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WO1995020580A1 - Macrocycles octa-aza, leurs complexes metalliques et leur utilisation en diagnostic et en therapie - Google Patents

Macrocycles octa-aza, leurs complexes metalliques et leur utilisation en diagnostic et en therapie Download PDF

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Publication number
WO1995020580A1
WO1995020580A1 PCT/EP1995/000124 EP9500124W WO9520580A1 WO 1995020580 A1 WO1995020580 A1 WO 1995020580A1 EP 9500124 W EP9500124 W EP 9500124W WO 9520580 A1 WO9520580 A1 WO 9520580A1
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Prior art keywords
complex
metal
acid
ion
mmol
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PCT/EP1995/000124
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German (de)
English (en)
Inventor
Herbert Schumann
Ulrike BÖTTGER
Heinz Gries
Johannes Platzek
Bernd Radüchel
Original Assignee
Schering Aktiengesellschaft
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Publication of WO1995020580A1 publication Critical patent/WO1995020580A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/002—Heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D259/00—Heterocyclic compounds containing rings having more than four nitrogen atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6524—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having four or more nitrogen atoms as the only ring hetero atoms

Definitions

  • the invention relates to the subject matter characterized in the claims, that is to say new octaaza macrocycles, their metal complexes, agents containing these complexes and the use of these in diagnostics and therapy.
  • the invention further relates to a process for the preparation of the octaaza macrocycles and their complexes.
  • Gd-DOTA 1,4,7,10-tetraazacyclododecanetetraacetic acid
  • the object is achieved by the present invention.
  • R 1 , R 2 , R 3 , R 4 independently of one another for a hydrogen atom, a straight-chain or branched CJ-CJQ alkyl or aralkyl radical which is optionally substituted by an amino group and / or 1 to 5 hydroxyl groups and / or by an oxygen atom or an imino group is interrupted or represents a C0-C 1-4 aryl or aralkyl radical, the aryl radical of which is optionally substituted by 1 to 3 halogen atoms or an isothiocyanate group, and
  • X independently of one another for a group -COOH, -COOM, -PO 3 H 2 , -PO 3 HM, - PO 3 M 2 , -PO 2 HR 8 , or -PO 2 MR 8 , where R 8 is a C r C 10 Means alkyl or aralkyl chain and M stands for a metal ion equivalent or a metal ion equivalent bridged via an oxygen atom of an ion of an element of atomic numbers 21-32, 37-39, 42-51 or 56-83,
  • A, D and W independently represent a radical of formula II
  • R 5 , R 6 , R 7 independently of one another have the meaning given for R 1 , and free carboxylic acid groups, if desired, are present as the salt of an inorganic or organic base or amino acid, surprisingly outstanding in diagnostics and therapy, particularly in NMR and X-ray diagnostics.
  • radicals R 1 , R 2 , R 3 , R 4 include a hydrogen atom, a methyl, ethyl, propyl, benzyl, methoxy, ethoxy, hydroxymethyl, hydroxyethyl or a dihydroxypropyl group.
  • R 1 , R 2 , R 3 , R 4 have the same meaning are preferred, including in particular compounds with R 1 , R 2 , R 3 , R 4 in the meaning of hydrogen.
  • radical R 8 which may be mentioned is a hydrogen atom, a methyl, ethyl, propyl or benzyl group
  • radicals A, D and W of the formula I advantageously represent a C2-C4 alkylene group, in particular an ethylene and / or a propylene group, ie radicals of the formula II in which R 5 , R 6 , R 7 are a hydrogen atom are preferred and where the sum of n and m is one or two.
  • radicals A and W or A, W and D preferably have identical meanings.
  • a 1,4,7,10,13, 16,19,22-octaazacyclotetracosane or a 1,4,7,10,14,17,20,23-octaazacyclohexacosan ring system are particularly preferred.
  • the radicals X are preferably a group —COOH and / or —COOM, with M meaning a metal ion equivalent.
  • the radicals X can be selected independently of one another, but preference is given to compounds which contain at least one, but preferably two, metal ion (s) of an element of atomic numbers 21-32, 37-39, 42-51 or 56-83. The choice of the suitable metal ion (s) depends on the respective area of application.
  • An oxygen-bridged metal ion is understood to mean a group M-O-M [hereinafter also referred to as M2 ( ⁇ -O)]. These metal atoms are bonded to the carboxylic acid groups of the complexing agent in the complexes according to the invention, but a charge of each metal ion is compensated for by the bridging oxygen atom, so that a metal ion in oxidation state 3+ only requires two carboxylic acid groups to bind to the complexing agent.
