WO2004087656A1 - Conjugues de derives de 3,6,9-acide triaza - nonanique-3n, 6n,9,9n-acide tetraacetique a pontage 2,4-ethano et 2,4-propano et de derives correspondants d'acide phosphorique-methylene, et leurs derives avec des biomolecules, procedes de production desdits conjugues et leur utilisation pour la - Google Patents

Conjugues de derives de 3,6,9-acide triaza - nonanique-3n, 6n,9,9n-acide tetraacetique a pontage 2,4-ethano et 2,4-propano et de derives correspondants d'acide phosphorique-methylene, et leurs derives avec des biomolecules, procedes de production desdits conjugues et leur utilisation pour la Download PDF

Info

Publication number
WO2004087656A1
WO2004087656A1 PCT/EP2004/003003 EP2004003003W WO2004087656A1 WO 2004087656 A1 WO2004087656 A1 WO 2004087656A1 EP 2004003003 W EP2004003003 W EP 2004003003W WO 2004087656 A1 WO2004087656 A1 WO 2004087656A1
Authority
WO
WIPO (PCT)
Prior art keywords
mmol
solution
stirred
amino
ethyl
Prior art date
Application number
PCT/EP2004/003003
Other languages
German (de)
English (en)
Inventor
Lutz Lehmann
Matthias Friebe
Thomas Brumby
Detlev Sülzle
Joahnnes Platzek
Original Assignee
Schering Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Publication of WO2004087656A1 publication Critical patent/WO2004087656A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • A61K49/06—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
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
    • A61K49/10—Organic compounds
    • A61K49/14—Peptides, e.g. proteins
    • A61K49/16—Antibodies; Immunoglobulins; Fragments thereof
    • 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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Definitions

