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
  • A61K49/0004—Screening or testing of compounds for diagnosis of disorders, assessment of conditions, e.g. renal clearance, gastric emptying, testing for diabetes, allergy, rheuma, pancreas functions
• • 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
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
  • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
  • A61K49/10—Organic compounds
  • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
  • A61K49/103—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being acyclic, e.g. DTPA
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P39/00—General protective or antinoxious agents
  • A61P39/02—Antidotes
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T436/00—Chemistry: analytical and immunological testing
  • Y10T436/24—Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Definitions

• the invention relates to the use of metal complexes in liver and biliary X-ray diagnostics by means of X-rays, in particular in the
• Scintigraphy offers a spatial resolution that is too low and its use 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 review article mentioned.
• Sonography is also currently not a sufficiently reliable technique for the detection of solid focal liver changes, since these often do not change in their acoustic properties differentiate sufficiently from the healthy liver tissue. Smaller lesions 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 tissue and the extracellular space. This period of time can only be achieved with the modern, very fast CT
• a catheter e.g. into the mesenteric artery the patient is then brought to the CT scanner and the
• 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 reached, with a concentration of 50 ⁇ g iodine / ml only barely twice the concentration, with 500 ⁇ g iodine / ml plasma this is
• X-ray contrast media that are specific and not effective in too high a dose, and so far, despite decades of efforts, there is not a single product on the market or even in a promising stage of the clinical trial.
• Such preparations are difficult to find due to the unpredictable species dependence of absorption, enrichment and excretion by the liver by means of animal experiments; In addition, after many disappointing results in animal experiments, animal findings are no longer to be regarded as an indication of the suitability or inappropriateness of a substance or class of substances.
• X-ray contrast medium is the much lower content of X-ray absorbing element in the molecules (iodinated X-ray contrast medium: 3 or 6 iodine atoms / molecule; MR contrast medium: 1 metal ion / molecule).
• the contrast is correspondingly weak, so that the metal complexes are almost only for
• the object of the present invention is therefore to select from the known pharmaceutical substances suitable for imaging diagnosis on the basis of metal chelates those which are suitable for the production of contrast media for X-ray diagnosis, in particular computer tomography, the liver and biliary tract.
• metal complexes consisting of a metal of atomic numbers 39-42, 44-51 or 56-83 and a complexing agent, for the production of contrast media for use in contrast-enhanced
• Acidic metal complexes with a molecular weight below 1500 D are generally suitable which contain at least one metal ion with the atomic number 39-42, 44-51 or 56-83 which is suitable for X-ray absorption. Those complexes are preferred which contain at least one lipophilic structural element, consisting of at least three carbon atoms, in the molecule.
• the total lipophilicity (determined as partition coefficient butanol / Tris buffer pH 7.6> 0.0002) of the complex must be higher than that of Gadolinium-DTPA.
• the complex formation constant must also exceed 10 14 .
• Such substances and their preparation are described in the examples of this application and in EP 0405 704; EP 0230893; US 4,880,008; US 4,899,755; US 5,250,285 and US 5,318,771.
• X independently of one another for a hydrogen atom, or for a
• k represents the numbers 0, 1 or 2 and
• R 1 independently of one another represents a hydrogen atom or a radical of the formula Ia
• R 2 independently of one another represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical and
• R 1 has the meaning given above and
• R 1 has the meaning of a
• n stands for the numbers 0, 1 or 2 and
• R 1 independently of one another represents a hydrogen atom or a radical of the formula Ia
• n stands for the numbers 0 or 1 R 1 independently of one another represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical and
• R 1 has the meaning given above and
• R 1 has the meaning of a
• n stands for the numbers 0, 1 or 2 and
• R 1 independently of one another represents a hydrogen atom or a radical of the formula Ia
• R 2 independently of one another represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical and
• R 1 has the meaning given above and
• R 1 has the meaning of a
• n stands for the numbers 0, 1 or 2 and
• R 1 independently of one another represents a hydrogen atom or a radical of the formula Ia
• R 2 independently of one another represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical and
• R 1 has the meaning given above and
• R 1 has the meaning of a
• n stands for the numbers 0, 1 or 2 and
• R 1 independently of one another represents a hydrogen atom or a radical of the formula Ia
• R 2 independently of one another represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical and
• R 1 has the meaning given above and
• n stands for the numbers 0, 1 or 2 and
• R 1 independently of one another represents a hydrogen atom or a radical of the formula Ia
• R 2 independently of one another for a hydrogen atom or a
• Sulfur atom an -N (H) - or -N (R 2 ) - group or a C 1 -C 10 - alkylene chain, which may be replaced by an oxygen or a
• Sulfur atom, an -N (H) - or an -N (R 2 ) - group is interrupted
• R 1 has the meaning given above and
• R 1 has the meaning of a
• X independently of one another for a hydrogen atom, or for a
• k represents the numbers 0, 1 or 2 and
• R 1 independently of one another represents a hydrogen atom or a radical of the formula Ia
• n stands for the numbers 0 or 1 R 2 independently of one another represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical and
• R 1 has the meaning given above and
• Ar independently of one another represents a saturated or unsaturated, optionally bicyclic, C 5 -C 10 ring which is optionally interrupted by one or two oxygen, sulfur and / or nitrogen atoms and
• R 1 has the meaning of a
• R 1 independently of one another represents a hydrogen atom or a radical of the formula Ia
• R 2 independently of one another represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical and
• R 1 has the meaning given above and
• Ar independently of one another represents a saturated or unsaturated, optionally bicyclic, C 5 -C 10 ring which is optionally interrupted by one or two oxygen, sulfur and / or nitrogen atoms and
• At least one of the radicals denoted by R 1 has the meaning of a radical of the formula Ia.
