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WO2004074267A1 - Derives de benzene trimeres substitues de maniere macrocyclique - Google Patents

Derives de benzene trimeres substitues de maniere macrocyclique Download PDF

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Publication number
WO2004074267A1
WO2004074267A1 PCT/EP2003/014149 EP0314149W WO2004074267A1 WO 2004074267 A1 WO2004074267 A1 WO 2004074267A1 EP 0314149 W EP0314149 W EP 0314149W WO 2004074267 A1 WO2004074267 A1 WO 2004074267A1
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Prior art keywords
tris
mmol
chz
general formula
filtered
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PCT/EP2003/014149
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German (de)
English (en)
Inventor
Johannes Platzek
Hanns-Joachim Weinmann
Heiko Schirmer
Jose Luis Martin
Juan R. Harto
Björn Riefke
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Schering Aktiengesellschaft
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Priority to BR0318125-1A priority Critical patent/BR0318125A/pt
Priority to EP03782386A priority patent/EP1594851A1/fr
Priority to CA002516467A priority patent/CA2516467A1/fr
Priority to AU2003290032A priority patent/AU2003290032B2/en
Priority to MXPA05008781A priority patent/MXPA05008781A/es
Priority to JP2004568408A priority patent/JP2006514664A/ja
Publication of WO2004074267A1 publication Critical patent/WO2004074267A1/fr
Priority to NO20054291A priority patent/NO20054291L/no

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    • 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
    • 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
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • 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
    • A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0438—Organic X-ray contrast-enhancing agent comprising an iodinated group or an iodine atom, e.g. iopamidol
    • 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
    • A61K49/085—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier conjugated systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0497—Organic compounds conjugates with a carrier being an organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
    • C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table

Definitions

  • the invention relates to the subjects characterized in the claims: new trimeric, macrocyclically substituted triiodine and tribromobenzene derivatives, their production and use as contrast agents in X-ray and MRI diagnostics.
  • Imaging techniques such as DAS, CT and RT have become the normal and indispensable tools in diagnostics and interventional radiology and today offer a spatial resolution of less than 1 mm.
  • the application possibilities of these techniques continue to be significantly increased through the use of contrast media.
  • This wide spread and acceptance of contrast media in X-ray diagnostics today is due to the introduction of nonionic monomeric triiodoaromatics in the 1980s and the isoosmolar dimeric iodine aromatics introduced in the 1990s.
  • These two classes of compounds reduced the frequency of - contrast-induced side effects to 2-4% (Bush WH, Swanson DP: Acute reactions to intravascular contrast media: Types, risk factors, recognition and specific treatment.
  • gadolinium and other lanthanides show a greater absorption than iodine, especially at higher voltages / energies of the X-radiation, so that they are in principle suitable as contrasting elements for X-ray diagnostics (Schmitz S., Wagner S., Schuhmann-Giampieri G., Wolf KJ : Evaluation of gadobutrol in an rabbit model as a new lanthanide contrast agent for Computer tomography. Invest. Radiol. 30 (11): 644-649, 1995).
  • the Gd-containing chelate compounds mentioned originally used in MRI are also readily water-soluble and are characterized by excellent compatibility. Compared to iodine-containing / non-ionic contrast media, the rate of mild pseudo-allergic reactions is greatly reduced, the rate of fatal reactions is extremely rare and is given as 1/1000000 (Runge VM: Safety of approved MR contrast media for intravenous injection. J. Magn Reson Imaging 12, 205-213, 2000). Pseudo-allergic reactions are in contrast to other contrast agent-induced side effects, e.g. kidney tolerance, regardless of the dose administered. Even the smallest doses can trigger a pseudo-allergic reaction.
  • the extraordinarily high rate speaks for a low incompatibility rate
  • Iodine aromatics have a lipophilicity factor 100-200 higher (greater partition coefficient between butanol / water) than metal chelates.
  • the aim is to produce compounds that have sufficient hydrophilicity - comparable to that of Gd chelates - and additionally have a high concentration of contrasting elements. Values that are significantly higher than the metal chelates at around 25% (g / g) would be desirable. At a higher concentration, there must still be very good water solubility. In addition to their good pharmacological properties, the highly concentrated solutions must also show a practical viscosity and a low osmotic pressure.
  • a 2 has the same meaning as A 1 or, in the case that A 1 has the first-mentioned meaning, also for the radical -NR 1 -CO- (NR) m - (CH 2 ) p -NR 2 - (CO-CHZ 1 -NH) m -CO-CHZ 2 -K, in which R 1 and R 2 independently represent a hydrogen atom, a CC 2 -
  • Z and Z 2 independently of one another are a hydrogen atom or a
  • n is the numbers 2-4
  • m is the numbers 0 or 1
  • p is the numbers 1-4
  • metal ion equivalents of atomic numbers 20-29,39, 42, 44 or 57-83 with the provisos that at least two X stand for metal ion equivalents and any free carboxy groups which may be present as salts of organic and / or inorganic bases or amino acids or Amino acid amides are present, show a very good solubility and a distribution coefficient that is comparable to that of Gd chelates. Furthermore, the new compounds have a high specific content of contrasting elements, a low viscosity and osmolality, and thus good tolerance tolerance, so that they are outstandingly suitable as contrast agents for X-ray and MR imaging.
