in a reaction vessel under N2 at 70°C for 4 days. The mixture was then filtered and concentrated under reduced pressure to obtain the crude labeled compound (3.60 g, 50% product by ESLD detection). LC-MS (Method 2):R t =1.25 min;MS(ESIpos):m / z=753.8[M+H] + .

[0379] Step 3 Ethyl-2-{4,10-bis(2-tert-butoxy-2-oxoethyl)-7-[1-ethoxy-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-methoxypropanoate [ka] Ethyl 2-[4,10-bis(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)propanoate (1.80g, 2.39mmol), ethyl-2-[(methanesulfonyl)oxy]-3-methoxypropanoate (intermediate 25, 1.24g, 5.50mmol), K2CO 3( 661 mg, 4.78 mmol;[584-08-7]) and MeCN (9 ml) were stirred at 80°C for 24 hours. The mixture was filtered, the filtered cake was washed with EtOH, the organic layers were combined and concentrated under reduced pressure to obtain the crude labeled compound as a mixture of diastereomers (2.74 g). LC-MS (Method 2):R t=1.10~1.17 min;MS(ESIpos):m / z=884.0[M+H] + .

[0380] Step 5 2,2'-{4-[1-ethoxy-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-oxopropan-2-yl]-10-[1-ethoxy-3-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}diacetic acid [ka] Crude ethyl-2-{4,10-bis(2-tert-butoxy-2-oxoethyl)-7-[1-ethoxy-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-methoxypropanoate (2.73 g, 3.09 mmol) was stirred with formic acid (40 ml) at 70°C for 4 hours. The mixture was then concentrated under reduced pressure and subsequently purified by RP chromatography (Biotage, SNAP C18 50 g, A=water, B=MeCN, 0%B to 50%B at 30 min, 100%B at 10 min) to obtain the marked compound as a mixture of diastereomers (229 mg, 10% yield over 5 steps). LC-MS (Method 2):R t =0.76min;MS(ESIpos):m / z=771.8[M+H] + . 1 H NMR(DMSO-d6,400 MHz):δ(ppm)7.10-7.31(m,2H),6.76-6.86(m,2H),3.61-4.16(m,12H), 3.37-3.60(m,14H),3.21(s,3H),2.53-3.13(m,18H),0.97-1.25(m,9H).

[0381] Step 6 Gadolinium 2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-methoxypropanoate [ka] Diastereomer mixture, 2,2'-{4-[1-ethoxy-3-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-oxopropan-2-yl]-10-[1-ethoxy-3-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}diacetic acid (220 mg, 285 μmol), Gd2O 3( 46.6 mg (128 μmol) and water (2.9 ml) were stirred at 120°C for 24 hours. Chelex100 (trademark) was added (sodium type, washed, approximately 5 g), and the pH was adjusted to 5 using NaOH (1 M, aqueous solution), and the mixture was stirred for 1 hour. Purification by filtration and RP chromatography (Biotage SNAP Ultra C18 30 g, 25 ml / min, A=water, B=MeCN, 0% B to 50% B at 25 min, 100% B at 10 min) yielded a racemic diastereomer mixture (45.1 mg, yield 18%). LC-MS (Method 3):R t =0.65 min (diastereomer 1, 72% UV), 0.69 min (diastereomer 2, 27% UV); MS (ESIpos): m / z = 435.7 [M + 2H] ++ ;870.5[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0382] Example 14 Step 1 Methyl-3-(4-butoxyphenyl)-2-[(methanesulfonyl)oxy]propanoate [ka] Racemethyl-3-(4-butoxyphenyl)-2-hydroxypropanoate (intermediate 10, 919 mg, 3.64 mmol), TEA (1.1 ml, 8.0 mmol; [121-44-8]), and THF (11 ml) were stirred under an N2 atmosphere at 0-5°C. MsCl (310 μl, 4.0 mmol; [124-63-0]) was added dropwise, and the mixture was heated to RT and stirred for 3 hours. The mixture was then dissolved in NaHCO3. 3( The compound was added to a 50% saturated aqueous solution, followed by extraction with MTBE (3 times), the organic phase was combined, washed with NaCl solution (2 times in saturated aqueous solution), dried on Na2SO4, and concentrated under reduced pressure to obtain the labeled compound (1.25 g, 99% yield). LC-MS (Method 4):R t =1.29min;MS(ESIpos):m / z=348.2[M+NH4] + . 1 H NMR(400 MHz,DMSO-d6)δ ppm 0.92(t,3H)1.35-1.47(m,2H)1.63-1.71(m,2H)2.93-3.17(m,5H)3.68(s,3H)3.83-3.95(t,2H)5.29(m,1H)6.86(d,2H)7.15(d,2H).