• y stands for the number zero or one
• R 3 represents a C 1 -C 5 alkyl radical or a benzyl radical.
• X independently of one another for a hydrogen atom, or for a
• R 3 represents a methyl, ethyl, n-propyl, n-butyl or a benzyl radical.
• radicals R 1 independently of one another represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 44-51 or 56-83
• one of the radicals R 1 represents a radical of the formula -CH 2 -C 6 H4- (O) r -R 2 , in which the aromatic ring can be substituted in the ortho, meta or para position and the other radical R 1 represents hydrogen stands,
• R 1 represents a radical of the formula Ib
• p stands for the number 0 or 1
• R 2 independently of one another for a hydrogen atom or a
• R 3 represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical or a
• L 1 stands for a direct bond or a C 1 -C 4 alkylene chain
• L 2 , L 3 each independently of one another for a direct bond
• Oxygen atom a sulfur atom or a C 1 -C 10 alkylene chain which is optionally interrupted by one to three oxygen and / or one to three sulfur atoms, whereby two or more heteroatoms must not be directly connected to one another and
• R 4 , R 5 independently of one another represent a hydrogen atom or a group R 1 or
• R 4 and R 5 together, including the common amide nitrogen atom, form a four- to eight-membered ring which can contain two further oxygen atoms and / or two carbonyl groups,
• X 2 independently of one another represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 39-51 or 57-83, in combination with the physiologically compatible inorganic and / or organic cations which may be required for charge balancing.
• R 1 5, 6 or 7 of the radicals denoted by R 1 are hydrogen and the others independently of one another are a radical of the formula Ic
• p stands for the number 0 or 1
• R 2 independently of one another for a hydrogen atom or a
• R 3 represents a hydrogen atom or a branched or unbranched, saturated or unsaturated C 1 -C 6 radical or a
• L 1 represents a direct bond, a sulfur atom, a C 1 -C 4 alkylene chain or an interrupted by a sulfur atom C 1 -C 4 - alkylene chain,
• L 2 , L 3 each independently for a direct bond
• Oxygen atom a sulfur atom or a C 1 -C 10 alkylene chain which optionally contains one to three oxygen and / or one to three sulfur atoms, where if p is zero two or more heteroatoms must not be directly connected to one another and
• R 4 , R 5 independently of one another represent a hydrogen atom or a radical R 1 or
• R 4 and R 5 together, including the common amide nitrogen atom, form a four- to eight-membered ring which can contain two further oxygen atoms and / or two carbonyl groups,
• X 2 independently of one another represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 39-51 or 57-83, in combination with the physiologically compatible inorganic and / or organic cations which may be required for charge balancing.
• Benzyl methoxybenzyl, ethoxybenzyl, propoxybenzyl, isopropoxybenzyl, butoxybenzyl, isobutoxybenzyl, tert.-butoxybenzyl, pentoxybenzyl,
• Benzyloxybenzyl methylbenzyl, ethylbenzyl, propylbenzyl, butylbenzyl, pentylbenzyl and benzylbenzyl radicals.
• Preferred radicals are the methoxybenzyl, ethoxybenzyl and the butylbenzyl radical, the is particularly preferred
• the lanthanides are preferred.
