WO1995012610A1 - Chelateurs n-alkylpeptidiques, leurs complexes metalliques avec des radionucleides, procedes pour leur preparation et compositions radiopharmaceutiques contenant ces composes - Google Patents

Chelateurs n-alkylpeptidiques, leurs complexes metalliques avec des radionucleides, procedes pour leur preparation et compositions radiopharmaceutiques contenant ces composes Download PDF

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WO1995012610A1
WO1995012610A1 PCT/DE1994/001295 DE9401295W WO9512610A1 WO 1995012610 A1 WO1995012610 A1 WO 1995012610A1 DE 9401295 W DE9401295 W DE 9401295W WO 9512610 A1 WO9512610 A1 WO 9512610A1
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general formula
group
cys
ile
leu
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PCT/DE1994/001295
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German (de)
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Hartmut Spies
Paul-Eberhard Schulze
Bernd Noll
Steffi Noll
Ludger Dinkelborg
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Institut für Diagnostikforschung GmbH an der Freien Universität Berlin
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Priority to EP95900059A priority Critical patent/EP0726909A1/fr
Priority to AU81038/94A priority patent/AU681919B2/en
Priority to JP7512959A priority patent/JPH09508351A/ja
Publication of WO1995012610A1 publication Critical patent/WO1995012610A1/fr
Priority to NO961743A priority patent/NO961743D0/no
Priority to KR1019960702247A priority patent/KR960705842A/ko

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/04—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid 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 in position 8
    • C07D457/06—Lysergic acid amides
    • 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
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/26—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D457/00—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid
    • C07D457/10—Heterocyclic compounds containing indolo [4, 3-f, g] quinoline ring systems, e.g. derivatives of ergoline, of the formula:, e.g. lysergic acid with hetero atoms directly attached in position 8
    • C07D457/12—Nitrogen atoms
    • 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
    • C07J41/0072—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the A ring of the steroid being aromatic
    • 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
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0804—Tripeptides with the first amino acid being neutral and aliphatic
    • C07K5/0806—Tripeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atoms, i.e. Gly, Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0827—Tripeptides containing heteroatoms different from O, S, or N