[0383] Step 2 Methyl-3-(4-butoxyphenyl)-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate [ka] 1,4,7,10-Tetraazacyclododecane (1.30 g, 7.57 mmol) was dissolved in MeCN (28 ml), K2CO3 (836 mg, 6.1 mmol) was added, and racemethyl-3-(4-butoxyphenyl)-2-[(methanesulfonyl)oxy]propanoate (2.00 g, 6.05 mmol) was added to MeCN (8.0 ml). The mixture was stirred overnight at 55°C. The mixture was filtered, the filtered cake was washed with EtOH, and the organic filtrates were combined and concentrated under reduced pressure to obtain the crude labeled compound (2.49 g). The presence of the corresponding ethyl ester was also detected in the crude product. LC-MS (Method 2):R t =0.67min;MS(ESIpos):m / z=407.3[M+H] + .

[0384] Step 3 Methyl-3-(4-butoxyphenyl)-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] Crude methyl-3-(4-butoxyphenyl)-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate (2.49 g, 6.12 mmol) is dissolved in MeCN (24 ml) and K2CO2 is used. 3( 7.19 g, 52.1 mmol; [584-08-7]) was added, and tert-butylbromoacetate (3.2 ml, 21 mmol) dissolved in MeCN (7.9 ml) was added dropwise under an N2 atmosphere. The mixture was stirred overnight in RT, the mixture was filtered, the filter cake was washed with EtOH, and the combined organic fraction was concentrated under reduced pressure to obtain the crude labeled compound (5.12 g). The presence of the corresponding ethyl ester was also detected in the crude product, possibly through prolonged contact with ethanol during workup. LC-MS (Method 2):R t =1.38min;MS(ESIpos):m / z=749.5[M+H] + .

[0385] Step 4 2,2',2”-{10-[3-(4-butoxyphenyl)-1-ethoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetic acid [ka] Crude methyl-3-(4-butoxyphenyl)-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate (5.12 g, 6.84 mmol, also containing the corresponding ethyl ester) was stirred with formic acid (88 ml) at 70°C for 4 hours, and the mixture was concentrated under reduced pressure. Purification by RP chromatography (Biotage Ultra C18 60 g, 50 ml / min, A=water, B=MeCN, 0% B to 50% B at 25 min, 100% B at 10 min) yielded the marked compound (262 mg, 6% yield over 4 steps). LC-MS (Method 2):R t =0.79min;MS(ESIpos):m / z=595.3[M+H] + . 13 C NMR(DMSO-d6,101 MHz):δ(ppm)171.1,171.0(br),169.7(br,2C),157.3,130.5(2C),129.6,114.1(2C),67.0,64.7(br),59.9,55. 2(br),55.0(br,2C),51.6(br,2C),51.3(br,2C),49.1(br,2C),46.8(br,2C),33.7(br),30.9,18.8,14.2,13.8.

[0386] Step 5 Gadolinium 2,2',2”-{10-[2-(4-butoxyphenyl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate [ka] Racemic 2,2',2”-{10-[3-(4-butoxyphenyl)-1-ethoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetic acid (253 mg, 425 μmol), Gd2O3 (69.4 mg, 191 μmol), and water (4.3 ml) were stirred at 105°C for 3 days. Chelex100 (trademark) was added (sodium type, washed, approximately 5 g), and the pH was adjusted to 5 using NaOH (1 M, aqueous solution). The mixture was stirred for 1 hour, indicating that the mixture was gadolinium-free. Purification by filtration and RP chromatography (Biotage Ultra C18 12 g, 12 ml / min, A=water, B=MeCN, 0% B to 50% B, 100% B at 25 mins, 100% B at 10 mins) yielded the marked compound (196 mg, 64%). LC-MS (Method 3):R t =0.75min;MS(ESIpos):m / z=361.7[M+2H] ++ ,722.3[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0387] Example 15 Step 1 Methyl(2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(trifluoromethanesulfonyl)oxy]pentanoate [ka] Intermediate 12, methyl(2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate (5.00 g, 14.7 mmol) was dissolved in DCM (50 ml), placed under N2, and cooled to -60°C. Lutidine (2.1 ml, 18 mmol; [108-48-5]) was added, followed by the dropwise addition of trifluoromethanesulfonic anhydride (15 ml, 1.0 M in DCM, 15 mmol; [358-23-6]) at -60°C. The reaction mixture was stirred for 2 hours, then warmed to approximately 8°C. Diethyl ether was added to precipitate lutidine triflate, the mixture was filtered, and the filtrate was washed with diethyl ether. The combined filtrate was extracted with water and HCl (1 M, aqueous solution), dried, (Na2SO4) was added, and concentrated under reduced pressure. 6.97 g (85%) of the compound was obtained as a reddish oil, which was used directly in the next step. 19 F NMR(CDCl3,377 MHz):δ(ppm)-76.04(s). 1 H NMR (CDCl3,400 MHz): δ(ppm)7.03-7.07(m,2H),6.82-6.87(m,2H),5.12(t,J=6.1 Hz,1H),4.10-4.14(m,2H),3.86(dd,J=5.6,4.3 Hz,2H),3.82(s,3H),3.70-3.74(m,2H),3.60-3.63(m,2H),3.54(q,J=6.9 Hz,2H),2.56-2.65(mc,2H),1.95-2.03(m,2H),1.70-1.79(m,2H),1.21(t,J=7.0 (Hz, 3H). The sample contains 1.1 equivalents (15%) of diethyl ether: 3.48 (q, J=7.1Hz, 0.48H), 1.21 (br t, J=7.0Hz, 0.69H).