  • the invention relates to the objects characterized in the claims, that is, conjugates 2,4-ethano- and 2,4-propano-bridged 3,6,9-triaza-nonanoic acid- 3 N, 6 N, 9.9 N-tetraacetic acid - And corresponding phosphoric acid methylene derivatives and their derivatives with biomolecules, processes for their preparation and their use for the manufacture of pharmaceutical agents for radio diagnostics, radiotherapy or NMR diagnostics.
  • radiopharmaceuticals for diagnostic and therapeutic purposes has long been known in the field of biological and medical research.
  • radiopharmaceuticals are used to represent certain structures such as the skeleton, organs or tissues.
  • Diagnostic use presupposes the use of such radioactive agents that, after application, accumulate specifically in the structures in the patient that are to be examined. These locally accumulating radioactive agents can then be detected, recorded or scintigraphed by means of suitable detectors, such as, for example, scintillation cameras or other suitable recording methods.
  • suitable detectors such as, for example, scintillation cameras or other suitable recording methods.
  • the distribution and relative intensity of the detected radioactive agent identifies the location of a structure in which the radioactive agent is located and can represent the presence of abnormalities in structures and functions, pathological changes, etc.
  • radiopharmaceuticals can be administered to the patient as therapeutic agents to irradiate certain pathological tissues or areas. Such treatment requires the provision of radioactive therapeutic agents that accumulate in certain structures, organs or tissues.
  • a company of IDEC Pharmaceuticals Corp. developed radiopharmaceutical for the therapy of non-Hodgkin's lymphoma is Zevalin ® (see eg Cancer (2002) Feb 15; 94, (4 Suppl): 1349-57).
  • Radiant ions are 111-ln or 90-Y, which have a Chelator (methyl-substituted-diethylene-triamine-penta-acetic acid derivative (mx-DTPA) are bound to a tumor-specific antibody.
  • Nuclear magnetic resonance is a widely used method for medical diagnostics used in Vo imaging, which can be used to measure the magnetic properties of protons in body water, body vessels and body tissue (including tumors).
  • contrast agents are used, for example, which, by influencing certain NMR parameters of the body protons (for example the relaxation times T 1 and T 2 ), bring about a contrast enhancement in the resulting images or only make these images readable.
  • complexes come paramagnetic ions such as gadolinium-containing complexes (such as Magnevist ®) due to the effect of the paramagnetic ions on the shortening of the relaxation times.
  • EP-A-0 071 564 describes, inter alia, the meglumine salt of the gadolinium (III) complex of diethylenetriaminepentaacetic acid (DTPA) as a contrast agent for NMR tomography.
  • DTPA diethylenetriaminepentaacetic acid
  • Magnevist ® This contrast medium is distributed extracellularly after intravenous administration and is excreted renally by glomerular secretion. A passage of intact cell membranes is practically not observed.
  • Magnevist ® is particularly well suited for the display of pathological areas (eg inflammation, tumors).
  • the known radiotherapeutics and contrast media cannot be used satisfactorily for all applications. Many of these agents are distributed throughout the extracellular space of the body. In order to increase the efficiency of these agents in in vivo diagnostics and therapy, attempts are being made to increase their specificity and selectivity, for example, to target cells or desired areas and structures of the body. These properties can be improved, for example, by coupling the metal complexes to biomolecules after "drug targeting". Principle. Plasma proteins, antibodies, their fragments, hormones, growth factors and substrates of receptors and enzymes are suitable as biomolecules (eg WO 97/12850, Institute for Diagnostic Research at the Free University of Berlin). So far, for example, the tumor specificity (tumor accumulation) has not yet been sufficiently high in many cases, which is an important goal, especially in radioimmunotherapy.
  • the retention in the tumor tissues or organs to be examined should be sufficient to achieve the quality of images or sufficient radiation required for efficient diagnosis and therapy with the lowest possible dosage.
  • the fastest and most complete elimination of the metals from the body should be guaranteed.
  • the NMR contrast media should show a high proton relaxivity and thus allow a reduction in the dose with an increase in the signal intensity.
  • Radiopharmaceutical Zevalin ® for the therapy of non-Hodgkin's lymphoma uses a DTPA derivative which is substituted at two defined positions.
  • US Pat. No. 5,28650 describes a DTPA in which one of the two ethylene radicals is part of a cyclohexane ring.
  • modified DTPA's sometimes have improved properties - e.g. increased complex stability compared to the unsubstituted DTPA - show, there is still a need to further increase the metal complex stability and to provide diagnostic and therapeutic agents that are as specific as possible.
  • DTPA derivatives in which an ethano or propano bridge is linked via one of the two outer nitrogen atoms, so that 2,5-substituted pyrrolidines or 2,6-substituted piperidines are formed, are more kinetic Stability in vivo and thus lower acute toxicity of the corresponding metal complexes.
  • the compounds according to the invention show increased relaxivity and / or water solubility and / or specificity, so that they are suitable as pharmaceutical agents, in particular for radio and NMR diagnostics and radiotherapy.
  • the invention thus relates to conjugates of the general formula I.
  • Z represents a hydrogen atom or a metal ion equivalent of an element of atomic numbers 21-29, 31, 32, 37-39, 42-44, 46, 47, 49, 58-71,
  • 75, 77, 82 or 83 stands for a group -COO-, a group -P (0) (OC C 6 -alkyl) -0- or a group -P (0) (OH) -0- stands for the digits 0 or 1,
  • R 1 - R 6 independently of one another for a hydrogen atom, a straight-chain or branched, saturated or unsaturated and optionally by one to six O atoms, phenylene, -NHCO-, -CONH-, -O- (CO) -