• 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 basically also suitable.
• the elements lutetium praseodymium, bismuth, lead and hafnium are also suitable. Other elements of the ordinal numbers mentioned in claim 1 can also be used.
• the complexing agent has more acid functions than the complexed metal carries positive elementary charges.
• the 3,6,9-triaza-3,6,9-tris (carboxymethyl) -2- (4-ethoxybenzyl) -undecanedioic acid described in Example 1 carries five acid groups, while the dysprosium in the dysprosium oxide (Dy 2 O 3 ) is in the oxidation state + III.
• a complex is thus neutralized only three of the five protons of the acid.
• a complex is thus formed which also contains two dissociable protons, an acid complex.
• Two protons and one dianion - formed from the metal and the complexing agent - are thus present in aqueous solution.
• physiologically compatible cations For purposes it is advantageous to exchange the protons for other physiologically compatible cations (neutralization) so that a salt is formed.
• physiologically compatible cations are sodium + , calcium 2+ ,
• 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, and substances for
• Contain magnesium 2+ and zinc 2+ to improve the excretion of heavy metal ions Contain 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 is 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 substance class described here has for the first time been able to achieve a specific contrast medium concentration in the liver in humans, that which is available today computed tomography technique to a useful diagnostic
• ⁇ the iodized X-ray contrast media did not meet the requirements despite the presence of all theoretically required molecular properties and a significantly higher content of contrasting element in the molecule, ⁇ the effect of the substances according to the invention in magnetic resonance tomography already occurs at concentrations 10 times lower than for X-rays Computer tomography is required and that these lower concentrations of a large number of x-ray contrast media are also achieved in the liver of humans, without these x-ray contrast media therefore being able to be used for computer tomography, MR or another imaging method for improving the diagnosis of focal liver changes,
• Dysprosium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -2- (4-ethoxybenzyl) -undecanedioic acid a) N-benzyl-tyrosine tert-butyl ester
• 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 for purification on silica gel with hexane / diethyl ether / triethylamine.
• Example f 7.59 g (20 mmol) of the compound prepared according to Example d) and 11.2 g (22 mmol) of 3,6-diaza-3- (tert-butoxycarbonylmethyl) -6- (2-bromethyl) octanedioic acid di Tert-butyl ester (Example f) are placed in 45 ml of acetonitrile and mixed with 25 ml of 2N phosphate buffer solution (pH 8.0). The mixture is stirred vigorously at room temperature for 22 hours, the aqueous phosphate buffer phase being replaced with fresh buffer solution after 2 and 7 hours. Then the organic phase is evaporated in vacuo and the residue on silica gel
• Dysprosium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -2- (4-ethoxybenzyl) -undecanedioic acid 6.9 g (13 mmol) of the pentic acid described in Example h) are taken up in 30 ml of water, 2.42 g (6.5 mmol) of dysprosium oxide are added and the mixture is stirred at 85 ° C. for eight hours. The pH is then adjusted to 7.2 with dilute sodium hydroxide solution, and the filtrate is filtered and freeze-dried.
• Ion exchanger to pH 1.9. After filtering off the exchanger, the aqueous solution is mixed with 3.79 g (9.61 mmol) of ytterbium oxide and stirred at 95 ° C. After complexation is complete, the mixture is filtered, adjusted to pH 7.2, stirred with 0.2 g of activated carbon at 90 ° C. for ten minutes, filtered again and the filtrate is lyophilized.
• Phosphate phase is exchanged for fresh buffer solution after 2, 8 and 18 hours. Then the organic phase is evaporated in vacuo and the residue is chromatographed on silica gel with hexane / ethyl acetate / triethylamine. The product-containing fractions are in a vacuum
• the egg is evaporated and dried in a high vacuum, causing the free complexing agent to develop.
• the penta acid is taken up in 250 ml of water and 6.22 g (12.2 mmol) of bismuth oxycarbonate are added. The suspension is stirred at 100 ° C. for 25 hours and filtered. The pH is then adjusted to 7.2 with a normal sodium hydroxide solution.
• Example 4 Ytterbium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -4,8-bis (4-ethoxybenzyl) -undecanedioic acid
• Example a 20 g (102.4 mmol) of 2- (4-ethoxybenzyl) -2-aminoethanol (Example a) are tert with 40 g (205 mmol) of bromoacetic acid. butyl ester implemented in an analogous manner to Example 3d). After chromatographic cleaning, you can get it
• Dialkylation product as a colorless oil.
