Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
  • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
  • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
  • A61K49/10—Organic compounds
  • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
  • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA

Definitions

• the present invention relates to the items characterized in the patent claims, i.e. to new gadolinium metal chelate compounds, particularly metal chelate compounds suitable for computed tomography, to methods of preparing said compounds, to the use of said compounds as contrast agents in diagnostic imaging such as magnetic resonance imaging (MRI) or computed tomography (CT) and to their use in a mammalian body.
• diagnostic imaging such as magnetic resonance imaging (MRI) or computed tomography (CT) and to their use in a mammalian body.
• CT computed tomography
• Unenhanced MRI scans of tissue anatomy and function make use of the hydrogen atoms in water to generate the image.
• the basic contrast in the MR image mainly results from regional differences in the intrinsic relaxation times T1 and T2, each of which can be chosen to dominate image contrast.
• the intrinsic contrast provided by the water T1 and T2 and changes in their values brought about by tissue pathology are often too limited to enable a sensitive and specific diagnosis.
• the proton relaxation times can be influenced by the presence of paramagnetic ions.
• GBCAs Gadolinium-based Contrast Agents
• Gd 3+ rare earth metal Gadolinium
• Paramagnetic contrast media shorten the T1 (longitudinal) and T2 (transversal) relaxation times of surrounding water protons to indirectly produce a signal-enhancing effect.
• relaxivity The efficacy of an agent to shorten relaxation times is called relaxivity (r1 and r2), which is dependent on the ligand surrounding the Gd 3+ ion and influenced by extrinsic factors including temperature, magnetic field strength and the matrix (water, solid tissue, or blood)
• r1 and r2 The efficacy of an agent to shorten relaxation times is called relaxivity (r1 and r2), which is dependent on the ligand surrounding the Gd 3+ ion and influenced by extrinsic 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).
• BHC213028-FC Besides non-targeted agents, two linear contrast agents (i.e., contrast agents where ethe Gadolinium ion is bound to a linear ligand structure) are available for Magnetic Resonance Imaging (MRI) of the liver: Gd-BOPTA (gadobenic acid, marketed as Multihance) and Gd-EOB- DTPA (gadoxetic acid, marketed as Primovist in Europe and as Eovist in the USA). Gd-EOB- DTPA (Bayer AG) and Gd-BOPTA (Bracco) have been approved for 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.
• Gd-BOPTA gadobenic acid, marketed as Multihance
• Gd-EOB- DTPA gadoxetic acid, marketed as Primovist in Europe and as Eovist in the USA.
• Both targeted agents have been used for MRI of the liver, for the detection of focal liver lesions in patients with known or suspected primary liver cancer (e.g. hepatocellular carcinoma HCC) or metastatic disease. They provide information regarding lesion vascularity in the arterial and venous phases, hepatocyte presence and function in the delayed hepatobiliary phase.
• the liver specific contrast agents are taken up by healthy liver cells (hepatocytes) while there is no uptake into malignant tumor tissue due to the lack of intact organic anion-transporting polypeptide (OATP) transporters. Therewith they improve the detection of focal liver lesions by increasing the lesion-to-liver contrast.
• the contrast-enhanced MRI provides important information for differential diagnosis.
• HCCs do not express the respective uptake transporters and thus do not accumulate the liver specific GBCA to an extent which is observed in healthy liver tissue.
• Gd-BOPTA is secreted 3-to-5% into the bile and enables the capture of images in the liver- specific phase 1 to 2 hours after its administration (Seale MK et al. Radiographics 2009; 29: 1725-1748).
• Gd-EOB-DTPA is excreted into the bile up to about 50% of the administered dose.
• Gd-EOB-DTPA can be administered as a bolus, guarantees a satisfactory assessment of the vascular interstitial phase and subsequently (after 10-20 minutes), an evaluation of the hepatobiliary phase.
• Literature studies have confirmed that liver MRI with Gd-EOB-DTPA is able to detect and identify focal liver lesions with high specificity and sensitivity, either in patients with a healthy liver or oncologic/cirrhotic liver patients (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).
• Gd-EOB-DTPA is mainly taken up by hepatocytes via organic anion-transporting polypeptides (OATP1B1, OATP1B3) and is subsequently primarily excreted into the bile canaliculi via the multidrug resistance-associated protein 2 (MRP2, synonym cMOAT: canalicular multispecific organic anion transporter) (Ringe KI et al. American Journal of Roentgenology.2010;195: 13- 28; Leonhardt M et al. Drug Metab Dispos.2010 Jul;38(7):1024-8).
