[go: up one dir, main page]

WO1996016678A1 - Utilisation de composes chelates comme agents diagnostics pour des examens radiographiques du foie et des canaux biliaires - Google Patents

Utilisation de composes chelates comme agents diagnostics pour des examens radiographiques du foie et des canaux biliaires Download PDF

Info

Publication number
WO1996016678A1
WO1996016678A1 PCT/EP1995/004547 EP9504547W WO9616678A1 WO 1996016678 A1 WO1996016678 A1 WO 1996016678A1 EP 9504547 W EP9504547 W EP 9504547W WO 9616678 A1 WO9616678 A1 WO 9616678A1
Authority
WO
WIPO (PCT)
Prior art keywords
complex
benzyl
carboxymethyl
triaza
tris
Prior art date
Application number
PCT/EP1995/004547
Other languages
German (de)
English (en)
Inventor
Franz-Karl Maier
Michael Bauer
Werner Krause
Ulrich Speck
Gabriele Schuhmann-Giampieri
Andreas Mühler
Thomas Balzer
Wolf-Rüdiger Press
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 FI972285A priority Critical patent/FI972285L/fi
Priority to JP8517855A priority patent/JPH10509734A/ja
Priority to AU41738/96A priority patent/AU4173896A/en
Priority to EP95940207A priority patent/EP0794800A1/fr
Priority to SK688-97A priority patent/SK68897A3/sk
Publication of WO1996016678A1 publication Critical patent/WO1996016678A1/fr
Priority to MXPA/A/1997/003974A priority patent/MXPA97003974A/xx
Priority to NO972458A priority patent/NO972458D0/no