• the reaction mixture is evaporated and dried at 100 ° C. in an oil pump vacuum for several hours.
• the backlog is in
• the penta acid is taken up in 120 ml of water and mixed with 2.81 g (7.77 mmol) of gadolinium oxide. The suspension is stirred at 90 ° C for 7 hours and filtered. The pH is then adjusted to 7.1 using a normal sodium hydroxide solution. The solution is then stirred at 70 ° C. for one hour after the addition of 1.4 g of activated carbon and filtered. The filtrate is lyophilized.
• N-Benzyloxycarbonyl-3- [4- (tert-butoxycarbonylmethoxy) phenyl] alanine tert-butyl ester 5.57 g (15 mmol) N-benzyloxycarbonyl-tyrosine tert. -butyl esters are reacted in analogy to example 1a) with tert-butyl bromoacetate to give the alkylated phenol.
• the methanol is then distilled off, taken up in water and concentrated with. Hydrochloric acid precipitated.
• the solid is filtered off with suction, washed neutral with water and the ligand is dried at 50 ° C. in vacuo.
• the bromide is obtained as a pale yellow oil from 5.6 g (10.6 mmol) of the diester from Example c) and triphenylphosphine and N-bromosuccinimide in an analogous manner to Example 3e).
• the penta acid is taken up in 100 ml of water and 0.85 g (1.7 mmol)
• Terbium carbonate hydrate added.
• the suspension is stirred at 70 ° C. for 15 hours and filtered.
• the pH is then adjusted to 7.1 using a normal sodium hydroxide solution.
• reaction mixture is evaporated and dried in an oil pump vacuum at 100 ° C for several hours.
• residue is taken up in isopropanol.
• Phosphate buffer phase is exchanged for fresh buffer solution after 2 and 7 hours. Then the organic phase is evaporated in vacuo and the residue is chromatographed on silica gel with hexane / ethyl acetate / triethylamine. The product-containing fractions are in a vacuum
• the batch is adjusted to pH 2 by carefully adding half-concentrated hydrochloric acid, then neutralized with concentrated aqueous sodium bicarbonate solution and after extensive evaporation of Methanol shaken out with ethyl acetate.
• the organic phase is dried over anhydrous magnesium sulfate, filtered and evaporated.
• the residue is on silica gel with diethyl ether / hexane / triethylamine
• N-benzyl-tyrosine tert. butyl ester (Example i) are dissolved in 50 ml of tetrahydrofuran and mixed with 5 ml of water and 9.54 g (69 mmol)
• the penta acid is taken up in 250 ml of water and 1.13 g (2.99 mmol) of holmium oxide are added. The suspension is stirred at 100 ° C. for 16 hours and filtered. Then pH 7.3 is adjusted with a normal sodium hydroxide solution. The solution is then stirred at 80 ° C for one hour after the addition of 0.6 g of activated carbon and filtered. After freeze drying, the filtrate gives a colorless solid. Yield 5.55 g (95.3% of theory)
• Phosphate buffer phase is exchanged for fresh buffer solution after 2 and 7 hours. Then the organic phase is evaporated in vacuo and the residue was chromatographed on silica gel with hexane / ethyl acetate / triethylamine. The product-containing fractions are in a vacuum
• the penta acid is taken up in 250 ml of water and 1.04 g (2.74 mmol) of erbium oxide are added. The suspension is stirred at 100 ° C. for 16 hours and filtered. Then pH 7.3 is adjusted with a normal sodium hydroxide solution. The solution is then stirred at 80 ° C. for one hour after the addition of 0.6 g of activated carbon and filtered. After freeze drying, the filtrate gives a colorless solid. Yield 5.78 g (90.3% of theory)
• mice sitting in a single compulsory cage (strain: NMRI (SPF), breeder: Schering, average weight: 20 g, same gender distribution) were placed in one of the caudal veins with a contrast medium
• the LD 50 for the ytterbium complex according to Example 4e is 15 mmol / kg
• Example 11 Lutetium complex of the disodium salt of 3,6,9-triaza-3,6,9-tris (carboxymethyl) -5- (4-ethoxybenzyl) -undecanedioic acid a) 3,6,9-triaza-3,6,9 -tris- (tert-butoxycarbonylmethyl) -5- (4-ethoxybenzyl) -undecanedioic acid di-tert-butyl ester
• reaction temperature rises to room temperature and is stirred for a further four hours.
• 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 on silica gel with hexane / diethyl ether / triethylamine chromatographed, the product-containing fractions are combined and evaporated.