• MRP2 multidrug resistance-associated protein 2
• BHC213028-FC The molecular structure of both marketed products (Gd-EOB-DTPA and Gd-BOPTA) includes a hydrophilic and lipophilic group.
• the linear DTPA-like ligand for the Gadolinium complexation comprises the hydrophilic group and the benzene (e.g. ethyl-oxy-benzyl, EOB) side chain is the lipophilic group.
• the lipophilic group is not only responsible for the marked biliary excretion but also results in some weak protein binding of approximately 10% (Weinmann HJ et al. Magn Reson Med 1991; 22:233–237).
• Gd-EOB-DTPA and Gd-BOPTA show higher r1 and r2 relaxivities (Rohrer M et al. Invest Radiol. 2005 Nov;40(11):715-24).
• the high relaxivity values depend on the affinity of the molecules with plasma proteins through the lipophilic group, which is also responsible for specific hepatocyte uptake.
• liver specific GBCAs (Gd-EOB-DTPA and Gd-BOPTA) are still accepted, because no alternative liver specific macrocyclic GBCA is commercially available.
• the observed increased signal intensity in the dentate nucleus was also seen after repeated administration of the linear Gd-EOB-DTPA (Kahn J et al. Radiology.2017;282(3):708 – 716). It is known that macrocyclic GBCAs are more stable against Gd release (Frenzel et al. Invest Radiol.
• Computed tomography is a non-invasive imaging technique to visualize anatomy and function of the human body using ionizing radiation.
• the signal intensity bases on the X-ray attenuation characteristics of the tissue and the contrast originates from differences in the to attenuate X- rays among different tissues.
• Unenhanced CT offers a strong signal contrast between bones BHC213028-FC and soft tissues as the calcium in the bones attenuates X-rays effectively.
• the CT contrast between different soft tissue is low. Therefore, contrast media that locally increase the X-ray attenuation were used (Clauss W, Speck U. Historical development of x-ray contrast media for urography and angiography. In: Vogl T, ClaußW, Li GZ, et al., eds. Computed tomography Berlin Heidelberg, Germany: Springer; 1996:1–11). All x-ray contrast media approved for intravascular use are iodine-containing monomeric or dimeric substances containing 1 or 2 triiodobenzene cores.
• contrast media are formulated with high iodine concentration (150-400 mgI/mL) to enable sufficient attenuation and signal. They passively distribute only in the extracellular volume and are called nonspecific or extracellular contrast media.
• Abdominal contrast enhanced CT with available iodinated contrast media is a major application, in especially the oncological field.
• multi-phasic contrast-enhanced CT scans are usually performed to image the distribution of contrast media in different phase of the blood circulation (e.g. arterial, portal- venous, venous).
• the diagnostic capabilities are limited to the native and dynamic contrast enhanced liver CT phases.
• Targeted CT contrast media comparable to the above-described linear liver specific GBCAs for MRI, are commercially not available.
• One reason is the lower contrast media sensitivity of CT; compared to MRI the amount of CM needed for a CT signal enhancement is order of magnitude higher (standard dose CT:300-600 mg Iodine/kg vs standard dose MRT: 0.025-0.1 mmol [3.9-15.7mg] Gd /kg).
• Besides the differences in dosage of iodine and gadolinium based contrast agents both offer a high attenuation in the x-ray energy spectrum of CT. At identical mass-concentrations the x- ray attenuation of gadolinium is higher than that of iodine (Nowak et al.
• WO199532741 describes bile acid conjugates claimed to be useful for imaging of liver and bile duct using magnetic resonance imaging (MRI).
• MRI magnetic resonance imaging
• WO2001082795 describes an MRI agent with a covalently bound therapeutic blocking moiety attached which elicits a change in signal intensity of said agent when therapeutic agent interacts with its intended target.
• WO2007009638 discloses metal complexes containing perfluoroalkyl groups which can be used as MRI and X-ray contrast agents in particular for lymphography.
• WO2004006965 discloses perfluoroalkyl containing MRI contrast agents, which exhibit micelle formation leading to high r 1 relaxivity, for representing intravascular thrombi.
• WO1997032862 describes a class of polychelates linked to alkene bridged amino groups for diagnostic imaging using magnetic resonance imaging.
• WO1999005145 details a process for the preparation of tetraazamacrocycles.
• WO1996016677 describes metal complexes for use as X-ray contrast media for imaging of liver and bile ducts.
• WO1995028392 reveals the use of amphiphilic chelates and their use for hepatobiliary imaging.
• WO2013083535 describes the preparation of hyperpolarized imaging agents for MR diagnostic analysis.