  • the compounds of general formula I are prepared in a manner known per se according to the method described by JE Richmann et al. in J. Am. Chem.Soc. 96 (1974) 2268, described method by using a tosylate of the formula V _3
  • Ts means a leaving group, e.g. a tosyl group, first reacted with two equivalents of a compound Hal-D-U, in which D has the meaning given, shark for a halogen atom preferably for a bromine atom and U for a protected oxygen atom, e.g. stands for a THP ether.
  • the oxygen protecting groups are split off in a manner known per se and e.g. with mesyl chloride to give compounds of the formula VI,
  • the compounds of the general formula V with W and A in the same meaning are easily accessible from the corresponding trialkylenetetramines by first e.g. is reacted with tosyl chloride and then the remaining acidic hydrogen atoms of the terminal amino groups with an alcoholate such as e.g. Be metallated.
  • Amines with A and W in different meanings are generally not commercially available, but can easily be obtained by first tosylating an appropriate alkylenediamine, metalating as described and then using a nitrile of the formula VIII, e.g. Bromoacetonitrile,
  • Tb Tb (IX) Tb Tb (IX).
  • the compounds of the formula IX can then be prepared in a manner known per se [see J.-M. Lehn et al., Helv. Chim. Acta 66 (1983) 1262], for example with diborane, to the desired amines.
  • the complexing agents according to the invention can be used in the form of their mono- or multinuclear, preferably their binuclear, complexes with metal ions of atomic numbers 21-32, 37-39, 42-51 and 56-83 for diagnostic and radiotherapeutic purposes.
  • the metal complexes according to the invention are prepared as in DE
  • 34 01 052 discloses by using the metal oxide or a metal salt (for example the nitrate, acetate, carbonate, chloride or sulfate) of the element of atomic numbers 21-32, 37, 42-51, 56-83 in water and / or a lower alcohol (such as methanol, ethanol or isopropanol) dissolved or suspended and reacted with the solution or suspension of the equivalent amount of the complexing ligand and then, if desired, substituted acidic hydrogen atoms present 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, ethanol or isopropanol
  • a process for the preparation of dinuclear complexes in which the metal ions, in particular metal ions of the rare earths, are present in a form bridged by an oxygen atom is that the complexing agents of the formula I with X meaning a -COOH group in a ligand exchange reaction implemented according to the following equation:
  • Cp is a cyclopentadienyl anion C5H5 "or a cyclopentadienyl derivative such as C5 (CH 3 ) 5" and HgL is a complexing agent of the general formula I with X in the meaning of -COOH.
  • any free acid groups still present are neutralized with the aid of inorganic bases (for example hydroxides, carbonates or bicarbonates) of, for example, sodium, potassium, lithium, magnesium or calcium and / or organic bases, such as primary, secondary and tertiary amines. such as, for example, ethanolamine, morpholine, glucamine, N-methyl and N, N-dimethylglucamine, and also basic amino acids, such as, for example, lysine, arginine and oraithine or of amides of originally neutral or acidic amino acids.
  • 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. It is often advantageous to neutralize the formed salts by adding 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) fail and so easy to isolate and easy to clean crystals. It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and thereby to save one process step.
  • 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) fail and so easy to isolate and easy to clean crystals. It has proven to be particularly advantageous to add the desired base already during the complex formation of the reaction mixture and
  • 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.
  • neutral complex compounds Another possibility of obtaining neutral complex compounds is to convert all or part of the remaining acid groups in the complex into, for example, esters or amides. This can be done by subsequent reaction on the finished complex (e.g. by exhaustive reaction of the free carboxy groups with dimethyl sulfate).
  • compositions according to the invention are likewise prepared in a manner known per se by suspending or dissolving the complex compounds according to the invention - optionally with the addition of the additives customary in galenics - in an aqueous medium and then, if appropriate, sterilizing the suspension or solution.
  • suitable additives are, for example, physiologically acceptable buffers (such as tromethamine).
  • Additions of complexing agents such as
  • Diethylenetriaminepentaacetic acid or - if necessary - electrolytes such as sodium chloride or - if necessary - antioxidants such as Ascorbic acid or, especially for oral dosage forms, mannitol or other saccharides.
