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WO1998013338A1 - Paires d'ions, leur procede de production et leur utilisation en tant qu'agents de contraste - Google Patents

Paires d'ions, leur procede de production et leur utilisation en tant qu'agents de contraste Download PDF

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Publication number
WO1998013338A1
WO1998013338A1 PCT/EP1997/005247 EP9705247W WO9813338A1 WO 1998013338 A1 WO1998013338 A1 WO 1998013338A1 EP 9705247 W EP9705247 W EP 9705247W WO 9813338 A1 WO9813338 A1 WO 9813338A1
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WO
WIPO (PCT)
Prior art keywords
dtpa
eob
ttha
dota
substituted
Prior art date
Application number
PCT/EP1997/005247
Other languages
German (de)
English (en)
Inventor
Werner Krause
Michael Bauer
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to AU47779/97A priority Critical patent/AU4777997A/en
Publication of WO1998013338A1 publication Critical patent/WO1998013338A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • 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

Definitions

  • the invention relates to novel ion pairs consisting of ionic metal complexes and halogenated compounds as counterions, methods for producing such ion pairs and their use in diagnostics and therapy.
  • Contrast agents are indispensable aids in modern diagnostics; many diseases cannot be diagnosed without the use of contrast media. Contrast agents can be found in all areas of diagnostics such as X-ray, radio or ultrasound diagnostics or magnetic resonance imaging use.
  • Contrast media are generally only suitable for one of the diagnostic methods described above, but not for several at the same time. Exceptions to this are the metal complexes described in WO 93/16375 or WO 97/1359, which are linked to iodine-substituted aromatics via amide bonds. With only one application of the contrast agent, these compounds should allow both NMR and X-ray examinations to be carried out. In many cases, a combination of the two imaging methods is advantageous for a differentiated display and a reliable diagnosis of certain diseases. These compounds are said to be particularly suitable for angiography.
  • T is an ionic, halogen-substituted compound
  • M stands for an ionic metal complex
  • e stands for the electrical charge of T
  • f stands for the electrical charge of M
  • n stands for the number of ions T
  • m stands for the number of ions M
  • the ion T e is an ionic, halogen-substituted compound, preferably an ionic, iodine-substituted benzene derivative, very particularly preferably an ionic 1,3,5-triiodo-substituted benzene derivative.
  • Suitable embodiments are, for example, triiodoaromatics of the general formula (II)
  • a 1 , A 3 , A 5 can independently represent hydrogen or halogen atoms
  • R1 can be L-COOH, L-SO 3 H, L-PO3H2 or L-NR 4 R 5 , in which L stands for a direct bond or for a linear or branched alkylene or fluoroalkylene radical (C1-C24) which is represented by 0-24 heteroatoms such as oxygen, sulfur or nitrogen can be interrupted and / or can be substituted with 0-24 hydroxyl groups and / or alkoxy and / or hydroxyalkoxy groups or carbohydrate residues,
  • NR 6 COR 7 or linear or branched alkyl or fluoroalkyl radicals (C1-C24), which can be interrupted by 0-24 heteroatoms such as oxygen, sulfur or nitrogen and / or with 0-24 hydroxyl groups and / or alkoxy and / or Hydroxyalkoxy groups or
  • R 2 and R 3 can be independently -CONR 6 R 7 or NR 6 COR 7 , wherein
  • R 6 and R 7 independently of one another represent hydrogen or linear or branched alkyl or fluoroalkyl radicals (C1-C24) which can be interrupted by 0-24 heteroatoms such as oxygen, sulfur or nitrogen and / or with 0-24 hydroxyl groups and / or Alkoxy and / or hydroxyalkoxy groups or carbohydrate residues can be substituted and e represents the elementary charge.
  • Suitable embodiments of the invention are also triiodoaromatics of the general formula (IM)
  • a 11 , A 12 , A 31 , A 32 , A 51 ⁇ A 52 independently of one another for hydrogen or
  • Halogen atoms can stand R11.
  • R "* are each independently L 1 -COOH, U-SO3H, -PO 3 H 2 L 1, L 1 -NR 1 6 R 17, L 1 is -CONR 16 R 17 or L 1 -NR 16 COR 17 can stand, wherein
  • U stands for a direct bond or for a linear or branched alkylene or fluoroalkylene chain (C1-C24) which can be interrupted by 0-24 heteroatoms such as oxygen, sulfur or nitrogen and / or with 0-24 hydroxyl groups and / or alkoxy and / or hydroxyalkoxy groups or carbohydrate residues can be substituted, - o -