• EP405704 relates to Gd 3+ complexes with derivatives of diethylentriaminopentaacetic acid (DTPA) such as Gd-EOB-DTPA and their use as contrast agents in magnetic resonance imaging of the liver, among others.
• DTPA diethylentriaminopentaacetic acid
• these linear compounds and complexes have come under increased scrutiny from the health authorities in recent years and are only still being used in a clinical environment due to the lack of suitable alternatives.
• MRI magnetic resonance imaging
• CT computed tomography
• liver specific GBCAs which show as many of the below-listed criteria as possible: - exhibit high water solubility, - are chemically stable, - are stable against metal release from the chelate, - exhibit high relaxivity, - exhibit high in vitro uptake into human transfected OATP1B1 HEK cells, - exhibit high in vitro uptake into human transfected OATP1B3 HEK cells, - have low protein binding, - show a favorable pharmacokinetic profile and dual elimination pathway, - are fast and completely excreted, - exhibit no long-term retention of Gd 3+ both in tissues and in organs, - are stable against metabolic degradation, - are well tolerated, BHC213028-FC - are suitable for liver imaging, - are suitable for biliary imaging, - are suitable for the imaging of liver diseases - and may exhibit high in vitro uptake (e.g.
• MRI magnetic resonance imaging
• CT computed tomography
• Multiphase abdominal CT is one of the most important CT applications in particular for oncological patients.
• CT offer the opportunity for image guided interventions as tissue biopsies or minimal invasive oncological treatment as RF-ablation. For these interventions tracking of the lesion during the procedure is essential.
• the available extracellular x-ray contrast media enhances the lesion only during a short time-window of the dynamic phase. A long- lasting contrast between lesion and liver would make that procedure much easier and has a great potential to increase the accuracy of targeted tissue sampling (biopsy) and therapeutic BHC213028-FC interventional treatment.
• a liver specific uptake of contrast media resulting in an enhancement of healthy liver tissue during the hepatobiliary phase would be needed.
• the issue is twofold: first the lower sensitivity of CT requires higher local contrast concentrations to generate the signal enhancement and second the limited uptake efficiency of the liver specific transports at higher contrast media doses. The lower sensitivity can be partially compensated by a higher dose.
• a macrocyclic structure is mandatory considering the SI increases in certain brain regions after repeated application of linear contrast agents, particularly GBCAs. The second point, the limited uptake rates at higher doses can only be addressed by the molecule structure/configuration.
• there is an increased medical need to provide new contrast agents for computed tomography imaging.
• the compounds of general formula (I) of the present invention in the form of a metal complex with a metal ion suitable for computed tomography, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same, said metal ion suitable for computed tomography being a metal ion with a k-edge energy in the range of from 33 to 91 keV and/or a metal ion having at least the x-ray attenuation of iodine in the energy range of medical x-ray imaging, including preferably computed tomography.
• the compounds of general formula (I) of the present invention and the compounds of general formula (I) of the present invention in the form of a metal complex with a metal ion suitable for computed tomography and the compounds of general formula (I) of the present invention in the form of a complex with Gd 3+ , and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same are hereinafter referred to as “compounds of the present invention”.
• the compounds of general formula (I) of the present invention in the form of a metal complex with a metal ion suitable for computed tomography and the compounds of general formula (I) of the present invention in the form of a complex with Gd 3+ , and stereoisomers, tautomers, N-oxides, BHC213028-FC hydrates, solvates, or salts thereof, or mixtures of same may also be referred to as “CT-suitable compounds of the present invention” and/or “metal compounds of the present invention” and/or “Gd 3+ -containing compounds of the present invention” It has been found, and this constitutes the basis of the present invention, that the compounds of the present invention have surprising and advantageous properties.
• the Gd 3+ -containing compounds of the present invention display the favorable stability of macrocyclic GBCAs and a high uptake in the liver. Further, the Gd 3+ - containing compounds of the present invention show high tolerability, improved relaxivity, excellent water solubility and a fast and complete excretion, making them well suited for diagnostic imaging, in particular for magnetic resonance imaging and/or computed tomography, more particularly for magnetic resonance imaging. Specifically, the Gd 3+ - containing compounds of the present invention, are particularly suited for liver imaging using magnetic resonance imaging or computed tomography, preferably in magnetic resonance imaging.
• the present invention describes a new class of liver-specific (non-linear) metal, particularly gadolinium chelate complexes, methods for their preparation and their use as l contrast agents, preferably as MRI contrast agents.