[0388] Step 2 Methyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)pentanoate [ka] 1,4,7,10-Tetraazacyclododecane (10.1 g, 58.8 mmol, approximately 5 equivalents) was dissolved in chloroform (100 ml), and DIPEA (2.0 ml, 12 mmol; [7087-68-5]) and a solution of methyl(2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-[(trifluoromethanesulfonyl)oxy]pentanoate (6.94 g) in chloroform (25 ml) were added. The reaction mixture was stirred overnight at RT. The mixture was extracted with water (3 times) to remove excess cyclone and saturated NaCl, dried (Na2SO4), and concentrated under reduced pressure to obtain the marked compound (7.55 g) as an orange-brown oil, a portion of which was used directly in the next step. LC-MS (Method 2):R t =0.72min;MS(ESIpos):m / z=496[M+H] + .

[0389] Step 3 Methyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(2S)-3-tert-butoxy-1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoate [ka] Methyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)pentanoate (5.81 g, 11.7 mmol) is dissolved in MeCN (150 ml) and K2CO2 is used. 3(5.68 g, 41.1 mmol) was added. Intermediate 26, methyl(2R)-3-tert-butoxy-2-[(trifluoromethanesulfonyl)oxy]propanoate (13.3 g, 90% purity, 38.8 mmol) in MeCN (50 ml) was added dropwise, and the mixture was stirred overnight under RT. The mixture was filtered, the filter cake was washed (MeCN), and the combined filtrate was concentrated under reduced pressure. 30.90 g of the resulting residue was absorbed into Isolute (trademark) and purified by RP chromatography (SNAP C18 400 g, 100 ml / min, 254 nm, A = water / 0.1% formic acid, B = MeCN, 10% B 6 CV, 10%~41% B at 8.8 CV, 41% B 1.7 CV, 41% B ~80% B at 11 CV, 80% B 2.9 CV). After freeze-drying, two fractions of the indicated compound were obtained. Fraction 1: 2.38g LC-MS (Method 2):R t =1.37min;MS(ESIpos):m / z=970[M+H] + . Fraction 2: 5.76g LC-MS (Method 2):R t =1.24 min;MS(ESIpos):m / z=970[M+H] + . Specific rotation:α D 20 =+14.60°+ / -0.18°(c=1, MeOH). LC-MS (Method 3):R t =1.17min(91%DAD);MS(ESIpos):m / z=485[M+2H] ++ ,970[M+H] + . 1 H NMR (CDCl3,400 MHz): δ(ppm)8.39(s,0.3H,formiate),7.01-7.08(m,2H),6.82(d,J=7.5 Hz,2H),4.07-4.13(m,2H),3.48-3.95(m,30H),2.49-3.43(m,18H),1.49-1.88(m,4H),1.09-1.25(m,30H). 13¹³C NMR (CDCl3, 101 MHz): δ (ppm) 173.4 (br), 171.9 (br, 3C), 157.5, 134.3, 129.6 (2C), 115.0 (2C), 74.4, 74.2 (2C), 71.3, 70.3, 70.2, 67.8, 67.1, 63.9 (br), 63.2 (br, 3C), 60.0 (br, 2C), 59.7 (br), 52.5, 52.2 (2C), 52.1 (br, 8C), 51.2, 35.2, 29.2, 27.8 (6C), 27.7 (3C), 15.6. Some signals are very broad, and one carbon atom in the propylene chain is not observed. The total yield calculated from Step 1 is 74%.

[0390] Step 4 Methyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoate [ka] Methyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(2S)-3-tert-butoxy-1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoate (2.38 g, 2.46 mmol) was dissolved in 1,4-dioxane (60 ml), and HCl (9.8 ml, 4 M, 39.2 mmol in dioxane) was added. The mixture was stirred at 80°C for 4 hours, and then evaporated to dryness under reduced pressure. The crude product, methyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoate 2.13 g was used directly in the next step.