  • Residues A 2 mentioned by way of example are: -NHCOCH 2 NHCOCH 2 NHCOCH (CH 3 ) -, -NHCOCH 2 NHCOCH 2 NHCOCH 2 -, -NHCOCH 2 NHCOCH 2 -, -NHCOCH 2 NHCOCH (CH 3 ) -, -N (CH 3 ) COCH 2 NHCOCH 2 - , -NHCONH (CH 2 ) 2 NHCONH 2 -, -NHCOCH 2 N (CH 2 CH 2 OH) COCH 2 -, -N (CH 3 ) COCH 2 N (CH 2 CH 2 OH) COCH 2 -.
  • the compounds of the general formula I according to the invention can be prepared by processes known to the person skilled in the art, for example by a) a triiodo or tribromoaromatic compound of the general formula II
  • a 1 has the meaning -CONR 1 - (CH 2 ) p - (CONR 2 CH 2 ) m -CH ( OH) CH 2 - and thus Y 3 in the meaning of -NR 1 - (CH 2 ) p - (CONR 2 CH 2 ) m -CH (OH) CH 2 -, and then the protective group optionally representing X ' removed and then reacted in a manner known per se with a metal oxide or metal salt of an element of atomic numbers 20-29,39,42,44 or 57-83 or c) a triiodo or tribromoaromatic of the general formula VI
  • W represents a hydrogen atom or a protective group, (after removing the protective groups which may be present and then introducing the radicals -CH 2 COOX in a manner known per se) into a metal complex of the general formula I with A in the meaning of the radical - CH 2 -O- (CH 2 ) p -CHOH-CH 2 - or d) a triiodo or tribromoaromatic of the general formula VIII
  • Nucleofug stands for a nucleofuge group, in a manner known per se with a macrocycle of the general
  • R 1 and W have the meaning given above, and B 2 represents the radical - (CHZ 1 -NHCO) m -CHZ 2 -, and then proceeds as indicated under a), so that metal complexes of the general formula I are used
  • a 1 in the meaning of the radical -CH 2 -NR 1 -CO- (CHZ 1 - NHCO) m -CHZ 2 is obtained, with acidic hydrogen atoms still present in the metal complexes of the general formula I obtained after a) -d) can be substituted by cations of inorganic or organic bases, amino acids or amino acid amides.
  • Amino protecting groups W are the benzyloxycarbonyl-, tertiary-butoxycarbonyl-, trifluoroacetyl-, fluorenylmethoxycarbonyl-, benzyl-, formyl-, 4-methoxybenzyl-, 2,2,2-trichloroethoxycarbonyl-, phthaloyl-, 1, 2-oxazoline which are familiar to the person skilled in the art -, Tosyl, dithiasuccinoyl, allyloxycabonyl, sulfate, pent-4-encarbonyl, 2-chloroacetoxymethyl (or ethyl) benzoyl, tetrachlorophthaloyl, alkyloxycarbonyl groups [Th. W.
  • Activated carboxyl groups are understood above to mean those carboxyl groups which are derivatized in such a way that they facilitate the reaction with an amine. It is known which groups can be used for activation and reference can be made, for example, to M. and A. Bodanszky, "The Practice of Peptide Synthesis", Springer Verlag 1984. Examples are adducts of carboxylic acid with carbodiimides or activated esters such as e.g. Hydroxybenzotriazole. Acid chloride, N-hydroxysuccinimide ester,
  • Suitable activating reagents are dicyclohexylcarbodiimide (DCC), 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and O- (benzotriazole) yl) -1, 1,3,3-tetramethyluronium hexafluorophosphate (HBTU), preferably DCC.
  • DCC dicyclohexylcarbodiimide
  • EDC 1-ethyl- 3- (3-dimethylaminopropyl) carbodiimide hydrochloride
  • EDC benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP)
  • X represents an acid protecting group, lower alkyl, aryl and aralkyl groups, for example the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis- (p-nitrophenyl) methyl group, and trialkylsilyl groups in question.
  • t-butyl and the benzyl group are preferred.
  • the protecting groups are removed by the processes known to the person skilled in the art (see, for example, E. Wünsch, Methods of Org. Chemistry, Houben-Weyl, Vol XV / 1, 4th edition 1974, p. 315), for example by hydrolysis, hydrogenolysis, alkaline hydrolysis the ester, in an aqueous-alcoholic solution at temperatures of 0 ° C to 50 ° C, acid saponification with mineral acids or in the case of tert-butyl esters with the aid of trifluoroacetic acid (Protective Groups in Organic Synthesis, 2 nd Edition, TW Greene and PGMWuts John Wiley and Sons Inc., New York, 1991).
  • the introduction of the desired metal ions can take place in the manner disclosed in the patents EP 71564, EP 130934 and DE-OS 34 01 052.