Links

Classifications

    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations

Definitions

  • the invention relates to the use of metal complexes in liver and 5-gall x-ray diagnostics by means of x-rays, in particular in computer tomography.
  • Scintigraphy offers a spatial resolution that is too low and its application is limited by the insufficient or too high specificity of the radiopharmaceuticals (which can only be used for a few types of tumor), so that it is not mentioned in the above-mentioned review article.
  • Sonography is currently also not a sufficiently reliable technique for the detection of solid focal liver changes, since these often do not differ sufficiently from the healthy liver tissue in their acoustic properties. Smaller lesions 5 in the liver tissue can only be detected intraoperatively after exposing the liver and when using high-frequency transducers.
  • Magnetic resonance imaging (MR) is able to record the entire liver with good spatial resolution and, depending on the measurement mode, also with good tissue differentiation.
  • CT Computer tomography
  • the contrast media are injected or infused rapidly and in high doses (50-200 g) intravenously. For a few minutes there may be a difference in contrast between the lesion and normal liver tissue due to differences in perfusion, the relative blood volume of the individual
  • a catheter e.g. are introduced into the mesenteric artery, the patient is then brought to the CT device and the scan is carried out during the infusion of approximately 150 ml of contrast medium.
  • This technique is invasive, time-consuming and expensive, but currently provides the safest information about the presence and location of liver metastases.
  • CT with arterial portography is therefore performed regularly preoperatively despite the effort.
  • Intravenous cholegraphics such as lotroxinate and loglycamat selectively accumulate in the liver.
  • this process is very limited in capacity.
  • concentration corresponding to 5 ⁇ g iodine / ml plasma the 5-fold concentration in the liver is still achieved, with a concentration of 50 ⁇ g iodine / ml only barely twice the concentration, with 500 ⁇ g iodine / ml plasma the concentration in the liver is clearly lower than in plasma and therefore largely diagnostically worthless, since it is impossible to differentiate between actively enriching tissue and mere perfusion.
  • computed tomography only detects iodine concentrations from approx.
  • Metallic contrast agents for magnetic resonance imaging also absorb X-rays.
  • attempts have therefore been made to use these substances for computed tomography (Schild, HH et al .: Gadolinium DTPA (Magnevist®) as contrast medium for arterial DSA. Progr. Röntgenstr. 160, 218-221 (1994); Quinn, AD et al .: Gd-DTPA: An alternative contrast medium for CT. J. Comput. Assist. Tomogr. 18, 634-636 (1994)).
  • the metal complexes available so far bind only one contrasting metal ion per molecule, while the iodinated X-ray contrast media contain 3 or 6 iodine atoms.
  • a major disadvantage of using metal chelates as X-ray contrast media is the significantly lower content of X-ray absorbing element in the molecules (iodinated X-ray contrast media: 3 or 6 iodine atoms / molecule; MR contrast media: 1 metal ion / molecule).
  • the contrast is correspondingly weak, so that the metal complexes were used almost only for experimental investigations in X-rays.
  • Low concentrations of the metal ions are sufficient in the MR because they influence the rapidly exchanging protons of the water, whereas the metal itself has to be made visible on the X-ray.
  • the object of the present invention application is therefore to select from the known pharmaceutical substances suitable for imaging diagnostics on the basis of metal chelates those which are suitable for the production of contrast media for X-ray diagnostics, in particular computed tomography, the liver and biliary tract.
  • metal complexes consisting of a metal of atomic numbers 44-51 or 56-83 and a complexing agent are suitable for the production of contrast media for use in contrast-enhanced computed tomography of the liver and the biliary tract.
  • X independently represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 44-
  • one of the radicals R 1 represents a radical of the formula -CH 2 -C 6 H - (0) r -R 2 , in which the aromatic ring can be substituted in the ortho, meta or para position and the other radical R 1 is hydrogen, R 2 is a hydrocarbon radical consisting of 1-6
  • radicals R 1 of the general formula I can be used substituted benzyl, such as methoxybenzyl, ethoxybenzyl, propoxybenzyl, Butoxybenzyl-, Pentoxybenzyl-, benzyloxybenzyl, methylbenzyl, ethylbenzyl, propylbenzyl, butylbenzyl, pentylbenzyl and benzylbenzyl remains.
  • Preferred radicals R 1 are ethoxybenzyl and butylbenzyl radicals.
  • the substituents of the benzyl radicals can be in the 2-, 3- or 4-position, that is to say ortho, meta or para. Ortho and para substituents are preferred, para residues are very particularly preferred.
  • the R 1 radicals can be in the 4- or 5-position of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -undecanedioic acid, the 4-position being preferred. In the other position R 1 there is a hydrogen atom.
  • the ethoxybenzyl radical is very particularly preferred.
  • the radicals R 2 may contain the compounds d to C 6 -alkyl radicals, for example methyl, ethyl, propyl, butyl, pentyl or hexyl radicals.
  • C 3 to C 6 alkyl radicals can be straight-chain or branched, such as, for example, isopropyl, isobutyl, tert-butyl, neopentyl or isohexyl radicals.
  • alkyl radicals can also contain up to 2 oxygen atoms (peroxo compounds naturally not being considered), for example as ethoxyethyl, ((ethoxy) ethoxy) ethyl or methoxypropyl radicals.
  • Lanthanoids are preferred among the metal ions.
  • holmium, erbium and ytterbium have proven to be more suitable than the elements gadolinium and dysprosium common in MR, thulium seems less suitable from an economic point of view because of the high price, but is also fundamentally suitable suitable.
  • other elements can also be used.
  • chelate compounds of lutetium, praseodymium, cerium, hafnium, lead and bismuth still have particularly favorable properties.
  • the carboxyl groups can also be present as amides, for example as alkyl or dialkyl amides - in which the alkyl groups have 1-4 carbon atoms - or as a morpholide group.
  • the amide functions are not negatively charged. As a result, the charge of the complex changes when a carboxyl function is converted into an amide function. As a rule, at most so many carboxyl functions are converted into amide functions that an electrically neutral complex is formed.