[0391] Step 5 (2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid [ka] Methyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(2S)-3-hydroxy-1-methoxy-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoate (2.13 g, 2.66 mmol) was dissolved in THF (13 ml), and a solution of lithium hydroxide (382 mg, 16.0 mmol) in water (13 ml) was added. After stirring overnight at RT, the reaction was almost complete. (The presence of one methyl ester adversely affects the complexation step, as the ester is hydrolyzed under the complexation conditions used. Therefore, complete saponification at this point is not essential.) The reaction mixture was evaporated to dryness under reduced pressure to obtain 2.36 g of crude product, which was used in the next reaction.

[0392] Step 6 Gadolinium(2S,2'S,2”S)-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate) [ka] (2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-{4,7,10-tris[(1S)-1-carboxy-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}pentanoic acid (5.50 g, 7.38 mmol) was dissolved in water (400 ml) and the pH was adjusted to 4 with formic acid. Gd2O 3(1.20 g, 3.32 mmol, 0.9 equivalents) was added, and the mixture was stirred at 100°C for 18 hours, overnight at RT, and for a further 4 hours at 100°C. Chelex100 (trademark) (sodium type, approximately 10 g) was added, and the mixture was stirred at RT for 2 days, after which the xylenol-orange test showed the absence of free gadolinium. The pH of the solution was adjusted to 7 by the addition of ammonium hydroxide (25%), and the volume was reduced to approximately 200 ml under reduced pressure. (Fraction 2 of step 3 was similarly obtained through steps 4-6. The retention times of the two fractions were different, but they showed the same behavior in the subsequent reaction, so they were combined at this point.) The combined reaction product (including the resin) was transferred to an empty Biotage cartridge and subjected directly to RP chromatography (SNAP C18 400 g, 100 ml / min, 254 nm. A = water, B = MeCN, 0% B 5 CV, 0%~45% B at 14 CV). When the target fractions were combined and freeze-dried, two fractions were obtained: gadolinium(2S,2'S,2”S)-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate). Fraction 1: 2.49g Specific rotation:α D 20 =+15.95°+ / -0.17°(c=0.84, H2O). LC-MS (Method 3):R t =0.73min(100% DAD);MS(ESIpos):m / z=450[M+2H] ++ , 900[M+H] + and some [2M+2H] ++ ;909[2M+H2O+2H] ++ The observed isotopic patterns are consistent with the structure. UPLC-MS (Method 2):R t =0.78 min (100% ELSD), 0.75 min (100% UV 220nm) MS(ESIpos): m / z=900[M+H] + . Fraction 2: 1.99g Specific rotation:αD 20 =+16.38°+ / -0.35°(c=0.84, H2O). LC-MS (Method 3):R t =0.73min(100% DAD);MS(ESIpos):m / z=450[M+2H] ++ , 900[M+H] + and some [2M+2H] ++ ;909[2M+H2O+2H] ++ The observed isotopic patterns are consistent with the structure. UPLC-MS (Method 2):R t =0.78 min (100% ELSD), 0.75 min (94% UV 220nm), 0.80 min (6%, UV, 220nm), both peak MS (ESIpos): m / z = 900 [M + H] + . Fraction 2 contains a stereoisomer, likely through a racemization event in one of the preceding steps. The total yield from step 3 is 42%.

[0393] Example 16 Step 1 tert-butyl3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-[(methylsulfonyl)oxy]propanoate [ka] tert-butyl-3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-hydroxypropanoate (intermediate 11, 2.13 g, 5.99 mmol), TEA (1.8 ml, 13 mmol; [121-44-8]), and THF (20 ml) were stirred at 0-5°C under an N2 atmosphere. MsCl (510 μl, 6.6 mmol; [124-63-0]) was added dropwise, and the mixture was heated to RT and stirred for 3 hours. The mixture was then dissolved in NaHCO3. 3(The sample was added to a 50% saturated aqueous solution, followed by extraction with MTBE (3 times), the organic phase was combined, washed with NaCl solution (2 times in saturated aqueous solution), dried on Na2SO4, and concentrated under reduced pressure to obtain the labeled compound (2.55 g). The sample contained approximately 20% impurities and was used directly in the next step. LC-MS (Method 4):R t =1.21 min;MS(ESIpos):m / z=434.2[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)8.02(d,J=2.0 Hz,1H),7.65(dd,J=8.6,2.5 Hz,1H),6.79(d,J=8.4 Hz,1H),5.16-5.20(m,1H),4.33(br dd,J=5.3,4.1 Hz,2H),3.69-3.73(m,2H),3.53-3.57(m,2H),3.45-3.50(m,2H),3.42(q,J=7.1 Hz,2H),3.11(s,3H),3.04-3.10(m,2H),1.36(d,J=0.5 Hz,9H),1.09(t,J=7.0 Hz,3H).

[0394] Step 2 tert-butyl-3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate [ka] Racemic tert-butyl-3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-[(methanesulfonyl)oxy]propanoate (1.27 g, 2.93 mmol), 1,4,7,10-tetraazacyclododecane (551 mg, 3.20 mmol), and MeCN (24 ml) were stirred overnight at 55°C under N2, followed by heating and stirring at 70°C for 2 days. The mixture was concentrated under reduced pressure to obtain the crude product (1.49 g). LC-MS (Method 2):R t =0.65min;MS(ESIpos):m / z=510.3[M+H]+ .

