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WO1997020841A2 - Nouveaux composes macrobicycliques, leur procede de fabrication et agents pharmaceutiques les renfermant - Google Patents

Nouveaux composes macrobicycliques, leur procede de fabrication et agents pharmaceutiques les renfermant Download PDF

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Publication number
WO1997020841A2
WO1997020841A2 PCT/DE1996/002234 DE9602234W WO9720841A2 WO 1997020841 A2 WO1997020841 A2 WO 1997020841A2 DE 9602234 W DE9602234 W DE 9602234W WO 9720841 A2 WO9720841 A2 WO 9720841A2
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compounds
groups
rule
compounds according
metal
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PCT/DE1996/002234
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German (de)
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WO1997020841A3 (fr
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Georg Rössling
Celal Albayrak
Johannes Tack
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Schering Aktiengesellschaft
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Priority to AU17181/97A priority Critical patent/AU1718197A/en
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Publication of WO1997020841A3 publication Critical patent/WO1997020841A3/fr

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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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed systems contains four or more hetero rings

Definitions

  • New macrobicyclic compounds processes for their preparation and pharmaceutical compositions containing these macrobicyclic compounds
  • the invention relates to new macrobicyclic compounds, their metal complexes and complex salts, pharmaceutical compositions containing these compounds, their use in diagnostics and therapy and methods for producing these new compounds.
  • macropolycyclic compounds with metal ions can form stable mono- and multinuclear complexes with different binding, electrochemical and photophysical properties.
  • REPLACEMENT BLA ⁇ (RULE 26)
  • de Mendoza et al in "Angewandte Chemie 103 (1991), No. 10 pp. 1365-1366” describe a macrobicyclic tris-2, 2'-bipyridine ligand and Cu2 (I) _ and Ag3 (I) - Complexes are described that are important in photochemistry and photophysics and for water splitting.
  • EP 0 321 353 describes cryptates with rare earth metals which can serve as fluorescent markers and are used for the detection of biological materials.
  • Macrobicyclic metal complexes are now also used as contrast agents in radio diagnostic techniques such as X-rays, magnetic resonance imaging and nuclear diagnostics.
  • Some metal complex compounds allow routine use, particularly in magnetic resonance imaging.
  • REPLACEMENT BLA ⁇ (RULE 26) A major reason for their good applicability in the clinic is their high level of vigor in magnetic resonance imaging, especially in many brain tumors. You can therefore use 0.1 mmol / kg
  • Body weight are dosed much lower than, for example, X-ray contrast media in many X-ray examinations.
  • these compounds are unsuitable as X-ray contrast agents and for NMR diagnosis of certain diseases outside the central nervous system because of their high osmomality.
  • EP 0 485 045 A2 describes macrocyclic metal complexes with reduced osmolality. These are tetraazacyclododecane compounds and their bis-gadolinium and bis-ytterbium complexes.
  • the compounds should, of course, be well tolerated and, if possible, give rise to no or only extremely low cardiovascular or allergic side effects.
  • REPLACEMENT BLA ⁇ (RULE 26)
  • the object of the invention is achieved by new macrobicyclic compounds of the general formula I.
  • R! -R 6 represent the radical -CH (R 7 ) -CÜ2Y, where Y is a hydrogen atom and / or a metal ion equivalent of an element of atomic numbers 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 means and
  • R ' is a hydrogen atom or an optionally substituted with 1 to 6 hydroxyl groups, branched or unbranched C ⁇ -C3Q-alkyl, c 6 ⁇ c 10 ⁇ Ar y 1- or C7-C3Q-aralkyl group, the alkyl groups optionally being 1 to 10 Oxygen atoms are interrupted and / or substituted by 1 to 6 -C ⁇ 2R 8 groups, and
  • R 8 is hydrogen or a branched or unbranched C] _- C4-alkyl or C7-C10 "aralkylyl group
  • the meaning of hydrogen is referred to as a complexing agent and with at least two of the substituents Y in the meaning of a metal ion equivalent as metal complexes.
  • the complexing agents of the general formula I according to the invention can complex up to 3 metal atoms and thus form homo- or heterotrinuclear metal complexes with a sufficiently high metal atom density.