• DESCRIPTION OF THE INVENTION covers compounds of general formula (I), BHC213028-FC in which: Ar represents a group selected from wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from C 2 -C 5 -alkoxy, (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 -C 3 -alkoxy
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
• the term “comprising” when used in the specification includes “consisting of” and “consisting essentially of”. If within the present text any item is referred to as “as mentioned herein”, it means that it may be mentioned anywhere in the present text.
• the terms as mentioned in the present text have the following meanings:
• the term “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly a fluorine, chlorine or bromine atom.
• Said C 1 -C 3 -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 group.
• the compounds of general formula (I) in the form of a complex with Gd 3+ may exist as salts in the form according to formula (Ia) (Ia), wherein: Ar, X and R 1 to R 6 represent the groups indicated in the different aspects, embodiments, examples and any other descriptions and/or depictions of the compounds of general formula (I) in the form of a complex with Gd 3+ , i.e. Gd 3+ complexes of the compounds of general formula (I), as described throughout this document, and Y + represents a hydrogen atom or a positively charged organic or inorganic counterion.
• the present invention covers compounds of general formula (I), supra, wherein: BHC213028-FC Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH2)2OH and -CH2OCH3; R 2 represents a group selected from (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 (H3C-CH2O)
• the present invention covers compounds of general formula (I), supra, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from (H3C-CH2O)-(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-; BHC213028-FC R 3 and R 4 represent, independently from each other, a hydrogen atom; and stereoisomers,
• the present invention covers compounds of general formula (I), supra, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a -CH2OH group; R 2 represents a group selected from (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-; R 3 and R 4 represent, independently from each other, a hydrogen atom; and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the present invention covers compounds of general formula (I), supra, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom; R 2 represents a group selected from (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-; BHC213028-FC R 3 and R 4 represent, independently from each other, a hydrogen atom; and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom; BHC213028-FC R 2 represents a group selected from 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)-(
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from C 2 -C 5 -alkoxy, (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 -C 3 -alkoxy)
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from C 2 -C 5 -alkoxy, (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 -C 3 -alkoxy)
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, BHC213028-FC X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from C 2 -C 5 -alkoxy, (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 -C
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from 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 )
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a group selected from -CH2OH and -(CH2)2OH; R 2 represents a group selected from 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 (C1-C3-alkoxy)-(CH2)2-O-(CH2)2-O-(CH2)2-O-, wherein said C 1 -C 3 -alkoxy groups and C 2 -C 5 -alk
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a CH 2 group; R 1 represents a hydrogen atom or a group selected from -CH 2 OH and -(CH 2 ) 2 OH; R 2 represents a group selected from 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 BHC213028-FC (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-(CH 2 ) 2 -O-, wherein said C 1 -C 3 -alkoxy groups and C 2
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a -CH 2 OH group; R 2 represents a group selected from 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-, wherein said C 1 -C 3 -alkoxy groups and C 2 -C 5 -alkoxy groups
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, BHC213028-FC X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom; R 2 represents a group selected from 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-, wherein said C 1 -C 3 -alkoxy groups and C 2 -C 5 -alkoxy groups are optionally
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a CH 2 group; R 1 represents a hydrogen atom; R 2 represents a group selected from 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-, wherein said C 1 -C 3 -alkoxy groups and C 2 -C 5 -alkoxy groups are optionally substituted, one, two, three or four times, with a fluor
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from BHC213028-FC wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from C 2 -C 4 -alkoxy, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-, (H 3 C-CH 2 O)-(CH
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; BHC213028-FC R 2 represents a group selected from (H 3 C-CH 2 O)-(CH 2 ) 2 -O-, (H 3 C-CH 2 O)-(CH 2 ) 2 -O-(CH
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from (H3C-CH2O)-(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-; R 3 and R 4 represent, independently from each other, a hydrogen atom;
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, BHC213028-FC X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a -CH 2 OH group; R 2 represents a group selected from (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-; R 3 and R 4 represent, independently from each other, a hydrogen atom; and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salt
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom; R 2 represents a group selected from (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-; R 3 and R 4 represent, independently from each other, a hydrogen atom; and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the present invention covers compounds of general formula (I), supra, in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, BHC213028-FC X represents a CH 2 group; R 1 represents a hydrogen atom; R 2 represents a group selected from (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-; R 3 and R 4 represent, independently from each other, a hydrogen atom; and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the present invention covers compounds of general formula (I), supra, in the form of a sodium (Na + ) salt of a complex with Gd 3+ , wherein Ar, X, R 1 , R 2 , R 3 , and R 4 are defined as described in any of the embodiments above, and stereoisomers, tautomers, hydrates, or solvates thereof, or mixtures of same.
