• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    Tetraazamacrocyclic ligands and the corresponding nickel complexes useful as contrast agents. Azamacrocyclic ligands that have non-adjacent nitrogens connected with ethylene chains and that are reinforced with an ethylene/propylene bridge that crosses the structure and that contain amide groups with aromatic rings substituted with CF3 or F groups hanging from the macrocycle, the corresponding nickel complexes of said ligands, and compositions comprising them. The complexes have the proper properties to generate contrast by means of the CEST and nucleus19 F mechanisms and are therefore especially useful as MRI contrast agents for diagnostic purposes. (Machine-translation by Google Translate, not legally binding)
    公开号:ES2759316A1
    申请号:ES201831074
    申请日:2018-11-07
    公开日:2020-05-08
    发明作者:Iglesias Carlos Platas；Gomez David Esteban；Paradela Rosa Pujales
    申请人:Universidade da Coruna；
    IPC主号:
    专利说明:

    [0001]
    [0002] Tetraazamacrocyclic ligands and corresponding nickel complexes useful as contrast agents
    [0003]
    [0004] The present invention relates to complexes of a transition metal (Ni) and a tetraazamacrocyclic ligand, compositions containing them, their preparation procedures, as well as their use as contrast agents for diagnostic imaging.
    [0005]
    [0006] STATE OF THE ART
    [0007]
    [0008] Magnetic resonance imaging (MRI) is a non-invasive technique for image acquisition that uses the phenomenon of nuclear magnetic resonance (NMR). It is mainly used in clinical medicine to examine almost all types of organs and tissues, and is considered one of the most valuable imaging techniques for diagnostic purposes. The contrast of the image obtained on MRI is a projection of intensity in three dimensions of the NMR signal of certain atomic nuclei, in particular, the protons of water molecules present in a given volume of tissue. It essentially depends on the differences in intensity of the water proton signals in the different tissues and on the longitudinal (T1) or transverse (T2) relaxation times of said protons. The greater the differences in proton density and the relaxation time of the nuclei that are present in the examined tissues, the greater the contrast in the image obtained.
    [0009]
    [0010] The function of contrast agents is to accentuate the intensities obtained and improve their specificity. Generally, the contrast agents used in MRI are small metal complexes, and may be a macrocyclic entity that houses the metal, or linear chelates, inside its cavity. The metals used for this application must have a paramagnetic, superparamagnetic or ferromagnetic character.
    [0011] Most of the contrast agents used in the clinic are Gd3 + paramagnetic metal ion complexes capable of reducing the longitudinal relaxation time (T1). The first contrast agent approved for in vivo use was the Gd3 + meglumine gadopentetate (NMG) 2 complex [Gd (dtpa) (H2O)] (Magnevist ®). Other complexes such as meglumine gadoterate (NMG) [Gd (dota) (H2O)] (Dotarem®) and other derivatives of the dtpa5- and dota4- ligands were subsequently approved. However, gadolinium-based contrast agents have some limitations since a connection has been established between the use of gadolinium contrast agents in patients with kidney damage and nephrogenic systemic fibrosis (FSN).
    [0012]
    [0013] Different alternatives to Gd3 + have been explored in order to obtain less toxic contrast agents. ' Unlike the Gd3 + ion, transition metals such as manganese, iron, and cobalt can exist stably in different oxidation states. Thus, the use of contrast agents that use the pair of oxidation states Mn2 + / Mn3 + to cause a change in the relaxation capacity as a function of the redox potential is known. As an example, Silvio Aime et al described contrast agents based on the manganese redox couple (II / III) (cf. S. Aime et al., P (O2) -Responsive MRI Contrast Agent Based on the Redox Switch of Manganese (II / III) - Porphyrin Complexes, Angew. Chem. Int. Ed. 2000, vol. 39, pp. 747-750).
    [0014]
    [0015] Paramagnetic complexes of divalent Co2 + and Ni2 + ions with tetraazamacrocyclic systems provided with acetamide groups hanging from their structure are also known. These complexes are of interest for their application as contrast agents type CEST 1H (Chemical Exchange Saturation Transfer, in English) due to the presence of protons capable of undergoing phenomena of exchange with water molecules of the solvent. These complexes enable the contrast to be activated / deactivated (cf. S. J Dorazio et al., "CoCEST: cobalt (II) amide-appended for CEST MRI contrast agents" Chem. Commun., 2013, vol. 49, pp. 10025-10027 ; and AO Olatunde et al., "The NiCEST Approach: Nickel (II) For CEST MRI Contrast Agents", J. Am.Chem. Soc. 2012, vol.
    [0016] 134, pp. 18503-18505).
    [0017] Probes based on 19F have also been used, which represent the best alternative to 1H given the high sensitivity of the 19F nucleus (83% with respect to 1H). These probes have the advantage that the concentration of fluorine in vivo is negligible, which eliminates any background signal and allows easier quantification of the MRI signal. However, 19F has fairly long relaxation times, so paramagnetic metal ions have been used to speed up relaxation times.
    [0018]
    [0019] Some examples of dual 1H / 19F complexes based on Ln3 + lanthanide ions have recently been reported. The combination of the CEST 1H and 19F response in a single contrast agent allows combining the advantages of two modalities of contrast agents (cf. N. Cakic et al., "Paramagnetic lanthanide chelates for multicontrast MRI", Chem Comm 2016, vol . 52, pp. 9224-9227). However, Ln3 + based probes have the drawback of their potential toxicity.
    [0020]
    [0021] Therefore, there is still a need to find contrast agents to obtain images of individual tissues and organs and their respective anatomical pathological and functional changes, which have a high sensitivity, and which allow reducing the acquisition times of resonance images. magnetic, as well as having a high stability to eliminate the toxicity associated with the release of the metal ion.
    [0022]
    [0023] EXPLANATION OF THE INVENTION
    [0024]
    [0025] The present inventors have found nickel complexes with certain ligands that exhibit a very stable complexation of the metal ion, meaning that they exhibit a high level of selectivity for the relevant paramagnetic ions as opposed to physiological ions. Furthermore, these compounds have the appropriate properties to generate contrast through the CEST 1H and 19F nucleus mechanisms, which allow improving image sensitivity and quality, producing brighter images and obtaining relevant information in a short period of time. Because contrast is generated using the CEST mechanism, it is possible to activate / deactivate contrast by applying a radiofrequency pulse. In addition, the absence of endogenous 19F signal also allows obtaining images lacking background noise as well as quantification of the agent concentration. These properties make the complexes of the present invention especially useful as MRI contrast agents for diagnostic purposes.
    [0026]
    [0027] The ligands of said dual complexes are characterized in that they are azamacrocycles that have non-adjacent nitrogens connected by ethylenic chains and that are reinforced with an ethylene / propylene bridge that crosses the structure. They also contain amide groups with aromatic rings substituted with CF3 / F groups hanging from the macrocycle.
