EP0731784A1 - Complexes metalliques substitues par halogenure d'aryle, substances pharmaceutiques contenant lesdits complexes, leur utilisation a des fins de diagnostic, et procedes de preparation desdists complexes et desdites substances pharmaceutiques - Google Patents

Complexes metalliques substitues par halogenure d'aryle, substances pharmaceutiques contenant lesdits complexes, leur utilisation a des fins de diagnostic, et procedes de preparation desdists complexes et desdites substances pharmaceutiques

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Publication number
EP0731784A1
EP0731784A1 EP95901440A EP95901440A EP0731784A1 EP 0731784 A1 EP0731784 A1 EP 0731784A1 EP 95901440 A EP95901440 A EP 95901440A EP 95901440 A EP95901440 A EP 95901440A EP 0731784 A1 EP0731784 A1 EP 0731784A1
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European Patent Office
Prior art keywords
mmol
acid
radical
yield
group
Prior art date
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EP95901440A
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German (de)
English (en)
Inventor
Werner Krause
Franz Karl Maier
Wolf-Rüdiger Press
Gabriele Schumann-Giampieri
Michael Bauer
Heribert Schmitt-Willich
Peter Mareski
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Bayer Pharma AG
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Schering AG
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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
    • A61K49/04—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/16—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/24—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/25—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/53—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • C07C233/54—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/46—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having carbon atoms of carboxamide groups, amino groups and at least three atoms of bromine or iodine, bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/26—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring
    • C07C271/28—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a six-membered aromatic ring to a carbon atom of a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C275/00—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups
    • C07C275/28—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C275/40—Derivatives of urea, i.e. compounds containing any of the groups, the nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of urea groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups

Definitions

  • Halogenaryl-substituted metal complexes include halogenaryl-substituted metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics, and methods for producing the complexes and compositions
  • the invention relates to the objects characterized in the claims, that is to say new halogenaryl-substituted metal complexes, pharmaceutical compositions containing these complexes, their use in diagnostics and methods for producing the complexes and compositions.
  • Contrast agents are indispensable aids in modern diagnostics; many diseases would not be diagnosed without the use of contrast agents. Contrast agents can be found in all areas of diagnostics such as X-ray, radio or ultrasound diagnostics or magnetic resonance imaging.
  • the choice of the preferred method depends in part on according to the diagnostic question, but is also determined by the available device options for the doctor. Magnetic resonance imaging in particular, due to the considerable technical and associated high cost, does not yet have the widespread use of other methods, e.g. X-ray diagnostic methods found.
  • the choice of a suitable contrast medium also varies depending on the particular question.
  • the suitability of the contrast medium for a specific task is determined not least by its (enrichment) distribution behavior in the organism.
  • contrast agents based on triiodobenzene have been able to prevail, since these compounds have a high X-ray density and have a low general and local toxicity and are very soluble in water.
  • metal complexes of an element with a high atomic number should also be suitable in addition to the iodine-containing compounds.
  • Such compounds are widely used in the field of NMR diagnostics. These are generally metal complexes, such as those e.g. be described in EP 0 071 564.
  • WO 93/16375 describes metal complexes which are linked to iodine-substituted aromatics via amide bonds. These compounds should allow both NMR and X-ray examinations to be carried out with only one application of the contrast medium. A combination of the two imaging methods is in many cases for a differentiated representation and a reliable one
  • Liver-specific NMR contrast media are described in EP 0 405 704. Because of the metal content in the complexes, these should in principle also be suitable for X-ray diagnostics. A reworking of the experimental examples in animal experiments did not show sufficient contrast of the liver in the X-ray image even when a high dose (conc.: 1 M / 1, dose: 0.5 mmol Gd / kg intravenously) was administered. A sufficient imaging effect in the
  • X-ray diagnostics are only achieved at a dose at which the safety margin is reduced to an unacceptable level.