[0395] Step 3 tert-butyl-3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate [ka] Racemic tert-butyl-3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate (1.49 g, 2.92 mmol) was stirred in MeCN (30 ml) under an N2 atmosphere. DIPEA (2.5 ml, 15 mmol; [7087-68-5]) was added, followed by tert-butyl bromoacetate (1.5 ml, 10 mmol) in MeCN (500 μl). The mixture was stirred at 60°C for 5 hours and then concentrated under reduced pressure. Ether was added, and the organic phase was washed with NaHCO3 solution (50% saturated aqueous solution) and NaCl (saturated aqueous solution), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude labeled compound (3.50 g). LC-MS (Method 2):R t =1.12min;MS(ESIpos):m / z=852.4[M+H] + .

[0396] Step 4 3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid [ka] Racemic tert-butyl-3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-[4,7,10-tris(2-tert-butoxy-2-oxoethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate (12.6 g, 14.8 mmol) was stirred in formic acid (53 ml) at 70°C for 4 hours, and the mixture was then concentrated under reduced pressure. Purification by RP chromatography (Biotage C18 Ultra 120 g, 50 ml / min, A=water, B=MeCN, 0% B to 50% B, 100% B at 25 mins, 100% B at 10 mins) yielded the marked compound (458 mg, 5% yield over 4 steps). LC-MS (Method 2):R t =0.50min;MS(ESIpos):m / z=628.9[M+H] + . 1 H NMR (DMSO-d6,400 MHz): δ(ppm)8.04(d,J=2.0 Hz,1H),7.71(dd,J=8.6,2.3 Hz,1H),6.72(d,J=8.4 Hz,1H),4.27-4.36(m,2H),3.69-3.75(m,2H),3.38-3.62(m,15H),2.81-3.09(m,14H),2.60-2.71(m,2H),1.09(t,J=7.0 Hz,3H). 13 C NMR(DMSO-d6,101 MHz):δ(ppm)172.0,170.9(br),169.6(br,2C),161.8,147.3,140.6,126.9,110.0,69.9,69.2,68.9,65.6 ,64.7,64.6(br),55.2(br,3C),51.4(br,2C),51.1(br,2C),49.3(br,2C),46.9(br,2C),30.2(br),15.2.

[0397] Step 5 Gadolinium 2,2',2”-{10-[1-carboxy-2-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate [ka] Racemic 3-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}-2-[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoic acid (458 mg, 730 μmol), Gd2O 3( 119 mg (328 μmol) and water (7.4 ml) were heated at 105°C for 24 hours, and then the mixture was heated at 120°C for 5 hours. Chelex100 (trademark) was added (sodium type, washed, approximately 5 g), and the pH was adjusted to 5 using NaOH (1 M, aqueous solution). The mixture was stirred for 1 hour, indicating that the mixture did not contain gadolinium. Purification by filtration and RP chromatography (Biotage Ultra C18 30 g, 25 ml / min, A=water, B=MeCN, 0%B~50%B, 100%B 0 min at 25 min) yielded the marked compound (355 mg, 62%). LC-MS (Method 3):R t =0.50min;MS(ESIpos):m / z=392.2[M+2H] ++ ;783.4[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0398] Example 17 Gadolinium-2,2',2”-{10-[1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate) [ka] The indicated compound was prepared as a mixture of stereoisomers from racemicethyl-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate (intermediate 13) and racemicethyl-3-tert-butoxy-2-{[(trifluoromethyl)sulfonyl]oxy}propanoate (intermediate 27) using the method described herein. LC-MS (Method 3):R t =0.66~0.74min;MS(ESIpos):m / z=450.6[M+2H] ++ ,900.2[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0399] Example 18 Gadolinium(2S,2'S,2”S)-2,2',2”-{10-[(1R)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate) [ka] The indicated compound was prepared from ethyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate (intermediate 14) and methyl(2R)-3-tert-butoxy-2-{[(trifluoromethyl)-sulfonyl]oxy}propanoate (intermediate 26). Specific optical rotation: -18.5°±0.1 (c=1, H2O, 20℃, 589nm). LC-MS (Method 3):R t =0.65min;MS(ESIpos):m / z=450.6[M+2H] ++ ;900.3[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0400] Example 19 Gadolinium(2R,2'R,2”R)-2,2',2”-{10-[(1R)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate) [ka] The indicated compound was prepared from ethyl(2S)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate (intermediate 14) and methyl(2S)-3-tert-butoxy-2-{[(trifluoromethyl)-sulfonyl]oxy}propanoate (intermediate 28) using the method detailed herein. Specific optical rotation: -12.6°±0.14 (H2O, 20℃, 589nm). LC-MS (Method 3):R t =0.71min;MS(ESIpos):m / z=450.6[M+2H] ++ ;900.3[M+H] + ;908.8[2M+H2O+2H] ++ The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0401] Example 20 Gadolinium(2R,2'R,2”R)-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate) [ka] The indicated compound was prepared from ethyl(2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate (intermediate 15) and methyl(2S)-3-tert-butoxy-2-{[(trifluoromethyl)-sulfonyl]oxy}propanoate (intermediate 28) using the method detailed herein. Specific optical rotation: 18.5°±0.1 (c=1, H2O, 20℃, 589nm). LC-MS (Method 3):R t =0.65min;MS(ESIpos):m / z=450.8[M+2H] ++ ;900.5[M+H] + ;908.8[2M+H2O+2H] ++ The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0402] Example 21 Gadolinium-2,2',2”-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate) [ka] The indicated compound was prepared from ethyl(2R)-5-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-hydroxypentanoate (intermediate 15) and racemethyl-3-tert-butoxy-2-{[(trifluoromethyl)-sulfonyl]oxy}propanoate (intermediate 27) using the method detailed herein. Specific optical rotation: 5.97°±0.16 (c=1, H2O, 20℃, 589nm). LC-MS (Method 3):R t =0.65~0.72min;MS(ESIpos):m / z=450.8[M+2H] ++ ,900.5[M+H] + The isotopic pattern matches the theoretical value for the corresponding gadolinium complex.