    [0028]
    [0029] Thus, a first aspect of the present invention is related to a compound / ligand of formula (L) or a pharmaceutically acceptable salt thereof,
    [0030]
    [0031]
    [0032]
    [0033] where: R1 is selected from the group consisting of: -OH ,; -HN-CH2-COOH, -HN-C1-C6-alkyl, -HN-NH-C1-C6-alkyl, and
    [0034]
    [0035]
    [0036]
    [0037]
    [0038] R2 and R4 are independently selected from the group consisting of F and CF3: R3 and R5 are independently selected from the group consisting of: H, (C1-C4) -alkyl; (C1-C4) -alkoxy, and a halogen selected from Cl, Br and I; m is an integer selected from 1,2, and 3; r is an integer selected from 2, 3, and 4; the sum of m and r is 5; n is an integer selected from 1,2, and 3; o is an integer selected from 2, 3, and 4; the sum of nyo is 5; s is an integer selected from 1 to 2; with the proviso that when R2 is F, m is 2 or 3 and r is 2 or 3, and when R4 is F, n is 2 or 3 and i is 2 or 3.
    [0039] In a particular embodiment, R2 is CF3. In another particular embodiment, R2 is CF3 and m is 2. In another particular embodiment, the two CF3 groups are in the meta position on the benzene ring. In another particular embodiment, R2 is CF3 and m is 1. In another particular embodiment, the CF3 group is in the para position on the benzene ring.
    [0040]
    [0041] In another particular embodiment, the compound / ligand of formula (L) has the formula (L ')
    [0042]
    [0043]
    [0044]
    [0045] where: R1 is selected from the group consisting of: -OH; -HN-CH2-COOH; and
    [0046]
    [0047]
    [0048]
    [0049] m and n are an integer independently selected from 1 and 2. Ligand L 'is a particular embodiment of ligand L where, among other limitations, R2 and R4 are CF3 and R3 and R5 are H.
    [0050]
    [0051] By the term "pharmaceutically acceptable salts" in compounds L and L 'of the present invention is meant those salts that according to medical criteria are suitable for contacting tissues or organs of the human and animal body without causing toxicity, irritation, allergic response unwanted and proportionate to the benefit / risk ratio. The salts can be prepared in situ or during the isolation and / or purification of the compounds of the present invention or in a separate step.
    [0052]
    [0053] Generally, the ligands of the present invention form salts with acids since the ligand is basic and the protons of the cycle are protonated very easily giving rise to ammonium salts. Examples of acids suitable for the formation of Salts with these ligands are formic acid and trifluoroacetic acid. These ligands can also form salts with appropriate bases, in the case where R1 is selected from OH and -HN-CH2-COOH. Examples of suitable bases are primary, secondary, tertiary amines, basic amino acids, in particular ethanolamine, diethanolamine, morpholine, lysine or arginine, as well as sodium, potassium or magnesium hydroxides, carbonates or bicarbonates.
    [0054]
    [0055] In a particular embodiment, the compounds of formula
    [0056]
    [0057]
    [0058]
    [0059]
    [0060] In another particular embodiment, the compounds of formula (L1) are selected from the group consisting of 1,8 - ((4- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecane (L1a ) and 1,8 - ((3,5- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecane (L1b).
    [0061] In another particular embodiment, the compounds of formula
    [0062]
    [0063]
    [0064]
    [0065]
    [0066] In another particular embodiment, the compounds of formula (L2) are selected from the group consisting of: 2- (11- (2-oxo-2 - ((4- (trifluoromethyl) phenyl) amino) ethyl) -1,4 acid , 8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) acetic (L2a) and 2- (11- (2 - ((3,5-bis (trifluoromethyl) phenyl) amino) -2-oxoethyl) acid -1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) acetic (L2b) having the following formulas:
    [0067]
    [0068]
    [0069]
    [0070]
    [0071] Ligands of formula L are soluble in water, in particular compounds of formula L2 are especially advantageous for their high solubility in water.
    [0072] Another aspect of the present invention is related to processes for the preparation of the compounds of formula (L). A first procedure to prepare compounds of formula L where R1 is
    [0073]
    [0074]
    [0075]
    [0076]
    [0077] where R4, R5, n and o are as defined above, comprises subjecting a compound of formula (V) to an alkylation reaction with a compound of formula (III),
    [0078]
    [0079]
    [0080]
    [0081] (V) (III)
    [0082]
    [0083] where: X is a halogen; R6 is selected from the group consisting of F and CF3; R7 is selected from the group consisting of: H, (C1-C4) -alkyl; (C1-C4) -alkoxy and a halogen selected from Cl, Br and I; z is an integer selected from 1, 2, and 3; q is an integer selected from 2, 3, and 4; where the sum of z and q is 5, with the proviso that when R6 is F, z is 2 or 3 and q is 2 or 3.
    [0084]
    [0085] In a particular embodiment, X is Br. In another particular embodiment the alkylation of compound (V) is carried out in acetonitrile in the presence of a base such as carbonate of an alkali metal. In another particular embodiment the base is potassium carbonate. In another particular embodiment, z is 1. In another particular embodiment, z is 2.
    [0086]
    [0087] The alkylation reaction can also be carried out with other solvents such as toluene or dimethylformamide and with other bases such as sodium carbonate, alkali metal bicarbonates such as sodium or potassium, or non-nucleophilic amines such as diisopropylethylamine or triethylamine.
    [0088]
    [0089] In a particular embodiment when the compound of formula L is the compound of formula (L) or
    [0090]
    [0091]
    [0092]
    [0093] (V) (III ')
    [0094]
    [0095] A second procedure for the preparation of compounds of formula L where R1 is -OH comprises a) subjecting a compound of formula (V) to a sequential alkylation reaction first with a compound of formula (VI) to give a compound of formula ( IV),
    [0096]
    [0097]
    [0098]
    [0099] (VI) (IV)
    [0100]
    [0101] and subsequently with a compound of formula (III) as defined above to give the compound of formula (II); and b) subjecting the compound (II) obtained in step a) to a hydrolysis reaction with an acid selected from trifluoroacetic acid, formic acid, and aqueous hydrochloric acid to give the compound of formula L where R1 is OH.
    [0102]
    [0103]
    [0104] In the compound of formula (VI), Y is a halogen; and in the compound of formula (II) R2 is selected from the group consisting of F and CF3: R3 is selected from the group consisting of: H, (C1-C4) -alkyl; (C1-C4) -alkoxy and a halogen selected from Cl, Br and I; m is an integer selected from 1,2, and 3; r is an integer selected from 2, 3, and 4; where the sum of m and r is 5 with the proviso that when in the compound of formula (III) R6esF, z is 2 or 3 and q is 2 or 3; and R2 is F, m is 2 or 3 and r is 2 or 3.
    [0105]
    [0106] When R1 in the ligand of formula L is -HN-CH2-COOH, the first alkylation of the 1,4,8,11-tetraazabicyclo [6.6.2] hexadecane precursor can be carried out by reaction with tert-butyl (2-chloroacetyl ) glycinate.