  • Ci - C 25 alkyl radical which optionally with one to six carboxyl groups, hydroxyl groups, amino groups and / or another functional binding group, which with a Biomolecule can be linked, substituted, or represent a phenyl -CC 25 alkyl group, the phenyl radical of which is optionally substituted with a nitro group, an amino group or another functional binding group which can be linked to a biomolecule, and their Salts with organic or inorganic bases, with the proviso that at least one of the substituents R 1 -R 6 does not represent H and that at least one of the substituents R 1 - R 6 contains a biomolecule linked via a functional group and at least two Z stand for a metal ion equivalent.
  • the carboazar ring is preferably c / s linked.
  • alkyl is preferably ethyl.
  • the compounds according to the invention contain at least three centers of chirality. Even if no distinction is made in the description and claims between the different enantiomers, the compounds mentioned always include both enantiomers and, in the presence of several stereocenters, also all possible diastereomers and mixtures thereof.
  • the radicals R 1 -R 6 can independently represent a hydrogen atom or an alkyl radical having 1-25 carbon atoms (at least one of the radicals contains a biomolecule bound via a functional group).
  • This alkyl radical can be straight-chain or branched, saturated or unsaturated (for example:
  • Azide acid chloride, hydroxide, sulfonyl chloride, vinyl sulfone, carbodiimide, maleimide,
  • Dioxo or other functional binding group e.g.
  • Ci - C 25 alkyl radical can optionally be replaced by one to six O atoms, phenylene
  • R -R 6 can also represent a phenyl-C 25 -aralkyl group, the phenyl radical of which, for example, with carboxyl, activated carboxyl, amino, nitro, isocyanate, isothiocyanate, hydrazine, semicarbazide, thiosemibarbazide, chloroacetamide, bromoacetamide, iodoacetamide, acrylic, acylamino , mixed anhydrides, azide, hydroxide, sulfonyl chloride, vinyl sulfone, carbodiimide, a maleimide, diazo (e.g.:
  • R 1 -R 6 substituents permit selective reaction with functional groups of the biomolecules in the optimal pH range, for example the addition to -SH groups (cysteine in the biomolecule), and exclusively of -SH groups, eg on maleimides ((2,5-dioxo-2,5-dihydro-pyrrol-1-yl) compounds, see above) or bromoacetamides if the coupling takes place in the weakly acidic pH range.
  • Activated carboxyl groups are understood above to mean those carboxyl groups which are derivatized in such a way that they facilitate the reaction with a biomolecule. 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 hydroxybenzotriazole esters.
  • the activated carboxyl group is particularly preferably selected from
  • the activated esters of the compounds described above are prepared as known to those skilled in the art.
  • isothiocyanates or ⁇ -haloacetates the corresponding terminal amine precursors are reacted with thiophosgene or 2-halo-acetic acid halides using methods known from the literature.
  • the reaction with correspondingly derivatized esters of N-hydroxysuccinimide such as:
  • R 1 -R 6 substituents are an amide group, this is produced, for example, by reacting an activated carboxylic acid with an amine. The activation of the
  • Carboxylic acid is made according to the usual methods. Examples of suitable ones
  • Activating reagents are dicyclohexylcarbodiimide (DCC), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP) and 0- (benzotriazole-
  • HBTU 1, 3,3-tetramethyluronium hexafluorophosphate
  • O-nucleophilic catalysts such as N-hydroxysuccinimide (NHS) or N-hydroxybenzotriazole. If the substituent is a carboxylic acid function, it can be used in a protected form (for example in the form of the benzyl ester), and the protective group can then be split off by hydrogenolysis.
  • activated esters are preferably generated intermediately, which are then attacked by a nucleophilic group of the biomolecule. This creates a covalent link between the biomolecule and the compound of formula I.
  • Preferred activated esters are the esters of N-hydroxysuccinimide, the esters of paranitrophenol or the esters of pentafluorophenol.
  • a terminal amine is preferably used first, which, if necessary, can be provided with a suitable protective group.
  • Suitable protective groups are known from peptide chemistry. After the protective group has been split off, the isothiocyanate can be produced by reacting the primary terminal amine with thiophosgene. Nucleophilic groups of the biomolecule can be added to this.
  • the functional group is a maleimide which e.g. can react selectively with thiol functions of the biomolecule.
  • the functional group is a nucleophile (NH 2 , SH), which attacks a suitable functionality of the biomolecule (activated ester, maleimide, etc.).
  • a nucleophile NH 2 , SH
  • suitable functionality of the biomolecule activated ester, maleimide, etc.
  • Numerous biomolecules functionalized with maleimides are commercially available.
  • the conjugates are usually synthesized in such a way that a derivatized and functionalized ligand or chelate complex is first generated, which is then linked to the biomolecule.
  • the ligand or chelate complex according to the invention is incorporated into the biomolecule during the synthesis thereof. This can be done, for example, during the sequential synthesis of oligopeptides on the synthesis robot.
  • the protective groups customary in the synthesis of the corresponding biomolecule can be added to the inventive groups Connection will be introduced. These are then split off again in the course of the usual synthesis algorithms on the synthesizer.
  • the compounds according to the invention contain at least three centers of chirality. Even if no distinction is made in the description and claims between the different enantiomers, the compounds mentioned always include both enantiomers and, in the presence of several stereocenters, also all possible diastereomers and mixtures thereof.
  • biomolecule is understood to mean any molecule that either naturally occurs in the body, for example, or that was produced synthetically with an analogous structure. In addition, these include. Understand molecules that can interact with a biological, for example occurring in the body or a structure occurring there, so that, for example, the conjugates accumulate at certain desired locations on the body.
  • body is understood to mean any plant or animal body, animal and in particular human bodies being preferred.