  • the metal oxide or a metal salt for example a chloride, nitrate, acetate, carbonate or sulfate
  • the desired element is dissolved or suspended in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) and with the solution or suspension of the equivalent Amount of complexing agent implemented.
  • any free carboxy groups still present are neutralized with the aid of inorganic bases (e.g. hydroxides, carbonates or bicarbonates) from e.g. Sodium, potassium, lithium, magnesium or calcium and / or organic bases such as primary, secondary and tertiary amines, e.g. Ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids, e.g. Lysine, arginine and ornithine or neutral or acidic amino acids originally from amides.
  • inorganic bases e.g. hydroxides, carbonates or bicarbonates
  • inorganic bases e.g. Sodium, potassium, lithium, magnesium or calcium and / or organic bases
  • primary, secondary and tertiary amines e.g. Ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine
  • basic amino acids e.g. Ly
  • the neutral complex compounds for example in acidic complex salts in aqueous solution or suspension, enough of the desired base can be added to achieve the neutral point.
  • the solution obtained can then be evaporated to dryness in vacuo.
  • water-miscible solvents such as lower alcohols (methanol, ethanol, Isopropanol and others), lower ketones (acetone and others), polar ethers (tetrahydrofuran, dioxane, 1, 2-dimethoxyethane and others) to precipitate and thus to obtain crystals that are easy to isolate and easy to clean. It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and thereby to save one process step.
  • the complexes thus obtained are purified, if necessary after adjusting the pH by adding an acid or base to pH 6 to 8, preferably about 7, preferably by ultrafiltration with membranes of suitable pore size (for example Amicon®YM1, Amicon®YM3), Gel filtration on e.g. suitable Sephadex® gels or by HPLC on silica gel or reverse phase material.
  • suitable pore size for example Amicon®YM1, Amicon®YM3
  • suitable pore size for example Amicon®YM1, Amicon®YM3
  • Gel filtration on e.g. suitable Sephadex® gels or by HPLC on silica gel or reverse phase material.
  • Cleaning can also be carried out by crystallization from solvents such as methanol, ethanol, i-propanol, acetone or their mixtures with water.
  • oligomeric complexes In the case of neutral complex compounds, it is often advantageous to give the oligomeric complexes via an anion exchanger, for example IRA 67 (OH " form) and, if appropriate, additionally via a cation exchanger, for example IRC 50 (H + form), to remove ionic components
  • an anion exchanger for example IRA 67 (OH " form)
  • a cation exchanger for example IRC 50 (H + form
  • shark, CO *, R 1 , R 2 , m have the meaning given above, according to the methods of amide formation known to the person skilled in the art (see above) in an aprotic solvent such as DMF, DMA, THF, dioxane, 1,2-dichloroethane , Chloroform, dichloromethane or toluene, optionally with the addition of an organic or inorganic base such as NEt 3 , pyridine, DMAP, Hünig base, Na 2 C0 3) K 2 C0 3 , CaC0 3 at temperatures from 0 ° C - 100 ° C.
  • an aprotic solvent such as DMF, DMA, THF, dioxane, 1,2-dichloroethane , Chloroform, dichloromethane or toluene
  • an organic or inorganic base such as NEt 3 , pyridine, DMAP, Hünig base, Na 2 C0 3) K 2 C0 3 , CaC
  • the diamonds or mono-protected diamines are known from the literature and can be purchased (e.g. Aldrich, Fluka).
  • the acid chloride of the compound of the general formula IV is preferably used.
  • the isocyanates are reacted in aprotic solvents as described above for amide formation.
  • the reaction temperature is 0 ° C to 100 ° C.
  • the acid chloride of the compounds IV is preferably used.
  • R 1 , Sg, p, m, R 2 have the meaning given above.
  • Reaction takes place in protic or aprotic solvents such as methanol, ethanol, butanol, propanol, DMF, toluene, CHCI 3 , DMA (if necessary with the addition of water) at temperatures from 0 ° C to 15 ° C.
  • protic or aprotic solvents such as methanol, ethanol, butanol, propanol, DMF, toluene, CHCI 3 , DMA (if necessary with the addition of water) at temperatures from 0 ° C to 15 ° C.
  • the addition has been a Lewis acid such as LiCI, LiBr, LiJ, LiCI0 4 or Y (triflate) 3 has been proven.
  • TriBoc-Cycles compound is described in Kimura et al., J. Am. Chem. Soc, 1997, 3068, the Tri Z-Cyclen compound in Delaney et al., J. Chem. Soc, Perkin Trans., 1991, 3329.
  • the reaction is carried out by first deprotonating the amide of the compounds of the general formula IX by the methods known to those skilled in the art, e.g. with NaH in DMF, THF, DMA, dioxane, toluene (temperatures 0 ° C - 100 ° C) or BuLi, LDA, Li-HMDS, Na-HMDS in THf, MTB at temperatures from -70 ° to 0 ° C and then reacted with compounds of general formula VIII (preferred temperatures -70 to 70 ° C).
  • the compounds according to the invention can be used both in X-ray and in MR diagnostics.