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom; R 2 represents a group selected from 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)-(
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from C 2 -C 5 -alkoxy, (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -O-, (C 1 -C
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH2)2OH and -CH2OCH3; R 2 represents a group selected from C 2 -C 5 -alkoxy, (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -O-, (
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, BHC213028-FC X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from C 2 -C 5 -alkoxy, (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from 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
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH2 and (CH2)2; R 1 represents a hydrogen atom or a group selected from -CH 2 OH and -(CH 2 ) 2 OH; R 2 represents a group selected from C2-C5-alkoxy, (C1-C3-alkoxy)-(CH2)2-O-, (C1-C3-alkoxy)-(CH2)2-O-(CH2)2-O- and (C 1 -C 3 -alkoxy)-(CH 2 ) 2 -O-(CH 2 ) 2 -O-, wherein said C 1 -C 3 -alkoxy groups and C 2 -C
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from BHC213028-FC wherein # indicates the point of attachment to X, X represents a group selected from CH 2 , (CH 2 ) 2 , (CH 2 ) 3 , (CH 2 ) 4 and *-(CH 2 ) 2 -O-CH 2 - # , wherein * indicates the point of attachment to Ar and # indicates the point of attachment to the acetic acid moiety; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from (H 3 C-CH 2 O)-(CH 2 ) 2 -O-, (H 3 C-CH 2 O)-(CH 2 )
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 ; R 2 represents a group selected from (H3C-CH2O)-(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-; R 3 and R 4 represent, independently from
• the present invention covers compounds of general formula (I), supra, in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from , wherein # indicates the point of attachment to X, X represents a group selected from CH 2 and (CH 2 ) 2 ; R 1 represents a hydrogen atom or a -CH2OH group; R 2 represents a group selected from (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-; R 3 and R 4 represent, independently from each other, a hydrogen atom; and stereoisomers, tautomers, N-oxides, hydrate
• the invention relates to compounds of formula (I), wherein: Ar represents a group BHC213028-FC , wherein # indicates the point of attachment to X, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I), wherein: R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 , BHC213028-FC and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I), wherein: R 2 represents a group selected from 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-, wherein said C 1 -C 3 -alkoxy goups and C 2 -C 5 -alkoxy groups are optionally substituted, one, two, three or four times, with a fluorine atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I), wherein: R 3 represents a hydrogen atom and R 4 represents a hydrogen atom or a group selected from 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-, and stereoisomers, tautomers, hydrates, solvates, or salts thereof, or mixtures of same.
• R 1 When all three of R 1 are different from a hydrogen atom, this includes the RRRR, SRRR, RSRR, RRSR, RRRS, SSRR, SRSR, SRRS, RSSR, RSRS, RRSS, RSSS, SRSS, SSRS, SSSR, SSSS stereoisomers of the compounds of formula (I), or mixtures thereof.
• the invention relates to compounds of formula (I) in the form of a complex with Gd 3+ , wherein: Ar represents a group selected from wherein # indicates the point of attachment to X, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a complex with Gd 3+ , wherein: Ar represents a group , wherein # indicates the point of attachment to X, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a complex with Gd 3+ , wherein: R 1 represents a hydrogen atom or a -CH 2 OH group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a complex with Gd 3+ , wherein: R 1 represents a hydrogen atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a complex with Gd 3+ , wherein: R 2 represents a group selected from (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-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group selected from BHC213028-FC wherein # indicates the point of attachment to X, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: Ar represents a group , wherein # indicates the point of attachment to X, BHC213028-FC and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: X represents a group selected from CH 2 and (CH 2 ) 2 , and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: X represents (CH 2 ), and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 1 represents a hydrogen atom or a group selected from C 1 -C 3 -alkyl, -CH 2 OH, -(CH 2 ) 2 OH and -CH 2 OCH 3 , and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 1 represents a hydrogen atom or a group selected from -CH 2 OH and -(CH 2 ) 2 OH, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 1 represents a hydrogen atom or a -CH 2 OH group, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 1 represents a hydrogen atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 2 represents a group selected from 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-, wherein said C1-C3-alkoxy goups and C2-C5-alkoxy groups are optionally substituted, one, two, three or four times, with a fluorine atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 2 represents a group selected from 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-, wherein said C 2 -C 4 -alkoxy group is optionally substituted, one, two, three or four times, with a fluorine atom, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 2 represents a group selected from (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-, and stereoisomers, tautomers, N-oxides, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 3 and R 4 represent, independently from each other, a hydrogen atom or a group selected from 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-, and stereoisomers, tautomers, hydrates, solvates, or salts thereof, or mixtures of same.