  • physiologically compatible cations are sodium *, calcium 2+ , magnesium 2+ and zinc 2+ and organic cations from the following organic bases: meglumine, glucosamine, arginine, ornithine, lysine, 2-amino-1,3,4-butanetriol and ethanolamine.
  • the metal complexes mentioned are preferably used in the form of their sterile aqueous solutions.
  • they can contain the usual pharmaceutical auxiliaries, such as buffers, bases, acids, stabilizers, solubilizers, substances for adapting the osmolality and viscosity, pharmacologically active additives and an excess of free complexing agent or their salts / complexes with weak contain bound physiologically compatible ions such as calcium 2+ , magnesium 2+ and zinc 2+ to improve the excretion of heavy metal ions.
  • suitable substances and their concentration ranges are known to the person skilled in the art or can be found in the literature.
  • the metal complexes are preferably used in a concentration of 0.1 mol to 1.0 mol based on the contrasting metal ion. Higher or lower concentrations are possible depending on the requirements and the solubility of the compounds in question.
  • the dosage for contrast enhancement in the liver is approximately 0.1-1.5 mmol / kg body weight, the range 0.2-0.6 mmol / kg being preferred.
  • the administration can take place in the usual ways in medicine. Intravenous infusion or injection over a period of about 1 minute to 30 minutes is preferred.
  • the mixture is taken up in toluene and shaken out several times against aqueous sodium hydrogen carbonate solution.
  • the organic phase is separated off, dried over magnesium sulfate, filtered and evaporated.
  • the oily residue is chromatographed on silica gel with hexane / diethyl ether / T ethylamine, the product-containing fractions are combined and evaporated. Yield: 16.4 g (94.8% of theory) of colorless oil.
  • o-tyrosine (2-hydroxyphenylalanine, Heraeus) are suspended in 48 ml of methanol, cooled in an ice bath, and 7.6 ml (105 mmol) of thionyl chloride are added dropwise. After one hour, the mixture is heated to reflux temperature and stirred for three hours. Then allowed to stir overnight at room temperature. The mixture is evaporated to dryness, the residue is taken up in methanol, the mixture is evaporated and the procedure is repeated twice. It is taken up in 50 ml of water, adjusted to pH 8.5 with 1.5 molar sodium carbonate solution and 22.1 ml (63 mmol) of benzyl chloroformate are added under pH control.
  • the title compound is obtained in a manner analogous to example a) if the complex acid is neutralized with 2-amino-1, 3,4-butanetriol.
  • Example 8b The title compound is obtained in an analogous manner to Example a) if the ligand (EP 0405704, Example 8b) is reacted with cerium carbonate and neutralized with sodium hydroxide solution. d) Ytterbium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4- (4-ethoxybenzyl) -undecanedioic acid
  • the corresponding bismuth complex made from bismuth oxycarbonate
  • the hafnium complex made from hafnium hydroxide
  • the lead complex can be used in an analogous manner (from lead carbonate), the lanthanum complex (from lanthanum carbonate), the dysprosium complex (from dysprosium oxide), the erbium complex (from erbium carbonate), the terbium complex (from terbium carbonate), the holmium complex (from holmium carbonate) and the praseodymium carbonate (obtained from praseodymium carbonate).
  • Example a are dissolved in 30 ml of tert-butyl methyl ether and mixed with 0.55 g (15 mmol) of sodium borohydride. At 3 ° C 8 ml of methanol are added and the mixture is stirred for five hours at constant temperature. Then 0.8 ml of acetic acid dissolved in 3 ml of tetrahydrofuran is added, 5 ml of water are added and the mixture is stirred at room temperature for ten minutes. The organic phase is separated off, washed with water and dried over sodium sulfate. The drying agent is suctioned off, the filtrate is evaporated and the residue is chromatographed on silica gel for purification. Yield: 3.4 g (86.5% of theory) of colorless oil. Analysis (based on solvent-free substance): calc .: C 70.56 H 7.61 N 3.92 0 17.90 found: C 70.43 H 7.60 N 4.07
  • the solution is infused at a dose of 0.3 mmol / kg body weight over 30 minutes.
  • CT scans are performed before the start of the infusion, at the end of the infusion and 30 minutes after the end of the infusion in the usual way.
  • J 50 110 25 500 914 27 A surprisingly high effectiveness of the rare earths against iodine turns out, which is presumably due to the special measuring conditions existing in abdominal CT.
  • erbium, ytterbium and holmium are preferable to the elements gadolinium and dysprosium, which have so far been the most studied.
  • liver CT 10 min, 60 min and (N 5) 120 min after intravenous infusion of 0.2, 0.35 and 0.5 mmol / kg Gd-EOB-DTPA (see Example 6) examined.
  • Gd-EOB-DTPA (0.25 mmol / L) was administered intravenously in a drip infusion into the arm vein.
  • the infusion time was 20 min for the doses 0.2 and 0.35 mmol / kg and 30 min for the highest dose of 0.5 mmol / kg.
  • Exclusion criteria for the patients were:
  • the entire liver was measured within 20-30 seconds with the breath stopped.
  • the table feed was 8 mm / sec, the collimation 8 mm.
  • the number and size of the metastases were qualitatively assessed by two independent observers (excellent, good, moderate, minimal, no improvement) and quantitatively (measurement of the Hounsfield units) evaluated.
  • Gd-EOB-DTPA The tolerance of Gd-EOB-DTPA was determined by determining the general condition, the recording of vital parameters and a laboratory analysis of serum and urine parameters.
  • FIG. 1 shows the time course of the CT density (Hounsfield units, HU) in the liver of patients with histologically proven primary tumor after the start of an infusion of 0.2 (o), 0.35 ( ⁇ ) or 0.5 mmol / kg Gd-EOB-DTPA ( ⁇ ).
  • the CT density in the liver metastases is shown with the symbol *.
  • the CT density of the metastases was unchanged.
  • the gallbladder and bile ducts were also visualized. Visualization of the metastases was improved in all dose groups after infusion of Gd-EOB-DTPA. It was excellent in the two upper dose groups. After the highest dose, an average of two additional metastases were discovered that were previously unknown. The mean size of the smallest metastases found decreased accordingly from 20.3 to 16.6 mm. In a patient with a known metastasis in the right lobe of the liver, an additional lesion of 7 mm in diameter was found after Gd-EOB-DTPA in the left lobe of the liver, which had not previously been found.
  • Gd-EOB-DTPA is a well-tolerated and effective liver or bile contrast agent for CT.