  • the dosage forms can contain calcium, magnesium or zinc salts of the complexing agents in an amount of 0.05 to 2 mol / 1.
  • 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 adjuvant (s) common in galenics (for example methyl cellulose, lactose, mannitol) and / or surfactant (s ) (for example lecithins, Tween ® Myrj ® and / or flavoring (s) for flavor correction (for example essential oils) mixed.
  • adjuvant common in galenics
  • s for example methyl cellulose, lactose, mannitol
  • surfactant for example lecithins, Tween ® Myrj ®
  • flavor correction for example essential oils
  • the invention therefore also relates to processes for the preparation of the complex compounds and their salts.
  • the final security is cleaning the isolated complex salt.
  • compositions according to the invention preferably contain 0.1 ⁇ mol - 1 mol / 1 of the complex salt and are generally dosed in amounts of 0.1 ⁇ mol / kg. They are intended for enteral and parenteral administration.
  • the complex compounds according to the invention are used:
  • the agents according to the invention meet the diverse requirements for their suitability as contrast agents for magnetic resonance imaging. So they are excellent for after oral or parenteral application by increasing the signal intensity to improve the meaningfulness of the image obtained with the aid of an MRI scanner. They also show the high effectiveness that is necessary to burden the body with the smallest possible amount of foreign substances and the good tolerance that is necessary to maintain the non-invasive character of the examinations.
  • the good water solubility and low osmolality of the agents according to the invention make it possible to produce highly concentrated solutions, so that the volume load of the circuit can be kept within reasonable limits and the dilution by the agents according to the invention
  • the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that the release or exchange of the ions which are not covalently bound in the complexes - in themselves toxic - within the time which the new contrast agents are completely excreted again, is extremely slow.
  • the agents according to the invention for use as NMR diagnostics are dosed in amounts of 0.0001-5 mmol / kg body weight of the complex according to the invention.
  • aqueous formulations with a concentration of 50 ⁇ mol / 1, preferably 100 mmol / 1 to 1 mol / 1, are used.
  • Rectal and oral use is preferably carried out with solutions with a concentration of 0.1 mmol to 100 mmol / 1 or as a solid in the corresponding concentration range.
  • the applied volumes are - depending on the diagnostic question - between 5 ml and 2 1. Details of the application are, for example, in H.J. Weinmann et al., Am. J. of Roentgenology 142, 619 (1984).
  • organ-specific NMR diagnostics can be used, for example, to detect tumors and heart attacks.
  • the complex compounds according to the invention can advantageously be used as susceptibility reagents and as shift reagents for in vivo NMR spectroscopy.
  • the agents according to the invention with radioisotopes of the elements of atomic numbers 21-32, 37-39, 42-51 and 56-83 are also due to their favorable radioactive properties and the good stability of the complex compounds contained in them Suitable for radio diagnostics. Details of their use and dosage are given, for example, in "Radiotracers for Medical Applications”. CRC-Ress, Boca Raton, Florida.
  • positron emission tomography which uses positron-emitting isotopes such as 3 Sc, ⁇ Sc, 52 Fe, 55 Co and 68 Ga (Heiss, WD; Phelps, ME; Positron Emission Tomography of Brain, Springer Verlag Berlin, Heidelberg, New York 1983).
  • the compounds according to the invention can also be used in radioimmunotherapy or radiation therapy. This differs from the corresponding diagnostics only in the amount and type of isotope used.
  • the goal is the destruction of tumor cells by high-energy short-wave radiation with the shortest possible range.
  • Suitable ⁇ -emitting ions are, for example, 46 Sc, 47 Sc, ⁇ Sc, 72 Ga, 73 Ga and 90 Y.
  • Suitable ⁇ -emitting ions with short half-lives are, for example, 211 Bi, 212 Bi, 213 Bi and 214 Bi, whereby 212 Bi is preferred.
  • a suitable photon and electron emitting ion is 158 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 fluorescence properties especially of the europium and terbium complexes, can be used for near-infrared imaging.
  • the therapeutic agents according to the invention When the therapeutic agents according to the invention are applied in vivo, they can be administered together with a suitable carrier such as serum or physiological saline and / or together with another protein such as human serum albumin.
  • a suitable carrier such as serum or physiological saline and / or together with another protein such as human serum albumin.