[0403] Example 22 Step 1 Triethyl 2,2',2”-{10-[1-tert-butoxy-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-1-oxopropan-2-yl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-tert-butoxypropanoate) [ka] tert-butyl 3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}-2-(1,4,7,10-tetraazacyclododecane-1-yl)propanoate, Example 2-Step 2, (1.80 g, 3.54 mmol) is dissolved in MeCN (30 ml) and K2CO2 3(1.71 g (12.4 mmol) was added. Ethyl 3-tert-butoxy-2-[(trifluoromethanesulfonyl)oxy]propanoate, intermediate 27 (3.76 g, 11.7 mmol) in MeCN (20 ml) was added dropwise by RT, and the mixture was stirred for 20 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in DCM, then treated with water and extracted with DCM (twice). The combined organic layers were washed with saturated NaCl solution, filtered using a hydr...

Claims

1. Compounds of general formula (I), 【Chemistry 1】 (In the formula, Ar is 【Chemistry 2】 and 【Transformation 3】 (In the formula, ＃ (This indicates the connection point with X.) Represents a base selected from, X is CH 2 、 (CH 2 ) 2 、 (CH 2 ) 3 、 (CH 2 ) 4 and ＊ -(CH 2 ) 2 -O-CH 2 - ＃ (In the formula, ＊ This indicates the bonding point with argon. ＃ (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 For each occurrence, independently, a hydrogen atom or C 1 ~C 3 -alkyl, -CH 2 OH, - (CH 2 ) 2 OH and -CH 2 OCH 3 Represents a base selected from, R 4 teeth, C 2 ~C 5 -alkoxy, (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- Represents a base selected from, Said C 1 ~C 3 - Alkoxy groups and C 2 ~C 5 - The alkoxy group is substituted with fluorine atoms one, two, three, or four times, depending on the case. R 5 is a hydrogen atom or C 2 ~C 5 -alkoxy, (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- Represents a base selected from, R 6 is a hydrogen atom or C 2 to C 5 -alkoxy, (C 1 to C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 to C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 to C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- (Represents a base selected from) or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof.

2. Ar 【Chemistry 4】 and 【Transformation 5】 (In the formula, ＃ (This indicates the connection point with X.) Represents a base selected from, X CH 2 、 (CH 2 ) 2 、 (CH 2 ) 3 、 (CH 2 ) 4 and ＊ -(CH 2 ) 2 -O-CH 2 - ＃ (In the formula, ＊ This indicates the bonding point with argon. ＃ (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, for each appearance independently, a hydrogen atom or C 1 ~C 3 -alkyl, -CH 2 OH, - (CH 2 ) 2 OH and -CH 2 OCH 3 Represents a base selected from, R 4 but, C 2 ~C 5 -alkoxy, (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- Represents a base selected from, Said C 1 ~C 3 - Alkoxy groups and C 2 ~C 5 - The alkoxy group is substituted with fluorine atoms one, two, three, or four times, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. The compound described in claim 1, or its stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts, or mixtures thereof.