Landscapes

  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Radiology & Medical Imaging (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un complexe métallique de dérivés de DTPA substitués en position 4 ou 5 par un groupe benzyle pouvant être utilisés comme agents de contraste pour la tomographie assistée par ordinateur du foie et des canaux biliaires.
PCT/EP1995/004547 1994-11-30 1995-11-20 Utilisation de composes chelates comme agents diagnostics pour des examens radiographiques du foie et des canaux biliaires WO1996016678A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
FI972285A FI972285L (fi) 1994-11-30 1995-11-20 Kelaattiyhdisteiden käyttö röntgendiagnostisina aineina maksa- ja sappitutkimuksissa
JP8517855A JPH10509734A (ja) 1994-11-30 1995-11-20 肝臓及び胆嚢用ｘ線診断薬剤としての金属錯体の使用
AU41738/96A AU4173896A (en) 1994-11-30 1995-11-20 Use of chelate compounds as diagnostic agents in the x-ray examination of liver and bile ducts
EP95940207A EP0794800A1 (fr) 1994-11-30 1995-11-20 Utilisation de composes chelates comme agents diagnostics pour des examens radiographiques du foie et des canaux biliaires
SK688-97A SK68897A3 (en) 1994-11-30 1995-11-20 Use of chelate compounds as diagnostic agents in the x-ray examination of liver and bile ducts
MXPA/A/1997/003974A MXPA97003974A (en) 1994-11-30 1997-05-29 Use of metal complexs as x-ray diagnostic agents for the liver and the bil vesicula
NO972458A NO972458D0 (no) 1994-11-30 1997-05-29 Anvendelse av metallkomplekser som lever- og galleröntgendiagnostika