    [0107]
    [0108] Compounds of formula L where R1 is HN-CH2-COOH, -HN-C1-C6 alkyl, or -HN-NH-C1-C6 alkyl, can be obtained by subjecting the compound of formula L where R1 is OH obtained prior to a reaction with the corresponding amine.
    [0109]
    [0110] The compounds of formula (III) and (VI) are either known, or can be prepared by methods analogous to those of the known compounds.
    [0111]
    [0112] In another particular embodiment the sequential alkylation of compound (V) first by reaction with compound (VI) and subsequently with compound (IV) is carried out in acetonitrile. In another particular embodiment, the second alkylation is carried out in the presence of a base such as carbonate of an alkali metal. In another particular embodiment the base is potassium carbonate.
    [0113]
    [0114] The hydrolysis step of the compound of formula (II) to give rise to the compound of formula (L) is carried out using trifluoroacetic acid, formic acid or acid aqueous hydrochloric. The reaction can also be carried out in the presence of solvent, for example trifluoroacetic acid / dichloromethane can be used or for example using only formic acid. The reaction is generally carried out at high temperatures, in particular at the reflux temperature of the reaction mixture.
    [0115]
    [0116] In a particular embodiment, when the compound of formula (L) or
    [0117]
    [0118]
    [0119] By the term halogen in the compounds of formula (VI), (III) and (III ') is meant an atom which is selected from chlorine, bromine and iodine. In a particular embodiment, Y is Br. In another particular embodiment, X is Cl.
    [0120]
    [0121] Another aspect of the present invention is related to a Ni2 + complex with the ligand of formula (L) as defined above having the formula [Ni (L)] (Z) p, where: Z is an anion selected from chloride , triflate and nitrate; and p is an integer that is selected from 1 to 2. In a particular embodiment the complex [NiL] (Z) p is one where the ligand (L) is L '. In another particular embodiment the complex [NiL] (Z) p is that where the ligand (L) is L1. In a particular embodiment the [NiL] (Z) p complex is one where the ligand (L) is L2.
    [0122]
    [0123] Another aspect of the present invention is related to a process for the preparation of the complexes of formula [NiL] (Z) p which comprises reacting ligand L with a nickel salt in the presence of a suitable solvent. In a particular embodiment, the reaction temperature is between 100-160 ° C. In another particular embodiment, the preparation of the complex is carried out at a temperature of between 150-160 ° C. In another particular embodiment, the nickel salt is selected from Ni (NO3) 26H2O, NiCl2 and Ni (CF3SO2) 2. In another particular embodiment, the nickel salt is selected from Ni (NO3) 26H2O and NiCl2. In another particular embodiment, the solvent used for the preparation of the salt is n-butanol.
    [0124]
    [0125] Another aspect of the present invention is related to a composition comprising one or more of the metal complexes defined above, together with one or more physiologically acceptable additives. Physiologically acceptable additives are those that are suitable for use in contact with a tissue or organ of the human or animal body without causing excessive toxicity, irritation or allergic response or other problems or complications.
    [0126]
    [0127] In a particular embodiment, the composition comprises one or more of the above defined [NiL] (Z) p metal complexes together with one or more nonionic surfactants and physiologically acceptable additives. Examples of suitable surfactants are for example lecithin, sorbitan ethoxylate monolaurate (Tween 20®) or sorbitan ethoxylate monooleate (Tween 80®). Suitable additives are, for example, buffers physiologically safe (such as tromethamine), small additions of complex formers (such as diethylene triamine pentaacetic acid) and, optionally, electrolytes (such as sodium chloride) or antioxidants such as ascorbic acid.
    [0128]
    [0129] In a particular embodiment, the composition is one where the complex together with one or more physiologically acceptable additives and, optionally, nonionic surfactants, is dissolved or suspended in water, physiological saline and / or protein solution, such as eg human serum albumin.
    [0130]
    [0131] The composition of the invention can be prepared by known methods. In particular, it can be prepared by incorporation of the complexes of the present invention, optionally with incorporation of usual physiologically acceptable additives in galenic in an aqueous medium where they are dissolved and then sterilized. The compositions of the invention should be practically free of non-complexed metal ions with a toxic effect. This can be ensured for example with the aid of color indicators such as xylenol orange by control titrations during the production process. The water solubility of the complexes of the invention is good, that of the complexes with the ligands of formula L2 being especially good.
    [0132]
    [0133] Another aspect of the present invention is related to the complex of formula:
    [0134] [NiL] (Z) p as defined above for use as a contrast agent in imaging of an organ and / or tissue of a human or animal body by nuclear magnetic resonance. Also forming part of the present invention is the composition comprising one or more of the metal complexes defined above together with one or more physiologically acceptable additives as defined above, for use as a contrast agent in the imaging of an organ and / or tissue from a human or animal body by nuclear magnetic resonance. These latter two aspects of the invention may also be formulated as use of a complex of formula [NiL] (Z) p as defined above or of a composition comprising one or more of these metal complexes together with one or more physiologically additives acceptable, for the preparation of a contrast agent for imaging an organ and / or tissue from a human or animal body by nuclear magnetic resonance. These aspects of the invention may also be formulated as a method of imaging an organ and / or tissue of a human or animal body by nuclear magnetic resonance imaging comprising the administration to the subject's area of interest of a complex of formula [ NiL] (Z) p as defined above or of a composition comprising one or more of these metal complexes together with one or more physiologically acceptable additives; and the subsequent acquisition of one or more images of the region of interest of the human or animal body.
    [0135]
    [0136] Magnetic resonance imaging is a very useful tool, for example to detect, diagnose and monitor various diseases such as cancer. In a particular embodiment, the images obtained are used for the diagnosis of a disease, that is, the complexes or the compositions comprising them according to the invention are for use in a method of diagnostic imaging of a region of interest (tissue and / or or organ) of a human or animal body. In a particular embodiment, the images are of the hepatobiliary system of a human or animal body. In a particular embodiment, the composition comprising one or more of these metal complexes of the present invention for use as defined above is for enteral or parenteral application.
    [0137]
    [0138] Throughout the description and claims, the word "comprises" and its variants are not intended to exclude other technical characteristics, additives, components or steps. Furthermore, the word "comprises" includes the case "consists of". For those skilled in the art, other objects, advantages, and features of the invention will emerge in part from the description and in part from the practice of the invention. The following examples and drawings are provided by way of illustration, and are not intended to be limiting of the present invention. Furthermore, the present invention covers all possible combinations of particular and preferred embodiments indicated herein.
    [0139] BRIEF DESCRIPTION OF THE DRAWINGS
    [0140]
    [0141] FIG. 1: 19F NMR spectra (282 MHz, 298 K) for the nickel complexes of the Ni2 + complexes of Examples 8 ([NiL2a] (NO3)), 9 ([NiL2b] Cl), and 11 ([NiL1b ] Cl2).