• the invention relates to compounds of formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, wherein: R 3 represents a hydrogen atom and R 4 represents a hydrogen atom or a group selected from 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-, and stereoisomers, tautomers, hydrates, solvates, or salts thereof, or mixtures of same.
• Gd 3+ complexes of the compounds of general formula (I) of the present invention demonstrate a valuable complex stability, solubility, uptake into hepatocytes, relaxivity and a valuable tolerability and pharmacokinetic profile, which could not have been predicted.
• Gd 3+ -containing compounds of general formula (I) of the present invention have surprisingly been found to effectively taken up into hepatocytes and providing a high relaxivity while maintaining a pharmacokinetic, good safety and tolerability profile and it is possible therefore that said compounds be used for diagnostic imaging.
• a further aspect of the invention is the use of a compound of general formula (I), supra, in the form of a complex with Gd 3+ for diagnostic imaging.
• a further aspect of the invention is the use of a Gd 3+ complex of a compound of general formula (I), supra, for diagnostic imaging.
• BHC213028-FC A further aspect of the invention is the use of a complex of a compound of general formula (I), in the form of a metal complex with a metal ion suitable for computed tomography, supra, for diagnostic imaging.
• a further aspect of the invention are compounds of general formula (I) in the form of a complex with Gd 3+ for use in computed tomography imaging, preferably of the vascular, renal or of the hepatobiliary system or of the gastrointestinal tract, more preferably for computed tomography imaging of the liver.
• a further aspect of the invention are Gd 3+ complexes of compounds of general formula (I), supra, for use in computed tomography imaging, preferably of the vascular, renal or of the hepatobiliary system or of the gastrointestinal tract, more preferably for computed tomography imaging of the liver.
• the invention also contains compounds of general formula (I) for the manufacture of diagnostic agents.
• the invention also contains compounds of general formula (I) in the form of a complex with Gd 3+ for the manufacture of diagnostic agents.
• a further aspect of the invention is the use of the compounds of general formula (I) or mixtures thereof for the manufacture of diagnostic agents.
• a further aspect of the invention is the use of the compounds of general formula (I) in the form of a complex with Gd 3+ or mixtures thereof for the manufacture of diagnostic agents.
• the invention also contains compounds of general formula (I) in the form of a metal complex with a metal ion suitable for computed tomography, for the manufacture of diagnostic agents.
• Scheme 2 Literature for the synthetic procedures shown in scheme 1 and 2 can be found (see for example L. Dai, J. Zhang, Y. Chen,L.E. Mackenzie, R. Pal, and G.-L. Law Inorg. Chem.
• the present invention also relates to a method of preparing a compound of general formula (I) in the form of a complex with Gd 3+ , i.e.
• a Gd 3+ complex of a compound of general formula (I), as defined supra said method comprising the step of allowing a compound of general formula (I): in which Ar, X and R 1 are as defined for the compounds of general formula (I), supra, to react with a Gadolinium-(III)-salt, thereby giving a compound of general formula (I), in which Ar, X and R 1 are as defined for the compounds of general formula (I), supra, in the form of a complex with Gd 3+ , i.e. a Gd 3+ complex of a compound of general formula (I).
• the present invention also relates to a method of preparing a compound of general formula (I) in the form of a complex with Gd 3+ , i.e.
• a Gd 3+ complex of a compound of general formula (I) as defined supra comprising the step of allowing a compound of general formula (I): in which Ar, X and R 1 are as defined for the compounds of general formula (I), supra, to react with gadolinium (III) oxide, thereby giving a compound of general formula (I), in which Ar, X and R 1 are as defined for the compounds of general formula (I), supra, in the form of a complex with Gd 3+ , i.e. a Gd 3+ complex of a compound of general formula (I).
• DESCRIPTION OF THE FIGURES Figure 1 Chemical stability of selected Examples during heat sterilization.
• Table 1 lists the abbreviations used in this paragraph and in the Examples section as far as they are not explained within the text body. Other abbreviations have their meanings customary per se to the skilled person.
• Table 1 Abbreviations BHC213028-FC BHC213028-FC Other abbreviations have their meanings customary per se to the skilled person.
• the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
• a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
• purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
• a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g.
• the residue was purified by reversed phase (Instrument: Agela-H1000GC500; Column: Welch Ultimate XB_C18 I.D.100mm*H400mm,20/40 ⁇ m; 100 ⁇ ; eluent A: water (0.1% formic acid), eluent B: acetonitrile; gradient:10%-25%,35min;25%,23min; flow: 400 ml/min; temperature: room temperature; Detector: UV 220/254 nm) to yield 19,1 g (30 % yield) of the title compound.