  • Biomolecules are, in particular, the molecules that occur in living beings, which, as products of an evolutionary selection through orderly and complex interaction, fulfill specific tasks for the organism and form the basis of its life functions (metabolism and shape, reproduction, energy balance). Larger molecules (proteins, nucleic acids, polysaccharides, lipids, etc.) are usually built up in biomolecules from simple building blocks (amino acids, nucleobases, monosaccharides, fatty acids, etc.). Corresponding macromolecules are also referred to as biopolymers.
  • the biomolecule can advantageously have, for example, a polypeptide skeleton of amino acids with side chains which can react with the reactive group of the compounds of the formula I '(see below).
  • side chains include, for example, the carboxyl groups of aspartic acid and glutamic acid residues, the amino groups of lysine residues, the aromatic groups of tyrosine and histidine residues and the sulphhydryl groups of cysteine residues.
  • biomolecules are particularly suitable for forming the conjugates according to the invention:
  • Biopolymers proteins, such as proteins that have a biological function, HSA, BSA, etc., proteins and peptides that accumulate at certain points in the organism (e.g. on receptors, cell membranes, channels etc.), peptides that can be cleaved by proteases, peptides with synthetic breaking points (e.g.
  • labile esters, amides etc. peptides that are cleaved by metal prostheses, peptides with photo-cleavable linkers, peptides with oxidative agents (oxidases) cleavable groups, peptides with natural and unnatural amino acids, glycoproteins (glycopeptides), signal Proteins, antiviral proteins and apoctosis, synthetically modified biopolymers, such as biopolymers derivatized with linkers, modified metalloproteases and derivatized oxidase etc., carbohydrates (mono- to polysaccharides), such as derivatized sugars, sugars that can be split in the body, cyclodextrins and their derivatives, amino sugars, chitosan , Polysulfates and acetylneuraminic acid derivatives, antibodies such as monoclonal e Antibodies, antibody fragments, polyclonal antibodies, minibodies, single chains (also those that are linked to link
  • RNA and DNA also with unnatural bases
  • PNAs Hoechst
  • antisense ß- Amino acids
  • Seebach vector amines for infiltration into the cell
  • biogenic amines pharmaceuticals
  • oncological preparations synthetic polymers that are aimed at a biological target
  • metal chelates can also be bound to a single biomolecule (if it has several reactive groups).
  • the compounds of the formula I are furthermore suitable for conjugation to all those molecules which are reacted with fluorescent dyes in the prior art, for example in order to determine their localization by epifluorescence microscopy within the cell.
  • the compounds can also be conjugated with any medication in order to then follow the transport within the organism by the NMR technique after administration of the medication.
  • the conjugates according to the invention from the compounds of the formula I and the biomolecules contain further additional molecules which have been conjugated to the biomolecules. So with the term "biomolecule" in the sense of the invention includes all molecules that occur in biological systems and all molecules that are biocompatible (see also above).
  • the relaxivity of the complexes according to the invention and in particular their conjugates with biomolecules is so high that if they contain a paramagnetic ion they are particularly suitable for NMR diagnostics.
  • the compounds according to the invention surprisingly bind to proteins. This property enables them to stay in the bloodstream for longer, bound to plasma proteins, and thus to enable a representation of the vasal space.
  • locations of increased permeability such as those found in tumors, are also possible.
  • This increased vascular permeability continues to form the basis of tumor therapy with radioactive metal complexes.
  • the drug leaves the vessel within the tumor, remains in the tissue and exposes it to its therapeutically effective radiation.
  • the plasma protein binding also enables imaging diagnostics for the localization of infarcts or necrosis as a result of the accumulation of the substances according to the invention in the infarction or necrosis.
  • the myocardial infarction does not immediately result in an irretrievably inoperable tissue, but initiates a dynamic process that extends over a longer period (weeks to months).
  • the disease runs in about three phases, which are not sharply separated, but overlapping.
  • the first phase the development of myocardial infarction, comprises the 24 hours after the infarction, in which the destruction progresses like a shock wave (wave front phenomenon) from the subendocardium to the myocardium.
  • the second phase the already existing infarction, involves the stabilization of the area in which fiber formation (fibrosis) takes place as a healing process.
  • the third phase the healed infarction, begins after all destroyed tissue has been replaced by fibrous scar tissue. Extensive restructuring is taking place during this period.
  • Infarctions occur not only in the myocardium, but also in other tissues such as the brain or kidney. While the infarction is curable to a certain extent, only the harmful consequences for the rest of the organism can be prevented or at least alleviated in the case of necrosis, the locally limited tissue death. Necrosis can arise in many ways: from injuries, chemicals, oxygen deficiency or from radiation. As with an infarction, knowledge of the extent and type of necrosis is important for the further medical procedure.
  • Z ' represents a carboxyl protecting group and R -R 6 have the meaning given for R 1 -R 6 , but the functional groups contained therein are free, ie are not bound to a biomolecule, if appropriate after splitting off the protecting groups Z with a biomolecule and then (after the protective groups Z 'have been split off) the acids thus obtained in a manner known per se with at least one metal oxide or metal salt of an element of the atomic numbers. 21-29, 31, 32, 37-39, 42-44, 46, 47, 49, 58-71, 75, 77, 82 or 83 and then, if desired, acidic hydrogen atoms present with inorganic and / or organic or Amino acids converted into physiologically acceptable salts.
  • Lower alkyl, aryl and aralkyl groups are suitable as carboxyl protective groups Z ' , for example the methyl, ethyl, propyl, butyl, phenyl, benzyl, diphenylmethyl, triphenylmethyl, bis (4-nitrophenyl) methyl group and trialkylsilyl.