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US35108694A 1994-11-30 1994-11-30
US38740895A 1995-02-13 1995-02-13
US08/387,408 1995-02-13
US08/351,086 1995-02-13
US48056695A 1995-06-07 1995-06-07
US08/480,566 1995-06-07

Publications (1)

Publication Number Publication Date
WO1996016678A1 true WO1996016678A1 (fr) 1996-06-06

Family

ID=27407981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1995/004547 WO1996016678A1 (fr) 1994-11-30 1995-11-20 Utilisation de composes chelates comme agents diagnostics pour des examens radiographiques du foie et des canaux biliaires

Country Status (13)

Country Link
EP (1) EP0794800A1 (fr)
JP (1) JPH10509734A (fr)
CN (1) CN1167443A (fr)
AU (1) AU4173896A (fr)
CA (1) CA2206558A1 (fr)
CZ (1) CZ166797A3 (fr)
FI (1) FI972285L (fr)
HU (1) HUT77553A (fr)
IL (1) IL116207A0 (fr)
NO (1) NO972458D0 (fr)
PL (1) PL320482A1 (fr)
SK (1) SK68897A3 (fr)
WO (1) WO1996016678A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817289A (en) * 1995-01-26 1998-10-06 Nycomed Imaging As Non-cluster type bismuth compounds
EP0885616A1 (fr) * 1997-06-20 1998-12-23 Schering Aktiengesellschaft Utilisation d'agents de contraste à administration intraveneuse, et appareil pour la mammographie
US6117412A (en) * 1995-01-26 2000-09-12 Nycomed Imaging As Non-cluster type bismuth compounds
WO2011154333A3 (fr) * 2010-06-11 2012-02-16 Bayer Pharma Aktiengesellschaft Procédé de préparation d'acide 3,6,9-triaza-3,6,9-tris(carboxyméthyl)-4-(4-éthoxybenzyl)-undécandioïque cristallin et son utilisation pour la préparation de primovist®

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2012254973A (ja) * 2011-05-18 2012-12-27 Sumitomo Chemical Co Ltd 脂肪族アミン配位セリウム錯体及び該錯体を含む素子
WO2015124581A1 (fr) * 2014-02-18 2015-08-27 Medesis Pharma Utilisation d'un système micellaire inverse dans la libération de chélateurs de radionucléides et de métaux

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
EP0450742A1 (fr) * 1990-04-06 1991-10-09 Schering Aktiengesellschaft DTPA-monoamides, compositions pharmaceutiques les contenant, leur utilisation et procédé pour leur préparation
WO1993008846A1 (fr) * 1991-10-30 1993-05-13 Cockbain, Julian, Roderick, Michaelson Milieux de contraste

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
EP0450742A1 (fr) * 1990-04-06 1991-10-09 Schering Aktiengesellschaft DTPA-monoamides, compositions pharmaceutiques les contenant, leur utilisation et procédé pour leur préparation
WO1993008846A1 (fr) * 1991-10-30 1993-05-13 Cockbain, Julian, Roderick, Michaelson Milieux de contraste

Non-Patent Citations (7)