Definitions

  • N-Al yl peptide chelating agents their metal complexes with radionuclides, processes for their preparation and radiopharmaceutical compositions containing these compounds
  • the invention relates to N-alkyl peptide chelating agents, their metal complexes with radionuclides, processes for their preparation and radiopharmaceutical compositions containing these compounds.
  • the invention further relates to radiopharmaceuticals which contain these chelates in a form complexed with metals, their diagnostic kits in which the chelate can be present in a non-complexed form and which is complexed either by adding technetium or rhenium ions and also via the use of such preparations for diagnostic and therapeutic purposes.
  • Radiolabeled chemical compounds that bind to so-called carrier molecules eg, steroids, Antikör- by, lipids, proteohormones etc.
  • carrier molecules eg. steroids, Antikör- by, lipids, proteohormones etc.
  • Targeting Drug on the principle of .
  • receptors e.g. steroid conjugates
  • REPLACEMENT LEAF Antibodies are substances which are able to pass the cell wall and the blood-brain barrier and substances for checking organ functions, for example before and after transplants and for finding vascular lesions.
  • complexing agents for a large number of radionuclides are increasingly being developed and coupled to tissue or metabolism-specific carrier molecules.
  • a radioactive isotope of rhenium For therapy, one is looking for ways to use a radioactive isotope of rhenium.
  • the most commonly used radionuclide is technetium-99m, which due to its favorable physical properties (no corpuscular radiation, favorable physical half-life, 140 KeV ⁇ radiation) and the associated low radiation exposure is particularly suitable as an isotope for in-vivo diagnostics.
  • Technetium-99m can be easily obtained from nuclide generators as [99m_ c _ -pertechnetate. In order to obtain technetium-99m chelates, the pertechnetate is converted by suitable reducing agents (eg SnCl2, S2O4 2 ", etc.) into a lower oxidation state, in which the technetium-99m forms complexes with chelating agents or proteins.
  • suitable reducing agents eg SnCl2, S2O4 2 ", etc.
  • REPLACEMENT LEAF Complexing agents have also been developed from the group of cyclic amines (Troutner, DE et al.; J. Nucl. Med. 1980, 21, 443 and Gurcke, H.; DE-3 911 816), Cyclame (Ketring, AR; Troutner , DE et al.; J. Nucl. Med., 1980, 21, 443-448, Int. J. Nucl. Med. Biol. 1984, 11, 113, Volkert et al., Applied Radiat. Isot., 1982, 33, 891-896), N 0 2 systems (Pillai, MRA; Troutner, DE et al .; Inorg. Chem.
  • the object of the invention is to provide short-chain N-alkyl peptide chelating agents which complex with technetium and rhenium in a wide pH range at room temperature, both ionic and non-ionic complexes being formed and thus providing compounds which provide the Disadvantages of known 99m Tc and 180 ' 188 Re complexes do not have.
  • n a number 0, 1 or 2
  • REPLACEMENT LEAF R 1 is a straight-chain or branched alkyl radical having 1 to 20 carbon atoms, which is optionally interrupted or substituted by one to three oxygen atoms, and which optionally has a terminal -
  • COOH, -OH or -NH group which is optionally esterified or etherified with glycolic acid or glycolic acid esters or ethers, the esters or ethers being formed with carboxylic acids or alcohols having up to 18 carbon atoms, or a phenyl or cyclohexyl radical which is optionally in the 4-position with a COOH, NH2 or OH group which is optionally esterified, etherified or amidated with carboxylic acids or alcohols having up to 6 carbon atoms or is substituted with a halogen atom,
  • R 4 is a methylene, propenylene amino, propinylene amino, methylene amino or methyleneoxy group
  • R 8 means a hydrogen atom or a methyl group
  • R 5 is an -NH-, -NH-CO-N ⁇ , -NH-CO-NH or methyleneoxy group
  • R 6 represents a hydrogen atom, a halogen atom or a methyl group
  • R 7 represents a hydrogen atom or a straight-chain or branched alkyl radical having up to 6 carbon atoms
  • R - * - is a hydrogen atom, an acetyl, benzoyl, p-methoxybenzyl, ace amidomethyl, benzamidornethyl, trimethylacetamidomethyl, hydroxyacetyl, ethoxyethyl, ethylthio, trityl or an easily removable sulfur protecting group
  • REPLACEMENT LEAF Formula IV shows an N3S-N-alkyl-peptide complex in the 99m Tc _ core (neutral)