  • the protective groups Z ' are split off in a manner known per se, for example by hydrolysis, alkaline saponification of the esters, preferably with alkali in aqueous / alcoholic solution at temperatures from 0 ° C. to 50 ° C.
  • the compound 1 By alkaline saponification and subsequent ion exchange treatment, the compound 1 can be converted into the compound I ' with free carboxylic acids.
  • Compound 1, in which the carboxylic acids are still present as esters, can be obtained by catalytic oxidation of the benzyl compound of formula 2.
  • the oxidation is carried out analogously to the specification by Ishibashi et al., Tetrahedron, (1996), 13867-13880 with sodium periodate using ruthenium chloride as a catalyst.
  • the N-benzyl compound 2 is accessible by reducing the amide 3 with borane-tetrahydrofuran complex. The conditions are followed, as described, for example, in J. Arner. Chem. Soc, (1990), 9608.
  • the amide 3 is prepared from the nitrophenylalanine derivative 4 by reaction with N-benzylpyrrolidine -2,5-dicarboxylic acid monoethyl ester 5.
  • the formation of amide 3 follows according to the methods well known to the person skilled in the art, for example acid activation by:
  • Acid 5 is readily obtainable from diethyl 2,5-dibromadipate and benzylamine with subsequent enantioselective enzymatic saponification according to literature instructions (Colombo et al., Gazz, Chim. Ital. 126.8, 1996, 543-554).
  • Compound 4 is obtained by splitting off the protective group from compound 6.
  • the N-methoxybenzyl group can be easily oxidatively split off with cerammonium nitrate (CAN) (Smith et al. Tetrahedron Lett. (1991), 4859).
  • the compound 6 is in turn by alkylation of the 4-methoxybenzyl-4-nitrophenylalanine 7 with the N, N-bis (t-butyloxycarbonylmethyl) -2-bromethylamine 8 available from Rappoport under conditions buffered with phosphate, as is also described by Rappoport in J. Org. Chem., 58, 1151 (1993).
  • N-alkylation described by Rappoport
  • methods of N-alkylation which are well known to the person skilled in the art can also be used, for example Houben-Weyl, Methods of Organic Chemistry XI / 2 nitrogen compounds, Georg Thieme Verlag, Stuttgart, 1957, p. 680; JE Rickman and TJJ Atkins, J. Am. Chem. Soc. 1974, 96, 2268.
  • the phenylalanine derivative 7 can be obtained by reductive amination of the 4-nitro-phenylalanine 9 with 4-nitrobenzaldehyde 10.
  • the reductive amination is carried out using sodium cyanoborohydride by the methods known to the person skilled in the art, for example as described in Eicher-Tietze, reactions and syntheses, Georg Thieme Verlag Stuttgart, 2nd edition 1991, p. 85.
  • connection 10 is available as a commodity from Bachern or Fluka.
  • the nitro group contained in compound 1 serves directly as a binding site for biomolecules, for example via amide formation with the aid of activated esters or reductive amination with carbonyl groups or after conversion into selectively reacting groups.
  • These conversion reactions are well known to those skilled in the art.
  • Gansow (EP 484984) and Meares (US 4622420) describe the preparation of haloacetamides from acyclic complexing agents which are used for coupling with -SH groups or -NH 2nd groups.
  • the isothiocyanato group enables selective coupling with amino groups.
  • Their preparation and the reaction with amines to give the corresponding thioureas has been described, for example, in US Pat. No. 4,680,338 by Immunomedics.
  • the reaction with hydrazides to the thiosemicarbazides is described in the application WO 95/15335 by Neorx Corp. described ..
  • the introduction of the desired metal ions from complexes for the production of NMR diagnostics can take place in the manner as 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, mitrate, 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 according to the invention 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 to obtain crystals that are easy to isolate and easy to clean.
  • 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.
  • the desired base already during the complex formation of the reaction mixture and thereby to save one process
  • the invention therefore also comprises a kit for the production of radiopharmaceuticals, comprising a compound of the formula I, in which Z represents a radioisotope.
  • the invention further relates to pharmaceutical compositions which contain at least one physiologically tolerable compound of the general formula I, optionally with the additives customary in galenics.
  • 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 optionally sterilizing the suspension or solution.
  • suitable additives are, for example, physiologically harmless buffers (such as tromethamine), additives 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 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 mixed with one or more auxiliary agents (eg methyl cellulose, lactose, mannitol) and / or surfactant (s) used in galenics. [eg lecithins, Tween ® , Myrj ® ] and / or flavoring (s) for flavor correction [eg essential oils] mixed.
  • auxiliary agents eg methyl cellulose, lactose, mannitol
  • surfactant eg lecithins, Tween ® , Myrj ®
  • flavoring (s) for flavor correction eg 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.
  • compositions according to the invention preferably contain 1 mol-1.3 mol / l of the complex salt and are generally dosed in amounts of 0.0001-5 mmol / kg. They are intended for enteral and parenteral administration.
  • the complex compounds according to the invention are used
  • 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 Because of their strong magnetic moment, gadolinium (III) -, terbium (III) -, dysprosium (III) -, holmium (III) -, erbium (III) -, manganese (II) - and are particularly preferred for NMR diagnosis iron (III) ion.
  • the agents according to the invention fulfill the diverse requirements for their suitability as contrast agents for magnetic resonance imaging. After oral 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 Compatibility, which 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 of the circulatory system can be kept within reasonable limits and to compensate for the dilution with the body fluid, i.e. NMR diagnostics must be 100 to 1000 times more water soluble than for them NMR spectroscopy.
  • 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 again, takes place only extremely slowly.
  • the agents according to the invention for use as NMR diagnostics 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., Am. J. of Roentgenology 142, 619 (1984).