  • the high x-ray density combined with the good water solubility of the iodinated x-ray contrast media is combined with the pronounced hydrophilicity of the metal chelates and the inherent good compatibility in one molecule.
  • the very high hydrophilicity of the new compounds means that the side effect profile corresponds to that of the very well-tolerated Gd compounds, as used in MR imaging. This property makes it particularly suitable for use in patients with a proven allergy to iodinated compounds or in the presence of atopy. The incidence is particularly severe
  • the contrast agents can be used exclusively for X-ray diagnostics (triiod complexes with diamagnetic metals) but also for X-ray and MRI diagnostics (triiod complexes with paramagnetic atoms, preferably Gd).
  • the connections are very advantageous e.g. Can be used in urography, computer tomography, angiography, gastrography, mammography, cardiology and neuroradiology.
  • the complexes used are also advantageous in radiation therapy.
  • the connections are suitable for all perfusion measurements. It is possible to differentiate between areas well supplied with blood and ischemic areas after intravascular injection. In general, these compounds can be used in all indications where conventional contrast agents are used in X-ray or MR diagnostics.
  • the new contrast agents can also be used for the magnetization transfer technique (see, for example, Journ. Chem. Phys. 39 (11), 2892 (1963), and WO 03/013616), provided that they contain mobile protons in their chemical structure. This is the case, for example, with the hydroxyl group-containing compounds as described in Examples 5 (page 41), Example 6 (page 44), Example 7 (page 47) and Example 8 (page 50).
  • the present application therefore also includes contrast media which are in principle suitable for this special MRI technique.
  • the metal ion of the signaling group must be paramagnetic.
  • these are in particular the divalent and trivalent ions of the elements of the Atomic numbers 21-29, 42, 44 and 58-70. Suitable ions are, for example, chromium (III), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III), samarium (III ) - and ytterbium (III) ion.
  • gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III), iron (III) and manganese (II) ions are preferred, particularly preferred gadolinium (III) and manganese (II) ions ..
  • the metal ion is preferably derived from an element of a higher atomic number in order to achieve sufficient absorption of the X-rays. It has been found that diagnostic agents which contain a physiologically compatible complex salt with metal ions of elements of atomic numbers 25, 26 and 39 and 57-83 are suitable for this purpose.
  • compositions according to the invention are prepared in a manner known per se by suspending or dissolving the complex compounds according to the invention - optionally with the addition of the additives customary in galenics - in an aqueous medium and then, if appropriate, sterilizing the suspension or solution.
  • suitable additives are, for example, physiologically harmless buffers (such as tromethamine), additions of complexing agents or weak complexes (such as diethylenetriaminepentaacetic acid or the Ca complexes corresponding to the metal complexes according to the invention) or - if necessary - electrolytes such as sodium chloride or - if necessary - Antioxidants such as ascorbic acid.
  • suspensions or solutions of the agents according to the invention in water or physiological saline solution are desired for enteral or parenteral administration or other purposes, they are mixed with one or more adjuvant (s) common in galenics [for example methyl cellulose, lactose, Mannitol] and / or surfactant (s) [for example lecithins, Tween ® , Myrj ® ] and / or flavoring (s) for flavor correction [for example essential oils] mixed.
  • adjuvant common in galenics
  • surfactant for example lecithins, Tween ® , Myrj ®
  • flavoring for flavor correction [for example essential oils] mixed.
  • the invention therefore also relates to processes for the preparation of the complex compounds and their salts.
  • the final security is cleaning the isolated complex.
  • agents according to the invention When the agents according to the invention are applied in vivo, they can be administered together with a suitable carrier such as, for example, serum or physiological saline and together with another protein such as, for example, human serum albumin (HSA).
  • a suitable carrier such as, for example, serum or physiological saline
  • another protein such as, for example, human serum albumin (HSA).
  • HSA human serum albumin
  • the agents according to the invention are usually administered parenterally, preferably IV. They can also be administered intraarterially or interstitially / intracutaneously, depending on whether a vessel / organ contrasts selectively (e.g. representation of the coronary arteries after intraarterial injection) or tissue or
  • Pathologies e.g. diagnosis of brain tumors after intravenous injection.
  • compositions according to the invention preferably contain 0.001-1 mol / l of said compound and are generally dosed in amounts of 0.001-5 mmol / kg.
  • the agents according to the invention meet the diverse requirements for suitability as contrast agents for magnetic resonance tomography. They are ideally suited to improve the meaningfulness of the image obtained with the aid of the MR tomograph after oral or parenteral application by increasing the signal intensity. They also show the high
  • the high effectiveness (relaxivity) of the paramagnetic compounds according to the invention is of great advantage for use in magnetic resonance tomography.
  • the relaxivity (L / mmor * sec ⁇ 1 of gadolinium-containing compounds is usually two to four times greater than that of conventional Gd complexes (eg Gadobutrol).