    [0142]
    [0143] FIGs. 2a-2d: CEST experiments obtained for (15 mM) in H2O: CD3CN (4: 1 mix) of the complexes [NiL2a] (NO3), [NiL2b] Cl.
    [0144]
    [0145] FIG. 3: 19F magnetic resonance phantom images of the [NiL2a] (NO3), [NiL2b] Cl complexes.
    [0146]
    [0147] FIG: 4: Structure of the complex [NiL2a] (NO3) determined by X-ray diffraction.
    [0148]
    [0149] FIG. 5: UV-Vis absorption spectrum of the complex [NiL2a] in 4M HCl recorded immediately after dissolving the sample and after 24 h. The insert corresponds to the mass spectrum of the solution recorded after 5 days.
    [0150]
    [0151] EXAMPLES
    [0152]
    [0153] The 2-chloro-N- (4- (trifluoromethyl) phenyl) acetamide precursor of formula (IIIa) was prepared as described in Q. Ji, D. Yang et al., "Design, synthesis and evaluation of novel quinazoline-2 , 4-dione derivatives as chitin synthase inhibitors and antifungal agents " Bioorg. Med. Chem., 2014, vol. 22, pp. 3405-3413.
    [0154]
    [0155]
    [0156]
    [0157]
    [0158] The 2-chloro-N- (3,5-di-trifluoromethyl-phenyl) acetamide precursor of formula (IIIb) was prepared as described in Z. Xiaohe et al., "Synthesis, Biological Evaluation and Molecular Modeling Studies N-aryl -2-arylthioacetamides as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors " Chem. Biol. Drug Des. 2010, vol. 76, pp. 330-339.
    [0159]
    [0160]
    [0161] The tert-butyl (2-doroacetyl) glycinate precursor of formula (IIIc) is prepared as described in MM Ali, et al., "Albumin-binding PARACEST agents" J. Biol. Inorg. Chem. 2007, vol. 12, pp. 855-865.
    [0162]
    [0163]
    [0164]
    [0165]
    [0166] Precursors with other halogens can be prepared analogously. Similarly, other precursors of formula (III) can be prepared in an analogous manner.
    [0167]
    [0168] The formulas NiLn (Z) p or NiLn have been used interchangeably in the examples to refer to the complexes of the invention.
    [0169]
    [0170] Example 1: Preparation of the intermediate compound tert-butyl 2- (1,4,8,11-tetraazabicyclo r6.6.21hexadecan-4-yl) acetate (IV)
    [0171]
    [0172] The 1,4,8,11-tetraazabicyclo [6.6.2] hexadecane precursor (0.3408 g, 1,506 mmol) was dissolved in acetonitrile (15 mL). To this solution another tert-butyl bromoacetate (234 uL, 1.05 eq) in CH3CN (35 mL) was added dropwise. The reaction mixture was stirred at room temperature for 12 hours. The solvent was removed on the rotary evaporator giving rise to the formation of a hygroscopic white foam that was purified by column chromatography on silica gel using a mixture of CHCl3 and methanol (gradient from 0 to 10% methanol). 0.2416 g of the product (47%) were obtained. 1H NMR (300 MHz, CDCfe): 5H (ppm): 11.29 (s, 1H, NH), 9.34 (s, 1H, NH), 3.64-2.40 (m, 20H, CH2), 1.90-1.26 (m, 16H , CH2 Q'CCH3). Mass spectrometry (ESI-) m / z (% BPI): 341.29 (100) ([C18H37N4O2I +); 285.23 (25) ([C14H29N4O2I +).
    [0173]
    [0174] Example 2: Preparation of 1-tert-butoxycarboxymethyl) - 8 - ((4- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.21hexadecane (IIa)
    [0175]
    [0176] The intermediate tert-butyl 2- (1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) acetate (IV) (0.1406 g, 0.413 mmol), K2CO3 (3 equivalents) and the precursor were used 2-chloro-N- (4- (trifluoromethyl) phenyl) acetamide of formula (IIIa) (0.540 mmol, 1.3 equivalents).
    [0177]
    [0178] The tert-butyl 2- (1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) acetate (IV) precursor was dissolved in acetonitrile (15 mL) and a solution of 2 -chloro-N- (4- (trifluoromethyl) phenyl) acetamide of formula (IIIa) at room temperature. The mixture was stirred at room temperature for 7 days until the alkylation was complete. The mixture was filtered and the solvent was removed in vacuo. The yellow solid obtained after removal of the solvent was purified by column chromatography using neutral alumina. A CHCl3 / methanol mixture was used as the mobile phase, using a 0 to 5% methanol gradient. 0.1657 g of 4a (74%) were obtained. 1H NMR (300 MHz, CDCl3): 5H (ppm): 10.93 (s, 1H, NH), 10.72 (s, 1H, NH), 8.07-8.05 (d, 2H, CHar), 7.52-7.50 (d, 2H , CHar), 3.99-3.78 (dd, 2H, CH2), 3.51-3.44 (dd, 2H, CH2), 3.30-2.73 (m, 20H, CH2), 1.45 (s, 9H, CH2), 1.35-1.18 ( m, 4H, CH2). Mass spectrometry (ESI-) m / z (% BPI): 542.33 (100) ([C27H43F3N5O3I +).
    [0179]
    [0180] Example 3: Preparation of 1-tert-butoxycarboxymethyl) - 8 - ((3,5- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.21hexadecane (IIb)
    [0181]
    [0182] The compound tert-butyl 2- (1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) acetate (IV) (0.101 g, 0.297 mmol), K2CO3 (3 equivalents) and the precursor were used 2-chloro-N- (3,5-di-trifluoromethyl-phenyl) acetamide (IIIb) (0.297 mmol, 1 eq).
    [0183]
    [0184] Tert-Butyl 2- (1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) acetate (IV) was dissolved in acetonitrile (15 mL) and a solution of 2- chloro-N- (3,5-ditrifluoromethyl-phenyl) acetamide (IIIb) at room temperature. The mixture was stirred at room temperature 3 days until the alkylation was complete. The mixture was filtered and the solvent was removed in vacuo. The yellow solid obtained after removal of the solvent was redissolved in CHCl3 (80 mL) and washed with water (2 x 40 mL). The phase Organic was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a yellow oil (quantitative). 1H NMR (300 MHz, CDCl3): 5H (ppm): 11.32 (s, 1H, NH), 10.61 (s, 1H, NH), 8.46 (s, 2H, CHar), 7.52 (s, 1H, CHar), 3.99-3.81 (m, 4H, CH2), 3.64-2.74 (m, 20H, CH2), 1.78 (m, 4H, CH2), 1.25 (m, 9H, CH2). Mass spectrometry (ESI-) m / z (% BPI): 609.32 (100) ([C28H42F6N5O3] +); 554.25 (8) ([C24H34F6N5O3] +).