* Cited by examiner, † Cited by third party
Title
E. UNGER & F. GUTTIERREZ: "Ytterbium-DTPA A potential intravascular contrast agent", INVEST. RADIOL., 1986, VOL. 21, NO. 10, PAGES 802-807, XP000566355 *
MARTIN V V ET AL: "Gadolinium(III) Di- and Tetrachelates Designed for in Vivo Noncovalent Complexation with Plasma Proteins: A Novel Molecular Design for Blood Pool MRI Contrast Enhancing Agents", BIOCONJUGATE CHEM., 1995, VOL. 6, NO. 5, PAGE(S) 616-23, XP000542464 *
MEYER D L ET AL: "Kinetics of the dissociation of indium-(para-substituted-benzyl)eth ylenediaminetetraacetic acid hapten analogs from the monoclonal anti-hapten antibody CHA255", BIOCONJUGATE CHEM., 1990, VOL. 1, NO. 4, PAGE(S) 278-84, XP002000359 *
R.L.J. SCHLUTE U.M.: "Zwischenentscheidung der Juristischen Beschwerdekammer vom 12. April 1995 J21/94 - 3.1.1", AMTSBLATT DES EUROPÄISCHEN PATENTAMTS, vol. 19, no. 1-2, January 1996 (1996-01-01) - February 1996 (1996-02-01), MÜNCHEN, DE, pages 16 - 25, XP002000361 *
UGGERI F ET AL: "Novel Contrast Agents for Magnetic Resonance Imaging. Synthesis and Characterization of the Ligand BOPTA and Its Ln(III) Complexes (Ln = Gd, La, Lu). X-ray Structure of Disodium (TPS-9-145337286-C-S)- [4-Carboxy-5,8,11-tris(carboxymethyl)-1- phenyl-2-oxa-5,8,11-triazatridecan- 13-oato(5-)]-", INORG. CHEM., 1995, VOL. 34, NO. 3, PAGE(S) 633-42, XP000565680 *
WILLIAMS M A ET AL: "Synthesis of enantiomerically pure diethylenetriaminepentaacetic acid analogs. L-Phenylalanine as the educt for substitution at the central acetic acid", J. ORG. CHEM., 1993, VOL. 58, NO. 5, PAGE(S) 1151-8, XP002000360 *
ZWISCHENENTSCHEIDUNG DER JURISTISCHEN BESCHWERDEKAMMER VOM J21/94 - 3.1.1, 12 April 1995 (1995-04-12), MÜNCHEN, DE *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5817289A (en) * 1995-01-26 1998-10-06 Nycomed Imaging As Non-cluster type bismuth compounds
US6117412A (en) * 1995-01-26 2000-09-12 Nycomed Imaging As Non-cluster type bismuth compounds
US6303101B1 (en) 1995-01-26 2001-10-16 Nycomed Imaging As Bismuth compounds
EP0805815B1 (fr) * 1995-01-26 2002-04-10 Nycomed Imaging A/S Utilisation de COMPOSES DE BISMUTH pour la fabrication de médicaments pour le traitement de troubles gastriques associées avec Helicobacter pylori
EP0885616A1 (fr) * 1997-06-20 1998-12-23 Schering Aktiengesellschaft Utilisation d'agents de contraste à administration intraveneuse, et appareil pour la mammographie
WO1998058679A1 (fr) * 1997-06-20 1998-12-30 Schering Aktiengesellschaft Utilisation d'agents de contraste intraveineux pour mammographie avec projection
CZ298462B6 (cs) * 1997-06-20 2007-10-10 Schering Aktiengesellschaft Použití intravenosních kontrastních prostredku pro projekcní mamografii
WO2011154333A3 (fr) * 2010-06-11 2012-02-16 Bayer Pharma Aktiengesellschaft Procédé de préparation d'acide 3,6,9-triaza-3,6,9-tris(carboxyméthyl)-4-(4-éthoxybenzyl)-undécandioïque cristallin et son utilisation pour la préparation de primovist®
CN103068790A (zh) * 2010-06-11 2013-04-24 拜耳知识产权有限责任公司 用于制备结晶的3,6,9-三氮杂-3,6,9-三(羧甲基)-4-(4-乙氧基苄基)十一烷二酸的方法以及用于制备普美显*（Primovist*）的用途

Also Published As

Publication number Publication date
PL320482A1 (en) 1997-09-29
SK68897A3 (en) 1998-10-07
AU4173896A (en) 1996-06-19
FI972285A0 (fi) 1997-05-29
FI972285A7 (fi) 1997-05-29
EP0794800A1 (fr) 1997-09-17
CZ166797A3 (en) 1997-11-12
HUT77553A (hu) 1998-05-28
CN1167443A (zh) 1997-12-10
FI972285L (fi) 1997-05-29
CA2206558A1 (fr) 1996-06-06
JPH10509734A (ja) 1998-09-22
MX9703974A (es) 1997-09-30
NO972458L (no) 1997-05-29
NO972458D0 (no) 1997-05-29
IL116207A0 (en) 1996-01-31