  • the dosage depends on the type of cellular disorder, the metal ion used and the type of method, e.g. Brachytherapy.
  • the therapeutic agents according to the invention are administered parenterally, preferably i.v. applied.
  • radiotherapeutics are described, for example, in RW Kozak et al. TIBTEC, October 1986, 262.
  • the agents according to the invention are also outstandingly suitable as X-ray contrast agents, and it should be emphasized in particular that they show no signs of the anaphylaxis-like reactions known from the iodine-containing contrast agents in biochemical-pharmacological studies. They are particularly valuable for digital subtraction techniques due to their favorable absorption properties in areas with higher tube voltages.
  • the agents according to the invention for use as X-ray contrast agents are dosed in analogy to, for example, meglumine diatrizoate in amounts of 0.1-5 mmol / kg, preferably 0.25-1 mmol / kg.
  • 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 relaxivity in the complexes according to the invention is synergistically enhanced by the incorporation of two paramagnetic metal ions, so that complexes with excellent imaging properties are obtained.
  • the agents according to the invention not only have a high stability in vitro, but also a surprisingly high stability in vivo, so that the ions bound in the complexes are released or exchanged within the time in which the new contrast agents are completely excreted again , not happened.
  • the redox potentials measured for the europium complex (produced according to Example lg) - which can be regarded as a relative measure of the complex stability - have comparable values for both metal ions in the complex.
  • reaction solution is allowed to warm to room temperature and stirred for 35 minutes. 6.6 g (62.35 mmol) of anhydrous sodium carbonate are dissolved in 62 ml of distilled water and added to the reaction solution within 8 minutes. A flaky, white precipitate falls out. The mixture is stirred for 35 minutes, then 30 ml of toluene are added and the mixture is stirred for a further 3.5 hours. After adding a further 50 ml of toluene, the reaction mixture is transferred to a shaking funnel, the phases are separated and the yellowish-colored toluene phase is concentrated. A yellowish solid is obtained as the crude product (75% yield).
  • OTEC 4,7,10,13,16,19,22-octaazacyclotetracosane-N, N ', N ", N'", N "", N '"" - octaacetic acid
  • gadolinium (III) oxide 224.7 mg (0.62 mmol) of gadolinium (III) oxide are added to 0.5 g (0.62 mmol) of the title compound from lb) dissolved in 30 ml of deionized water.
  • the suspension is heated to 80 ° C. under reflux with stirring. After two hours, the clear, yellowish solution is allowed to cool, if necessary, undissolved gadolinium oxide is filtered off and the solvent is removed on a rotary evaporator or vacuum. A yellowish solid which contains 2.9% of water is obtained in quantitative yield.
  • the suspension is heated under reflux with stirring. After about 2 hours a clear solution is obtained, after a further two hours the product precipitates out of the boiling reaction solution.
  • the mixture is allowed to cool, the solvent is filtered off, the product is dissolved in methylene chloride and the ion exchanger is filtered off. After removing the solvent on a rotary evaporator, 148.13 g (73% of theory) of the title compound are obtained in the form of a white solid.
  • the reaction mixture is transferred to a separatory funnel, the phases are separated and the toluene phase is concentrated.
  • the crude product is by means of column chromatography on silica gel with methylene chloride-methanol (10: 1) as the eluent. 2.28 g (25% of theory) of a yellow, viscous oil are obtained.
  • Gadolinium oxide suspended in 40 ml of water and heated under reflux at 80 ° C for 3 hours. The solution is filtered and dried in vacuo. This gives quantitatively 0.5 g of a yellowish solid which contains 1.6% water.
  • Example 2 1 Analogously to Example 2 1), 0.5 g (0.597 mmol) of the title compound from 2 h) are reacted with 0.314 g (0.597 mmol) of ytterbium (III) carbonate. The title compound is obtained in quantitative yield as a slightly yellow colored powder with a water content of 12.2%.
  • OTEC Analogous to that of JV Dubrawski and AA Diamantis [Inorg. Chem., 20 (1981) 1142] and NA Ezerskaya and TP Solovykh [ZA. Neorg. Khim., 11 (1966) 1855], 0.5 g (0.620 mmol) OTEC [prepared according to Example 1b)] are first dissolved in 15 ml deionized water and 24.5 ml 0.1 N NaOH are added. The solution is stirred for 30 min and then the solvent is removed on a rotary evaporator. The sodium salt of OTEC obtained as a white powder is dissolved in 10 ml of a 0.001 N HCIO4, heated to 80 ° C.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Radiology & Medical Imaging (AREA)
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Abstract