    [0185]
    [0186] Example 4: Preparation of 2- (11- (2-oxo-2 - ((4- (trifluoromethyl) phenyl) amino) ethyl) -1,4,8,11-tetraazabicyclo [6.6.21hexadecan-4-yl ligand ) acetic (L2a)
    [0187]
    [0188] The L2a ligand was obtained by hydrolysis of the tertbutyl ester groups of the compound 1-tert-butoxycarboxymethyl) -8 - ((4- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetra azabicyclo [6.6.2] hexadecane ( IIa) using formic acid (5 mL) .The mixture was refluxed for 48 hours, after which the formic acid was removed on the rotavapor.The residue was treated with water (10 mL), which was then evaporated on the rotavapor. This process was repeated 5 times Finally, the product was dissolved in water and lyophilized, to give a yellow solid (0.1226 g, 75%). 1H NMR (300 MHz, D2O): 5H (ppm): 8.00 (s, 2H, CHar), 7.85 (s, 1H, CHar), 4.25-3.92 (dd, 2H, CH2), 3.66-2.97 (m, 20H, CH2), 2.85-2.65 (dd, 2H, CH2), 2.33 (m , 2H, CH2), 1.74-1.69 (d, 2H, CH2). Mass Spectrometry (ESI ') m / z (% BPI): 554.25 (100) ([^ ^ F a ^ O ^); 576.24 (10 ) ([C24H33F6N5NaO3] +).
    [0189]
    [0190] Example 5: Preparation of 2- (11- (2 - ((3,5-bis (trifluoromethyl) phenyl) amino) -2-oxoethyl) -1,4,8,11-tetraazabicyclo [6.6.21hexadecan-4 -il) acetic (L2b)
    [0191]
    [0192] Ligand L2b was obtained by hydrolysis of the tert-butyl ester groups of compound 1-tert-butoxycarboxymethyl) - 8 - ((3,5- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.2 ] hexadecane (IIb) using formic acid (5 mL). The mixture was refluxed for 48 hours, after which the formic acid was removed on the rotavapor. The residue was treated with water (10 mL), which was then evaporated in the rotary evaporator This process was repeated 5 times Finally, the product was dissolved in water and lyophilized, to give a yellow solid (0.0735 g, 50%) 1H NMR (300 MHz, D2O): 5H (ppm): 7.68 -7.60 (m, 4H, CHar), 4.25-4.02 (dd, 2H, CH2), 3.74-3.03 (m, 18H, CH2), 2.82-2.64 (dd, 2H, CH2), 2.34 (m, 2H, CH2 ), 1.73-1.69 (d, 2H, CH2). masses (ESI-) m / z (% BPI): 486.26 (100) ([C24H35F3N5O3I +).
    [0193]
    [0194] Example 6: Preparation of 1,8 - ((4- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.21hexadecane (L1a)
    [0195]
    [0196] The 1,4,8,11-tetraazabicyclo [6.6.2] hexadecane (V) precursor (0.092 g, 0.4064 mmol) was dissolved in acetonitrile (20 mL), in the presence of diisopropylethylamine DIPEA (290 ^ L, 4.1 eq) and A solution of the precursor 2-chloro-N- (4- (trifluoromethyl) phenyl) acetamide of formula (IIIa) (0.198 mg, 0.833 mmol, 2.05 eq) in 20 ml of acetonitrile was added dropwise. The reaction mixture was heated under reflux for 13 days until the dialkylation was fully carried out. The reaction mixture was allowed to reach room temperature, filtered, and the solvent was evaporated by rotary evaporator to give a deep yellow oil. An intense yellow oil (0.5595 g, quantitative yield) was obtained. 1H NMR (400 MHz, CDCl3): 5H (ppm): 10.36 (s, 1H, NH), 9.66 (s, 1H, NH), 7.94-7.92 (d, 4H, CHar), 7.47-7.45 (d, 4H , CHar), 4.24-2.89 (m, 28H, CH2). 13C-NMR (101 MHz, CDCh) 5C (ppm): 170.02 (quaternary, CO), 141.50 (quaternary, CHar), 125.88-125.85 (quaternary, CHar), 122.93 (tertiary, CHar), 119.66 (tertiary, CHar ), 58.37 (secondary, CH2), 56.23 (secondary, CH2), 55.80 (secondary, CH2), 54.79 (secondary, CH2), 53.63 (secondary, CH2), 51.00 (secondary, CH2), 50.03 (secondary, CH2) , 43.06 (secondary, CH2), 24.69 (secondary, CH2), 18.12 (secondary, CH2), 12.42 (secondary, CH2). 19F-NMR (376 MHz, CDCl3) 5F (ppm): -61.95 (CF3). Mass spectrometry (ESI +) m / z (% BPI): 629.30 (100) ([C30H39F6N6O2I +). HR-MS (ESI +) m / z: [M] +, theoretical: 629.3034, experimental: 629.3033.
    [0197]
    [0198] Example 7: Preparation of 1,8 - ((3,5- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.21hexadecane (L1b)
    [0199]
    [0200] A solution of the 2-chloro-N- (3,5-di-trifluoromethyl-phenyl) acetamide precursor of formula (IIIb) (0.250 g, 0.817 mmol, 2.05 eq.) In 20 mL of acetonitrile was slowly dripped onto a dissolution of the compound 1,4,8,11-tetraazabicyclo [6.6.2] hexadecane (V) (0.090 g, 0.399 mmol) in the presence of diisopropylethylamine DIPEA (282 ^ L, 4.1 eq). The reaction mixture was refluxed for 6 days until the dialkylation was fully carried out. The The reaction mixture was allowed to reach room temperature, filtered and the solvent was evaporated by rotary evaporator to give a deep yellow oil (0.4094 g, quantitative yield). 1H NMR (400 MHz, CDCfe): 5H (ppm): 10.25 (s, 1H, NH), 9.92 (s, 1H, NH), 8.30 (s, 4H, CHar), 7.39 (s, 4H, CHar), 3.92-2.87 (m, 28H, CH2). 13C-NMR (101 MHz, CDCl3) 5C (ppm): 170.24 (quaternary, CO), 139.86 (quaternary, CHar), 132.04-131.05 (quaternary, CF3), 127.25 (quaternary, CHar), 124.54 (quaternary, CHar) , 121.83 (tertiary, CHar), 119.47 (tertiary, CHar), 116.71 (tertiary, CHar), 58.12 (secondary, CH2), 56.13 (secondary, CH2), 55.60 (secondary, CH2), 54.99 (secondary, CH2), 53.50 (secondary, CH2), 49.85 (secondary, CH2), 43.27 (secondary, CH2), 24.61 (secondary, CH2), 18.58 (secondary, CH2), 17.24 (secondary, CH2), 12.41 (secondary, CH2). 19F-NMR (376 MHz, CDCh) 5F (ppm): -62.90. (CF3). Mass spectrometry (ESI +) m / z (% BPI) :) 765.28 (100 ([C32H37F12NaO2] +).
    [0201]
    [0202] Example 8: General procedure of synthesis of the complexes [NiL2] (NO3) where L2 = 2- (11- (2-oxo-2 - ((4- (trifluoromethyl) phenyl) amino) ethyl) -1,4, 8,11-tetraazabicyclo [6.6.21 hexadecan-4-yl) acetic (L2a)
    [0203]
    [0204] 2- (11- (2-oxo-2 - ((4- (trifluoromethyl) phenyl) amino) ethyl) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl) acetic acid ( L2a) was dissolved in n-BuOH (10 mL) in the presence of DIPEA with the assistance of an ultrasound bath. Nickel salt (Ni (NO3) 26H2O was added to the reaction mixture in solid state. The reaction was held for 6 h at 155 ° C. The reaction was stopped and allowed to cool. It was concentrated in vacuo and the product was washed repeatedly with dichloromethane Pink solid (20mg, 30%) Mass spectrometry (ESI +) m / z (% BPI): 542.19 (100) ([C23H33F3N5NiO3] +). HR-MS (ESI +) m / z: [M] +, theoretical: 542.1883, experimental: 542.1888.
    [0205]
    [0206] Example 9: General procedure for synthesis of the complexes [NiL21Cl where L2 = 2- (11- (2 - ((3,5-bis (trifluoromethyl) phenyl) amino) -2-oxoethyl) -1,4,8, 11-tetraazabicyclo [6.6.21hexadecan-4-yl) acetic (L2b)
    [0207]
    [0208] 2- (11- (2 - ((3,5-bis (trifluoromethyl) phenyl) amino) -2-oxoethyl) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecan-4-yl acid) acetic (L2b) was dissolved in n-BuOH (10 mL) in the presence of DIPEA with the assistance of an ultrasound bath. NiCl2 was added to the mixture solid state reaction. The reaction was held for 6 hr at 155 ° C. The reaction was stopped and allowed to cool. It was concentrated in vacuo and the product was washed repeatedly with dichloromethane. Pink solid (21.7 mg, 35%). Mass spectrometry (ESI +) m / z (% BPI): 610.18 (100) ([C ^ F a ^ N iO ^), 632.16 (8) ([C24H33N5F6NaNiO3r). HR-MS (ESI +) m / z: [M] +, theoretical: 610.1757, experimental: 610.1753.
    [0209]
    [0210] Example 10: Procedure for the preparation of the complexes [NiL1] Cl2 where L1 = 1,8 - ((4- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.21hexadecane (L1a)
    [0211]
    [0212] 1,8 - ((4- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecane (L1a). It was dissolved in pre-dried n-butanol (15 mL) with the assistance of a bath ultrasonic and purged with an argon stream. Nickel salt, NiCl2, was added in solid state to the solution. The reaction was kept at 120 ° C for 7 h. Then the reaction was stopped and allowed to cool to temperature ambient. The reaction mixture was concentrated in vacuo to obtain a pink product. The solid was purified by MPLC using a reversed phase C18 column. An aqueous solution of the compound under the elution conditions (CH3CN: H2O, v: v, containing 0.1% triethylamine) was prepared and filtered through a cellulose filter (0.20 µm pore size) before injection.The purification method carried out was performed using a gradient of solvent B (CH3CN, from 5 to 10%) in solvent A (H2O) Fractions containing the complex were combined and the solvent was eli vacuum mined. The final product was redissolved in water and lyophilized to obtain the final complexes. Solid pink. Mass spectrometry (ESI +) m / z (% BPI): 343.12 (100) ([C30H38F6N6NiO2] 2+).
    [0213]
    [0214] Example 11: Procedure for preparing the complexes [NiL11Cl2 where L1 = 1,8 - ((3,5- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.21hexadecane (L1b
    [0215]
    [0216] 1,8 - ((3,5- (trifluoromethylphenyl) acetamide) -1,4,8,11-tetraazabicyclo [6.6.2] hexadecane (L1b) was dissolved in pre-dried n-butanol (15 mL) with the assistance of a ultrasonic bath and purged with a stream of argon. Nickel salt, NiCl2, was added in solid state to the solution. The reaction was kept at 120 ° C for 7 h. Then the reaction was stopped and allowed to cool to room temperature The reaction mixture was concentrated in vacuo to obtain a pink product The solid was purified by MPLC using a reversed phase C18 column. An aqueous solution of the compound under the elution conditions (CH3CN: H2O, v: v, containing 0.1% triethylamine) was prepared and filtered through a cellulose filter (0.20 µm pore size) prior to injection. The purification method carried out was performed using a gradient of solvent B (CH3CN, 5 to 10%) in solvent A (H2O). Fractions containing the complex were combined and the solvent was removed in vacuo. The final product was redissolved in water and lyophilized to obtain the final complexes. Solid pink. Mass spectrometry (ESI +) m / z (% BPI) :) 411.11 (100) ([C32H36F12N6NiO2] 2+).
    [0217]
    [0218] Example 12: Study of the 19F NMR spectra of the complexes of examples 8, 9 and 11
    [0219]
    [0220] The 19F NMR spectra of the Ni2 + complexes of examples 8, 9 and 11 give rise to a single signal (FIG. 1), evidencing the presence of a single species in solution. In the case of the complex of Example 8 Ni (L2a), another 19F signal can be observed in the 19F spectrum due to the triflate counterion (Z). The paramagnetism of the metal ion produces an alteration in the T1 and T2 values of 19F, resulting in a shortening in relaxation times (Table 1). This is important for the application of these compounds as contrast agents, since it allows a faster acquisition.
    [0221]
    [0222] Table 1. Longitudinal (T1) and transverse (T2) relaxation times and chemical shifts (282 MHz, 298 K, pH 7.22 (NiL2a), 6.85 (NiL2b) and 6.96 (NiL1b) for the L2a, L2b nickel complexes, and L1a.
    [0223]
    [0224]
    [0225] Example 13: Study of 1H CEST NMR spectra (Chemical Exchange Saturation transfer)
    [0226]
    [0227] All NMR spectra have been acquired on a Bruker Avance III 300 MHz spectrometer and processed using TopSpin 2.1 software (Bruker GmbH). The results have been analyzed using the MestRenova software (Mestrelab Research, S.L.). The concentrations of the complexes have been determined by elemental analysis using a ThermoQuest Flash EA 1112 kit.
    [0228]
    [0229] CEST experiments were carried out for NiLn complexes (15mM) in a H2O: CD3CN mixture (4: 1). The Z spectrum has been recorded at 25 and 37 ° C and at different powers (B1 = 2.5, 5, 10, 15, 20, 25 and 30 ^ T), using a saturation time of 10 s and an irradiation time of 2 s (cf. FIGs 2a-2d).
    [0230]
    [0231] Values to highlight: a B1 = 10 ^ T: NiL2a (Example 8) (25 0C, 56 ppm, 3%; 37 0C, 54 ppm, 5%), NiL2b (Example 9) (25 0C, 56 ppm, 2% ; 37 0C, 53 ppm, 2%). A CEST signal around 56 ppm can be observed that varies in amplitude depending on the power of the saturation pulse.
    [0232]
    [0233] Through these experiments, the rate of exchange of the water molecule for each of the complexes has been determined, using the method described for the MATLAB software by Dr. Zaiss (cf. M. Zaiss, er al., "A combined analytical solution for chemical exchange saturation transfer and semi-solid magnetization transfer " NMR Biomed. 2015, vol. 28, pp. 217-230). The exchange speed of the protons of the amides that make up the NiL2a and NiL2b complexes at 25 and 37 ° C vary significantly depending on the number of CF3 groups available [kex (NiL2a) 7.1 kHz (25 ° C) and 6.6 kHz (37 ° C); kex (NiL2b) 10.9 kHz (25 ° C) and 17.2 kHz (37 ° C)]. Previous studies showed that NiL2a and NiL2b complexes provide a significant in vitro CEST effect.
    [0234]
    [0235] Example 14: Magnetic Resonance 19F phantom image study
    [0236]
    [0237] The measurements of the magnetic resonance images have been recorded on the Bruker BioSpec 70/30 USR (Paravision 5.1 software version), using a Bruker surface bovine (RF SUC 300 1H / 19F_20mm LIN TR). The images of 19F they were acquired using a Fast Low Angle Single Shot (FLASH) sequence.
    [0238]
    [0239] The phantom solutions consisted of 400 ^ L vials containing the complex solutions in a 15 mM concentration, using as reference a sodium triflate solution in the same concentration.
    [0240]
    [0241] The experimental parameters for the fluorine 19 images are: FOV = 32 x 32, MTX 32 x 32, cut thickness of 5 mm. The rest of the parameters are considered in Table 2. The SNR values (signal-to-noise ratio) for fluorine MRI are shown in Table 3.
    [0242]
    [0243] Table 2. 19F MRI parameters.
    [0244]
    [0245]
    [0246]
    [0247]
    [0248] Table 3. SNR Values for NiL2b and NiL2a Complexes
    [0249]
    [0250]
    [0251]
    [0252]
    [0253] FIG 3 shows 19F magnetic resonance phantom images of NiL2a and NiL2b. In the case of NiL2a, the brightest image corresponds to the resonance of the CF3 groups of the ligand, and the least bright to the triflate counterion.
    [0254]
    [0255] The in vitro 19F imaging study confirms the ability of these complexes to provide contrast at the 19F frequency, providing much brighter images than those of trifluoroacetic acid (TFA).
    [0256] Example 15: Determination of the structure of the complex of Example 8 by X-ray diffraction
    [0257]
    [0258] Crystals suitable for study were obtained by single-crystal X-ray diffraction by slow evaporation of an aqueous solution of the complex. Crystallographic data was recorded at 100K on a Bruker D8 Venture diffractometer coupled to a Photon 100 CMOS detector using Mo-Ka radiation (X = 0.71073A) generated on an Incoatec high-gloss microfocal source equipped with Incoatec Helios multilayer optics. The APEX3 software was used in the collection of the data of the diffraction images, indexing of the reflections and determination of those of the cell parameters. SAINT software was used to integrate the intensity of the reflections, while SADABS was used for scaling and empirical correction of the absorption. The structure was solved by the dual-space method using the SHELXT program. All the atoms (except for the hydrogen ones) were refined with anisotropic thermal parameters by means of full-matrix least-squares calculations in F2 using the SHELXL-2014 program. Hydrogen atoms were incorporated at calculated positions and restricted with isotropic thermal parameters. Crystal data and structure refinement details: Formula: C16H36Cl2N6NiO4; P.M .: 506.10; Crystal system: monoclinic; space group: P21 / c; a = 9.0398 (10) Á;
    [0259] 424 (18) Á; p = 101,726 (4) °; V = 2227.8 (4) Á3; F (000) = 1072; Z = 4;
    [0260]
    [0261]
    [0262] The structure of the [NiL2a] complex (as the trifluoromethanesulfonate salt) was determined using X-ray diffraction measurements (FIG. 4). The X-ray diffractogram shows that the metal ion coordinates directly with the four N atoms of the macrocyclic unit, with distances of Ni N in the range of 2.07-2.10 Á. The oxygen atoms in the hanging arms complete the distorted octahedral coordination around the metal ion. The Ni-O distance involved by the carboxylate oxygen atom (2,026 Á) is slightly shorter than that of the oxygen amide atom (2,075 Á).
    [0263] Example 16: Stability study of the complexes
    [0264]
    [0265] The kinetic inertia of the complex [NiL2a] with respect to its dissociation was studied by means of UV-Vis absorption spectroscopy, using a UVIKON-XS double-beam spectrophotometer (Bio-Tek instruments). The composition of the solution was investigated by mass spectrometry using the positive mode electrospray technique. The spectra were recorded with an LC-Q-q-TOF Applied Biosystems QSTAR Elite spectrometer. The [NiL2a] complex was dissolved in a 4M hydrochloric acid solution, and the absorption spectrum was recorded immediately (FIG.
    [0266] 5). The spectrum recorded after 24 hours coincides with the spectrum recorded immediately after dissolution of the sample, suggesting that the complex does not dissociate under these conditions. The integrity of the complex is confirmed by mass spectrometry, since the spectrum recorded after 5 days shows a peak at m / z = 542.19 due to the entity [NiL2a] +. On the other hand, the spectrum does not show the signal at m / z = 486.26 due to the protonated free ligand HL2a +, which confirms the stability of the complex under these conditions.
    [0267]
    [0268] As an example, the [Gd (DOTA)] complex "dissociates under these conditions with a half-life time of 2.4 hours (E. Toth, et al." Kinetiks of Formation and Dissociation of Lantanide (III) -DOTA Complexes " , Inorg. Chem. 1994, vol. 33, pp. 4070 4076), reflecting the very high inertia of the Ni2 + complexes described here.
    [0269]
    [0270] APPOINTMENT LIST
    [0271]
    [0272] Patent literature
    [0273]
    [0274] - WO2014 / 107722A1
    [0275]
    [0276] Non-patent literature
    [0277]
    [0278] - S. Aime et al., "P (O2) -Responsive MRI Contrast Agent Based on the Redox Switch of Manganese (M / IM) - Porphyrin Complexes", Angew. Chem. Int. Ed. 2000, vol. 39, pp.
    [0279] 747-750
    [0280] - S. J Dorazio et al., "CoCEST: cobalt (II) amide-appended to CEST MRI contrast agents. Chem. Commun., 2013, vol. 49, pp. 10025-10027)
    [0281]
    [0282] - Q. Ji, D. Yang et al., "Design, synthesis and evaluation of novel quinazoline-2,4-dione derivatives as chitin synthase inhibitros and antifungal agents" Bioorg. Med. Chem., 2014, vol. 22, pp. 3405-3413.
    [0283]
    [0284] - Z. Xiaohe et al., "Synthesis, Biological Evaluation and Molecular Modeling Studies N-aryl-2-arylthioacetamides as Non-nucleoside HIV-1 Reverse Transcriptase Inhibitors" Chem. Biol. Drug Des. 2010, vol. 76, pp. 330-339.