  • the good water solubility is achieved by the residues R ⁇ -R ⁇ . Because of the high metal atom density and the water solubility of the compounds of general formula I according to the invention of 1 g / ml of water and more, galenical formulations of these compounds can also be used very well as in vivo contrast media, in particular for NMR and X-ray diagnostics.
  • two or more such cages can also be coupled to one another and used as contrast agents in conventional radio diagnostic techniques such as X-rays, magnetic resonance imaging and nuclear diagnostics.
  • REPLACEMENT BLA ⁇ (RULE 26) It has been found that particularly suitable compounds are those in which at least two of the substituents Y are metal ion equivalents of at least one element of atomic numbers 20-29, 31, 32, 37-39, 42-44, 47, 49 or 57-83 or a radionuclide an element of atomic numbers 21, 26, 27, 29, 31, 32, 37-39, 43, 47, 49, 62-64, 67, 70, 71, 75, 77, 79 and 83. Particularly preferred compounds are those in which three of the substituents Y are metal ion equivalents of at least one element with the atomic numbers 21-29, 42-44 and 58-70.
  • the compounds are very particularly preferred in which at least two of the substituents Y by the metal ions Mn 2+ , Fe 3+ , Co 3+ , Ni 2+ , Cu 2 +, Pr 3+ , Nd 3+ , Sm3 + , Yb 3+ , Eu 2+ , Eu 3+ , Gd 3+ , Tb 3+ , Dy 3+ , Ha 3+ or mixtures thereof.
  • Such heterotrinuclear metal complexes of the general formula I with the metal ions Cu 2+ / Fe 3+ / Cu 2+ ' * Gd 3+ / Mn 2+ / Gd 3+ are particularly suitable; Fe 3+ / Mn 2+ / Fe 3+ ; Cu 2+ / Mn 2+ / cu 2+ ; Gd 3+ / Fe 3 + / Gd 3+ .
  • the radical R 7 represents in the general formula I is preferably a C ⁇ -C20 -A lkyl- or C7 ⁇ C20 ⁇ aralkyl group wherein the alkyl group branched, unbranched, may be saturated or unsaturated and optionally substituted by 1 to 6, preferably 1 to 3, hydroxy groups.
  • the alkyl groups in the R 7 radical can also preferably be interrupted by 1 to 5 oxygen atoms and / or substituted by 1 to 3 -CO2R 8 groups, for example by -CO2CH3, - CO2C2H5, -C ⁇ 2iProp, -C ⁇ 2tBut or -CO2CH2C6H5.
  • R 7 examples of preferred radicals R 7 are: -CH 3 , -C 2 H 5 , -iC 3 H 7 , -C 8 H 17 , -C 15 H 31 , -C 16 H 33 , -C 17 H 35 , - CH 2 OH, -CH 2 CH 2 OH, -CH (OH) CH 2 OH, -C 6 H 5 , -CH 2 C 6 H 5 , -CH (OH) CH (OH) CH 2 OH, -OCH3, -OC 2 H 5 , -OCH 2 C 6 H 5 , -OCH 2 CH 2 OCH 3 ,
  • radicals for R 7 are hydrogen, -CH 2 OH, -CH 2 CH 2 OH or -CH (OH) CH 2 OH.
  • the remaining acidic hydrogen atoms that is to say those which have not been substituted by the central ion, can optionally be wholly or partly replaced by cations of inorganic and / or organic bases, amino acids or amino acid amides.
  • Suitable inorganic cations are, for example, lithium ion, potassium ion, calcium ion, magnesium ion, zinc ion and in particular sodium ion.
  • Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as ethanolamine, diethanolamine, morpholine, glucamine, N, N-
  • Dimethylglucamine and especially N-methylglucamine are, for example, those of lysine, arginine and ornithine and the amides of otherwise acidic or neutral amino acids such as e.g. Lysine methyl amide, glycine ethyl amide and serine methyl amide.
  • R 7 has the abovementioned meaning, hydroxyl groups which may be present in the radical R 7 being optionally protected
  • R 9 represents an acid protecting group
  • water-miscible solvents e.g. Acetonitrite, DMF, DMA, ethanol, methanol, dioxane, THF, DMSO, DME or a mixture thereof can be used.
  • Potassium, sodium, lithium, calcium, barium or magnesium oxide or sodium or potassium carbonate are suitable as inorganic bases.
  • Hydroxy protective groups R 9 are all those which are easy to introduce and later regress to the ultimately desired free ones
  • protecting groups are ether groups such as e.g. the benzyl, 4-methoxybenzyl, 4-nitrobenzyl, trityl, di and triphenylmethyl, trimethylsilyl, dimethyl-t-butylsilyl, diphenyl-t-butylsilyl group.
  • the hydroxyl groups are preferably protected in the form of ketals with, for example, acetone, acetaldehyde, cyclohexanone or benzaldehyde.
  • REPLACEMENT BUIP (RULE 26)
  • the hydroxyl protective groups are split off in a manner known per se, for example in the case of a benzyl ether by reductive cleavage with lithium ammonia or by hydrogenolytic cleavage in the presence of, for example, palladium-carbon and in the case of ether or ketal cleavage by acid treatment with the aid of, for example Cation exchangers, trifluoroacetic acid or mineral acids [see, for example, TW Greene "Protective Groups in Organic Synthesis", John Wiley and Sons (1991)].