  • the agents according to the invention make it possible to produce highly concentrated solutions, thus keeping the volume load of the circulation within reasonable limits and compensating for the dilution by the body fluid. Furthermore, the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that the ions bound in the complexes - which are toxic in themselves - are released or exchanged within the time in which the new contrast medium are completely excreted again, takes place only extremely slowly.
  • the agents according to the invention for use as MRI diagnostic agents are dosed in amounts of 0.001-5 mmol Gd / kg, preferably 0.005-0.5 mmol Gd / kg.
  • the agents according to the invention are outstandingly suitable as X-ray contrast agents, it being particularly emphasized that they do not show any signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological reactions Let examinations be identified. In the case of strong X-ray absorption, they are particularly effective in areas with higher tube voltages (e.g. CT and DSA).
  • the agents according to the invention are used for use as X-ray contrast agents in analogy to, for example, meglumine diatrizoate in amounts of 0.01-5 mmol / kg, preferably 0.02-1 mmol of substance / kg, which in the case of e.g. Iodine-Dy compounds corresponds to 0.06-6 mmol (1 + Dy) / kg.
  • formulations can be selected that can be used in both X-ray and MR diagnostics. In order to achieve optimal results for both imaging modalities, it may be advantageous to choose formulations in which the proportion of paramagnetic ions is reduced, since for many applications of MR diagnostics an excessively high proportion of paramagnetic ions does not provide any further gain.
  • formulations can be used in which the percentage of paramagnetic substances (e.g. Gd) is reduced to 0.05 to 50, preferably to 2-20%.
  • An application in cardiac diagnostics may be mentioned as an example.
  • a formulation consisting of the substances according to the invention is used in a
  • X-ray imaging of the coronary arteries is followed by an MR diagnosis of the heart in order to be able to differentiate vital from necrotic myocardial areas.
  • the amount of about 110 ⁇ mol Gd / kg previously applied for the examination is optimal for this. example 1
  • the mixture is then stirred for 2 hours with 10 g of ion exchanger (IR 267 H form), filtered off, mixed with 2 g of activated carbon, heated to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml. To remove the remaining dimethyl sulfoxide the solution is poured into 1000 ml of acetone and the precipitate is filtered off. The residue is dissolved in 250 ml of water, with a little
  • Ion exchanger H-form and OH-form
  • HCI set a pH of 1 and the solution evaporated in vacuo.
  • the residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated.
  • the residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H + form). It is then washed with 2 l of water and the acidic eluate is evaporated.
  • the residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
  • the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1).
  • the fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
  • HCI set a pH of 1 and the solution evaporated in vacuo.
  • the residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated.
  • the residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H + form). It is then washed with 2 l of water and the acidic eluate is evaporated.
  • the residue is dissolved in 70 ml of methanol and added dropwise to 900 ml of diethyl ether, the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
  • the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1). The fractions containing the product are combined and with 10 g
  • Ion exchanger (IR 267 H form) stirred for 2 h and filtered off, then stirred with 10 g ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g activated carbon, heated to 60 ° C. for 2 h, filtered off and freeze-dried. Yield 7.1 g (41% of theory) of a colorless solid, water content (Karl-Fischer): 5.6%
  • the organic phase is separated off, the aqueous phase is extracted three times with 250 ml of dichloromethane each time, the combined organic phases are dried over magnesium sulfate and evaporated to dryness.
  • the residue is dissolved in 1200 ml of acetonitrile and 176.2 g (1,275 mol) of potassium carbonate are added. 248.7 g (1,275 mol) of tert-butyl bromoacetate are then added with vigorous stirring and the mixture is heated to 60 ° C. for 3 h.
  • Insoluble constituents are filtered off, evaporated to dryness and chromatographed on silica gel (mobile phase dichloromethane / methanol 20: 1). The fractions containing the product are combined and evaporated.
  • the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 20/20/1).
  • the fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
  • the mixture is poured into 500 ml of diethyl ether, the solid which precipitates out is filtered off, rewashed three times with 100 ml of diethyl ether each time and dried in vacuo.
  • the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 20/20/1).
  • the fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
  • the mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCI set a pH of 1 and the solution evaporated in vacuo.
  • the residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated.
  • the residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H + form). It is then washed with 2 l of water and the acidic eluate is evaporated.
  • the batch is poured into 500 ml of diethyl ether, the solid which precipitates is filtered off, washed three times with 100 ml of diethyl ether each time and dried in vacuo.
  • Toluene sulfonic acid chloride was added dropwise and the mixture was then stirred for 12 h. It is mixed with 300 ml of water and extracted twice with 200 ml of toluene. The combined organic phases are dried over sodium sulfate, the solvent is evaporated to dryness and chromatographed on silica gel (mobile solvent hexane / ethyl acetate 10: 1). The fractions containing the product are combined and evaporated. Yield 47.2 g (51% of theory) of a colorless solid. Elemental analysis: calc .: C 35.73 H 2.70 I 37.75 found: C 36.03 H 2.77 I 37.56
  • the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1).
  • the fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
  • fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
  • 1, 4,7,10-tetrazacyclododecane are dissolved in 500 ml THF and 1.71 g (71 mmol) sodium hydride are added at 0 ° C under argon and 1 h at room temperature. touched.