  • formula VII shows an N2S2 * -N-alkyl * peptide complex in 99m Tc core (with positive charge) from R 3 S-CH 2 -CO-NR 1 [CH2-CO-NH] 0 -CH 2 -CO-R 2 .
  • 99m-p c compounds has not been described and is outstandingly suitable for displaying plaques in vascular lesions and for measuring kidney function, it being possible for the compounds to be coupled in each case to bioactive ligands.
  • REPLACEMENT LEAF or Rl is a phenyl, a p-phenylamine, a cyclohexylamine, p-hydroxyphenyl, 4-hydroxycyclohexyl, p-halophenyl or 4-halocyclohexyl group.
  • R 1 is equal to - (__H 2 ) q -00C-CH 2 -00C- (CH 2 ) r " CH 3,
  • R 1 is a straight-chain or branched alkyl radical having 1 to 6 carbon atoms or a P-bromophenyl radical.
  • R 2 is a radical of the general formula II
  • REPLACEMENT LEAF R 4 is a methylene, propenylamino, propinylamino, methylenamino or methyleneoxy group and
  • R 8 represents a hydrogen atom or a methyl group.
  • a 17 ⁇ -ethynyl group of estradiol can also be coupled to an ethene.
  • the order of the ethyne and ethene groups is interchangeable; doubling the ethyne or ethene group is also advisable. It is important to have a minimum distance between the chelator and estradiol molecule, preferably a rigid ethyne or ethene group, so that the side chain cannot fold.
  • N3S-K01T1 plex as a steroid 17 ⁇ -ethynyl chelate, of the thioacetyl-glycyl-glycyl-glycyl-O-ester type (own experiments), penetrate the N - * - alkylated complexes according to the invention (N 1 methyl ) the cell wall and accumulate after iv
  • the enrichment expressed as the quotient between blood / uterus, is 0.2 and can be varied depending on the N ** alkyl chain length or substituents. Mamma-ca early detection using the SPECT method is thus possible.
  • the compound according to Example 10 is particularly preferred here.
  • R 5 is an -NH-, -NH-CO-N ⁇ , -NH-CO-NH or methylene oxy group
  • REPLACEMENT LEAF R 6 represents a hydrogen atom, a halogen atom or a methyl group
  • R 7 represent a straight-chain or branched alkyl radical having up to 6 carbon atoms.
  • the 8 ⁇ -amino-6-methyl-ergoline is optionally with alkyl substituents in the 2- and / or 6-position with a chain length of C * j_ in the 2 position or C ⁇ _3 in the 6 position and / or a methyl or halogen substituents in position 2 are preferred.
  • the substituent in the 8-position of ergoline can also be ß-CH 2 0- or ⁇ NH-CO-N ⁇ or ⁇ NH-CO-NH-.
  • the compounds of general formula I according to the invention carry a radical R 3 at the terminal sulfur atom.
  • This radical R 3 represents a sulfur protecting group which is necessary during the synthesis of the compounds of the general formula I according to the invention. Such a protective group must be easily removable. Suitable
  • R 3 are, for example, acetyl, benzoyl, p-methoxybenzyl, acetamidomethyl, benzamidomethyl, trimethylacetamidomethyl, hydroxyacetyl, ethoxyethyl or trityl groups.
  • the benzyol group is particularly preferred.
  • the present invention furthermore relates to the metal chelate complexes of radioactive metal ions with the compounds of the general formula I according to the invention, in which R 1 , R 2 and R 3 have the meaning indicated above.
  • radioactive metal ions are, for example, ions of the radioisotopes of the elements Tc, Re, Cu, Ga, Gd, Y and In.
  • the selection of the radionuclide depends on the desired type of use of the metal chelate complexes of the general formula I according to the invention.
  • Radionuclides are used for radio diagnostics or radiotherapy.
  • Radioactive metal ions of the isotopes of the elements Tc and Re are preferred.
  • the radioisotope technetium-99m is particularly preferred.
  • Another object of the present invention are to provide a third object of the present invention.
  • Endothelins endothelins, endothelin analogs, endothelin derivatives or endothelin antagonists.
  • REPLACEMENT LEAF peptides accumulating in diseased tissue the peptides having the following sequences
  • the present invention further provides a process for the preparation of the compounds of the general formula I according to the invention
  • n a number 0, 1 or 2
  • R 1 is a straight-chain or branched alkyl radical having 1 to 20 carbon atoms, which is optionally interrupted or substituted by one to three oxygen atoms and which optionally carries a terminal -COOH, -OH or -NH 2 group which