  • Low doses (below 1 mg / kg body weight) of organ-specific NMR diagnostics can be used, for example, to detect tumors and heart attacks.
  • Particularly low doses of the complexes according to the invention are suitable for use in radiotherapy and radio diagnostics.
  • Doses of 0.5 pM / kg - 5 ⁇ M / kg, preferably 50 pM / kg - 500 nmol / kg, are used for both therapeutic and diagnostic purposes.
  • About 100-100,000 times lower molar concentrations are usually used with regard to the radioactive metal ion than is the case for the chelators or chelator bioconjugates, so that the chelators or chelator bioconjugates are therefore present in excess.
  • the complex compounds according to the invention can advantageously be used as susceptibility reagents and as s ⁇ reagents for in v / Vo NMR spectroscopy. Because of their favorable radioactive properties and the good stability of the complex compounds they contain, the agents according to the invention are also suitable as radio-diagnostic and radiotherapeutic agents. Details of their use and dosage are described, for example, in "Radiotracers for Medical Applications", CRC-Press, Boca Raton, Florida, 1983, and in Eur. J. Nucl. Med. 17 (1990) 346-364 and Chem. Rev. 93 (1993) 1137-1156.
  • the complexes with the isotopes 111 ln and 99m Tc are suitable for SPECT.
  • positron emission tomography which uses positron-emitting isotopes such as 43 Sc, 44 Sc, 52 Fe, 55 Co, 68 Ga, 64 Cu, 86 Y and 94 Tc (Heiss, WD; Phelps, ME; Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).
  • the compounds according to the invention are surprisingly also suitable for differentiating malignant and benign tumors in areas without a blood-brain barrier.
  • the substances according to the invention accumulate in malignant tumors (no diffusion into healthy tissue, but high permeability of tumor vessels), they can also support the radiation therapy of malignant tumors. This differs from the corresponding diagnostics only in the amount and type of isotope used.
  • the aim is to destroy tumor cells by high-energy short-wave radiation with the shortest possible range. Interactions of the metals contained in the complexes (such as iron or gadolinium) with ionizing radiation (eg X-rays) or with neutron beams are used for this purpose. This effect significantly increases the local radiation dose where the metal complex is located (e.g. in tumors).
  • the metal complex conjugates according to the invention are therefore also suitable as Radiosensitizing substance in the radiation therapy of malignant tumors (eg taking advantage of Mössbauer effects or in neutron capture therapy).
  • Suitable ⁇ -emitting ions are, for example, 46 Sc, 47 Sc, 48 Sc, 72 Ga, 73 Ga, 90 Y, 67 Cu, 109 Pd, 111 Ag, 149 Pm, 153 Sm, 166 Ho, 177 Lu, 186 Re and 188 Re, with 90 Y, 177 Lu, 72 Ga, 153 Sm and 67 Cu being preferred.
  • Suitable D-emitting ions which have short half-lives are, for example, 211 At, 211 Bi, 212 Bi, 213 , Bi and 214 Bi, 212 Bi being preferred.
  • a suitable photon and electron-emitting ion is 58 Gd, which can be obtained from 157 Gd by neutron capture.
  • the central ion must be derived from a Mössbauer isotope such as 57 Fe or 151 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 together with another protein such as e.g. Human serum albumin can be administered.
  • a suitable carrier such as e.g. Serum or physiological saline
  • another protein such as e.g. Human serum albumin
  • the dosage depends on the type of cellular disorder, the metal ion used and the type of imaging method.
  • the therapeutic agents according to the invention are preferably administered parenterally, preferably IV.
  • radiotherapeutics are e.g. in R. W. Kozak et al. TIBTEC, October 1986, 262 (see also Bioconjugate Chem. 12 (2001) 7-34).
  • AAV stands for general working procedure
  • RP-18 denotes a “reversed phase” stationary chromatography phase.
  • the number of complexes per biomolecule was determined using scintigraphy or ICP (inductively coupled plasma atomic emission spectroscopy).
  • the batch solution is filtered, the filtrate is ultrafiltered on an AMICON ® YM30 (cut off 30,000 Da), the retentate is chromatographed on a Sephadex ® G50 column and the product fractions are freeze-dried.
  • Washed sodium chloride solution dried with magnesium sulfate and concentrated.
  • the aqueous phase was extracted four times with 100 ml of diethyl ether each time.
  • the combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated.
  • the crude product was purified by column chromatography (Si0 2 , hexane-ethyl acetate (5: 1)).
  • the desired product 8e was obtained in 69.7% yield (6.18 g; 9.97 mmol).
  • the aqueous phase was extracted four times with 100 ml dichloromethane each time.
  • the combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated.
  • the crude product was purified by column chromatography (Si0 2 , hexane-ethyl acetate (2: 1)).
  • the intermediate was dissolved in 200 ml of dichloromethane and 73 g (279 mmol) of triphenylphosphine and 93 g (279 mmol) of tetrabromomethane in 100 ml of dichloromethane were added at 0 ° C.
  • the solution was Stirred overnight and poured onto 400 ml of stirred ice water.
  • the organic phase was separated.
  • the aqueous phase was extracted four times with 100 ml of diethyl ether each time.
  • the combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated.
  • the crude product was taken up in 400 ml of hexane and stirred at 0 ° C. overnight.
  • the suspension was filtered.
  • the filtrate was concentrated and purified by column chromatography (Si0 2 , hexane-ethyl acetate (5: 1)).
  • Acidic ion exchanger IRA 120 was added until the pH was 3. The ion exchanger was separated by filtration. Dioxane was removed on a rotary evaporator, the aqueous solution was diluted with water and freeze-dried. The residue was taken up in 80 ml of dichloromethane and 30 g (263 mmol) of trifluoroacetic acid were added dropwise. The solution was stirred for 30 minutes at room temperature. The solution was concentrated on a rotary evaporator. Soaked in distilled water and freeze-dried. The residue was taken up in water again and freeze-dried again. The desired product 8g resulted in a yield of 67.9% (2.37 g; 4.56 mmol). MS-FAB (M + +1, 21): 519