  • a solution of 20.2 g (20 mmol) of 1,3,5-triiodo-2,4,6-tris (toluenesulfonyloxy) methylbenzene in 150 ml of THF is then added dropwise and the mixture is left under reflux for 20 hours. After cooling, insoluble constituents are filtered off and evaporated to dryness. The residue is taken up in 500 ml of ethyl acetate and extracted twice with 500 ml of water.
  • the pH is adjusted to 7.4 with ammonia and the residue is chromatographed on silica gel (mobile solvent: dichloromethane / methanol / ammonia: 10/10/1).
  • the fractions containing the product are combined and stirred with 10 g of ion exchanger (IR 267 H form) and filtered for 2 h, then stirred with 10 g of ion exchanger (IRA 67 OH form) for 2 h, filtered off, mixed with 2 g of activated carbon, 2 h heated to 60 ° C, filtered off and freeze-dried.
  • the mixture is then stirred for 2 hours with 10 g of ion exchanger (IR 267 H form), filtered off, mixed with 2 g of activated carbon, heated to 60 ° C. for 2 hours, filtered off and the solution is concentrated to 100 ml.
  • the solution is poured into 1000 ml of acetone and the precipitate is filtered off.
  • the mixture is heated at 70 ° C. for 10 hours, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temp. is with conc. HCI set a pH of 1 and the solution evaporated in vacuo.
  • the residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated.
  • the residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H + form). It is then washed with 2 l of water and the acidic eluate is evaporated.
  • the residue is dissolved in 70 ml of methanol and added dropwise in 900 ml of diethyl ether the resulting solid is suction filtered, washed several times with diethyl ether and dried in vacuo.
  • the filter residue is dissolved in 1000 ml of ethyl acetate, shaken twice with saturated sodium hydrogen carbonate solution, the organic phase is dried over sodium sulfate and the solvent is evaporated in vacuo. Yield: 28.7 g (94% of theory) of a colorless solid. Elemental analysis: calc .: C 20.47 H 0.79 N 3.67 found: C 20.52 H 0.77 N 3.71
  • the mixture is heated to 70 ° C. for 10 h, the pH of the reaction mixture being continuously adjusted to 9.5. After cooling to room temperature. is with conc. HCI set a pH of 1 and the solution evaporated in vacuo.
  • the residue is stirred with 250 ml of methanol, insoluble constituents are filtered off and the filtrate is evaporated.
  • the residue is dissolved in 100 ml of water and placed on an ion exchange column (600 ml, IR 120, H + form). It is then washed with 2 l of water and the acidic eluate is evaporated.
  • Ion exchanger (IRA 67 OH form) stirred for 2 h, filtered off, with 2 g
  • Example 1B was investigated in rats using computer tomography (CT).
  • CT computer tomography
  • a Siemens Somatom CR was available for the CT examinations.
  • the 5-second recordings were made with a layer thickness of 2 mm and a tube voltage of 125 kV.
  • Substance 1B was formulated as an aqueous solution in a concentration of 0.17 mol / L (corresponds to 145 mg (l + Gd) / mL.
  • Fig. 1 a baseline
  • Fig. 1 b 15 sec pi
  • a very clear contrast of the blood-carrying vessels (A) and the renal cortex (N) was observed even with the low dose of 127 mg (I + Gd).
  • This early phase reflects blood perfusion in the renal cortex.
  • the renal pelvis was already contrasted 15 minutes later in the parenchyma phase, which can be attributed to rapid renal excretion of the substance (Fig. 2).
  • the same substance (IB) was examined with the help of magnetic resonance tomography (MRT) as a contrast medium.
  • MRT magnetic resonance tomography
  • the angiography (MRA, Fig. 3) was done from 0-60 sec pi and the organ representation (Fig. 4 a and b) 15 min after the injection.
  • the substance 1 B was an aqueous solution in a concentration of 0.17 mol / L (corresponds to 0.5 mol Gd / L) and injected intravenously in a dose of 0.03 mmol substance or 0.1 mmol Gd / kg.
  • the MRA is an excellent representation of the large arteries (aorta, a. Femoralis) and the heart.
  • Fig. 4 a baseline
  • Fig. 4 b (15 min pi)
  • a clear contrast of the liver (L) and the kidneys (renal pelvis N) can be seen in the whole body image (Fig. 4 b).
  • the urethers (U) could also be shown, which also underlines the rapid renal excretion of the substance.
  • Example 3F The relative X-ray attenuation of Example 3F was determined at concentrations of 0.05, 0.1 and 0.2 mol / L of the substance, equivalent to 0.3, 0.6 and 1.2 mol / L contrasting elements (Gd + iodine), against equimolar concentrations of lopromide and gadobutrol. A phantom was used for this, in which dilutions of the starting formulations (Example 3F - 0.27M,
  • Ultravist® 300 mg l / mL equivalent to 0.788 mol / L lopromide and Gadobutrol 1 mol / L) were pipetted into distilled water in well plates (Oster 3524).