  • REPLACEMENT LEAF optionally esterified or etherified with glycolic acid or glycolic acid esters or ethers, the esters or ethers being formed with carboxylic acids or alcohols having up to 18 carbon atoms, or representing a phenyl or cyclohexyl radical which may optionally be in the 4-position with a COOH, NH 2 or OH group which is optionally esterified, etherified or amidated or substituted with a halogen atom with carboxylic acids or alcohols having up to 6 carbon atoms,
  • R 4 is a methylene, propenylene amino, propinylene amino, methylene amino or methyleneoxy group
  • R 8 represents a hydrogen atom or a methyl group
  • R 5 is an -NH-, -NH-CO-N ⁇ , -NH-CO-NH or methylene oxy group
  • R 6 represents a hydrogen atom, a halogen atom or a methyl group
  • R 7 represents a hydrogen atom or a straight-chain or branched alkyl radical with up to 6 carbon atoms
  • R 3 represents a hydrogen atom, an acetyl, benzoyl, p-methoxybenzyl, acetamidomethyl, benzamidomethyl, trimethylacetamidomethyl, hydroxyacetyl, ethoxyethyl, ethylthio, trityl or an easily cleavable sulfur protecting group
  • R 2 has the meaning given above, with a halocarboxylic acid halide and then with an alkylamine or arylamine of the general formula VI
  • R 3 has the meaning given in above, and these compounds are optionally converted into their salt with a pharmaceutically acceptable acid or base.
  • the compounds of the general formula I according to the invention can also be prepared in such a way that starting from a compound of the general formula I according to the invention, where n is 0 or 1, this is reacted with a compound which has terminal groups, and thus after the coupling forms a radical R 2 on the above-mentioned compound.
  • REPLACEMENT LEAF Compounds of general formula I are formed in which n is 1 or 2. This means that part of the chain of the compounds of the general formula I according to the invention is provided by the coupled radical R 2 .
  • the production of metal chelate complexes of radioactive metal ions of the elements Tc and Re with compounds of the general formula I is carried out by adding technetium-99m or Re in the form of pertechnetate or perrhenate in the presence of a reducing agent and optionally an auxiliary ligand with a compound of the general formula I.
  • R 1 , R 2 and R 3 have the meaning given above, implemented.
  • REPLACEMENT LEAF System when complexing a chelate complex, which both shows an N 2 S -N-alkyl system or is a further dimer is an 0 S 2 -N-alkyl complex, without a chemical covalent bridge function connecting the complex.
  • the N-alkyl chelates according to the invention can be used for the early detection of atherosclerotic vascular diseases.
  • WHHL rabbits have high LDL levels in the blood due to a missing or defective LDL receptor and therefore develop atherosclerotic vascular changes
  • R 2 is an endothelin, a partial sequence of endothelin, an endothelin analogue, an endothelin derivative or an endothelin antagonist, from activity in the plaque and undamaged vessel, was 1: 5 (see Figures 1 and 2) .
  • the affinity for plaques in atherosclerotic changes in the vessels can be influenced by varying the R 1 alkyl group.
  • the lipophilicity can be controlled via the nature of the residue in R 1 , and at the same time R 2 as a free carboxyl group offers the necessary prerequisite for good water solubility.
  • R 2 as the free carboxylic acid, however, an amidation of this carboxyl group with an amino hydrocarbon can also contribute to water solubility.
  • N-alkyl complexing agents of general formula I with endothelines (examples 11 and 12) from chelating precursors shown here is a new method for generating such complexing sites.
  • the stability of the new N-alkyl complexes of the general formula I corresponds to the known N3S complexes.
  • the compounds according to the invention are prepared by the processes known to those skilled in the art [A Specialist Periodical Report; Amino acids, peptides and proteins;
  • REPLACEMENT LEAF Glycine is then reacted with N-methylamine or, for the introduction of longer residues, with N-alkylamines, phenylamines, alkyloxaalkylamines, cycloalkylamines or glycatedlycolic acid esters.
  • N-alkylamines phenylamines, alkyloxaalkylamines, cycloalkylamines or glycatedlycolic acid esters.
  • R 1 stands for the variations on the sarcosyl nitrogen atom
  • the compounds A, B, C react in a conventional manner with reaction partners carrying amino groups or hydroxyl groups.