3. Ar 【Transformation 6】 and 【Transformation 7】 (In the formula, ＃ (This indicates the connection point with X.) Represents a base selected from, X is CH 2 and (CH 2 ) 3 Represents a base selected from, R 1 and R 3 However, for each appearance independently, a hydrogen atom or -CH 2 Represents an OH group, R 2 However, hydrogen atoms or C 1 ~C 3 -alkyl, -CH 2 OH, - (CH 2 ) 2 OH and -CH 2 OCH 3 Represents a base selected from, R 4 but, C 2 ~C 5 -alkoxy, (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (C 1 ~C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- Represents a base selected from, Said C 1 ~C 3 - Alkoxy groups and C 2 ~C 5 - The alkoxy group is substituted with fluorine atoms one, two, three, or four times, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. A compound according to claim 1 or 2, or its stereoisomer, tautomer, hydrate, solvate, or salt, or a mixture thereof.

4. Ar 【Transformation 8】 and 【Chemistry 9】 (In the formula, ＃ (This indicates the connection point with X.) Represents a base selected from, X CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and ＊ - (CH 2 ) 2 -O-CH 2 - ＃ (In the formula, ＊ This indicates the bonding point with argon. ＃ (This indicates the bond point with the acetic acid portion.) Represents a base selected from, R 1 , R 2 and R 3 However, for each appearance independently, a hydrogen atom or C 1 ~C 3 -alkyl, -CH 2 OH, - (CH 2 ) 2 OH and -CH 2 OCH 3 Represents a base selected from, R 4 but, C 2 ~C 4 -alkoxy, (H 3 C-CH 2 )-O-(CH 2 ) 2 -O-, (H 3 C-CH 2 )-O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (H 3 C-CH 2 )-O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- Represents a base selected from, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. A compound according to claim 1 or 2, or its stereoisomer, tautomer, hydrate, solvate, or salt, or a mixture thereof.

5. Ar 【Chemistry 10】 and 【Chemistry 11】 (In the formula, ＃ (This indicates the connection point with X.) Represents a base selected from, X is CH 2 and (CH 2 ) 3 Represents a base selected from, R 1 , R 2 and R 3 However, for each appearance independently, a hydrogen atom or C 1 ~C 3 -alkyl, -CH 2 OH, - (CH 2 ) 2 OH and -CH 2 OCH 3 Represents a base selected from, R 4 (H 3 C-CH 2 )-O-(CH 2 ) 2 -O-, (H 3 C-CH 2 )-O-(CH 2 ) 2 -O-(CH 2 ) 2 -O- and (H 3 C-CH 2 )-O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 Represents the base selected from -O-, R 5 This represents a hydrogen atom, R 6 This represents a hydrogen atom. A compound according to claim 1, 2, or 4, or its stereoisomer, tautomer, hydrate, solvate, or salt, or a mixture thereof.

6. Gd 3＋ A compound of general formula (I) as described in any one of claims 1 to 5, in the form of a complex with, or a stereoisomer, tautomer, N-oxide, hydrate, solvate or salt thereof, or a mixture thereof.