  • Suitable acid protective groups are C 1 -C 6 -alkyl, Cg-Cig-aryl and C 6 -C 6 -ar (C1-C4) -alkyl groups and trialkylsilyl groups.
  • the methyl, ethyl, propyl, ⁇ " propyl, n-butyl, - * " butyl and the tert • " butyl group are preferred.
  • this acid protective groups takes place according to known in the art methods, for example by hydrolysis, hydrogenolysis, alkaline saponification of esters with alkali in aqueous-alcoholic solution at temperatures of 0 to 50 ° C, acid saponification with mineral acids or in the case of tert - "butyl esters with the help of trifluoroacetic acid.
  • the compound of general formula II is prepared in a manner known per se - such as e.g. in "J. Chem. Soc, Chem Commun, 1992 pp. 602-603" - by reaction of TREN (tris (2-aminoethyl) amine), which is known as an excellent ligand for transition metal ions, with 5, 5 ' -Diformyl-2, 2'-bipyridine and subsequent hydrogenation to macrobicyclic polyamine II.
  • TREN tris (2-aminoethyl) amine
  • the metal complexes according to the invention are prepared in the manner disclosed in German Offenlegungsschrift 34 01 052 by adding the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate of the element of atomic numbers 20-29), 31, 32, 37-39, 42-44, 47, 49, 57-83) 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 the complexing Reacts ligands and then - if desired - substitute existing acidic hydrogen atoms with cations of inorganic and / or organic bases or amino acids.
  • a metal salt for example the nitrate, acetate, carbonate, chloride or sulfate of the element of atomic numbers 20-29
  • a lower alcohol such as methanol, ethanol or isopropanol
  • the desired metal ions can be introduced either before or after the hydroxyl protective groups are split off.
  • any free carboxy groups still present are neutralized with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and / or organic bases, such as primary, secondary and tertiary amines, such as Example ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids, such as lysine, arginine and ornithine or amides of originally neutral or acidic amino acids.
  • inorganic bases for example hydroxides, carbonates or bicarbonates
  • inorganic bases for example hydroxides, carbonates or bicarbonates
  • organic bases such as primary, secondary and tertiary amines, such as Example ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, as well as basic amino acids, such as lysine, arginine and ornithine or amides of originally
  • the acidic complex salts in aqueous solution or suspension can contain as much of the desired bases
  • REPLACEMENT BLA ⁇ (RULE 26) add that the neutral point is reached.
  • 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 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.
  • neutral complex compounds Another possibility of obtaining neutral complex compounds is to convert all or part of the remaining acid groups in the complex into, for example, esters or amides. This can be done by subsequent reaction on the finished complex (e.g. by exhaustive reaction of the free carboxy groups with dimethyl sulfate).
  • the compounds of general formula I or their pharmaceutical agents are preferably used as in vivo contrast agents for MRI (magnetic resonance images) and as in vivo x-ray contrast agents. Furthermore, they are used as contrast agents for nuclear diagnostics, the metal ions of the elements being present as radioactive isotopes, or as susceptibility reagents in NMR diagnostics.
  • the compounds according to the invention can also be used in neutron capture therapy, in positron
  • REPLACEMENT BLA ⁇ (RULE 26) Emission tomography (PET), and used as a luminescence marker in biology and medicine.
  • Compounds with the metal ions Eu 3+ , Tb 3+ , Gd 3+ are particularly preferably used as luminescence markers.
  • the invention also relates to pharmaceutical compositions which contain at least one physiologically tolerable compound of the general formula I, if appropriate with the additives customary in galenics.
  • the pharmaceutical compositions are suitable for enteral and parenteral use.
  • the pharmaceutical compositions are prepared by bringing a metal complex of the general formula I, dissolved or suspended in water, physiological salt or protein solution, optionally with the additives customary in galenics, into a form suitable for enteral or parenteral administration.
  • Suitable additives are, for example, physiologically acceptable buffers (such as tromethamine), additives of complexing agents (such as diethylenetriaminepentaacetic acid) or - if necessary - electrolytes such as e.g. Sodium chloride - or if necessary - antioxidants such as Ascorbic acid.
  • physiologically acceptable buffers such as tromethamine