Similar Documents

Publication Publication Date Title
EP0794799A2 (fr) Utilisation de complexes metalliques comme agents de radiodiagnostic du foie et de la vesicule biliaire en tomographie informatisee
DE68908185T2 (de) Chelat-zusammensetzung.
EP0071564B1 (fr) Sels complexes paramagnétiques, leur préparation et leur utilisation en diagnostique avec RMN
DE69636635T2 (de) Kontrastmittel für diagnostische bildgebung mit verlängerter verweilzeit im blut
EP1960002B1 (fr) Dispersions aqueuses de particules superparamagnetiques monodomaine, leur production et leur utilisation dans le diagnostic et la therapie
DE69528046T2 (de) Polychelate
EP0736059B1 (fr) Complexes metalliques de macromolecules dendrimeres, moyens de diagnostic contenant ces complexes et procede pour la preparation des complexes et des moyens de diagnostic
US5817289A (en) Non-cluster type bismuth compounds
DE69320173T2 (de) Kontrastmittel
EP0500919A1 (fr) Nouveaux agents pour imagerie a resonance magnetique
DE60220765T2 (de) Komplexverbindungen aus paramagnetischem metall und phthalocyanin und kontrastmittel, bei dem diese verbindungen verwendet werden
WO1996016678A1 (fr) Utilisation de composes chelates comme agents diagnostics pour des examens radiographiques du foie et des canaux biliaires
EP1307237B9 (fr) Complexes perfluoroalkyles a residus polaires, leur procede de fabrication et leur utilisation
DE69717269T2 (de) T1-zeitgewichteten kernspintomogram der res-orgäne
DE19808079A1 (de) Hydroxyethylstärke-Konjugate, Verfahren zu ihrer Herstellung und diese enthaltende pharmazeutische Mittel
DE69214215T2 (de) Magnetisches Kernresonanz Bilderzeugungsmittel
DE60026743T2 (de) Verwendung von Kontrastmitteln zur Herstellung eines Diagnostischen Mittels für die Darmlumenbildgebung
EP0775104B1 (fr) Derives dimeres de dtpa et leurs complexes metalliques, agents pharmaceutiques contenant ces complexes, leur utilisation en diagnostic et en therapie et procede de preparation de ces complexes et agents pharmaceutiques
EP0680464B1 (fr) Complexes derives de dtpa, agents pharmaceutiques renfermant ces composes, leur utilisation comme produits de contraste pour rmn et radiographie, et leur procede de fabrication
DE19507820A1 (de) Neuartig substituierte DTPA-Derivate, deren Metallkomplexe, diese Komplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik, sowie Verfahren zur Herstellung der Komplexe und Mittel
DE3633243A1 (de) Phosphonat-komplexe
DE10117242C1 (de) Unsymmetrische dimere Metallkomplexe, Liganden für diese Metallkomplexe, Verfahren zu deren Herstellung, Arzneimittel bzw. Diagnosemittel, die die Metallkomplexe enthalten, insbesondere Kontrastmittel
EP0730586A1 (fr) Derives de 1,4,7,10-tetra-azacyclododecane, leur utilisation, substances pharmaceutiques les contenant et procedes permettant de les preparer
CA1335819C (fr) Chelate metallique contenant un milieu contrastant pour l'imagerie diagnostique
MXPA97003974A (en) Use of metal complexs as x-ray diagnostic agents for the liver and the bil vesicula

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 95196523.9

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AU BY CA CN CZ FI HU JP KR MX NO NZ PL RU SK UA VN

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1995940207

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 296981

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2206558

Country of ref document: CA

Ref document number: 2206558

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PV1997-1667

Country of ref document: CZ

Ref document number: 972285

Country of ref document: FI

Ref document number: 1019970703601

Country of ref document: KR

Ref document number: PA/a/1997/003974

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 68897

Country of ref document: SK

WWP Wipo information: published in national office

Ref document number: 1995940207

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1997-1667

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019970703601

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV1997-1667

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1995940207

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1019970703601

Country of ref document: KR