  • R 1 represents a hydrogen atom, a carboxylic acid radical, a straight-chain or branched C r C 15 alkyl, C 6 -C 15 aryl or a C 7 -C 15 aralkyl radical which is optionally substituted by 1-5 hydroxy and / or 1-2 carboxy groups and / or interrupted by 1-4 oxygen atoms, or wherein
  • R 1 represents a radical of the general formula II or III
  • R 4 , R 5 independently of one another represent a hydrogen atom, a straight-chain or branched C r C 15 alkyl, C 6 -C 15 aryl or a C 7 -C 15 aralkyl radical which may contain 1-5 hydroxy, Contains 1-2 carboxy groups and / or 1-4 oxygen atoms or wherein R 4 , r 25 R 5 together including the nitrogen atom, one. optionally form an oxygen, another acylated nitrogen atom or a sulfonyl group, optionally substituted with 1-3 hydroxyl groups, 5 or 6 ring,
  • R 7 represents a hydrogen atom, a straight-chain or branched C r C 15 alkyl, C 6 -C 15 aryl or a C 7 -C 15 aralkyl radical which optionally contains 1 to 2 hydroxyl groups or a carboxy group or in which R 7 together with R 6 , including the nitrogen atom and the carbonyl group, forms a 5 or 6 ring which may optionally contain an oxygen, another acylated nitrogen atom or a sulfonyl group and is optionally substituted by 1-3 hydroxyl groups,
  • R 2 , R 3 independently of one another represent a hydrogen atom, a C j -C ⁇ alkyl radical, a C 6 -C 15 aryl radical or a C 7 -C 15 aralkyl radical which is optionally substituted by 1-5 hydroxyl groups and / or through 1-4
  • Oxygen atoms is interrupted, stand or together form a trimethylene or tetramethylene group, or have the meaning given for U 1 (U 2 ),
  • Z 1 , Z 2 , Z 3 independently of one another for a hydroxyl group or a radical
  • R 17 represents a hydrogen atom, a methyl or methoxyethyl group and U 1 , U 1 ', U 2 , V 1 , V 2 and V 3 each independently
  • R 8 , R 9 independently of one another represent a group -NR 6 -CO-R 7 and / or the meaning given for R 1 , with the exception of a C r C 15 alkyl, C 6 -C 15 aryl or a C.
  • R 8 , R 9 independently of one another represent a group -NR 6 -CO-R 7 and / or the meaning given for R 1 , with the exception of a C r C 15 alkyl, C 6 -C 15 aryl or a C.
  • R 10 , R 11 independently of one another represent a halogen or a hydrogen atom
  • X represents a halogen atom or a bridge member of the general formula V and
  • Y represents R 9 or a bridge member of the general formula V
  • R 12 stands for a direct bond, a carbonyl, a carboxyl, a -CO-NR 18 -, a -NR 18 -CO-, a -NH-CS-, a CS-NH- group, in which R 18 represents a hydrogen atom, a straight-chain or branched -C ⁇ alkyl, C 6 -C 15 aryl or a C 7 -C 15 aralkyl radical which may contain 1-4 hydroxyl, 1-2 carboxy groups and / or 1-2 Contains oxygen atoms or in which R 12 is a straight-chain or branched C r C 4 -
  • Alkylene radical which is optionally a carbonyl and / or
  • Y is a bridge member of the formula V when X is halogen and Y is R 9 when X is a bridge member of the formula V and at least one of the radicals R 2 , R 3 , Z 1 , Z 2 , Z 3 , U 1 , U 2 , V 1 , V 2 or V 3 represents or contains the rest of the general formula IV and, if desired, free ones, not for complexing the metal ions of the above
  • R 8 and / or R 9 contains an aryl radical and / or that Z 1 and / or Z 2 only represent a radical of the general formula IV if at least one of the substituents R 2 , R 3 , U 1 , U 2 , V 1 , V 2 or V 3 does not represent a hydrogen atom, and / or that if Z 3 contains a fully substituted aromatic of the formula IV, Z 1 and / or Z 2 does not contain a fully substituted aromatic of the formula IV contain, and / or that if all substituents R 2 , R 3 , U 1 , U 2 , V 1 , V 2 and V 3 are hydrogen, at least one of the radicals R 8 , R 9 , R 10 or R 11 for a Hydrogen atom and / or R 8 and / or R 9 represent a radical which contains a carboxylic acid which is not directly bound, excellent for the production of contrast media for NMR and / or X-ray diagnostics, preferably contrast media
  • the complexes according to the invention preferably contain a manganese (II) -, iron (HI) -, iron (II) -, praseodymium (HI) -, neodymium (III) -, samarium ( ⁇ i) -, dysprosium (III) - as metal ion, a ytterbium (III) or a bismuth (III) ion, in particular a gadolinium (III) ion.