  • additives of complexing agents such as diethylenetriaminepentaacetic acid
  • electrolytes such as e.g. 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 administration or other purposes, they are combined with one or more auxiliary substances (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (e.g. lecithins) , Tween®,
  • ERSATZBU ⁇ (RULE 26) Myrij® and / or flavoring (s) mixed for flavor correction (e.g. essential oils).
  • 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 salt.
  • compositions according to the invention preferably contain 0.1 ⁇ mol-3 mol / l of the complex salt and are generally metered in amounts of 0.1 ⁇ mol / kg. They are intended for enteral and parenteral administration.
  • the central ion of the complex salt must be paramagnetic.
  • Suitable ions are, for example, chromium (III), manganese (II), iron (II), cobalt (II), nickel (II), copper (II), praseodymium (III), neodymium (III ) -, samarium (III) - and ytterbium (III) ion. Because of their very strong magnetic moment are particularly preferred
  • REPLACEMENT BUIP (RULE 26) the gadolinium (III), terbium (III), dysprosium (III), holmium (III), erbium (III) and iron (III) ions.
  • the central ion must be radioactive for the use of the agents according to the invention in nuclear medicine.
  • radioisotopes of the elements copper, cobalt, gallium, germanium, yttrium, strontium, technetium, indium, ytterbium, gadolinium, samarium, silver, gold, rhenium and iridium are suitable.
  • the central ion must be derived from an element with a higher atomic number in order to achieve sufficient absorption of the X-rays. It has been found that diagnostic agents containing a physiologically compatible complex salt with central ions of elements of atomic numbers between 21-29, 42, 44, 57-83 are suitable for this purpose; these are, for example, the lanthanum (III) ion and the above-mentioned ions of the lanthanide series.
  • REPLACEMENT BUIP (RULE 26) 39, 43, 47, 49, 62-64, 67, 70, 71, 75, 77, 79 and 83.
  • the agents according to the invention meet the diverse requirements for their suitability as contrast agents for magnetic resonance imaging. After enteral or parenteral application, they are ideally suited to improve the meaningfulness of the image obtained with the aid of an MRI scanner by increasing the signal intensity. They also show the high effectiveness that is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerance that is necessary to maintain the non-invasive character of the examinations.
  • the agents according to the invention make it possible to produce highly concentrated solutions, so that the volume load of the circulation is kept within reasonable limits and the dilution is compensated for by the body fluid, i.e. NMR diagnostics have to be 100 to 100 times more soluble in water than for NMR - spectroscopy. Furthermore, the agents according to the invention not only have high stability in vitro, but also surprisingly high stability in vivo.
  • the agents according to the invention for use as NMR diagnostic agents are dosed in amounts of 0.0001-5 mmol / kg, preferably 0.005-0.5 mmol / kg. Details of the application are e.g. in H.J. Weinmann et al .; At the. J. of Roentgenology 142, 619 (1984).
  • the complex compounds according to the invention can advantageously be used as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy.
  • the agents according to the invention are also suitable as radio diagnostic agents. Details of the use of radio diagnostics and dosage are e.g. in "Radiotracers for Medical Applications", CRC Press, Boca Raton, Florida.
  • positron emission tomography Another imaging method with radioisotopes is positron emission tomography, which uses positron-emitting isotopes such as ⁇ 3 ⁇ c, ⁇ Sc, 52 F ⁇ / 55 Co unc j 68 Ga (Heiss. WD: Phelps, ME; Positron Emission Tomography of Brain , Springer Verlag Berlin, Heidelberg, New York 1983).
  • the compounds according to the invention can also be used in radioimmunotherapy or radiation therapy. This differs from the corresponding diagnostics only in the amount and type of isotope used.
  • the goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range.
  • Suitable ⁇ -emitting ions are, for example, 46 Sc, 47 Sc, 48 Sc, 72 Ga, 73 Ga and 90 Y.
  • Suitable ⁇ -emitting ions with short half-lives are, for example, 211 Bi, 212 Bi, 213 Bi, and 2 ⁇ 4 Bi , 2 ⁇ 2 Bi being preferred.
  • a suitable photon and electron emitting ion is I ⁇ Q ⁇ which can be obtained from 157 Gd by neutron capture.
  • REPLACEMENT BUIP (RULE 26) Is the agent according to the invention for use in the RL Mills et al. [Nature Vol. 336, (1988), p. 787] proposed variant of radiation therapy, the central ion must be derived from a Mössbauer isotope such as ⁇ Fe or l ⁇ Eu.
  • the therapeutic agents according to the invention can be used together with a suitable carrier such as e.g. Serum or physiological saline and can be administered together with another protein such as human serum albumin.
  • a suitable carrier such as e.g. Serum or physiological saline
  • another protein such as human serum albumin.
  • the dosage depends on the type of cellular disorder, the metal ion used and the type of method, e.g. Brachytherapy.
  • the therapeutic agents according to the invention are preferably administered parenterally.
  • radiotherapeutics are e.g. in R.W. Kozak et al. TIBTEC, October 1986, 262 discussed.
  • the agents according to the invention are outstandingly suitable as X-ray contrast agents, and it should be emphasized in particular that they show no signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological studies. They are particularly valuable because of the favorable absorption properties in areas of higher
  • the agents according to the invention are used for use as X-ray contrast agents in analogy to e.g. Meglumine diatrizoate in amounts of 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg.
  • REPLACEMENT BUIP (RULE 26) Details of the use of X-ray contrast media are discussed, for example, in Barke, X-ray contrast media, G. Thieme, Leipzig (1970) and P. Thurn, E. Bücheier - "Introduction to X-ray diagnostics", G. Thieme, Stuttgart, New York (1977).
  • TREN tris (2-aminoethyl) amine
  • REPLACEMENT BUIP (RULE 26) 5,5'-Diformyl-2,2'-bipyridine added dropwise in acetonitrile. The orange-colored precipitate obtained is filtered off and recrystallized from methanol to form colorless crystals.
  • the macrobicyclic sixfold Schiff base (21.6 g corresponding to 26 mmol) prepared under a) is dissolved in 750 ml of methanol.
  • the solution is heated to 40 ° C. and solid NaBH4 (21.5 g corresponding to 570 mmol) is carefully added with stirring. A strong gas development is observed.
  • the mixture is stirred at 40 ° C. for one hour and then filtered.
  • the methanol is removed in vacuo on a rotary evaporator. 133 ml of water and 860 ml of dichloromethane are added to the solid. The mixture is stirred until the solid has dissolved.
  • the aqueous phase is discarded, the dichloromethane is removed in vacuo and the colorless solid obtained is dried in a high vacuum.
  • REPLACEMENT BUIP (RULE 26) removed on a rotary evaporator at approx. 40 ° C. and the residue extracted with a mixture of 160 ml of water and 800 ml of dichloromethane. It is filtered and the phases are separated. The aqueous phase is discarded, the solvent is removed from the organic phase in vacuo using a rotary evaporator. The slightly yellowish glassy solid is then dried under high vacuum for 12 hours.
  • REPLACEMENT BUIP (RULE 26) (approx. 0.5 1) until the solution runs colorless or until a test with Fe 2+ reacts only weakly.
  • the water is removed in vacuo on a rotary evaporator and the glassy red solid which remains is dried for 12 hours under high vacuum. It is then largely crushed and dried again at 10 ⁇ 6 mbar for 36 hours.
  • the gadolinium complex of I is prepared analogously to Example 2. The gadolinium complex is then dissolved in 15 ml of water and heated to 80 ° C. with stirring.
  • REPLACEMENT BUILD (RULE 2 » then stirred for 24 hours at 80 ° C and then freeze-dried.
  • the gadolinium complex obtained in Example 2 is dissolved in water and heated to 80 ° C., then 35 mg of copper sulfate, dissolved in 10 ml of water, are added, and the mixture is then stirred at 80 ° C. for 24 hours.
  • the solution obtained is passed through an ion exchanger.
  • the aqueous solution obtained is then freeze-dried to obtain the corresponding heterometal complex.
  • the lanthanide complex obtained in this way has high magnetic properties, which indicate molecular ferromagnets.
  • REPLACEMENT BUIP (RULE 26) solved.
  • the resulting solution with dark red color is then stirred at 80 ° C for 12 hours.
  • 25.3 mg of manganese carbonate, dissolved in 10 ml of water, are then slowly added to the iron solution.
  • the mixture obtained is stirred for a further 24 hours at 80 ° C. and then freeze-dried.
  • I is complexed with 3 iron ions.
  • the complex has the following physical properties: Solubility in water:> 1 g / g susceptibility in water: ⁇ > 0, i.e. paramagnetic behavior can be observed,
  • REPLACEMENT BUIP (RULE 26) pH adjusted to 7.2 with HCl ad 1 ml with water pi
  • the aqueous formulation thus obtained can be prepared pharmaceutically in a conventional manner and can be autoclaved in the final container.