  • the residue was taken up in 50 ml of dichloromethane, cooled to -5 ° C. and mixed with 50 ml of trifluoroacetic acid. The solution was warmed to room temperature and stirred for 2 hours. The reaction solution was quickly concentrated on a rotary evaporator. The residue was concentrated using an oil pump vacuum and taken up in 40 ml of dioxane. 50 ml of distilled water and 15 ml (30 mmol) of a 2N sodium hydroxide solution were added. The solution was stirred at 40 ° C for 2 hours. The solution was cooled. Acidic ion exchanger IRA 120 was added until the pH was 3. The ion exchanger was filtered off.
  • the antibody has 200 ⁇ g of an antibody with freely accessible thiol groups (for example HuM195 (cf. Michael R. McDevitt, J. Nuc. Med.
  • the antibody has 200 ⁇ g of an antibody with freely accessible thiol groups (for example HuM195 (cf. Michael R. McDevitt, J. Nuc. Med. 40, 1999, 1722; commercially available from Protein Design Labs Inc., Mountainview, CA, USA) no freely accessible thiol groups, these can be generated by using 2-lminothiolan HCI (e.g. EP 0 607 222 B1)) were diluted in 1.2 ml borate buffer (50 miVi, pH 8.5) with 154 ⁇ g (240 nmol ) Product from Example 11, dissolved in 50 ⁇ l borate buffer (see above), added and stirred at 37 ° C. for 3 hours.
  • freely accessible thiol groups for example HuM195 (cf. Michael R. McDevitt, J. Nuc. Med. 40, 1999, 1722; commercially available from Protein Design Labs Inc., Mountainview, CA, USA
  • 2-lminothiolan HCI e.g. EP 0 607 222
  • the borate buffer solution was exchanged for an acetate buffer by placing the sample solution three times for 1 hour in Slide-A-Lyzer 10000, Pierce MWCO (dialysis method) against 200 ml of NaOAc buffer 0.1 M (pH 6.0) , Finally, it was placed overnight against 400 ml of NaOAc buffer 0.1M (pH 6).
  • the solution was mixed with 80 ⁇ l (0.05M HCl) [ 11 In ] InCl 3 (27.88 MBq) and stirred for 30 min at room temperature. It was purified on a NAP-5 column (Amersham Pharmacia Biotech AB, Sephadex G-25, Mobile Phase: PBS).
  • Example 22 (1 ' R, 2R, 5S) -5 - ⁇ [ ⁇ 2 - [(5-amino-1-carboxy-pentyl) - (ethoxy-hydroxy-phosphorylmethyl) - amino] -ethyl ⁇ - (ethoxy-hydroxy-phosphorylmethyl ) -amino] -methyi ⁇ -1-carboxymethyl-pyrrolidine-2-carboxylic acid
  • a mixture of about 1 g of dried silica gel, 100 mg (1.0 mmol) of maleic anhydride, 550 mg (1.0 mmol) of 2 g and 35.6 mg (0.1 mmol) of tantalum (V) chloride were in the Microwave (300W) heated for 5 min.
  • the residue was eluted with methanol over a frit.
  • the filtrate was concentrated.
  • the residue was taken up in water.
  • the solution was freeze-dried. Part of the residue was purified by semipreparative RP-HPLC. Acetonitrile-water mixture (20:80).
  • the aqueous phase was extracted four times with 150 ml of dichloromethane each time.
  • the combined organic phases were washed with saturated aqueous sodium chloride solution, dried with magnesium sulfate and concentrated.
  • the crude product was purified by column chromatography (Si0 2 , hexane-ethyl acetate (4: 1)).
  • the desired product 25a was obtained in 68% yield (8.37 g, 11.3 mmol).
  • an antibody with freely accessible thiol groups for example HuM195 (cf. Michael R. McDevitt, J. Nuc. Med. 40, 1999, 1722; commercially available from Protein Design Labs Inc, Mountainview, CA, USA) - if the antibody does not have any freely accessible thiol groups, these can be generated by using 2-lminothiolan HCl (e.g. EP 0 607 222 B1)) were placed in 1.2 ml borate buffer (50 mM, pH 8.5), diluted with 154 ⁇ g (240 nmol) product from Example 11, dissolved in 50 ⁇ l borate buffer (see above), and stirred at 37 ° C. for 3 hours.
  • 2-lminothiolan HCl e.g. EP 0 607 222 B1
  • the borate buffer solution was exchanged for an acetate buffer by dissolving the sample solution three times for 1 h in Slide-A-Lyzer 10000, Pierce, MWCO (dialysis method) against 200 ml of NaOAc buffer 0.1 M (pH 6.0). was asked. Finally, 0.1M (pH 6) was placed against 400 ml of NaOAc buffer overnight. The solution was mixed with 50 MBq [ 90 Y] YCI 3 and stirred for 30 min at room temperature. It was purified on a NAP-5 column (Amersham Pharmacia Biotech AB, Sephadex G-25, Mobile Phase: PBS).
  • the antibody has 200 ⁇ g of an antibody with freely accessible thiol groups (for example HuM195 (cf. Michael R. McDevitt, J. Nuc. Med. 40, 1999, 1722; commercially available from Protein Design Labs Inc., Mountainview, CA, USA) no freely accessible thiol groups, these can be generated by using 2-lminothiolan HCI (e.g. EP 0 607 222 B1)) were diluted in 1.2 ml borate buffer (50 mM, pH 8.5) with 154 ⁇ g (240 nmol ) Product from Example 11, dissolved in 50 ⁇ l borate buffer (see above), added and stirred at 37 ° C. for 3 hours.
  • freely accessible thiol groups for example HuM195 (cf. Michael R. McDevitt, J. Nuc. Med. 40, 1999, 1722; commercially available from Protein Design Labs Inc., Mountainview, CA, USA
  • 2-lminothiolan HCI e.g. EP 0 607 222
  • the borate buffer solution was exchanged for an acetate buffer by placing the sample solution three times for 1 hour in Slide-A-Lyzer 10000, Pierce, MWCO (dialysis method) against 200 ml of NaOAc buffer 0.1 M (pH 6.0) has been. Finally, 0.1M (pH 6) was placed against 400 ml of NaOAc buffer overnight. The solution was mixed with [ 46 Sc] ScCI 3 [ 47 Sc] ScCI 3 or [ 48 Sc] ScCI 3 and stirred for 30 min at room temperature. It was purified on a NAP-5 column (Amersham Pharmacia Biotech AB, Sephadex G-25, Mobile Phase: PBS).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Radiology & Medical Imaging (AREA)
  • Immunology (AREA)
  • Optics & Photonics (AREA)
  • Physics & Mathematics (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Conjugués de dérivés 3,6,9-acide triaza-nonanique-N,N,N-acide tétraacétique à pontage 2,4-éthano et 2,4-propano et de dérivés correspondants ester d'acide phosphorique-méthylène de formule (I), les substituants étant tels que définis dans la revendication 1. La présente invention concerne également des dérivés de ces conjugués avec des biomolécules, des procédés de production desdits conjugués et leur utilisation en tant qu'agents de contraste de diagnostic de RMN et de radiodiagnostic, ainsi que pour la radiothérapie.
PCT/EP2004/003003 2003-04-03 2004-03-20 Conjugues de derives de 3,6,9-acide triaza - nonanique-3n, 6n,9,9n-acide tetraacetique a pontage 2,4-ethano et 2,4-propano et de derives correspondants d'acide phosphorique-methylene, et leurs derives avec des biomolecules, procedes de production desdits conjugues et leur utilisation pour la WO2004087656A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE10316824 2003-04-03
DE10316824.9 2003-04-03