  • the X-ray images were taken in the "high pulse" modality with the DSA X-ray machine Stenoskop D6 (General Electrics) with a cesium filter / iodine intensifier of 16 cm and 2 mm aluminum filter at different voltages of the X-ray anode. All images were taken after manual selection of the anode voltage of the X-ray tube and variation of the mA in order to optimize the image contrast at the respective anode voltage.
  • the images of the stenoscope D6 were then transferred to an image analysis device (Quantimet 500+, Leica) and displayed on a scale of 256 gray values.
  • an image analysis device Quantimet 500+, Leica
  • a circular ROI (Region Of Interest) was analyzed for each well and the background was subtracted at the respective anode voltage.
  • FIG. 110 kV Figure 5 Comparison of the X-ray absorption of Example 3F, Gadobutrol and lopromid. X-ray images of the phantom at 60 and 110 kV anode voltage taken with the C-arm device Stenoscope D6 (General Electrics).
  • Example 3F The relationship between the concentrations of Example 3F, lopromide and gabobutrol was linear in all cases.
  • the evaluation showed a significantly higher X-ray absorption of Example 3F than lopromid and Gadobutrol at equimolar concentrations (Figure 5).
  • Figure 6 Relative X-ray absorption of Example 3F in comparison with Gadobutrol and lopromid at different anode voltages of the X-ray tube (Stenoskop D6, General Electrics).
  • Example 3F showed a 3.08 times higher X-ray absorption than lopromide and 3.77 times higher than Gadobutrol. Even higher differences in the X-ray absorption of Example 3F are to be expected for higher anode voltages, as are used in modern X-ray CT methods (helicoidal and multi-line CT). Additionally occurring radiation hardening in the in vivo situation also favor elements such as Gd, Dy, Yb or Bi.
  • Example 3F has excellent X-ray absorption and is suitable for use in modern DSA and CT, especially multi-line CT.
  • Example 3F The distribution coefficient of Example 3F was determined in comparison to Gadovist, lopromid and lotrolan in 1-butanol and Tris-HCl buffer at pH 7.6.
  • the contrast media were dissolved in the buffer with a final concentration of 0.1 mmol Gd / L, the iodine-containing contrast media were used with an initial concentration of 1 mg l / mL.
  • Table 1 Distribution coefficient of Example 3F compared to commercially available MR and X-ray contrast media.
  • Example 3F is a very hydrophilic substance with a low partition coefficient of butanol / water and even better values than the very well tolerated MR contrast agent Gadovist.
  • the commercially available iodine-containing compound lopromid has a much lower hydrophilicity with an up to 255 times higher partition coefficient butanol / water (0.051 vs. 0.0002).
  • the neutral red test in epithelial cells of the distal renal tubule was used to determine the IC-50. This test is also very helpful in predicting the LD-50 values of new synthesized compounds with high accuracy.
  • Epithelial cell line MDCK from renal distal kidney tubule of the dog kidney (ECACC No. 85011435) were from 10,000 cells / well in Alpha MEM Eagle (10% fetal bovine serum) at 37 ° C and 5% CO 2 , 95% humidity for 20 h with various examples 1 B, 3F and 5F incubated. Neutral red was used as an indicator of cell viability and to measure lysosomal integrity and was used to determine the contrast medium concentration at which a 50% reduction in cell viability (IC-50) occurred after 24 h.
  • Table 2 Comparison of the IC 5 o values of various inventive examples with Gadobutrol and the expected LD 50 value in mice.

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Abstract

L'invention concerne des complexes métalliques de formule (I), dans laquelle Hal représente brome ou iode, et A1 et A2 présentent différentes significations. Les complexes métalliques de l'invention peuvent être utilisés en tant que produit de contraste.
PCT/EP2003/014149 2003-02-19 2003-12-12 Derives de benzene trimeres substitues de maniere macrocyclique WO2004074267A1 (fr)

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BR0318125-1A BR0318125A (pt) 2003-02-19 2003-12-12 Derivados de benzeno trìmeros macrociclicamente substituìdos
EP03782386A EP1594851A1 (fr) 2003-02-19 2003-12-12 Derives de benzene trimeres substitues de maniere macrocyclique
CA002516467A CA2516467A1 (fr) 2003-02-19 2003-12-12 Derives de benzene trimeres substitues de maniere macrocyclique
AU2003290032A AU2003290032B2 (en) 2003-02-19 2003-12-12 Trimeric macrocyclically substituted benzene derivatives
MXPA05008781A MXPA05008781A (es) 2003-02-19 2003-12-12 Derivados trimeros, sustituidos macrociclicamente, de benceno.