  • a to C are dissolved in N-methylpyrrolidone, with BOP (B. Castro et al. Tetrahedron Letters 14 (1975) 1219) or TBTU (Knorr et al. Tetrahe- dron Letters 30 (1989), 1927 ) pre-activated and then reacted with the amino component.
  • BOP B. Castro et al. Tetrahedron Letters 14 (1975) 1219
  • TBTU Knorr et al. Tetrahe- dron Letters 30 (1989), 1927
  • REPLACEMENT LEAF are preferably carried out with dicyclohexylcarbodiimide in the presence of dimethylaminopyridine.
  • an estrogen which already has an unsaturated substituent in 17 ⁇ such as propargylamine or propargyl alcohol residue and reacts this with one of the compounds A to C in the manner described.
  • the compounds A to C are reacted with peptides, in particular with endothelin components, according to methods customary in peptide chemistry, either conventionally in solution, preferably in dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethyl sulfoxide or mixtures of these components.
  • the solid-phase method can also be used to acylate the amino component under customary conditions on the synthetic resin. Cleavage from the synthetic resin provides the desired compounds. Preparative cleaning, if necessary, is carried out chromatographically on an RP 18
  • reaction with peptides in solution was carried out analogously to the reactions with peptides in the reaction with amino groups or hydroxyl group-bearing ergolines.
  • the reactions were carried out in N-methylpyrrolidone.
  • the preparative cleaning is also carried out as indicated for peptides.
  • the complex formation is preferred in an aqueous medium, at a pH between 6 and 9 and at room temperature, by reducing Na pertechnetate with e.g.
  • Tin (II) chloride or dithionide optionally carried out via an auxiliary ligand such as sodium citrate or sodium tartrate, the protective group R 3 being split off beforehand or in situ.
  • R 2 OH
  • replacement of the carboxyl group by an NCS or similarly reactive group lead to peptide chelates covalently attached to a larger protein or proteohormones, endotheline, endothelin analogues, endothelin antagonists, endothelin derivatives To bind partial sequences of endothelins and subsequently carry out complexation.
  • the protective group is cleaved off according to methods known to the person skilled in the art (see “Protective groups in organic synthesis” T.N. Greene, John; Wiley and Sons 1981).
  • REPLACEMENT LEAF Between 370 MBq and 1850 MBq, preferably 740 to 1480 MBq, are usually used for use in human diagnostics.
  • the compounds according to the invention are provided in the form of a kit for use in humans.
  • the kit contains at least one chelator according to the general formula I in free form or bound to ligands.
  • Another object of the invention is a cold kit, which a chelating agent according to the general formula I in free form or to a bioactive molecule, such as. contains an ergoline, estradiol or endothelin derivative, which is capable of binding metal atoms.
  • activated groups are: acid chlorides, mixed anhydrides [Org. Prep. Proc. Int. 1975, 7, 215], activated esters [Adv. Org. Chem. Part B, 472].
  • the linkage with biomolecules can take place directly or via linkers, here the carbodiimide method (Fieser, Reagents for Organic Synthesis 10, 142) is mentioned.
  • the linkage is such that a covalent bond is formed between the chelate and the biomolecule.
  • estradiol derivatives with substituents in the 17 ⁇ position are preferably used.
  • the synthesis of such compounds is e.g. described by Collinsenstaff for 17 ⁇ -ethynyl derivatives of estradiol. (Blickenstaff A.; Steroids 46, 889 (1985); USP 462.426).
  • the synthesis of Magnoliaenstaff, Brandes and Poirier is described for estradiol derivatives with 17 ⁇ -propargyl substituents with terminal NH2 or OH function. (Blickenstaff et al.; Steroids 48, 223 (86); Brandes, A. et al. Dissertation 87-01441, 1986, University of Illinois, D. Poirier et al. J. Steroids. Biochem. Molec. Biol. 38, No. 6, 759-774, 1991).
  • a preferred dopaminergic ligand is ergoline.
  • An overview of synthetic routes to 8-substituted ergolines can be found at Ergot Alkaloids and Related Compounds, Editors B. Berde and H.O. Schild, Springer-Verlag Berlin, Heidelberg, New York, 1978, Chapter II Chemical Background, J. Ruisemmann and P.A. Stadler.
  • reaction with the 8 ⁇ -amino or 8 ⁇ -hydroxy-methyl-ergoline is preferred. It takes place via an activated group in R 2 , for example that with benzotriazol-1-yl-tetra-methyl-uronium tetrafluoroborate or according to the known carbodiimide method.
  • REPLACEMENT LEAF Another object of the invention is the use of the metal chelates for diagnostic and / or therapeutic purposes and pharmaceutical compositions which contain at least one chelate of the general formula I according to the invention, optionally with the additives customary in galenics.
  • the compounds according to the invention are provided in the form of a cold or hot kit.
  • the kit contains at least one chelator according to formula I in free or bound form, the ligands preferably being obtained from the class of ergolines, estriols, endothelins, short-chain synthetic peptides and cholecystokinins.
  • reaction product precipitates as a brown oil, which is separated from the supernatant solution and extracted with chloroform.
  • the chloroform is removed under reduced pressure and ether is added to the residue.
  • the reaction product is precipitated by cooling and intensive stirring, filtered off and dried on the clay plate.
  • reaction product consisted of a mixture of 60% methyl ester and 40% free amino acid.
  • 0.08 mmol of the mixture obtained are suspended in 2 ml of absolute methanol, 2 mg of Pd / CaC03 (5%) are added, and at a hydrogen pressure of 66 kPa with stirring, a solution of 0.13 mmol of sodium methylate in 1 ml of absolute methanol implemented.
  • the mixture is stirred for a further 15 min and then the solution is neutralized with methanolic Dowex 50WX8.
  • the catalyst and the resin are filtered off, the substance is lyophilized and the impurities are extracted with 2 ml of benzene. The benzene is then separated off and the substance is lyophilized from ethanol.
  • the oil is extracted several times with hot water and used as a colorless oil for the next synthesis step without further purification.
  • Tc-gluconate solution 1 ml of 99m Tc-gluconate solution is mixed with a solution of 0.4 mg of pure substance from precursor 4 in 0.5 ml of water. The reaction is complete after 30 minutes.
  • TLC (silica gel 60, 95% ethanol): two components Rf 0-0.1 (40%), Rf 0.8 (60%) electrophoresis (pH 7.0): both components migrate as anions.
  • 0.0022 mol of hexylglycyl diglycine are dissolved in 5 ml of 1N sodium hydroxide solution and stirred for 30 minutes at room temperature. The solution is then cooled. At 0 ° C., 0.3 ml of chloroacetyl chloride and 4 ml of 1N sodium hydroxide solution are added alternately within 30 minutes. Then stirring is continued for 30 minutes without cooling.
  • REPLACEMENT LEAF slowly added and stirring continued for 12 hours.
  • the methanol is removed under reduced pressure and the residue is taken up in 2N HCl.
  • the hydrochloric acid is also removed under reduced pressure, the residue is washed with water and the wash water is thoroughly washed through
  • reaction mixture is prepared on a VYDAc column (40 x 300 mm) without further pretreatment
  • the substance shows an Rf of 0.4 in TLC (CH Cl 2 / MeOH] 5: 5.
  • Example 10 The compound obtained according to Example 10 is complexed with 99m Tc according to the method given as the general method (Example 1).
  • REPLACEMENT LEAF 0.010 mol of His (Trt) -Leu-Asp (OBut) -Ile-Ile-Trp-OH, produced on sasrin resin, are dissolved in a mixture of DMF / NMP with the addition of 0.010 mol of diisopropylethylamine and with stirring with 0.010 mol of S-Bzl-acetyl-Sar-OH, prepared as in Example 11, dissolved in 3 ml of DMF.
  • the mixture is stirred for 2 hours and then the solvent is removed.
  • the remaining residue is stirred with water and suction filtered, washed and dried.
  • the protective groups are removed as usual and the product is obtained by pouring it into ether. The cleaning is carried out as described for example 5.
  • REPLACEMENT LEAF 4th stage S-Bzl-acetyl- [N 1 -Bromphenyl] -Gly-Gly-Gly-OH
  • 0.08 mmol of substance from stage 4 are suspended with 2 ml of anhydrous methanol, mixed with 2 mg of Pd / CaC03 (5%), and stirred at a hydrogen pressure of 66 kPa with a solution of 0.13 mmol of sodium methylate 1 ml of absolute methanol implemented. The mixture is stirred for a further 15 minutes and then the solution is neutralized with methanolic Dowex 50WX8. The catalyst and the resin are filtered off, the substance is lyophilized and extracted with 2 ml of benzene. The benzene is then separated off and the substance is lyophilized from ethanol. The cleaning is done by preparative HPLC.

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Abstract

L'invention concerne des chélateurs N-alkylpeptidiques, leurs complexes métalliques avec des radionucléides, des procédés pour leur préparation et des compositions radiopharmaceutiques contenant ces composés. L'invention concerne également des produits radiopharmaceutiques contenant ces chélates sous une forme complexée avec des métaux, des trousses de diagnostic dans lesquelles le chélate peut se présenter sous une forme non complexée et être complexé par addition d'ions technétium ou rhénium, et elle concerne également l'utilisation de ces préparations à des fins diagnostiques et thérapeutiques.
PCT/DE1994/001295 1993-11-01 1994-10-27 Chelateurs n-alkylpeptidiques, leurs complexes metalliques avec des radionucleides, procedes pour leur preparation et compositions radiopharmaceutiques contenant ces composes WO1995012610A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
EP95900059A EP0726909A1 (fr) 1993-11-01 1994-10-27 Chelateurs n-alkylpeptidiques, leurs complexes metalliques avec des radionucleides, procedes pour leur preparation et compositions radiopharmaceutiques contenant ces composes
AU81038/94A AU681919B2 (en) 1993-11-01 1994-10-27 N-alkyl peptide chelate formers, their metal complexes with radionuclides, processes for producing them and radio-pharmaceutical compositions containing these compounds
JP7512959A JPH09508351A (ja) 1993-11-01 1994-10-27 Ｎ‐アルキルペプチドキレート化剤、その放射性核種との金属錯体、その製造方法、およびこの化合物を含む放射性医薬
NO961743A NO961743D0 (no) 1993-11-01 1996-04-30 N-alkyl-peptid-chelatdannere, deres metallkomplekser med radionuklider, fremgangsmåte ved deres fremstilling og radiofarmasöytiske sammensetninger inneholdende disse forbindelser
KR1019960702247A KR960705842A (ko) 1993-11-01 1996-04-30 N-알킬 펩티드 킬레이트 형성제, 방사핵종을 갖는 그의 금속 착물, 이들의 제조방법 및 이들 화합물을 함유한 방사성의약 조성물(n-alkyl peptide chelate formers, their metal complexes with radionuclides, processes for producing them and radio-pharmaceutical compositions containing these compound)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4337600A DE4337600A1 (de) 1993-11-01 1993-11-01 N-Alkyl-Peptidchelatbildner, deren Metallkomplexe mit Radionukliden, Verfahren zu ihrer Herstellung und diese Verbindungen enthaltende radiopharmazeutische Zusammesetzungen
DEP4337600.2 1993-11-01

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WO1995012610A1 true WO1995012610A1 (fr) 1995-05-11

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Country Status (11)

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EP (1) EP0726909A1 (fr)
JP (1) JPH09508351A (fr)
KR (1) KR960705842A (fr)
CN (1) CN1134158A (fr)
AU (1) AU681919B2 (fr)
CA (1) CA2173844A1 (fr)
DE (1) DE4337600A1 (fr)
HU (1) HUT74881A (fr)
NO (1) NO961743D0 (fr)
WO (1) WO1995012610A1 (fr)
ZA (1) ZA948411B (fr)

Cited By (3)

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Publication number Priority date Publication date Assignee Title
US6162378A (en) * 1999-02-25 2000-12-19 3D Systems, Inc. Method and apparatus for variably controlling the temperature in a selective deposition modeling environment
US6171578B1 (en) 1999-04-14 2001-01-09 Diatide, Inc. Benzodiazepine derivatives for imaging thrombi
US6969728B2 (en) * 2000-05-12 2005-11-29 Genzyme Corporation Modulators of TNF-α signaling

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6241963B1 (en) * 1995-10-19 2001-06-05 The Trustees Of The University Of Pennsylvania Dopamine and serotonin transporter ligands and imaging agents

Citations (6)

