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.

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• 1995
  • 1995-11-20 AU AU41738/96A patent/AU4173896A/en not_active Abandoned
  • 1995-11-20 CA CA002206558A patent/CA2206558A1/en not_active Abandoned
  • 1995-11-20 PL PL95320482A patent/PL320482A1/xx unknown
  • 1995-11-20 WO PCT/EP1995/004547 patent/WO1996016678A1/de not_active Ceased
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  • 1995-11-20 CN CN95196523A patent/CN1167443A/zh active Pending
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  • 1995-11-20 EP EP95940207A patent/EP0794800A1/de not_active Withdrawn
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• 1997
  • 1997-05-29 NO NO972458A patent/NO972458L/no not_active Application Discontinuation

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