  • R 12 , R 13 can be independently -CONR 16 R 17 or NR 16 COR 17 , wherein
  • R 16 , R 17 independently of one another represent hydrogen or linear or branched alkyl or fluoroalkyl radicals (C1-C24) which can be interrupted by 0-24 heteroatoms such as oxygen, sulfur or nitrogen and / or with 0-24 hydroxyl groups and / or Alkoxy and / or hydroxyalkoxy groups or carbohydrate residues can be substituted and
  • X may be a direct bond or -CONR 18 YNR 19 CO-, -NR 18 COYNR 19 CO-, or -NR 18 COYCOR 19 N-, wherein
  • R 18 , R 19 independently of one another represent hydrogen or linear or branched alkyl or fluoroalkyl radicals (C ⁇ -C Q ) which can be interrupted by 0-6 heteroatoms such as oxygen, sulfur or nitrogen and / or with 0-5 hydroxyl groups and / or alkoxy and / or hydroxyalkoxy groups or carbohydrate residues can be substituted and
  • Y represents a direct bond or a linear or branched alkylene or fluoroalkylene chain (CC 2 4) which can be interrupted by 0-24 heteroatoms such as oxygen, sulfur or nitrogen and / or with 0-24 hydroxyl groups and / or alkoxy and or
  • Hydroxyalkoxy groups or carbohydrate residues can be substituted and e represents the elementary charge.
  • the Triiodaromat T e can be present as a cation or as an anion.
  • Cationic triiodoaromatics have one or more quaternary ammonium groups. As a rule, these are present as protonated amino groups.
  • Anionic triiodoaromatics have one or more carboxylate (-COO-), sulfate (-SO3H) or phosphate groups (-PO 3 H 2 ).
  • the charge e can have the values -5, -4, -3, -2, -1, +1, +2, +3, +4, +5.
  • the monocations are very particularly preferred as triiodoaromatics.
  • Molecules in which all positions labeled A x contain iodine atoms are particularly preferred.
  • the metal complex M f consists of a metal ion with atomic numbers 20-32, 39-51 or 57-83 and a chelating ligand.
  • Open-chain polyaminopolycarboxylic acids such as EDTA, DTPA, EOB-DTPA, BOPTA, 3,6,9-triaza-3,6,9-tris (carboxymethyl) -undecanoic acid-bis-methylamide, 3,6,9- Triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) -undecanoic acid ( Figure 1) and cyclic polyaminopolycarboxylic acids such as DOTA, DO3A, butriol ( Figure 2) or their substituted derivatives, the total charge by Choice of ligands and metal ions can be controlled.
  • Open-chain polyaminopolycarboxylic acids such as EDTA, DTPA, EOB-DTPA, BOPTA, 3,6,9-triaza-3,6,9-tri
  • Suitable embodiments of the invention are, for example, the ions: [Gd-DTPA] 2 -, [Yb-DTPA] 2 ** , [Dy-DTPA] 2 ", [Tb-DTPA] 2 ** , [Ho-DTPA] 2 * * , [Er-DTPA] 2 ** , [Fe-DTPA] 2 -, [Mn-DTPA] 3 ", [Cr-DTPA] 2 ** , [Fe-DTPA] 3 -, [C0-DTPA] 3 -, [Ni-DTPA] 3 ", [Cu-DTPA] 3 ", [Pr-DTPA] 2 ** , [Nd-DTPA] 2 ", [Sm-DTPA] 2 -, [Hf-DTPA]", [Gd-EOB-DTPA] 2 -, [Yb-EOB-DTPA] 2-, [Dy-EOB-DTPA] 2 ", [Tb-EOB-DTPA] 2 ** , [Ho-EOB-DTPA]
  • the metal complex M f can also be present as a cation or as an anion.
  • the charge f can have the values -7, -6, -5, -4, -3, -2, -1, +1, +2, +3, +4, +5, +6, +7.
  • the invention therefore relates to the compounds of the general formula I.
  • the compounds according to the invention are in any case suitable for X-ray diagnostics.
  • Compounds in which the metal complex additionally contains a central atom of a higher atomic number element are particularly suitable in order to achieve additional absorption of the X-rays. It has been found that elements of atomic numbers 57-83 are particularly suitable for this purpose. If the compound is to be used for both NMR and X-ray diagnostics, the metal ion must be paramagnetic.
  • the chromium (III) - iron (II) -, cobalt (II) -, nickel (II) -, copper (II) -, praseodymium (III) -, neodymium (III) - , Samarium (lll) -, and the ytterbium (lll) -lon are suitable.
  • Complexes of the ions gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) are particularly preferred.
  • the metal ion must be radioactive.
  • the radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium, silver, gold, rhenium, bismuth and iridium are suitable.
  • the radioisotopes of gallium, indium and technetium are preferred.
  • the 'triiodoaromatic component' can be prepared analogously to processes as described, for example, in EP 0 105 752, EP 0 015 867.
  • the ready-to-use pharmaceutical agents can be prepared in analogy to the methods mentioned in EP 0 405 704.
  • the pharmaceutical additives mentioned there can be used to produce the agents according to the invention.
  • the ion pairs according to the invention must be electrically neutral for use.
  • the charges of T e and M compensate each other
  • Charge compensation can be used.