• the mixture was concentrated under reduced pressure, diluted in DCM/EtOH 9:1 and extracted with a mixture of sodium bicarbonate solution and brine.
• the water phase was extracted 2 times with DCM/EtOH (9:1).
• the combined organic layers were dried by filtration through a water repellent filter and concentrated under reduced pressure to yield 640 mg (80% purity, 76% yield) of the title compound.
• Example 4 Gadolinium-2,2',2''- ⁇ (2S)-10-(carboxymethyl)-2-[4-(2-ethoxyethoxy)benzyl]-1,4,7,10- tetraazacyclododecane-1,4,7-triyl ⁇ triacetate
• aqueous sodium hydroxide 2 M
• Example 7 Gadolinium-2,2',2''-[10-(carboxymethyl)-2-(4-ethoxybenzyl)-1,4,7,10- tetraazacyclododecane-1,4,7-triyl]triacetate
• BHC213028-FC Table 3 Relaxivities of investigated compounds in water and human plasma at 1.41 T and relaxivities of Reference compounds 1-3 (RC1-RC3) at 1.5 T in water and bovine plasma. All values are measured at 37°C and normalized to Gd and given in L mmol -1 s -1 . * values are depicted in L mmol -1 s -1 ⁇ Relaxivities from reference compounds from Rohrer et. al. at 1.5 T (Invest. Radiol.2005; 40, 11: 715-724) and in bovine plasma (Kreaber GmbH, Pharmaceutical Raw Material, Ellerbek, Germany) instead of human plasma
• the prepared rat hepatocyte plates were incubated with test solutions (500 ⁇ L/well) at 37°C for 10 min using a thermoshaker (Fa. Grant Bio, PHMP). Triplicates were performed for each test item. After incubating the cells were washed once with cold PBS buffer (Fa. Gibco, Dulbeccos PBS (+)). After washing the intact hepatocytes were lysed by addition of 500 ⁇ L cold 0.01 % Triton-X 100 in Millipore water for 1h. The strongly hypo-osmolar water led to cell membrane rupture and the release of the intracellular Gd- compound.
• BHC213028-FC Table 4 Uptake of compounds into freshly isolated rat hepatocytes in % compared to reference compound 1 (RC1, Gd-EOB-DTPA). n.d. not determined
• Example F Uptake into stable transfected OATP1B1 HEK 293 cells Human stable transfected OATP1B1 human embryonic kidney 293 cells (OATP1B1 HEK 293, SLCO1B1, Entrez Gene ID: 10599) were used (Leonhardt M et al. Drug Metab Dispos.2010 Jul;38(7):1024-8).
• the following culture medium was used: 500 mL DMEM (Dulbecco's Modified Eagle Medium – high Glucose, D6429), 50 mL FCS (fetal bovine serum, Fa. Sigma, F7524), 5.8 mL G418 (Geneticin, Fa. Gibco 10131-027) and 5 mL Pen-Strep. (Penicillin- Streptomycin, Fa. Gibco, Ref 15140-122). Cryopreserved cells were shortly thawed in water bath and diluted in 10 mL warm culture medium (37°C). After medium change the cells were grown for 3d in a 25 cm 2 cell culture flask. After 3 to 5d the cells were transferred into 75 cm 2 flasks.
• the cells were incubated with 1.5 mL trypsin (Trypsin-EDTA (1x) 0,05%, Ref 25300-054100ml, Fa. Gibco) for 3-5min in the incubator (37°C, 5% CO 2 and 95% oxygen). After centrifugation and washing with medium the cells were counted (50 ⁇ L cell suspension and 50 ⁇ L trypan blue (Trypan Blue Solution, 93595-50ml, Fa. Fluka). Cells were cultured (1x10 5 cells/well) in poly-D-lysine coated 24-well plates (Fa. Corning, Ref: 354414) in 1.5 mL medium per well.
• the transport buffer contains the following ingredients: 500 mL HBSS (Hank ⁇ s balanced salt solution, Hyclone, SH30268.01), 5 mL HEPES buffer (4-(2-hydroxyethyl)-1-piperazine- ethanesulfonic acid, Gibco 15630-056) and 3.9 mL glucose (Sigma, G8270-100, 90 g/200mL MilliQ water). All test items were prepared in transport buffer at a final concentration of 100 ⁇ M from stock solutions (180 to 500 mM concentration). The OATP1B1 HEK 293 cells were incubated with test solutions (test item in transport buffer 500 ⁇ L) for 40min on a thermoshaker without shaking (PHMP, Fa. Grant Bio).