  • the complexes according to the invention contain, as halogen atom (s), chlorine, bromine or iodine, preferably (bromine) or iodine, but especially (i) iodine atom (s).
  • Preferred halogenated aromatics of the formula IV are triiodinated aromatics, ie aromatics in which X, R 10 and R 11 are iodine and in which R 8 and R 9 independently of one another represent a hydrogen atom, a group -OH, -COOH, -O- CH 2 -CH (OH) -CH 2 -OH, -O-CH3, -O-CH 2 -CH 3 , -CO-NH-CH (CH 2 OH) - (CHOH-CH 2 OH), -CO- NR4-CH- (CH 2 OH) 2 , -NR6-CO-CH 2 OH, -CO-NR -CH 2 -CH 2 OH, -CO-NH 2 , -N (CH 3 ) -CO-CH 3 , -NH-CO-CH3, -CO-NH -CH3, -N (CH 3 ) -CO- (CH 2 ) 2 COOH, -CO-N- (C 2 H
  • Preferred bridge members of the formula V are in the event that one of the radicals
  • - U stands for a halogenated aromatic radical, the groups -CH -,
  • Suitable radicals R 1 are straight-chain or branched alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl radicals, but preference is given to hydrogen, C ⁇ -C4-alkyl and hydroxyalkyl radicals, such as the hydroxymethyl radical and alkoxy alkyl radicals, such as the methoxymethyl radical.
  • Suitable radicals R 1, R 3 are the radicals listed for R *, but hydrogen atoms are preferred.
  • ionic complexes are particularly preferred, in which free carboxyl groups present in the molecule (ie carboxyl groups which are not required for the charge balance of the metal ions of the elements of the atomic numbers mentioned) are present as free acid or as a salt of an inorganic and / or organic base or amino acid .
  • Suitable cations of inorganic bases are, for example, the lithium, the potassium, the calcium, the magnesium and in particular the sodium ion.
  • Suitable cations of organic bases include those of primary, secondary or tertiary amines, such as. As ethanolamine, diethanolamine, morpholine, glucamine, N, N-dimethylglucamine and especially N-methylglucamine.
  • Suitable cations of amino acids are, for example, those of lysine, arginine and ornithine.
  • the complexes according to the invention can be prepared in a variety of ways.
  • the various processes and the starting compounds required therefor are known in principle to the person skilled in the art.
  • the compounds can be prepared analogously to already known complexes or complexing agents by reacting a reactive species of the halogenated aromatic with a reactive species of the complexing agent in a suitable solvent.
  • the selection of the most appropriate synthetic route depends on the desired link between the halogenated aromatic (s) and the polyaminopolycarboxylic acid.
  • the complexes can then be divided into three groups.
  • Complexing agents or complexes of group I can be prepared analogously to the processes described in European patent application EP 0 230 893. Further universally applicable synthesis options for the complexing agents are mentioned below by way of example.
  • An alternative process for the preparation of ⁇ -C-substituted polyaminopolycarboxylic acids starts from an acid-protected polyaminocarboxylic acid (for example from the pentamethyl ester of diethylenetriaminepentaacetic acid). This is reacted with the lithium salt of a precursor of the desired aromatic.
  • a corresponding lithium salt can be obtained from benzyl halide (for example 3-nitrobenzyl chloride, 3,5-dinitrobenzyl chloride, 3-benzyloxybenzyl chloride) by reaction with lithium diisopropylamine in THF / hexane.