  • the following ions are particularly suitable for the purpose according to the invention:
  • the gadolinium complex of 3,6,9-triaza-3,6,9-ths (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanoic acid (Gd-EOB-DTPA, cf. Formula IV) is the disodium salt for the Suitable for MR tomography of the liver.
  • the preparation of this compound is familiar to the person skilled in the art and is described in EP 0 405 704 and US 4,880,008.
  • the acid of the complexing agent is replaced with an amine, e.g. neutralized the triiodoaromatic represented in formula V, a salt is obtained which contains two protonated triiodoaromatic amine instead of the two sodium ions.
  • the triiodoaromatic amine can be prepared in a manner familiar to those skilled in the art.
  • the dysprosium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxy-benzyl) -undecanoic acid was obtained in accordance with the specification mentioned in EP 0405 704 manufactured.
  • the complex was neutralized with the amine mentioned in example 1a instead of with NaOH.
  • the compound was made and pharmacologically examined.
  • the compound contains 7.26% dysprosium and 34.0% iodine. It turned out to be well tolerated.
  • the substance is particularly well suited as a contrast agent for the representation of the liver.
  • Gd-DTPA 3,6,9-triaza-3,6,9-tris (carboxymethyl) -undecanoic acid
  • triiodoaromatic e.g. neutralized the compound shown in formula VI
  • a salt is obtained which contains two protonated triiodoaromatic amine.
  • the triiodoaromatic amine can be prepared in a manner familiar to those skilled in the art.
  • the gadolinium complex of the complexing agent DOTA (formula VII) is suitable as disodium or dimeglumin salt (or also as mixed salt) for MR tomography.
  • the preparation of this compound is familiar to the person skilled in the art.
  • triiodoaromatic e.g. neutralized the compound represented in formula VIII
  • a salt is obtained which contains two protonated triiodoaromatic amine.
  • the triiodoaromatic amine can be prepared in a manner familiar to those skilled in the art.
  • the “combined" compound obtained (Gd + iodine as contrasting elements) is an excellently tolerated extracellular contrast medium which is suitable for both MR tomography and X-ray technology.
  • Gd-DTPA (Formula IV) is suitable as a dimeglumin salt for MR tomography.
  • the preparation of this compound is familiar to the person skilled in the art.
  • a salt which contains a protonated dimeric triiodoaromatic amine.
  • the dimeric triiodoaromatic amine can be prepared in a manner familiar to those skilled in the art.
  • the “combined" compound obtained (Gd + iodine as contrasting elements) is an excellently tolerated extracellular contrast medium which is suitable for both MR tomography and X-ray technology.
  • Gd-EOB-DTPA 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanoic acid
  • the acid of the complexing agent is replaced with an amine, e.g. neutralized the triiodoaromatic represented in formula X, a salt is obtained which contains two protonated triiodoaromatic amine instead of the two sodium ions.
  • the triiodoaromatic amine can be prepared in a manner familiar to those skilled in the art.
  • the substance is suitable as a combined contrast medium for the representation of the liver.
  • the gadolinium complex of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-butylbenzyl) - undecanoic acid (cf. Formula XI) is suitable as a disodium salt for MR tomography of the liver.
  • the preparation of this compound is familiar to the person skilled in the art.
  • the acid of the complexing agent is replaced with an amine, e.g. neutralized the triiodoaromatic represented in formula VI, a salt is obtained which contains a protonated triiodoaromatic amine twice instead of the two sodium ions.
  • the triiodoaromatic amine can be prepared in a manner familiar to those skilled in the art.
  • Hydrogen uptake is filtered off from the catalyst and the residue is evaporated to dryness.
  • 6.2 g (10 mmol) of 3,6,9-triaza-6- (aminocarbonylmethyl) -3,9-bis- (tert-butoxycarbonylmethyl) -undecanedioic acid bis- (2-methoxyethyl) amide are 4 ml (44 mmol) trifluoroacetic acid dissolved and stirred for 20 hours at room temperature. For working up, dilute with water and evaporate to dryness. This process is repeated several times. An aqueous solution of the product is then freeze-dried.
  • the crude product is purified by RP chromatography and then evaporated. The residue is taken up in water and this aqueous solution is used to prepare the mixed complex.