7. Gadolinium 2,2',2''-(10-{1-carboxy-2-[2-(4-ethoxyphenyl)ethoxy]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate, Gadolinium 2,2',2''-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[(1S)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[(1R)-1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-[7-(1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl)-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]propanoate, Gadolinium 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]butanoate, Gadolinium (2S,2'S,2''S)-2,2',2''-{10-[(1S)-5-(4-butoxyphenyl)-1-carboxypentyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2''-{10-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[(1S)-1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[(1R)-1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-methoxypropanoate, Gadolinium 2,2',2''-{10-[2-(4-butoxyphenyl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium (2S,2'S,2''S)-2,2',2''-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2''-{10-[1-carboxy-2-{6-[2-(2-ethoxyethoxy)ethoxy]pyridine-3-yl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2,2',2''-{10-[1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2S,2'S,2''S)-2,2',2''-{10-[(1R)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2R,2'R,2"R)-2,2',2"-{10-[(1R)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2R,2'R,2"R)-2,2',2"-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium-2,2',2''-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2''-{10-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium 2,2',2''-{10-[1-carboxy-2-{5-[2-(2-ethoxyethoxy)ethoxy]pyridine-2-yl}ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[1-carboxy-3-(4-propoxyphenyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[(1S)-1-carboxy-5-(4-ethoxyphenyl)pentyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[1-carboxy-4-(4-ethoxyphenyl)butyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2-{7-[1-carboxy-2-(4-ethoxyphenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}pentanoate, Gadolinium 2,2',2"-{10-[(1S)-4-(4-butoxyphenyl)-1-carboxybutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-(10-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl) triacetate, Gadolinium (2S)-2-[4,10-bis(carboxylatomethyl)-7-{1-carboxy-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1-yl]-3-hydroxypropanoate, Gadolinium (2S,2'S,2''S)-2,2',2''-{10-[(1S)-4-(3-butoxyphenyl)-1-carboxybutyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}tris(3-hydroxypropanoate), Gadolinium (2S,2'S)-2,2'-{4-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1R)-1-carboxylate-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(3-hydroxypropanoate), Gadolinium-2,2'-{4-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[1-carboxylat-3-hydroxypropyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(4-hydroxybutanoate), Gadolinium-2,2'-{4-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-10-[1-carboxylat-3-hydroxypropyl]-1,4,7,10-tetraazacyclododecane-1,7-diyl}bis(4-hydroxybutanoate), Gadolinium 2-[7-{1-carboxy-2-[4-(2-ethoxyethoxy)phenyl]ethyl}-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl]-3-methoxypropanoate, Gadolinium 2,2',2"-{10-[2-{3,5-bis[2-(2-ethoxyethoxy)ethoxy]phenyl}-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium 2,2',2''-{10-[(1S)-2-(2,4-bis{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2-{7-[1-carboxy-2-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-hydroxypropanoate, Gadolinium-2-{7-[1-carboxy-2-(4-{2-[2-(2-ethoxyethoxy)ethoxy]ethoxy}phenyl)ethyl]-4,10-bis(carboxylatomethyl)-1,4,7,10-tetraazacyclododecane-1-yl}-3-hydroxypropanoate, Gadolinium-2-{4,10-bis(carboxylatomethyl)-7-[1-carboxypropyl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}propanoate, Gadolinium 2,2',2''-{10-[2-(5-butoxypyridine-2-yl)-1-carboxyethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium-2-{4,10-bis(carboxylatomethyl)-7-[1-carboxy-2-methoxyethyl]-1,4,7,10-tetraazacyclododecane-1-yl}-3-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]propanoate, Gadolinium 2,2',2''-(10-{1-carboxy-2-[4-(2,2,3,3-tetrafluoropropoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium 2,2',2''-(10-{(1R)-1-carboxy-2-[4-(2,2,2-trifluoroethoxy)phenyl]ethyl}-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetate, Gadolinium 2,2',2''-{10-[1-carboxy-2-(4-propoxyphenyl)ethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triyl}triacetate, Gadolinium (2R,2'R)-2,2'-{7-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1S)-1-carboxylat-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,4-diyl}bis(3-hydroxypropanoate) and Gadolinium (2S,2'S)-2,2'-{7-[(1S)-1-carboxy-4-{4-[2-(2-ethoxyethoxy)ethoxy]phenyl}butyl]-10-[(1R)-1-carboxylate-2-hydroxyethyl]-1,4,7,10-tetraazacyclododecane-1,4-diyl}bis(3-hydroxypropanoate) A compound according to claim 6, or its stereoisomer, tautomer, N-oxide, hydrate, solvate, or salt, or a mixture thereof, selected from the group consisting of the above.

8. Gd 3＋ Sodium (Na) complex with ＋ ) A compound of general formula (I) as described in claim 6 or 7 in the form of a salt, or a stereoisomer, tautomer, N-oxide, hydrate or solvate thereof, or a mixture thereof.

9. Gd according to claim 6 or 7 3＋ A method for preparing a compound of general formula (I) in the form of a complex with, the compound of general formula (I): 【Chemistry 12】 or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof (wherein the formula is Ar, X, R 1 , R 2 and R 3 (as defined for the compound of general formula (I) described in any one of claims 1 to 5) is reacted with a gadolinium (III) salt, Therefore, Gd 3＋ Compounds of general formula (I) in the form of complexes with (wherein Ar, X, R) 1 , R 2 and R 3 A method comprising the step of obtaining a compound of general formula (I) as defined in any one of claims 1 to 5.

10. An agent for use in diagnostic imaging, comprising the compound according to any one of claims 1 to 8.

11. An agent for use in magnetic resonance imaging, comprising the compound according to any one of claims 1 to 8.

12. The agent according to claim 11 for use in magnetic resonance imaging of blood vessels, kidneys, hepatobiliary system, or gastrointestinal tract.

13. The agent according to claim 11 or 12 for use in magnetic resonance imaging of the liver.

14. A diagnostic agent comprising a compound or mixture thereof according to any one of claims 1 to 8.

15. A contrast agent for magnetic resonance imaging comprising a compound or a mixture thereof according to any one of claims 1 to 8.

16. A method for imaging the tissue of a patient, comprising the steps of administering to the patient an effective amount of one or more compounds according to any one of claims 6 to 8 in a pharmaceutically acceptable carrier, and subjecting the patient to magnetic resonance imaging.

17. Gd according to claim 6 or 7 3＋ An agent for preparing a compound of general formula (I) in the form of a complex with the compound of general formula (I) 【Chemistry 13】 or its stereoisomers, tautomers, N-oxides, hydrates, solvates or salts, or mixtures thereof (wherein the formula is Ar, X, R 1 , R 2 and R 3 An agent comprising (as defined for a compound of general formula (I) as described in any one of claims 1 to 5).

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