Publications (1)

Publication Number Publication Date
WO2004087656A1 true WO2004087656A1 (fr) 2004-10-14

Family

ID=33103344

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2004/003003 WO2004087656A1 (fr) 2003-04-03 2004-03-20 Conjugues de derives de 3,6,9-acide triaza - nonanique-3n, 6n,9,9n-acide tetraacetique a pontage 2,4-ethano et 2,4-propano et de derives correspondants d'acide phosphorique-methylene, et leurs derives avec des biomolecules, procedes de production desdits conjugues et leur utilisation pour la

Country Status (1)

Country Link
WO (1) WO2004087656A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006069678A1 (fr) * 2004-12-23 2006-07-06 Schering Ag Conjugues de complexes metalliques de derives d'hydroxypyridinone et de biomolecules et leur utilisation pour la production d'agents servant au diagnostic par irm
WO2006082088A1 (fr) * 2005-02-07 2006-08-10 Glaxo Group Limited Composes tensioactifs jumeaux a liaison ester pour la therapie genique
US8268810B2 (en) 2005-03-24 2012-09-18 Guerbet Lipophilic chelates and their use in imaging

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHONG ET AL., J. ORG. CHEM., vol. 66, 2001, pages 7745 - 7750, XP002285311 *
PICKERSGILL ET AL, J. ORG. CHEM., vol. 65, 2000, pages 4048 - 4057, XP002285310 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006069678A1 (fr) * 2004-12-23 2006-07-06 Schering Ag Conjugues de complexes metalliques de derives d'hydroxypyridinone et de biomolecules et leur utilisation pour la production d'agents servant au diagnostic par irm
WO2006082088A1 (fr) * 2005-02-07 2006-08-10 Glaxo Group Limited Composes tensioactifs jumeaux a liaison ester pour la therapie genique
US7425645B2 (en) 2005-02-07 2008-09-16 Glaxo Group Limited Ester-linked gemini surfactant compounds for use in gene therapy
JP2009525259A (ja) * 2005-02-07 2009-07-09 グラクソ グループ リミテッド 遺伝子治療用のエステル結合したジェミニ界面活性剤化合物
US7569720B2 (en) 2005-02-07 2009-08-04 Glaxo Group Limited Compounds
US8268810B2 (en) 2005-03-24 2012-09-18 Guerbet Lipophilic chelates and their use in imaging

Similar Documents

Publication Publication Date Title
DE10135355C1 (de) Konjugate makrocyclischer Metallkomplexe mit Biomolekülen und deren Verwendung zur Herstellung von Mitteln für die NMR- und Radiodiagnostik sowie die Radiotherapie
DE10135356C1 (de) Makrocyclische Metallkomplexe und deren Verwendung zur Herstellung von Konjugaten mit Biomolekülen
EP0255471B1 (fr) Derivés de tétra-azo-1,4,7,10 cyclododécane
DE69317771T2 (de) Carboxamid-modifizierte polyamin-chelatoren, radioaktive komplexe und konjugate
EP0836485B1 (fr) Complexes polymeres en cascade, leur procede de production et produits pharmaceutiques les contenant
EP0355041B1 (fr) Composés complexes de porphyrine substituée en 13,17 par l'acide propionique et les dérivés d'acide propionique, procédé pour leur préparation et compositions pharmaceutiques les contenant
EP0305320B1 (fr) Complexants à multinoyaux substitués, complexes et sels complexes, procédé pour leur préparation et expédients pharmaceutiques qui les contiennent
EP0438206B1 (fr) Composés tétraaza-macrocycliques contenant un noyau à six membres, procédés pour leur préparation et agents pharmaceutiques les contenant
EP0352218B1 (fr) Composés polyaza macrocycliques, leur procédé de préparation et compositions pharmaceutiques les contenant
DE3713842A1 (de) Substituierte cyclische komplexbildner, komplexe und komplexsalze, verfahren zu deren herstellung und diese enthaltende pharmazeutische mittel
DE19744003B4 (de) Kontrastmittel für das Infarkt- und Nekroseimaging
DE3710730A1 (de) Substituierte komplexbildner, komplexe und komplexsalze, verfahren zu deren herstellung und diese enthaltende pharmazeutische mittel
EP1590317B1 (fr) Acides (4s,8s)-4-p-nitrobenzyl-8-methyl-3,6,9-triaza- sp 3 /sp n, sp 6 /sp n, sp 9 /sp n-tricarboxymethyl-1,11-undecanoique et (4r,8r)-4-p-nitrobenzyl-8-methyl-3,6,9-triaza- sp 3 /sp n, sp 6 /sp n, sp 9 /sp n-tricarboxymethyl-1,11-undecanoique enantiomeriquement purs et derives de ceux-ci, procedes
WO2004087656A1 (fr) Conjugues de derives de 3,6,9-acide triaza - nonanique-3n, 6n,9,9n-acide tetraacetique a pontage 2,4-ethano et 2,4-propano et de derives correspondants d'acide phosphorique-methylene, et leurs derives avec des biomolecules, procedes de production desdits conjugues et leur utilisation pour la
DE102006049821A1 (de) Metallchelate mit perfluoriertem PEG-Rest, Verfahren zu deren Herstellung, sowie deren Verwendung
EP1590005B1 (fr) CONJUGUES D'ACIDES (4S,8S)-4-P-BENZYL-8-METHYL-3,6,9-TRIAZA- SP 3 /SP N, SP 6 /SP N, SP 9 /SP N-TRICARBOXYMETHYL-1,11-UNDECANOIQUE ET (4R,8R)-4-P-BENZYL-8-METHYL-3,6,9-TRIAZA- SP 3 /SP N, SP 6 /SP N, SP 9 /SP N-TRICARBOXYMETHYL-1,11-UNDECANOIQUE ENANTIOMERIQUEMENT PURS AVEC DES BIOMOLECULES, leur PROCEDE de préparation et leur utilisation pour la préparation d'agents pharmaceutiques
US20120064002A1 (en) Enantiomer-pure (4S,8S)- and (4R,8R)-4-p-Nitrobenzyl-8-methyl-3,6,9-triaza-3N,6N,9N-tricarboxymethyl-1,11-undecanedioic Acid and Derivatives Thereof, Process for their Production and Use for the Production of Pharmaceutical Agents
DE10133435A1 (de) (Ethylen)-(Propylen)-Triaminpentaessigsäure-Derivate, Verfahren zu deren Herstellung und deren Verwendung zur Herstellung pharmazeutischer Mittel
WO2003029257A1 (fr) Dérivés d'acide (éthylène)-(propylène/butylène)-phosphodiester-triamine-penta-acétique

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BW BY BZ CA CH CN CO CR CU CZ DK DM DZ EC EE EG ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NA NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase