EP0770063A1 - Technetium-sulfonamid-komplexe, deren verwendung, diese enthaltende pharmazeutische mittel, sowie verfahren zur herstellung der komplexe und mittel - Google Patents

Technetium-sulfonamid-komplexe, deren verwendung, diese enthaltende pharmazeutische mittel, sowie verfahren zur herstellung der komplexe und mittel

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Publication number
EP0770063A1
EP0770063A1 EP95924304A EP95924304A EP0770063A1 EP 0770063 A1 EP0770063 A1 EP 0770063A1 EP 95924304 A EP95924304 A EP 95924304A EP 95924304 A EP95924304 A EP 95924304A EP 0770063 A1 EP0770063 A1 EP 0770063A1
Authority
EP
European Patent Office
Prior art keywords
mmol
group
yield
solution
found
Prior art date
Legal status (The legal status 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 status listed.)
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Application number
EP95924304A
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German (de)
English (en)
French (fr)
Inventor
Johannes Platzek
Bernd Radüchel
Wolfgang Kramp
Ludger Dinkelborg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Bayer Pharma AG
Original Assignee
Schering AG
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Publication of EP0770063A1 publication Critical patent/EP0770063A1/de
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/32—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C331/00—Derivatives of thiocyanic acid or of isothiocyanic acid
    • C07C331/16—Isothiocyanates
    • C07C331/28—Isothiocyanates having isothiocyanate groups bound to carbon atoms of six-membered aromatic rings
    • 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
    • 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
    • A61K51/0474—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group
    • A61K51/0478—Organic compounds complexes or complex-forming compounds, i.e. wherein a radioactive metal (e.g. 111In3+) is complexed or chelated by, e.g. a N2S2, N3S, NS3, N4 chelating group complexes from non-cyclic ligands, e.g. EDTA, MAG3
    • 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
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen 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
    • C07F13/00—Compounds containing elements of Groups 7 or 17 of the Periodic Table
    • C07F13/005—Compounds without a metal-carbon linkage
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J31/00—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring
    • C07J31/006—Normal steroids containing one or more sulfur atoms not belonging to a hetero ring not covered by C07J31/003
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
    • C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
    • C07J41/0055—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by an uninterrupted chain of at least three carbon atoms which may or may not be branched, e.g. cholane or cholestane derivatives, optionally cyclised, e.g. 17-beta-phenyl or 17-beta-furyl derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J51/00—Normal steroids with unmodified cyclopenta(a)hydrophenanthrene skeleton not provided for in groups C07J1/00 - C07J43/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J9/00—Normal steroids containing carbon, hydrogen, halogen or oxygen substituted in position 17 beta by a chain of more than two carbon atoms, e.g. cholane, cholestane, coprostane
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to the subject matter characterized in the claims, that is to say new chelating agents containing sulfonamide groups, their metal complexes, pharmaceutical compositions containing these compounds, their use in radiodiagnostics and radiotherapy, methods for producing these compounds and compositions, and conjugates of these compounds with them in diseased tissue selectively enriching substances, especially peptides.
  • 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.
  • the diagnostic application 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 tracked down, plotted or scintigraphed using suitable detectors, such as scintillation cameras or other suitable recording methods.
  • suitable detectors such as scintillation cameras or other suitable recording methods.
  • the distribution and relative intensity of the detected radioactive agent characterizes the location of a structure in which the radioactive agent is located and can represent the presence of abnormalities in structure and function, pathological changes etc.
  • radiopharmaceuticals can be used as therapeutic agents to irradiate certain pathological tissues or areas.
  • Such treatment requires the production of radioactive therapeutic agents that accumulate in certain structures, tissues or organs. By enriching these agents, the therapeutic radiation is carried directly to the pathological tissue.
  • metallic radionuclides are used as diagnostics or therapeutic agents, it being possible for the metal to be present in free form, as an ion or in the form of a metal complex.
  • Technetium-99m and various rhenium isotopes are examples of metallic radionuclides that can form complexes.
  • the former is used in diagnostics, the latter in therapy.
  • radiopharmaceuticals In addition to the metal (complex), radiopharmaceuticals generally also contain suitable carriers and additives which permit injection, inhalation or ingestion by the patient, such as physiological buffers, salts, etc.
  • suitable carriers and additives which permit injection, inhalation or ingestion by the patient, such as physiological buffers, salts, etc.
  • the most frequently used radionuclide for nuclear medicine questions is technetium-99m, which due to its favorable physical properties (no corpuscular radiation, 6 h physical half-life, 140 KeV gamma radiation) and the resulting low radiation exposure is particularly suitable as a radioisotope for in vivo Diagnostics are suitable.
  • Technetium-99m can be easily obtained from nuclide generators as pertechnetate and can be used directly in this form for the production of kits for routine clinical needs.
  • the production of radiopharmaceuticals first requires the synthesis of a suitable ligand.
  • the complex is then produced in the clinic immediately before use from the respective complexing agent (hereinafter also referred to as ligand or chelator) and the desired radionuclide (labeling).
  • the complexing agent which is always in the form of a lyophilized kit, is reacted with a solution containing the radionuclide under complexing conditions.
  • the ligand produced is mixed with a pertechnetate solution with the addition of a suitable reducing agent and the corresponding technetium complex is produced under suitable reaction conditions.
  • the solution containing the radionuclide can, as in the case of technetium-99m, be obtained from a commercially available Mo-99 / Tc-99m nuclide generator or, as in the case of rhenium-186, can be obtained directly from a manufacturer.
  • the complex formation reaction is carried out under suitable temperatures (for example 20 ° -100 ° C.) within a few minutes to several hours. To ensure complete complex formation, a large excess (more than 100-fold excess) of the ligand produced and an amount of reducing agent (for example SnCl 2 , S 2 O 4 etc.) sufficient for a complete reduction of the radionuclide used are required.
  • technetium can exist in a number of oxidation states (+7 to -1) that can change the pharmacological properties by changing the charge of a complex, it is necessary to provide chelators that can stably bind technetium in a defined oxidation state in order to prevent an in vivo redox processes or technetium releases from the corresponding radio diagnostics Biodistribution takes place, which complicates the safe diagnosis of corresponding diseases.
  • radionuclides in in vivo diagnostics as well as therapy depends on the specificity and the selectivity of the labeled chelates to the target cell. These properties can be improved by coupling the chelates to biomolecules according to the "drug targeting" principle. Antibodies, their fragments, hormones, growth factors and substrates of receptors and enzymes are suitable biomolecules.
  • the British patent application GB 2,109,407 describes the use of radioactively labeled monoclonal antibodies against tumor-associated antigens for tumor diagnosis in vivo.
  • direct protein labels via donor groups (amino, amide, thiol, etc.) of the protein (Rhodes, BA et al., J. Nukl. Med. 1986, 27, 685-693) or by introducing complexing agents (US 4,479,930 and Fritzberg, AR et al., J. Nucl. Med. 1986, 27, 957) with Technetium-99m.
  • Suitable complexing agents for technetium and rhenium isotopes are, for. B. cyclic amines, as described by Volkert et al. (Appl.Radiol.Isot. 1982, 33; 891) and Troutner et al. (J. Nucl. Med. 1980, 21; 443), which have the disadvantage, however, that they are only able to bind technetium-99m in good yields from a pH> 9.
  • N2 ⁇ 2 systems are in clinical use, but have the disadvantage that the corresponding metal complexes are not very stable in vivo. According to studies by Pillai and Troutner, the complexes in the plasma lose up to 30% of the complexed metal after 1 hour (Pillai, MRA, Troutner, DE et al .; Inorg. Chem. 1990, 29; 1850).
  • Non-cyclic N 4 systems such. B. the HM-PAO have a major disadvantage of their low complex stability. Tc-99m-HM-PAO must because of its instability (Ballinger, JR et al., Appl. Radiat. Isot. 1991, 42; 315), Billinghurst, MW et al., Appl. Radiat. Isot. 1991, 42; 607) can be applied within 30 minutes after its labeling, so that the proportion of decay products that have a different pharmacokinetics and excretion can be kept low. Such radiochemical contaminants complicate the detection of diagnosing diseases. A coupling of these chelates or chelating agents to other substances that selectively accumulate in foci of disease cannot be solved with simple means, so that they are generally distributed nonspecifically in the organism.
  • NS 2 chelators (Bormans, G. et al .; Nucl. Med. Biol. 1990, 17; 499), such as e.g. B. ethylenedicysteine (EC; Verbruggen, AM et al .; J. Nucl. Med. 1992, 33; 551) meet the requirement for sufficient stability of the corresponding technetium-99m complex, but only form from a pH value of the complexing medium > 9 radio diagnostics with a purity of more than 69%.
  • B. ethylenedicysteine ethylenedicysteine
  • NßS systems (Fritzburg, A.; EP 0 173 424 and EP 0 250 013) form stable technetium-99m complexes, but must be heated to temperatures of approximately 100 ° C. in order to form a uniform radiopharmaceutical.
  • bifunctional complexing agents which carry both functional groups for binding the desired metal ion and one (other, several) functional group for binding the selectively enriching molecule.
  • Such bifunctional ligands enable a specific, chemically defined binding of technetium or rhenium isotopes to a wide variety of biological materials, even if so-called pre-labeling is carried out.
  • EP 0 247 866 EP 0 188 256 and EP 0 200 492 describe some chelating agents which are coupled to monoclonal antibodies or fatty acids.
  • N2S2 systems are used as chelating agents, which are not very suitable due to their low stability. Since both the selectively enriching substances in their properties, as well as the mechanisms, after to which they are enriched are very different, it is still necessary to vary the couplable chelating agent and the physiological
  • the invention is therefore based on the object of finding complexes or complexing agents which overcome the disadvantages of the prior art, i.e. the
  • the corresponding complexing agent and the respective metal oxide / salt can be prepared at low temperatures, preferably at room temperature, from the corresponding complexing agent and the respective metal oxide / salt, show high complex stability even under in vivo conditions , - Show a high selectivity or tissue / organ specificity.
  • the complexes must meet the requirements that are generally placed on pharmaceuticals, such as good tolerance (i.e. no side effects), good solubility and complete elimination.
  • the object is achieved by the present invention.
  • V 1 , V 2 , V 3 , V 4 independently of one another represent a carbonyl,> CH (COOH) or -CH2 group, ⁇ l for a hydrogen atom, one optionally with a
  • Carboxyl an amino or a thiocyanate group substituted C 1 -C ⁇ alkyl radical or a metal ion equivalent of a radioactive metal ion of an element of atomic number 43, 45, 46, 75, 82 or 83,
  • X 2 , X 3 independently of one another for a hydrogen atom or a
  • U stands for a direct bond, a straight-chain or branched, saturated or unsaturated C 1 -C 2 -alkylene radical which, if desired, a maleimide, a succinimide, an optionally substituted by 1 to 5 fluorine atoms, an amino or nitro group
  • Phenyl radical one or two imino, phenylene, phenyleneoxy, phenylenamino, amide, hydrazide, carbonyl, ureido, thiourido-, thioamide, ester group (s), 1 to 2 oxygen, sulfur and / or nitrogen atom (s) and optionally 1 to 5 hydroxy,
  • R 2 a straight-chain or branched C ⁇ -C alkyl radical, which optionally contains a -COOH group, a C7-C12 - aralkyl radical or an aromatic, optionally substituted with one
  • R 4 represents a hydrogen atom or a carboxyl group or in the event that R 1 represents a hydrogen atom or a
  • Carboxyl group means additionally also represents a group -UZ, in which U and Z have the meanings given, R 3 represents a hydrogen atom, a metal ion equivalent of an element of the atomic numbers mentioned, a trifluoroacetate, acetate, benzoate, - acyl, a benzoyl, a hydroxyacetyl, an acetamidomethyl, if desired with a chlorine or bromine atom, a methyl, ethyl, carboxyl and / or methoxy group substituted benzoic acid residue, a p-methoxybenzyl, one
  • R 4 have the meanings given, where at least one and at most two radicals V 1 , V 2 , V 3 , V 4 stand for a carbonyl group, are outstandingly suitable as or for the production of radiodiagnostics and therapeutics.
  • complexing agents ie compounds of the general formula I with X 1 , X 2 , X 3 and R 3 in the meanings indicated, with the exception of one metal ion equivalent, meet the requirement profile mentioned. They are characterized in particular by the fact that they have the desired metal 3 complex quickly at physiological pH and low temperatures. They are therefore particularly suitable for routine use in the clinic.
  • the dimeric chelators with R 3 as a radical of the general formula ⁇ become monomeric metal complexes of the formula I with R 3 as a metal ion equivalent.
  • Radioactive metal ions of elements of atomic numbers 43, 45, 46, 75, 82 or 83 such as e.g. the radioisotopes technetium-99m, rhodium-103, palladium-109, rhenium-186, lead-212 and bismuth-212 use, the choice of the metal isotope depending on the desired field of application. According to the invention, metal complexes of the elements technetium and rhenium are preferred.
  • ⁇ -radiation-emitting isotopes e.g. Tc-99m
  • these can be used in single photon emission tomography (SPECT).
  • SPECT single photon emission tomography
  • ⁇ -particle-emitting isotopes such as e.g. Bi-211, Bi-212, Bi-213, Bi-214 or ß-emitting
  • Isotopes such as Re-186 or Re-188, these can be used in radiotherapy.
  • V 1 and V 4 each represent a carbonyl group
  • V 2 and V 3 each represent a -CH group
  • p represents the number 0.
  • Suitable radicals R 1 are hydrogen or a carboxylic acid group and in particular a group -UZ in which Z is a hydrogen atom, but preferably for the rest of a biomolecule with tissue or structure-specific properties or a functional group which may be present in activated form via the desired such a biomolecule can be stands.
  • biomolecules are residues of an amino acid, a peptide or a steroid, such as the known steroid hormones (androgens, gestagens, estrogens, cholesterol, cholic acid derivatives, Pregnane, etc.), and polynucleotides such as RNA or DNA.
  • Examples of functional groups that can be used to bind a biomolecule are a -COOH, a -SCN, a -OH, a -Cl or an -NH 2 group.
  • Such groups can also be present in their activated form, for example as succinimide esters or acid chloride.
  • U can preferably represent a direct bond, however, a straight-chain or branched, saturated or unsaturated C 1 -C 2 o -alkylene radical which, if desired, a succimide, a phenyl radical which is optionally substituted by 1 to 5 fluorine atoms, an amino or a nitro group, one or two imino, phenylene, phenyleneoxy, phenylenamino, amide, hydrazide, carbonyl, ureido, thiourido-, thioamide, ester group (s), 1 to 2 oxygen, sulfur and / or nitrogen atom (e) and optionally 1 to 5 hydroxyl, mercapto, oxo, thioxo, carboxy, alkyl carboxylic acid, ester, thiocyanate and / or amino groups.
  • a succimide a phenyl radical which is optionally substituted by 1 to 5 fluorine atoms, an amino or
  • the radicals -UZ with Z in the meaning of hydrogen are -CH 2 -C 6 H 4 -O-CH 2 -COO-C 6 F 5 , -CH 2 -C 6 H 4 -O-CH 2 -C 6 H 5 , -CH 2 -C 6 H 4 -O-CH 3 , -CH 2 -C 6 H 4 -OC 6 H 3 , -CH 2 -C 6 H 4 -OC 12 H 25 or a -CH 2 -C 6 H 4 -O-CO-C 15 H 31 group.
  • radicals -UZ with Z meaning an optionally activated functional group are -CH 2 - (CH 2 ) -NCS, -CH 2 -C 6 H 4 -O-CO- (CH 2 ) 2 -COOH,
  • -COO-N ie Z stands for an -NCS, -COOH, -NH 2 , -NO 2 , -OH or an S ⁇ group
  • radicals R 2 are a -C 6 H 4 -NCS - or a - C $ H 4 -COOH group, but in particular a -CH 3 group or a phenyl ring.
  • R 3 may be mentioned as examples, a) in the case of the complexing agents: -SH protective groups, such as, for example, a -CO-CH 3 ,
  • R 3 can also represent a metal ion equivalent of a radioactive metal ion of an element of the atomic numbers mentioned.
  • X 2 , X 3 represent a hydrogen atom and X 1 represents a hydrogen atom or an optionally substituted C r C 12 alkyl radical; in the case of the complexes, depending on the oxidation state of the metal in the complex, at least 2 of the radicals X 1 , X 2 , X 3 or R 3 the meaning of a metal ion equivalent.
  • R 4 represents hydrogen or a carboxyl group. However, R 4 can also stand for a group -UZ with U and Z in the meanings given above, it always being true that at most one of the two radicals R 1 or R 4 denotes a group -UZ. Compounds with R 4 in the meaning of hydrogen are preferred according to the invention.
  • indices m and n stand for the digits 0 or 1. Since isomers can be obtained in the synthesis of the complexing agents according to the invention, the sum of m and n is always 1.
  • the invention also relates to processes for the preparation of the complexing agents and complexes according to the invention, different reaction paths advantageously being followed in the synthesis of the complexing agent depending on the desired target structure.
  • Some typical syntheses are described below by way of example.
  • Further complexing agents can be prepared analogously to the synthetic routes described.
  • ligands are to be prepared which contain an —O — CgH 4 —CH 2 - group in R 1 , then a tyrosine ester, whose II amino group is initially protected in a manner known to the person skilled in the art by reaction with a reagent Z 1 -Cl, in which Z 1 stands for any amino protective group, preferably for benzyloxycarbonyl group (hereinafter also referred to as Z group).
  • Z 1 stands for any amino protective group, preferably for benzyloxycarbonyl group (hereinafter also referred to as Z group).
  • the phenolic hydroxyl group is then alkylated with an alkyl iodide in a manner known per se, the amino protecting group is split off acidically and then tosylated, for example, with toluenesulfonyl chloride.
  • T-butyl bromoacetate alkylated and the amino protecting group split off in a conventional manner The tosylation and aminolysis of the ester function with ethylenediamine is carried out as described under 1, but the reaction is then carried out with chloroacetyl chloride. Chlorine is substituted in a manner known per se by reaction with potassium or sodium thioacetate and the t-butyl ester is saponified with acid. If desired, the resulting carboxylic acid group can be activated with hydroxysuccinimide and then reacted with the desired biomolecule.
  • Ligands according to the invention in which R 1 is an SCN-C 6 H -CH 2 radical can be obtained by first tosylating the amino group of a p-nitrophenylalanine ester in a manner known per se. The nitro group is then hydrogenated and the resulting aromatic amino group is protected, for example by reaction with benzyl chloroformate. As described in the preceding cases, this reaction step is followed by aminolysis of the ester function with ethylenediamine, followed by reaction with S-protected mercaptoacetic acid. This is followed by the elimination of the benzyloxycarbonyl group. The isothiocyanate group is introduced by reaction with thiophosgene.
  • Toluene sulfonyl chloride is tosylated.
  • the ester function is then reacted with ethylenediamine in an aminolysis.
  • the resulting free amino group is identified with a tert-butoxycarbonyl group (hereinafter referred to as the BOC group protected and the nitrogen substituted with a tosyl radical is N-alkylated with an alkyl iodide in a manner known per se.
  • the reaction with 2-acetylmercapto-succinic anhydride follows, again giving a mixture of isomers.
  • Ligands according to the invention with R 1 in the meaning of an aminobutyl radical can be obtained by first tosylating the LOC sine ester protected on a nitrogen atom on the remaining unprotected primary amino group and then reacting it with ethylenediamine in an aminolysis. The reaction is then carried out with 2-acetylmercapto-succinic anhydride (forming an isomer mixture) and the amino protecting group is split off by known methods.
  • the preparation of ligands according to the invention which contain an isomiocyanate phenyl radical as R 2 is carried out by reacting a glycine methyl ester with nitrobenzenesulfonyl chloride, then reducing the nitro group and protecting the resulting amino group.
  • the intermediate compound thus obtained is reacted in an aminolysis with ethylenediamine and then with S-protected mercaptoacetic acid.
  • the (BOC) protective group is subsequently split off in a known manner.
  • the free amino group is then reacted with thiophosgene to form the corresponding isothiocyanate group.
  • the metal complexes of the general formula I according to the invention with at least two radicals X 1 , X 2 , X 3 and / or R 3 in the meaning of a metal ion equivalent are prepared in a manner known per se by the complexing agents according to the invention (which can be obtained as described above) ) with the addition of a reducing agent, preferably tin salts, such as tin chloride or tartrate - and optionally with the addition of the additives customary in galenics, such as physiologically acceptable buffers (e.g. tromethamine), small additions of electrolytes (e.g. sodium chloride), stabilizers (e.g. gluconate , Phosphates or phosphonates) etc.
  • a reducing agent preferably tin salts, such as tin chloride or tartrate -
  • the additives customary in galenics such as physiologically acceptable buffers (e.g. tromethamine), small additions of electrolytes (e.
  • the complexing agent is generally added in at least a 100-fold excess, ie the agents according to the invention contain, in addition to the 3 desired metal complex additionally also the metal-free complexing agent, which is advantageously added in the form of its potassium salt.
  • reaction solutions containing the metal complex described above can in principle be applied directly without further workup.
  • auxiliary ligands are gluconheptonic acid, tartaric acid, citric acid (including the salts thereof) or other substances known to the person skilled in the art.
  • the metal complexes obtained can be mixed with pharmacologically acceptable radiological carriers.
  • This radiological carrier should have favorable properties for the application of the radiopharmaceutical in the form of an injection, inhalation or ingestion.
  • excipients are HSA, aqueous buffer solutions such as tris (hydroxymethyl) aminoethane (or their salts), phosphate, citrate, bicarbonate etc., sterile water, physiological saline, isotonic chloride or dicarbonate ion solutions or normal plasma ions like Ca 2 +, Na +, K + ; and Mg +.
  • the agents according to the invention are dosed in amounts of 10 " 5 to 5 x 10 4 nmol / kg body weight, preferably in amounts between 10" 3 to 5 x 10 2 nmol / kg body weight (based on the metal complex) .
  • the radioactivity required for diagnostic applications is between 1.85 MBq and 1.85 GBq per application.
  • the application is usually carried out by intravenous, intraarterial, peritoneal or intratumoral injection of 0.1 to 2 ml of a solution of the agent according to the invention. Intravenous administration is preferred.
  • the metal complexes according to the invention with metal ions of the elements mentioned and the pharmaceutical compositions prepared from them are notable for good Compatibility and high stability in vivo.
  • the complexing agents according to the invention are notable for easy labeling, ie they complex the desired metals in high yields at room temperature and neutral pH.
  • Np-toluenesulfonyl-2 [(4-hexyloxy) benzyl] -2-aminoacetic acid methyl ester 8.38 g of the amine (30 mmol) prepared according to Example lc) are dissolved in 50 ml dichloromethane and at 0 ° C. with 5.72 g Toluene sulfonyl chloride in 30 ml dichloromethane. With intensive stirring, 3.0 g of triethylamine are added dropwise at 0 ° C. and the mixture is stirred at room temperature for 1 hour. After the reaction is complete, ice water is added and the mixture is extracted several times with dichloromethane.
  • the catalyst is filtered off and the solvent is stripped off.
  • Np-toluenesulfonyl-2 [(4-methyloxy) benzyl] -2-aminoacetic acid methyl ester 6.28 g of the amine (30 mmol) prepared according to Example 2b) are dissolved in 50 ml of dichloromethane and at 0 ° C. with 5.72 g of toluenesulfonic acid chloride 30 ml dichloromethane added. With intensive stirring, 3.0 g of triethylamine are added dropwise at 0 ° C. and the mixture is stirred at room temperature for 1 hour. After the reaction is complete, ice water is added and the mixture is extracted several times with dichloromethane. The combined organic extracts are washed 2x with cold 10% HCl, 3x with 10% NaHC03 and 2x with saturated NaCl solution. After drying, the solvent is removed. Yield: 76%
  • Np-toluenesulfonyl-2 [(4-dodecyloxy) benzyl] -2-aminoacetic acid methyl ester 10.91 g of the amine (30 mmol) prepared according to Example 3b) are dissolved in 50 ml dichloromethane and at 0 ° C. with 5.72 g toluenesulfonic acid chloride added in 30 ml dichloromethane. With intensive stirring, 3.0 g of triethylamine are added dropwise at 0 ° C. and the mixture is stirred at room temperature for 1 hour.
  • the thiophosgene was added dropwise in a little dichloromethane and the mixture was stirred at room temperature for 4 h.
  • Np-toluenesulfonyl-2 [(4-cholesteryldiethylene glycolyl) benzyl] - 2-aminoacetic acid methyl ester 19.53 g of the amine (30 mmol) prepared according to Example 9d) are dissolved in 50 ml dichloromethane and at 0 ° C. with 5.72 g toluenesulfonyl chloride in 30 ml dichloromethane added. With intensive stirring, 3.0 g of triethylamine are added dropwise at 0 ° C. and the mixture is stirred at room temperature for 1 hour. After the reaction is complete, ice water is added and the mixture is extracted several times with dichloromethane.
  • Np-toluenesulfonyl-2 [(4-cholesteryldiethylene glycolyl) benzylJ-2-aminoacetic acid [N- (2-aminoethyl)] amide.
  • a solution slowly becomes a solution of 1.2 g of ethylenediamine (20 mmol) in 1 ml of anhydrous dichloromethane 806 mg of the tosylglycine ester (1 mmol) prepared according to Example 9e in 1 ml of anhydrous dichloromethane were added dropwise and the mixture was boiled under reflux. When the reaction is complete, the mixture is concentrated in vacuo and the residue is chromatographed (silica gel, MeOH). Yield: 85% Ber. : C 70.55% H 9.06% N 5.04% O 11.51% S 3.84%
  • 50 ⁇ l of this solution are added to 250 ⁇ l of a 0.1 M phosphate buffer (pH 8.5) and then with 50 ⁇ l of a citrate solution (50 mg of trisodium citrate in 1.0 ml of water) and 2.5 ⁇ l of a tin (TI) chloride Solution (5.0 mg of tin (II) chloride in 1 ml of 0.1 N HCl) was added. 50 ⁇ l of a Tc-99m generator eluate are then added and the mixture is left to stand for 15 minutes. The labeling yield is determined by means of HPLC.
  • a solution of 27 g (100 mmol) of the amino compound prepared according to Example 10a) in 500 ml of dioxane is mixed with 74 g of di-tert-butyl dicarbonate (340 mmol) in one portion.
  • the solution is stirred for 3 hours at room temperature, then poured onto ice water and extracted 3 times with ethyl acetate.