  • the aromatic is converted to the desired halogenated aromatic of the formula IV, for example by reducing the nitro groups which may be present to amino groups, which, if desired, are reacted with acetyl chloride to give the amide.
  • Benzyloxy radicals can be converted into hydroxy radicals, for example by catalytic hydrogenation.
  • the aromatics are also iodinated in a manner known per se, for example by reaction with iodine monochloride solution in the hydrochloric acid medium.
  • the acid protecting groups of the pentaester are saponified in basic.
  • Nf stands for a nucleofug such as chloride, bromide, iodide, methanesulfonate or toluenesulfonate
  • R 14 stands for an acid protecting group such as a lower alkyl, aryl, aralkyl or trialkylsilyl group
  • R 1 , R 2 , R 3 , U 1 , U 2 , V 1 , V 2 , V 3 , Z 1 , Z 2 and Z 3 have the meaning given above.
  • Polyaminopolycarboxylic acid for example from a phenylamino acid such as 3-aminophenylalanine. This is initially done in a manner known per se halogenated, the acid group then protected as an ester. The intermediate product thus obtained is reacted with two equivalents of N, N-bis [(benzyloxycarbonyl) methyl] - 2-bromomethylamine. If desired, the substituents on the aromatic are converted into the desired radicals before the acid protecting groups are split off.
  • Group II complexing agents can be prepared analogously to the methods described in EP 0 405 704 and DE 43 02 289. For example, starting from known compounds (DE 37 10 730 and literature cited therein) of the general formula IX,
  • R 14 , R 1 , R 2 and R 3 have the meanings given, in which the phenolic OH group is reacted with a reactive form of the desired halogenated aromatic (or its precursor, for example benzyl halide) of the formula X.
  • R 8 ', R 9 ', R 10 'and R 11 ' represent the desired groups R 8 , R 9 , R! 0 and R 11 or a precursor thereof. If the groups R 8 ', R 9 ', RIO 'and R * • ** • *' stand for preliminary stages of the desired groups, these are generated from those.
  • the acid protecting groups R14 are known in a known manner [see, for example, E. Wünsch, Methods of Org. Chemistry (Houben Weyl), Vol. XV / 1, 4 ed. 1974, p 315 ff], for example by hydrolysis, hydrogenolysis or alkaline hydrolysis the Rule before halogenation of the aromatic, split off. Both acidic and aqueous-alkaline reaction conditions can be selected for the relaxation of the t-butyl esters which are particularly advantageous for the present reaction.
  • the aromatic radical can also be used in a manner known per se e.g. is iodinated with iodine monochloride.
  • the phenolic -OH groups can be etherified with alkyl halide / sodium hydride in a manner known per se. The acid protection groups are released in the manner described above.
  • Rl5 stands for a protective group such as a benzyl group.
  • the hydroxyl group in the compounds of the general formula XIV can be reacted, for example, with N-chlorosuccinimide to give the corresponding chloride of the formula XVI ⁇
  • R 8 , R 9 , R ⁇ and R - * * - * have the meanings given and Y 'represents an OH or COOH group, converted to the corresponding ethers or esters.
  • the acid protection groups R * 4 are released in the manner described above.
  • the compounds of general formula XVI can be reacted with an azide (e.g. sodium azide) to give the corresponding azido compound, which is subsequently reduced to the amino compound in a known manner. This is then a) either with an isocyanato compound of the formula XV to the corresponding azide (e.g. sodium azide) to give the corresponding azido compound, which is subsequently reduced to the amino compound in a known manner. This is then a) either with an isocyanato compound of the formula XV to the corresponding
  • R ⁇ for an amino protecting group, preferably a benzyloxycarbonyl group and R13 ' is an unhalogenated precursor of the desired aromatic or a "linker" to which the desired halogenated aromatic is bound in a later reaction step.
  • the aminoethyl alcohol is first reacted in a manner known per se, for example with methanesulfonyl chloride, toluenesulfonyl chloride or trifluoroacetic anhydride to give the corresponding mesylate, tosylate or triflate and then reacted with an optionally substituted ethylenediamine.
  • R 13 ' is an unhalogenated precursor of the desired aromatic of the general formula IV
  • iodine is used, for example, with iodine monochloride; if, on the other hand, it is a "linker", this is reacted with a reactive species of the desired aromatic (or its unhalogenated precursor) to react.
  • the amino protecting groups are split off and with
  • Halogenoacetic acid ester converted to the desired amino acids (complexing agents).
  • the group III complexing agents i.e. Complexing agents in which the halogenated aromatic radical in the form of an amide bond to the carboxylic acid groups of the
  • Polyaminopolycarbon yarnre is bound, can be analogous to that in the
  • complexing agents can be prepared by partial conversion of activated carboxyl groups e.g. the desired pentacarboxylic acid in amide groups. All synthetic possibilities known to the person skilled in the art are suitable for this process
  • R 8 ', R 9 ', R 10 'and R 11 ' represent the desired groups R 8 , R 9 , R 10 and RH or a precursor thereof and Q represents the remainder of a linker of the general formula V.
  • the aromatics of the general formula XXII are prepared as described, for example, in DE 25 23 567.
  • H 2 NQ radical examples include an H 2 N-CH 2 -CO-NH-, H 2 N-NH-CO-NH-, H 2 N-CH 2 CH 2 -CO-NH-, H 2 N- NH-CO-CH 2 CH 2 -, H 2 N-CH 2 CH 2 -NH-CO - or an H 2 N-CH 2 CH 2 -N (CO-CH 3 ) - group.
  • reaction media are, for example, water, dipolar aprotic solvents such as diethyl ether, tetrahydrofuran, dioxane, acetonitrile, N-methylpyrrolidone, dimethylformamide,
  • the reaction temperatures are between approx. -80 ° C and 160 ° C, with temperatures from 20 ° C to 80 ° C are preferred.
  • the reaction times are between 0.5 hours and 7 days, preferably between 1 hour and 36 hours.
  • the acid anhydrides of general formula XX can be prepared by known processes, e.g. by the process described in US Pat. No. 3,660,388 or in DE 16 95 050 with acetic anhydride in pyridine. In certain cases, however, it is advantageous to dehydrate with carbodiimides in a suitable solvent, e.g. Dimethylformamide or dimethylacetamide, to be carried out gently.
  • a suitable solvent e.g. Dimethylformamide or dimethylacetamide
  • halogenated aromatics used in the various processes are known or can easily be generated from known ones.
  • Aromatics containing acid chloride groups are implemented.
  • Corresponding chlorine or bromine compounds can be prepared as described in the patents EP 0 055 689 or DE 10 03 743, EP 0 073 715 or EP 0 118 347 - or analogously to the compounds described there.
  • Aromatics containing amino groups, e.g. required for the preparation of acetic acid-substituted compounds of group III can be obtained analogously to the compounds described in DE 25 23 567.
  • the metal complexes according to the invention are prepared from the complexing agents of groups I-III described above in the manner as has been disclosed in the patents EP 0 071 564, EP 0 130 934 and DE 34 01 052 by using the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 12, 13, 20-31, 39-42, 44-50 or 57-83 in water and / or a lower alcohol (such as methanol, ethanol, Isopropanol and / or N, N-dimethylformamide) dissolves or suspended and reacted with the solution or suspension of the equivalent amount of the complexing agent. If desired, further acidic hydrogen atoms of acid groups can then be substituted by cations of inorganic and / or organic bases or amino acids.
  • a metal salt for example the nitrate, acetate, carbonate, chloride or sulfate
  • a lower alcohol such as methanol
  • Suitable bases are inorganic bases (e.g. hydroxides, carbonates or bicarbonates) of e.g. B. sodium, potassium or lithium and / or organic bases such as primary, secondary and tertiary amines such as e.g. Ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, and basic amino acids such as B. lysine, arginine and ornithine.
  • inorganic bases e.g. hydroxides, carbonates or bicarbonates
  • B. sodium, potassium or lithium e.g. sodium, potassium or lithium
  • organic bases such as primary, secondary and tertiary amines such as e.g. Ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, and basic amino acids such as B. lysine, arginine and ornithine.
  • the acidic complex salts in aqueous solution or suspension can be added with enough of the desired bases that the neutral point is reached.
  • the solution obtained can then be evaporated to dryness in vacuo.
  • water-miscible solvents such as. B. lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.) to precipitate and thus to easily isolate and easy to clean crystals .
  • water-miscible solvents such as. B. lower alcohols (methanol, ethanol, isopropanol, etc.), lower ketones (acetone, etc.), polar ethers (tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.)
  • acidic complex compounds contain several free acidic groups, it is often expedient to prepare neutral mixed salts which contain both inorganic and organic cations as counterions.
  • the order of base addition can also be reversed.
  • the invention further relates to agents which contain at least one of the compounds according to the invention.
  • the invention further relates to a process for the preparation of these agents, which is characterized in that the paramagnetic complex salt dissolved in water is brought into a form suitable for enteral or parenteral administration with the additives and stabilizers customary in galenics, so that the complex salt is present in a concentration of 1 to 1500 mmol / 1, preferably in a concentration of 10 - 1000 mmol / 1.
  • the halogen content of the solutions is usually in the range between 10-400 mg / ml.
  • the resulting agents are then sterilized if desired. Depending on the halogen content and the diagnostic question, they are usually applied in a dose of 1-300 ml.
  • Suitable additives are, for example, physiologically harmless buffers (such as tromethamine), minor additions of complexing agents (such as diethylenetriaminepentaacetic acid) or, if necessary, electrolytes such as. B. sodium chloride or, if necessary, antioxidants such as. B. ascorbic acid.
  • physiologically harmless buffers such as tromethamine
  • complexing agents such as diethylenetriaminepentaacetic acid
  • electrolytes such as. B. sodium chloride or, if necessary, antioxidants such as. B. ascorbic acid.
  • suspensions or solutions of the agents according to the invention in water or physiological saline are desired for enteral administration or other purposes, they are mixed with one or more adjuvants common in galenics (e.g. methyl cellulose, lactose, mannitol) and / or surfactants (e.g. B. lecithins, Tweens ® , Myrj ® and / or flavoring agents for flavor correction (z. B. essential oils) mixed.
  • adjuvants common in galenics
  • surfactants e.g. B. lecithins, Tweens ® , Myrj ® and / or flavoring agents for flavor correction (z. B. 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 salt.
  • the substances according to the invention fulfill the diverse requirements that are to be placed on contrast agents in modern diagnostics.
  • the compounds and means made from them are characterized by:
  • the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that a release or an exchange of the ions which are not covalently bound in the complexes - in themselves toxic - within the time in which the new contrast medium are completely excreted, did not occur.
  • the compounds according to the invention have a positive effect in X-ray diagnostics in that the complex compounds according to the invention surprisingly permit examinations with short-wave X-rays than is possible with conventional contrast agents, which significantly reduces the radiation exposure of the patient, as is known to be soft radiation from the tissue is absorbed much more strongly than hard (R. Felix, Das Röntgensent; Thieme Stuttgart 1980).
  • the agents are also particularly suitable for digital subtraction techniques (which work with higher tube voltages).
  • digital subtraction techniques which work with higher tube voltages.
  • the favorable in vivo distribution behavior of the agents according to the invention For the first time, this allows x-rays of high diagnostic value to be taken in the area of the liver with a dose that is usual for x-ray contrast media (halogen content: 50 - 400 mg / ml; dose 0.1 - 1 ml / kg body weight).
  • FIG. 1 top picture shows the liver of a rat before administration of the contrast agent.
  • the lower picture shows the liver of the same rat 10 minutes after injection of 0.5 mmol / kg of the compound according to the invention prepared according to Example ld).
  • a picture taken under otherwise identical conditions after administration of the same dose of the disodium salt of the gadolinium complex of (4s) 4- (4-ethoxybenzyl) -3, 6, 9-tris (carboxylatomethyl) -3, 6, 9-triazaundecanedioic acid shows no diagnostically usable contrasting of the liver (see Fig. 2 bottom picture).
  • the picture above shows the liver before contrast medium administration.
  • FIG. 3 shows in comparison the increase in density (which can be regarded as a measure of the effectiveness of a contrast agent) as a function of time, for a compound according to the invention (example Id) and a compound of EP 0 405 704 (example 8c). Thereafter, significantly higher density values are observed in the rat liver over the entire investigation period for the compound according to the invention.
  • the maximum values for the substance according to the invention are 60 Houndsfield units (HU) for the comparison substance, but only 15 HU.
  • body weight 200 - 280 g
  • the gadolinium complex of 1,13-bis- [5- (propion-3-ylamido) -2,4,6-triiodoisophthalic acid bis- (2-hydroxy-l-hydroxymethylethyl) isomeric to example 1 of WO 93/16375 was -diamide] -4,7, 10-tris- (carboxymethyl) - (2, 12-dioxo) -l, 4,7,10, 13-pentatriazadecans (Example 17 b) almost completely excreted via the kidney. Only 1.3% of the total was eliminated from the body in other ways. Even assuming that this 1.3% of the complex is complete accumulated in the liver, this amount would be far below the dose required for an imaging effect.
  • Gadolinium concentrations determined using ICP atomic emission spectroscopy. The half-life of 0.32 hours and the volume of distribution show a distribution in the extracellular space with renal excretion through glomerular filtration through the kidney.
  • the agents according to the invention which contain a paramagnetic metal ion of an element of order numbers 21-29, 42, 44 or 57-70 in the complex, can be used in NMR diagnostics as well as in X-ray diagnostics. This dual character opens up further areas of application. Thus, these agents according to the invention are always to be used with advantage when a combination of X-ray and NMR diagnostics is required for the differentiated representation and reliable determination of certain diseases. This applies e.g. too for suspected recurrence after tumor surgery or radiation therapy. In these cases, the patient is spared the additional burden of double application by using a contrast agent that is equally suitable for both techniques.
  • the suspension is then cooled to 10 ° C., filtered, the residue is stirred for 30 minutes with 300 ml of N, N-dimethylformamide and the suspension is filtered.
  • the filtrate is evaporated in vacuo, the residue is stirred with water, filtered off and dried in vacuo.
  • the crude product is stirred in hot acetonitrile with activated carbon, then it is filtered and the filtrate is cooled to 0 ° C., whereby a precipitate forms. This is suctioned off and dried in vacuo.
  • a suspension of 11.8 g (12.2 mmol) of the penta acid prepared according to Example lc) in 118 ml of water is mixed with 2.21 g (6.1 mmol) of gadolinium oxide and stirred at 80 ° C. for 2 hours. Then 24.4 ml of normal sodium hydroxide solution are added with a microburette and the mixture is stirred for 1 hour. The solution is then stirred at 80 ° C. for 2 hours after the addition of 0.5 g of activated carbon and filtered. After freeze-drying, the filtrate gives a colorless solid.
  • the reaction mixture is 3 hours at 50 ° C and a further 12 hours
  • a methanolic solution of 12.7 g (21.2 mmol) of the nitro compound from Example 12b) is hydrogenated at room temperature with the addition of 1.35 g of palladium on carbon (10%) at 4 bar.
  • the hydrogenation is complete after 5 hours and the catalyst is filtered off. The filtrate is evaporated to dryness and used in the next step without further purification.
  • the remaining residue is taken up in 300 ml of water and adjusted to pH 2.0 with a cation exchanger (H + form).
  • the filtrate obtained after suction extraction from the ion exchanger supplies the pentacarboxylic acid as a colorless powder after freeze-drying.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • 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 complexes métalliques qui contiennent un ion d'un élément des nombres atomiques 12, 13, 20-31, 39-42, 44-50 ou 57-83 et un ligand complexant halogéné de formule (I), dans laquelle R1, R2, R3, Z1, Z2, Z3, U1, U2, V1, V2 ou V3 ont différentes notations. L'invention concerne des substances pharmaceutiques contenant lesdits complexes, leur utilisation dans la résonance magnétique nucléaire et/ou dans le radiodiagnostic, notamment dans celui du foie, ainsi que des procédés de préparation desdits complexes et desdites substances pharmaceutiques.
EP95901440A 1993-12-03 1994-11-26 Complexes metalliques substitues par halogenure d'aryle, substances pharmaceutiques contenant lesdits complexes, leur utilisation a des fins de diagnostic, et procedes de preparation desdists complexes et desdites substances pharmaceutiques Withdrawn EP0731784A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE4341724A DE4341724A1 (de) 1993-12-03 1993-12-03 Halogenaryl-substituierte Metallkomplexe enthaltende pharmazeutische Mittel, deren Verwendung in der Diagnostik, sowie Verfahren zur Herstellung der Komplexe und Mittel
DE4341724 1993-12-03
PCT/EP1994/003919 WO1995015306A1 (fr) 1993-12-03 1994-11-26 Complexes metalliques substitues par halogenure d'aryle, substances pharmaceutiques contenant lesdits complexes, leur utilisation a des fins de diagnostic, et procedes de preparation desdists complexes et desdites substances pharmaceutiques

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EP0731784A1 true EP0731784A1 (fr) 1996-09-18

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EP (1) EP0731784A1 (fr)
JP (1) JPH09506347A (fr)
KR (1) KR960706467A (fr)
CN (1) CN1136805A (fr)
AU (1) AU687477B2 (fr)
CA (1) CA2177977A1 (fr)
DE (1) DE4341724A1 (fr)
HU (1) HUT74389A (fr)
IL (1) IL111817A (fr)
NO (1) NO962243L (fr)
NZ (1) NZ276413A (fr)
WO (1) WO1995015306A1 (fr)
ZA (1) ZA949604B (fr)

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TW319763B (fr) 1995-02-01 1997-11-11 Epix Medical Inc
ES2217408T3 (es) 1996-04-01 2004-11-01 Epix Medical, Inc. Agentes diagnosticos de contraste para formacion de imagenes bioactivados.
US6458337B1 (en) 1996-08-02 2002-10-01 Dibra S.P.A Diagnostic imaging contrast agent with improved in serum relaxivity
IT1283651B1 (it) * 1996-08-02 1998-04-23 Bracco Spa Chelati paramagnetici ad alta relassivita' in siero
DE19641197C2 (de) * 1996-09-24 1999-02-18 Schering Ag Ionenpaare und ihre Verwendung als Kontrastmittel
DE19740403C2 (de) * 1997-09-09 1999-11-11 Schering Ag Neue Kontrastmittel
FI20055653A (fi) 2005-12-08 2007-06-09 Wallac Oy Leimausreagenssi
KR100749087B1 (ko) * 2006-06-02 2007-08-14 경북대학교 산학협력단 신규한 ｄｔｐａ-비스-아미드 리간드들 및 이들이 결합된가돌리늄 착물

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DE3922005A1 (de) * 1989-06-30 1991-01-10 Schering Ag Derivatisierte dtpa-komplexe, diese verbindungen enthaltende pharmazeutische mittel, ihre verwendung und verfahren zu deren herstellung
US5324503A (en) * 1992-02-06 1994-06-28 Mallinckrodt Medical, Inc. Iodo-phenylated chelates for x-ray contrast

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Title
See references of WO9515306A1 *

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NO962243L (no) 1996-08-01
CA2177977A1 (fr) 1995-06-08
HU9601478D0 (en) 1996-07-29
AU1067595A (en) 1995-06-19
JPH09506347A (ja) 1997-06-24
IL111817A (en) 1998-12-27
IL111817A0 (en) 1995-01-24
HUT74389A (en) 1996-12-30
ZA949604B (en) 1995-08-15
DE4341724A1 (de) 1995-06-08
CN1136805A (zh) 1996-11-27
NZ276413A (en) 1998-04-27
NO962243D0 (no) 1996-05-31
AU687477B2 (en) 1998-02-26
KR960706467A (ko) 1996-12-09
WO1995015306A1 (fr) 1995-06-08

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