L'invention concerne des macrocycles octa-aza de formule générale (I), dans laquelle A, D, W, X, R?1, R2, R3 et R4¿ sont des groupes de notation diverse, ainsi que leurs complexes métalliques et leur utilisation pour le diagnostic médical et en thérapie. L'invention concerne également un procédé de fabrication des macrocycles octa-aza et de leurs complexes.
PCT/EP1995/000124 1994-01-28 1995-01-13 Macrocycles octa-aza, leurs complexes metalliques et leur utilisation en diagnostic et en therapie WO1995020580A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP4403039.8 1994-01-28
DE19944403039 DE4403039A1 (de) 1994-01-28 1994-01-28 Oktaazamakrocyclen, deren Metallkomplexe, Verfahren zu deren Herstellung, diese Komplexe enthaltende Mittel sowie deren Verwendung in Diagnostik und Therapie

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU90834B1 (en) * 2001-09-17 2003-03-18 Europ Economic Community Bifunctional chelating agent for actinium
US7132513B2 (en) * 2000-03-14 2006-11-07 European Community Bifunctional chelating agent
US7279502B2 (en) 1999-04-30 2007-10-09 Cellgate, Inc. Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
US7491849B2 (en) 2001-10-16 2009-02-17 Progen Pharmaceuticals, Inc. Oligoamine compounds and derivatives thereof for cancer therapy

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0197437A2 (fr) * 1985-03-30 1986-10-15 Konica Corporation Solution de traitement pour un matériau photographique à l'halogénure d'argent sensible à la lumière et sa méthode de traitement
WO1992008725A1 (fr) * 1984-10-18 1992-05-29 Board Of Regents, The University Of Texas System Composes polyazamacrocycliques pour la complexation des ions metal
WO1993012097A1 (fr) * 1984-10-18 1993-06-24 Board Of Regents, The University Of Texas System Synthese de polyazamacrocycles presentant plus d'un type de groupes chelateurs de chaines laterales

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008725A1 (fr) * 1984-10-18 1992-05-29 Board Of Regents, The University Of Texas System Composes polyazamacrocycliques pour la complexation des ions metal
WO1993012097A1 (fr) * 1984-10-18 1993-06-24 Board Of Regents, The University Of Texas System Synthese de polyazamacrocycles presentant plus d'un type de groupes chelateurs de chaines laterales
EP0197437A2 (fr) * 1985-03-30 1986-10-15 Konica Corporation Solution de traitement pour un matériau photographique à l'halogénure d'argent sensible à la lumière et sa méthode de traitement

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7279502B2 (en) 1999-04-30 2007-10-09 Cellgate, Inc. Polyamine analog conjugates and quinone conjugates as therapies for cancers and prostate diseases
US7132513B2 (en) * 2000-03-14 2006-11-07 European Community Bifunctional chelating agent
LU90834B1 (en) * 2001-09-17 2003-03-18 Europ Economic Community Bifunctional chelating agent for actinium
WO2003024940A1 (fr) * 2001-09-17 2003-03-27 European Community Agent chelatant bifonctionnel pour l'actinium
JP2005507885A (ja) * 2001-09-17 2005-03-24 ヨーロピアン コミュニティ アクチニウムのための二元機能キレート剤
US7045606B2 (en) 2001-09-17 2006-05-16 European Community Bifunctional chelating agent for actinium
AU2002337093B2 (en) * 2001-09-17 2008-03-13 European Community Bifunctional chelating agent for actinium
NO326695B1 (no) * 2001-09-17 2009-02-02 The European Community Represented By The European Commission Bifunksjonelt metallchelat av ligand hvor metallet er aktinium og anvendelser derav.
US7491849B2 (en) 2001-10-16 2009-02-17 Progen Pharmaceuticals, Inc. Oligoamine compounds and derivatives thereof for cancer therapy

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