• the penta acid is taken up in 250 ml of water and mixed with 3.98 g (10 mmol) of lutetium oxide. The suspension is stirred at 100 ° C. for 36 hours and filtered. Then pH 7.3 is adjusted with a normal sodium hydroxide solution. The solution is then stirred at 80 ° C. for one hour after the addition of 1.6 g of activated carbon and filtered. After freeze drying, the filtrate gives a colorless solid. Yield: 14.1 g (94.8% of theory)
• reaction mixture is evaporated, the residue is taken up in ethyl acetate and washed with water.
• the organic phase is cooled in an ice bath and concentrated with. Hydrochloric acid added.
• the resulting precipitate is filtered off, washed with cold isopropanol and dried at 50 ° C.
• 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 with
• the complexation is neutralized with 1N sodium hydroxide solution. You filter the
• Bismuth oxycarbonate Bismuth oxycarbonate
• hafnium complex from hafnium hydroxide
• Lead complex from lead carbonate
• the lanthanum complex from lanthanum carbonate
• dysprosium complex from dysprosium oxide
• erbium complex from hafnium hydroxide
• Holmium complex made of holmium carbonate
• the praseodymium complex made of praseodymium carbonate
• reaction mixture is mixed with water and extracted with ethyl acetate.
• the organic phase is over
• the penta acid is taken up in 150 ml of water and mixed with 3.94 g (7.5 mmol) of ytterbium carbonate. The suspension is stirred at 60 ° C for 3 hours and filtered. Then pH 7.3 is adjusted with a normal sodium hydroxide solution. The solution is then stirred at 80 ° C. for one hour after the addition of 1.0 g of activated carbon and filtered. After freeze drying, the filtrate gives a colorless solid. Yield 11.4 g (91.6% of theory)
• the solution is dosed at 0.3 mmol / kg 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.
• 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 16) 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 tolerance of Gd-EOB-DTPA was determined by determining the tolerance of Gd-EOB-DTPA
• 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 *.
• Gd-EOB-DTPA The general tolerability of Gd-EOB-DTPA was good. Only four mild or moderate side effects were observed. They reported in two cases
• Gd-EOB-DTPA is a well-tolerated and effective liver or bile contrast agent for computed tomography.

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• 1995
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  • 1995-11-20 CA CA002206397A patent/CA2206397A1/en not_active Abandoned
  • 1995-11-20 AU AU39227/95A patent/AU3922795A/en not_active Abandoned
  • 1995-11-20 CA CA002206522A patent/CA2206522A1/en not_active Abandoned
  • 1995-11-20 EP EP95936963A patent/EP0794799A2/de not_active Withdrawn
  • 1995-11-20 JP JP8517148A patent/JPH10511934A/ja not_active Withdrawn
  • 1995-11-20 JP JP8518026A patent/JPH11503405A/ja active Pending
  • 1995-11-20 CA CA002206576A patent/CA2206576A1/en not_active Abandoned
  • 1995-11-20 WO PCT/EP1995/004549 patent/WO1996016929A1/de not_active Application Discontinuation
  • 1995-11-20 WO PCT/EP1995/004548 patent/WO1996016928A1/de not_active Application Discontinuation
  • 1995-11-20 CN CN95196529A patent/CN1167444A/zh active Pending
  • 1995-11-20 JP JP8517856A patent/JPH10509961A/ja not_active Withdrawn
  • 1995-11-30 IL IL11620895A patent/IL116208A0/xx unknown
  • 1995-11-30 US US08/565,397 patent/US5853699A/en not_active Expired - Fee Related
  • 1995-11-30 IL IL11620995A patent/IL116209A0/xx unknown
  • 1995-11-30 IL IL11620695A patent/IL116206A0/xx unknown
  • 1995-11-30 US US08/565,025 patent/US5746995A/en not_active Expired - Fee Related
  • 1995-11-30 US US08/565,024 patent/US5885548A/en not_active Expired - Fee Related
• 1997
  • 1997-05-29 NO NO972460A patent/NO972460D0/no unknown
  • 1997-05-29 FI FI972286A patent/FI972286A/fi unknown
  • 1997-05-29 FI FI972287A patent/FI972287A/fi unknown
  • 1997-05-29 NO NO972459A patent/NO972459L/no unknown
  • 1997-05-29 FI FI972288A patent/FI972288A/fi unknown
  • 1997-05-29 NO NO972457A patent/NO972457L/no unknown

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