JP2004568408A JP2006514664A (ja) 2003-02-19 2003-12-12 三量体である大環状で置換されたベンゼン誘導体
NO20054291A NO20054291L (no) 2003-02-19 2005-09-16 Trimert makrosyklisk substituerte benzenderivater

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DE10307759A DE10307759B3 (de) 2003-02-19 2003-02-19 Trimere makrocyclisch substituierte Benzolderivate, deren Herstellung und Verwendung als Kontrastmittel sowie diese enthaltende pharmazeutische Mittel
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WO2005108379A1 (fr) * 2004-05-05 2005-11-17 Schering Aktiengesellschaft Derives trimeres de benzene halogene substitues par des macrocycles
FR2870744A1 (fr) * 2004-05-31 2005-12-02 Almirall Prodesfarma S A Sa Combinaison, produit, kit de parties, conditionnement comprenant des agents muscariniques et des agonistes beta-adrenergiques et procede de traitement les utilisant
WO2005115997A1 (fr) * 2004-05-25 2005-12-08 Schering Aktiengesellschaft Derives trimeres a substitution macrocyclique, acide aminoisophtalique-halogene-benzene
DE102007058220A1 (de) 2007-12-03 2009-06-04 Bayer Schering Pharma Aktiengesellschaft Dimere macrocyclisch substituierte Benzolderivate
US9056100B2 (en) 1999-07-14 2015-06-16 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9254262B2 (en) 2008-03-13 2016-02-09 Almirall, S.A. Dosage and formulation
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
US10137209B2 (en) 2015-06-04 2018-11-27 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11814369B2 (en) 2016-11-28 2023-11-14 Bayer Pharma Aktiengesellschaft High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging
US11944690B2 (en) 2018-11-23 2024-04-02 Bayer Aktiengesellschaft Formulation of contrast media and process of preparation thereof

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WO2012027727A2 (fr) * 2010-08-26 2012-03-01 Kunyuan Cui Lipomacrocycles et leurs utilisations
CN104721844B (zh) * 2015-02-02 2017-11-03 湖北大学 一种新型ct，mri，稀土荧光三功能微球及其制备方法和应用
CN104672259B (zh) * 2015-02-02 2017-04-05 湖北大学 一种含碘稀土铕(ⅲ)配合物及其制备方法和应用
CN105254529B (zh) * 2015-09-21 2017-05-31 西南石油大学 一种树形席夫碱缓蚀剂的制备方法
CN107445911B (zh) * 2017-06-19 2019-07-05 南京科技职业学院 一种二核含钆磁共振对比剂及其制备与应用

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FR2794744B1 (fr) * 1999-06-09 2001-09-21 Guerbet Sa Complexes metalliques de polyaminoacides bicycliques, leur procede de preparation et leur application en imagerie medicale

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Cited By (20)

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US9687478B2 (en) 1999-07-14 2017-06-27 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9333195B2 (en) 1999-07-14 2016-05-10 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US10034867B2 (en) 1999-07-14 2018-07-31 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US9056100B2 (en) 1999-07-14 2015-06-16 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
US10588895B2 (en) 1999-07-14 2020-03-17 Almirall, S.A. Quinuclidine derivatives and medicinal compositions containing the same
WO2005108379A1 (fr) * 2004-05-05 2005-11-17 Schering Aktiengesellschaft Derives trimeres de benzene halogene substitues par des macrocycles
US7385054B2 (en) 2004-05-05 2008-06-10 Schering Ag Trimeric, macrocyclically substituted halo-benzene derivatives
DE102004026103A1 (de) * 2004-05-25 2005-12-22 Schering Ag Trimere makrocyclisch substituierte Aminoisophthalsäure-Halogen-Benzolderivate
WO2005115997A1 (fr) * 2004-05-25 2005-12-08 Schering Aktiengesellschaft Derives trimeres a substitution macrocyclique, acide aminoisophtalique-halogene-benzene
FR2870744A1 (fr) * 2004-05-31 2005-12-02 Almirall Prodesfarma S A Sa Combinaison, produit, kit de parties, conditionnement comprenant des agents muscariniques et des agonistes beta-adrenergiques et procede de traitement les utilisant
DE102007058220A1 (de) 2007-12-03 2009-06-04 Bayer Schering Pharma Aktiengesellschaft Dimere macrocyclisch substituierte Benzolderivate
US10085974B2 (en) 2008-03-13 2018-10-02 Almirall, S.A. Dosage and formulation
US9254262B2 (en) 2008-03-13 2016-02-09 Almirall, S.A. Dosage and formulation
US11000517B2 (en) 2008-03-13 2021-05-11 Almirall, S.A. Dosage and formulation
US9737520B2 (en) 2011-04-15 2017-08-22 Almirall, S.A. Aclidinium for use in improving the quality of sleep in respiratory patients
US10722601B2 (en) 2015-06-04 2020-07-28 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US10137209B2 (en) 2015-06-04 2018-11-27 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11491245B2 (en) 2015-06-04 2022-11-08 Bayer Pharma Aktiengesellschaft Gadolinium chelate compounds for use in magnetic resonance imaging
US11814369B2 (en) 2016-11-28 2023-11-14 Bayer Pharma Aktiengesellschaft High relaxivity gadolinium chelate compounds for use in magnetic resonance imaging
US11944690B2 (en) 2018-11-23 2024-04-02 Bayer Aktiengesellschaft Formulation of contrast media and process of preparation thereof

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