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GB2077719A (en) * 1980-06-09 1981-12-23 Norton Norwich Products Inc (N-(Cycloalkyl)amino acid compounds and compositions containing same
WO1992019274A1 (fr) * 1991-05-08 1992-11-12 Mallinckrodt Medical, Inc. Chelates de technetium utilisables pour l'examen de la fonction renale
JPH0570484A (ja) * 1991-09-12 1993-03-23 Hitachi Chem Co Ltd ペプチドおよびその塩
WO1993015771A1 (fr) * 1992-02-06 1993-08-19 Mallinckrodt Medical, Inc. Ligands permettant d'ameliorer la cinetique de formation d'agents chelateurs
WO1993023085A1 (fr) * 1992-05-21 1993-11-25 Diatech, Inc. PEPTIDES MARQUES AU TECHNETIUM-99m DESTINES A L'IMAGERIE DE THROMBUS
WO1994022491A1 (fr) * 1993-03-31 1994-10-13 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Agents chelateurs bifonctionnels et leur utilisation dans des compositions radiopharmaceutiques

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Publication number Priority date Publication date Assignee Title
GB2077719A (en) * 1980-06-09 1981-12-23 Norton Norwich Products Inc (N-(Cycloalkyl)amino acid compounds and compositions containing same
WO1992019274A1 (fr) * 1991-05-08 1992-11-12 Mallinckrodt Medical, Inc. Chelates de technetium utilisables pour l'examen de la fonction renale
JPH0570484A (ja) * 1991-09-12 1993-03-23 Hitachi Chem Co Ltd ペプチドおよびその塩
WO1993015771A1 (fr) * 1992-02-06 1993-08-19 Mallinckrodt Medical, Inc. Ligands permettant d'ameliorer la cinetique de formation d'agents chelateurs
WO1993023085A1 (fr) * 1992-05-21 1993-11-25 Diatech, Inc. PEPTIDES MARQUES AU TECHNETIUM-99m DESTINES A L'IMAGERIE DE THROMBUS
WO1994022491A1 (fr) * 1993-03-31 1994-10-13 Institut für Diagnostikforschung GmbH an der Freien Universität Berlin Agents chelateurs bifonctionnels et leur utilisation dans des compositions radiopharmaceutiques

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Title
CHEMICAL ABSTRACTS, vol. 119, no. 13, 27 September 1993, Columbus, Ohio, US; abstract no. 139794, page 947; column r; *
J.P. DIZIO ET AL.: "Progestin-Rhenium Complexes: Metal-Labeled Steroids with High Receptor Binding Affinity, Potential Receptor-Directed Agents for Diagnostic Imaging or Therapy", BIOCONJUGATE CHEMISTRY, vol. 2, no. 5, WASHINGTON US, pages 353 - 366 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6162378A (en) * 1999-02-25 2000-12-19 3D Systems, Inc. Method and apparatus for variably controlling the temperature in a selective deposition modeling environment
US6171578B1 (en) 1999-04-14 2001-01-09 Diatide, Inc. Benzodiazepine derivatives for imaging thrombi
US6969728B2 (en) * 2000-05-12 2005-11-29 Genzyme Corporation Modulators of TNF-α signaling
US7034031B2 (en) 2000-05-12 2006-04-25 Genzyme Corporation Modulators of TNF-α signaling
US8518999B2 (en) 2000-05-12 2013-08-27 Genzyme Corporation Modulators of TNF-αsignaling
US8921547B2 (en) 2000-05-12 2014-12-30 Genzyme Corporation Modulators of TNF-α signaling
US9579325B2 (en) 2000-05-12 2017-02-28 Genzyme Corporation Modulators of TNF-α signaling

Also Published As

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AU8103894A (en) 1995-05-23
NO961743L (no) 1996-04-30
EP0726909A1 (fr) 1996-08-21
AU681919B2 (en) 1997-09-11
HU9601140D0 (en) 1996-07-29
NO961743D0 (no) 1996-04-30
DE4337600A1 (de) 1995-05-04
CN1134158A (zh) 1996-10-23
CA2173844A1 (fr) 1995-05-11
HUT74881A (en) 1997-02-28
ZA948411B (en) 1995-06-30
KR960705842A (ko) 1996-11-08
JPH09508351A (ja) 1997-08-26

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