  • the combined organic phases are washed 3 times with water and once with saturated sodium chloride solution, dried (MgSO.j.), concentrated and recrystallized. There remain 27.9 g of white crystals.
  • N-a-toluenesulfonyl-lysine [N- (2- (piperonylmercapto) acetylaminoethyl)] amide 651 mg N- ⁇ -toluenesulfonyl-N- ⁇ -tert-butyloxycarbonyllysine
  • 50 ⁇ l of this solution are added to 250 ⁇ l of a 0.1 M phosphate buffer pH 8.5 and with 50 ⁇ l of a citrate solution (50 mg of trisodium citrate in 1.0 ml of water) and 2.5 ⁇ l of a tin (III) chloride Solution (5.0 mg of tin (II) chloride in 1.0 ml of 0.1 N HCl) was added. 50 ⁇ l of a Tc-99m generator eluate is then added and the mixture is left to stand for 15 minutes. The labeling yield is determined by HPLC (> 95%).
  • Trifluoroacetic acid removed in vacuo, the residue taken up in tetrahydrofuran, concentrated and chromatographed.
  • N-Toluenesulfonyl-0-t-butyloxycarbonylmethyltyrosine [N. (2- (benzoylmercapto) - acetylaminoethyl)] amide 2 mmol S-benzoyl-2-mercaptoacetic acid (394 mg) and 4 mmol NEt 3 (560 ⁇ l) and 2 5 ml of dichloromethane are added to mmol (982 mg) of the compound obtained according to Example 8d) and the mixture is cooled to 10 ° C.
  • the precipitate is filtered off and washed with plenty of water. Then over
  • Trißuoressigklad ⁇ 10 g (18.19 mmol) of the title compound from Example 25c) are stirred for 1 mouth in 100 ml of trifluoroacetic acid at room temperature. It is evaporated to dryness in a vacuum. 9.95 g of a glassy foam are obtained, which solidifies on standing. Yield: 97%

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EP95924304A 1994-07-14 1995-06-22 Technetium-sulfonamid-komplexe, deren verwendung, diese enthaltende pharmazeutische mittel, sowie verfahren zur herstellung der komplexe und mittel Withdrawn EP0770063A1 (de)

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DE4425781A DE4425781A1 (de) 1994-07-14 1994-07-14 Technetium-Sulfonamid-Komplexe, deren Verwendung, diese enthaltende pharmazeutische Mittel, sowie Verfahren zur Herstellung der Komplexe und Mittel
DE4425781 1994-07-14
PCT/EP1995/002404 WO1996002500A1 (de) 1994-07-14 1995-06-22 Technetium-sulfonamid-komplexe, deren verwendung, diese enthaltende pharmazeutische mittel, sowie verfahren zur herstellung der komplexe und mittel

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US5028422A (en) * 1986-05-27 1991-07-02 Schering Corporation Treatment of basal cell carcinoma intralesionally with recombinant human alpha interferon

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WO2002004412A2 (en) * 2000-07-06 2002-01-17 Array Biopharma Inc. Tyrosine derivatives as phosphatase inhibitors
KR100445971B1 (ko) * 2002-04-15 2004-08-25 한국원자력연구소 수소화붕소 교환수지를 이용한 테크네튬 또는 레늄의표지방법
EP2258401B1 (en) * 2002-05-06 2014-07-09 Endocyte, Inc. Folate-receptor targeted imaging agents

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US4980147A (en) * 1984-06-25 1990-12-25 University Of Utah Research Foundation Radiolabeled technetium chelates for use in renal function determinations
ATE52516T1 (de) * 1986-05-28 1990-05-15 Mallinckrodt Inc Technetiumchelate fuer die bestimmung der nierenfunktion.

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US5028422A (en) * 1986-05-27 1991-07-02 Schering Corporation Treatment of basal cell carcinoma intralesionally with recombinant human alpha interferon

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