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

Abstract

L'invention concerne de nouvelles paires d'ions, constituées de complexes métalliques chargés électriquement et de composés halogénés à charge électrique opposée. L'invention concerne également un procédé de production desdites paires d'ions et leur utilisation à des fins de diagnostic et de thérapie.
PCT/EP1997/005247 1996-09-24 1997-09-24 Paires d'ions, leur procede de production et leur utilisation en tant qu'agents de contraste WO1998013338A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU47779/97A AU4777997A (en) 1996-09-24 1997-09-24 Ion pairs, process for producing the same and their use as contrast agents

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19641197.1 1996-09-24
DE1996141197 DE19641197C2 (de) 1996-09-24 1996-09-24 Ionenpaare und ihre Verwendung als Kontrastmittel

Publications (1)

Publication Number Publication Date
WO1998013338A1 true WO1998013338A1 (fr) 1998-04-02

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AU (1) AU4777997A (fr)
DE (1) DE19641197C2 (fr)
WO (1) WO1998013338A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998048844A3 (fr) * 1997-04-29 1999-02-11 Schering Ag Paires d'ions, procede permettant de les preparer et leur utilisation comme agents de contraste
CN108148012A (zh) * 2018-01-04 2018-06-12 复旦大学 近红外第二窗口发射小分子稀土配合物荧光探针及其制备方法

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU6386000A (en) * 1999-07-29 2001-02-19 Epix Pharmaceuticals, Inc. Targeting multimeric imaging agents through multilocus binding
AU2003249999A1 (en) * 2002-07-10 2004-02-02 Hans Robert Kalbitzer 1,4,7,10-tetraazacyclododecanes as modulators of the guanine-binding protein for treating tumours

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405704A2 (fr) * 1989-06-30 1991-01-02 Schering Aktiengesellschaft Dérivés de DTPA-complèxes, compositions pharmaceutiques les contenant, leur utilisation et procédé pour leur fabrication
WO1991001149A1 (fr) * 1989-07-21 1991-02-07 Nycomed As Substances de contraste
WO1993016375A1 (fr) * 1992-02-06 1993-08-19 Mallinckrodt Medical, Inc. Agents de contraste utilises pour les radiographies et l'irm

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2909439A1 (de) * 1979-03-08 1980-09-18 Schering Ag Neue nichtionische roentgenkontrastmittel
JP2568166B2 (ja) * 1982-10-01 1996-12-25 ニユコメド・イメージング・アクシェセルカペト Ｘ線造影剤
US4687659A (en) * 1984-11-13 1987-08-18 Salutar, Inc. Diamide-DTPA-paramagnetic contrast agents for MR imaging
US5250285A (en) * 1985-05-08 1993-10-05 The General Hospital Corporation Hydroxy-aryl metal chelates for diagnostic NMR imaging
US4899755A (en) * 1985-05-08 1990-02-13 The General Hospital Corporation Hepatobiliary NMR contrast agents
US4880008A (en) * 1985-05-08 1989-11-14 The General Hospital Corporation Vivo enhancement of NMR relaxivity
IT1213029B (it) * 1986-01-30 1989-12-07 Bracco Ind Chimica Spa Chelati di ioni metallici paramagnetici.
US5457183A (en) * 1989-03-06 1995-10-10 Board Of Regents, The University Of Texas System Hydroxylated texaphyrins
DE4240592A1 (de) * 1992-12-03 1994-06-09 Bosch Gmbh Robert Aggregat zum Fördern von Kraftstoff aus einem Vorratstank zur Brennkraftmaschine eines Kraftfahrzeugs
DE4302287A1 (de) * 1993-01-25 1994-07-28 Schering Ag Derivatisierte DTPA-Komplexe, diese Verbindungen enthaltende pharmazeutische Mittel, ihre Verwendung und Verfahren zu deren Herstellung
DE4341724A1 (de) * 1993-12-03 1995-06-08 Schering Ag Halogenaryl-substituierte Metallkomplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik, sowie Verfahren zur Herstellung der Komplexe und Mittel
DE4431175A1 (de) * 1994-09-01 1996-04-11 Medico Pharma Vertriebs Gmbh Neue, Chelatbildner enthaltende Arzneimittel
DE19507820A1 (de) * 1995-02-21 1996-08-22 Schering Ag Neuartig substituierte DTPA-Derivate, deren Metallkomplexe, diese Komplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik, sowie Verfahren zur Herstellung der Komplexe und Mittel

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0405704A2 (fr) * 1989-06-30 1991-01-02 Schering Aktiengesellschaft Dérivés de DTPA-complèxes, compositions pharmaceutiques les contenant, leur utilisation et procédé pour leur fabrication
WO1991001149A1 (fr) * 1989-07-21 1991-02-07 Nycomed As Substances de contraste
WO1993016375A1 (fr) * 1992-02-06 1993-08-19 Mallinckrodt Medical, Inc. Agents de contraste utilises pour les radiographies et l'irm

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ERIC W. AINSCOUGH ET AL.: "The Synthesis and Characterization of New Phenolato Complexes of Copper(II) and Some Adducts with Ethylenediamine", JOURNAL OF CHEMICAL RESEARCH (S), no. 2, 1988, pages 60 - 61, XP002052160 *
PIER LUCIO ANELLI ET AL.: "A New Approach to Hepatospecific MRI Contrast Agents: Gadolinium Complexes Conjugated to Iodonated Synthons", GAZZETTA CHIMICA ITALIANA, vol. 126, no. 2, February 1996 (1996-02-01), pages 89 - 97, XP002052161 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998048844A3 (fr) * 1997-04-29 1999-02-11 Schering Ag Paires d'ions, procede permettant de les preparer et leur utilisation comme agents de contraste
CN108148012A (zh) * 2018-01-04 2018-06-12 复旦大学 近红外第二窗口发射小分子稀土配合物荧光探针及其制备方法

Also Published As

Publication number Publication date
AU4777997A (en) 1998-04-17
DE19641197A1 (de) 1998-05-14
DE19641197C2 (de) 1999-02-18

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