• PHMP Fa. Grant Bio
• Gadolinium concentrations in the lysate were measured using ICP-MS (Agilent 8900, singleQuad, integr. Time 0.3 s, no gas, 5 replicates, Gd m/z 157, Tb m/z 159) the samples were centrifuged at 4000 rpm for 2min.
• Gd-EOB-DTPA gadoxetate
• the OATP1B1 HEK 293 uptake of the test compound is calculated relative to gadoxetate (resulting in the unit % of RC1). The results are summarized in Table 5.
• BHC213028-FC Table 5 Uptake of compounds into stably transfected OATP1B1-HEK 293 cells in % compared to reference compound 1 (RC1, Gd-EOB-DTPA). n.d. not determined
• RC1, Gd-EOB-DTPA reference compound 1
• Example G Uptake into stable transfected OATP1B3 HEK 293 cells Human transfected OATP1B3 human embryonic kidney 293 cells (OATP1B3 HEK 293, SLCO1B3, Entrez Gene ID: 28234) were used (Leonhardt M et al. Drug Metab Dispos.2010 Jul;38(7):1024-8).
• the following culture medium was used: 500 mL DMEM (Dulbecco's Modified Eagle Medium – high Glucose, D6429), 50 mL FCS (fetal bovine serum, Fa. Sigma, F7524), 5.8 mL G418 (Geneticin, Fa. Gibco 10131-027) and 5 mL Pen-Strep. (Penicillin- Streptomycin, Fa. Gibco, Ref 15140-122). Cryopreserved cells were shortly thawed in water bath and diluted in 10 mL warm culture medium (37°C). After medium change the cells were grown for 3d in a 25 cm 2 cell culture flask. After 3 to 5d the cells were transferred into 75 cm 2 flasks.
• the transport buffer contains the following ingredients: 500 mL HBSS (Hank ⁇ s balanced salt solution, Hyclone, SH30268.01), 5 mL HEPES buffer (4-(2- hydroxyethyl)-1-piperazine-ethanesulfonic acid, Gibco 15630-056) and 3.9 mL glucose (Sigma, G8270-100, 90 g/200mL MilliQ water). All test items were prepared in transport buffer at a final concentration of 100 ⁇ M from stock solutions (180 to 500 mM concentration). The OATP1B3 HEK 293 cells were incubated with test solutions (test item in transport buffer 500 ⁇ L) for 40min on a thermoshaker without shaking (PHMP, Fa. Grant Bio).
• PHMP Fa. Grant Bio
• Gadolinium concentrations in the lysate were measured using ICP-MS (Agilent 8900, singleQuad, integr. Time 0.3 s, no gas, 5 replicates, Gd m/z 157, Tb m/z 159) the samples were centrifuged at 4000 rpm for 2 min.
• Gd-EOB-DTPA gadoxetate
• the OATP1B3 HEK 293 uptake of the test compound is calculated relative to gadoxetate (resulting in the unit % of RC1). The results are summarized in Table 6.
• BHC213028-FC Table 6 Uptake of compounds into stably transfected OATP1B3-HEK 293 cells in % compared to reference compound 1 (RC1, Gd-EOB-DTPA).
• CT imaging was performed using a Dual Source CT Scanner (Somatom Force, Siemens Healthcare, Erlangen, Germany) operating in single source mode.
• the scan parameters were 120 kV tube voltage, 200 mAs, 0.5s rotation time and image reconstruction as performed using a Br36 kernel, 1 mm slice thickness and a field of view of 240 mm2.
• CT imaging showed a high and very similar x-ray signal enhancement of all 6 Gd containing test samples.
• the signal enhancement was higher than that of RC4 formulated at identical molar attenuating element (iodine) concentration.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Organic Chemistry (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• Epidemiology (AREA)
• Radiology & Medical Imaging (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Chemistry (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Applications Claiming Priority (2)

Publications (1)

Family

ID=83270970

Family Applications (2)

Family Applications Before (1)

Country Status (2)

Families Citing this family (1)

Family Cites Families (14)

• 2022
  • 2022-09-09 EP EP22194915.9A patent/EP4335840A1/de active Pending
• 2023
  • 2023-09-08 EP EP23767910.5A patent/EP4584251A1/de active Pending
  • 2023-09-08 WO PCT/EP2023/074771 patent/WO2024052549A1/en not_active Ceased

Also Published As

Similar Documents

Legal Events