    [0285]
    [0286] - MM Ali, et al., "Albumin-binding PARACEST agents" J. Biol. Inorg. Chem. 20007, vol. 12, pp. 855-865.
    [0287]
    [0288] - N. Cakic et al., "Paramagnetic lanthanide chelates for multicontrast MRI", Chem Comm 2016, vol. 52, pp. 9224-9227.
    [0289]
    [0290] - M. Zaiss, et al. "A combined analytical solution for chemical exchange saturation transfer and semi-solid magnetization transfer", NMR Biomed. 2015, vol. 28, pp. 217 230.
    [0291]
    [0292] - E. Toth, et al., "Kinetiks of Formation and Dissociation of Lantanide (III) -DOTA Complexes", Inorg. Chem. 1994, vol. 33, pp. 4070-4076.
    权利要求:
    Claims (15)
    [1]
    1. Compound of formula (L) or a pharmaceutically acceptable salt thereof,

    [2]
    2. The compound according to claim 1, wherein the compound of formula (L) has the formula (L '):

    [3]
    3. Compound according to claim 2 of formula (L1), where m and n have the values defined in claim 2.

    [4]
    4. Compound according to claim 3, which is selected from:

    [5]
    5.
    [6]
    6. Compound according to claim 5, selected from:

    [7]
    7. Ni2 + complex with the ligand of formula (L) as defined in any one of claims 1-6 having the formula [NiL] (Z) p
    where:
    Z is an anion selected from chloride, triflate, and nitrate; and
    p is an integer that is selected from 1 to 2.
    [8]
    8. Composition comprising one or more of the metal complexes of claim 7, together with one or more physiologically acceptable additives.
    [9]
    9. Composition according to claim 8, wherein the complex together with one or more physiologically acceptable additives are dissolved in water, physiological saline and / or protein solution.
    [10]
    10. Complex according to claim 7, for use as a contrast agent in the imaging of an organ and / or tissue of a human or animal body by nuclear magnetic resonance.
    [11]
    11. Composition according to any of claims 8-9, for use as a contrast agent in imaging an organ and / or tissue of a human or animal body by nuclear magnetic resonance.
    [12]
    12. Composition for use according to claim 11, wherein the composition is for enteral or parenteral application.
    [13]
    13. Complex for use according to claim 10 or composition for use according to any of claims 11-12, wherein the image is used for the diagnosis of a disease.
    [14]
    14. Procedure for the preparation of a compound of formula (L) comprising:
    or, subjecting a compound of formula (V) to an alkylation reaction with a compound of formula (III),

    [15]
    15. Procedure for the preparation of the complexes of formula [NiL] (Z) p which comprises reacting the ligand L with a nickel salt at a temperature of between 100-160 ° C.
    类似技术:
    公开号 | 公开日 | 专利标题
    CA2211100C|2007-03-20|Diagnostic imaging contrast agents with extended blood retention
    JP6542748B2|2019-07-10|CEST system showing concentration-independent response
    JPH10152447A|1998-06-09|Nmr contrast agent for hepatic bile duct
    AU2016368545B2|2020-09-03|Dimeric contrast agents
    AU9668698A|1999-04-27|Contrast-enhanced diagnostic imaging method for monitoring interventional therapies
    ES2814555T3|2021-03-29|Gadolinium chelate compounds with high relaxivity for use in magnetic resonance imaging
    EP0556240B1|1996-07-10|Chelating agents
    JP6909234B2|2021-07-28|Contrast
    KR20190091441A|2019-08-06|Dimer contrast agent
    ES2759316B2|2020-09-15|TETRAAZAMACROCICLIC LIGANDS AND THE CORRESPONDING NICKEL COMPLEXES USEFUL AS CONTRASTING AGENTS
    CN109641900B|2021-08-24|Chelate compound
    US6251367B1|2001-06-26|Paramagnetic 3-,8-substituted deuteroporphyrin derivatives, pharmaceutical agents that contain the latter, process for their production, and their use for MR imaging of necrosis and infarction
    ES2205863T3|2004-05-01|PARAMAGNETIC DERIVATIVES OF SUBSTITUTED DEUTEROPORPHIRINES IN POSITIONS 3, 8, PHARMACEUTICAL AGENTS CONTAINING THESE DERIVATIVES, PROCEDURES FOR THEIR PREPARATION AND THEIR USE FOR REPRESENTATION IN IMAGES BY MR OF THE NECROSIS AND THE INFARTOS.
    WO2006051142A1|2006-05-18|1-pyrazolylethyl-1,4,7,10-tetraazacyclododecane-4,7,10-triacetic acids and application of the gadolinium | complexes thereof in clinical diagnosis
    ES2835065T3|2021-06-21|Contrast agents
    CA2933005A1|2016-12-12|Methods and compounds for enhancing contrast in magnetic resonance imaging |
    ES2253125B1|2007-07-01|ACIDS 1-PIRAZOLILETIL-1,4,7,10-TETRAAZACICLODODECANO-4,7,10-TRIACETICS. APPLICATION OF ITS GADOLINUM COMPLEXES | IN THE CLINICAL DIAGNOSIS.
    Weitz2015|Fluorinated Metal Complexes as MRI Contrast Agents
    Lewis2014|New Ligands for Lanthanides and Transition Metals toward Magnetic Resonance Imaging Contrast Agents
    ES2277760A1|2007-07-16|New pyrazolylethyl-diethylenetriaminotetraacetic acids and their lanthanide complexes, useful as contrast agents for diagnostic magnetic resonance imaging
    同族专利:
    公开号 | 公开日
    WO2020094899A1|2020-05-14|
    ES2759316B2|2020-09-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    WO2014195416A1|2013-06-06|2014-12-11|Cnrs - Centre National De La Recherche Scientifique|Chelates of lead and bismuth based on trans-di-n-picolinate tetraazacycloalkanes|
    法律状态:
    2020-05-08| BA2A| Patent application published|Ref document number: 2759316 Country of ref document: ES Kind code of ref document: A1 Effective date: 20200508 |
    2020-09-15| FG2A| Definitive protection|Ref document number: 2759316 Country of ref document: ES Kind code of ref document: B2 Effective date: 20200915 |
    优先权:
    申请号 | 申请日 | 专利标题
    ES201831074A|ES2759316B2|2018-11-07|2018-11-07|TETRAAZAMACROCICLIC LIGANDS AND THE CORRESPONDING NICKEL COMPLEXES USEFUL AS CONTRASTING AGENTS|ES201831074A| ES2759316B2|2018-11-07|2018-11-07|TETRAAZAMACROCICLIC LIGANDS AND THE CORRESPONDING NICKEL COMPLEXES USEFUL AS CONTRASTING AGENTS|
    PCT/ES2019/070746| WO2020094899A1|2018-11-07|2019-11-04|Tetraaza macrocyclic ligands and the corresponding nickel complexes which can be used as contrast agents|
    [返回顶部]