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

Abstract

L'invention concerne de nouveaux composés macrobicycliques de formule générale (I), dans laquelle R1-R6 représentent le reste -CH(R7)-CO2Y, où Y est un atome d'hydrogène et/ou un équivalent d'ion métal d'un élément de nombre atomique 20-29, 31, 32, 37-39, 42-44, 47, 49 ou 57-83, R7 désigne un atome d'hydrogène ou un groupe alkyle en C¿1?-C30, aryle en C6-C10 ou aralkyle en C7-C30, ramifié ou non ramifié, éventuellement substitué par 1 à 6 groupes hydroxy, les groupes alkyle étant éventuellement interrompus par 1 à 10 atomes d'oxygène et/ou substitués par 1 à 6 groupes -CO2R?8, et R8¿ désigne un hydrogène ou un groupe alkyle en C¿1?-C4 ou aralkyle en C7-C10 ramifié ou non ramifié, ainsi que leurs sels avec des bases inorganiques et/ou organiques, aminoacides ou aminoacide-amides. Les complexes métalliques de ces composés ou les agents pharmaceutiques les renfermant sont utilisés en particulier comme agents de contraste pour diagnostic par RMN et par rayons X.
PCT/DE1996/002234 1995-12-04 1996-11-18 Nouveaux composes macrobicycliques, leur procede de fabrication et agents pharmaceutiques les renfermant WO1997020841A2 (fr)

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AU17181/97A AU1718197A (en) 1995-12-04 1996-11-18 New macrobicyclic compounds, methods of preparing them and pharmaceutical agents containing them

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DE1995146234 DE19546234C1 (de) 1995-12-04 1995-12-04 Neue makrobicyclische Verbindungen, Verfahren zu ihrer Herstellung und diese makrobicyclischen Verbindungen enthaltende pharmazeutische Mittel
DE19546234.3 1995-12-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2563824A (en) * 2017-06-19 2019-01-02 Georg August Univ Gottingen Stiftung Oeffentlichen Rechts Contrast agents for magnetic resonance imaging

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4035760A1 (de) * 1990-11-08 1992-05-14 Schering Ag Mono-n-substituierte 1,4,7,10-tetraazacyclododecan-derivate, verfahren zu ihrer herstellung und diese enthaltende pharmazeutische mittel
US5385893A (en) * 1993-05-06 1995-01-31 The Dow Chemical Company Tricyclopolyazamacrocyclophosphonic acids, complexes and derivatives thereof, for use as contrast agents
AU1681795A (en) * 1994-01-14 1995-08-01 Mallinckrodt Medical, Inc. Functionalized aza-macrobicyclic ligands for imaging applications

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2563824A (en) * 2017-06-19 2019-01-02 Georg August Univ Gottingen Stiftung Oeffentlichen Rechts Contrast agents for magnetic resonance imaging

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DE19546234C1 (de) 1997-08-28
AU1718197A (en) 1997-06-27

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