EP0851770A2 - Agents de chelation amidosulfoniques sulfures bifonctionnels du type s 2?ny pour isotopes radioactifs - Google Patents

Agents de chelation amidosulfoniques sulfures bifonctionnels du type s 2?ny pour isotopes radioactifs

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Publication number
EP0851770A2
EP0851770A2 EP96945141A EP96945141A EP0851770A2 EP 0851770 A2 EP0851770 A2 EP 0851770A2 EP 96945141 A EP96945141 A EP 96945141A EP 96945141 A EP96945141 A EP 96945141A EP 0851770 A2 EP0851770 A2 EP 0851770A2
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EP
European Patent Office
Prior art keywords
ile
asp
cys
leu
phe
Prior art date
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EP96945141A
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German (de)
English (en)
Inventor
Ludger Dinkelborg
Christoph Stephan Hilger
Wolfgang Kramp
Johannes Platzek
Bernd Radüchel
Sebastian Erber
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Bayer Pharma AG
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Institut fuer Diagnostikforschung GmbH
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Publication of EP0851770A2 publication Critical patent/EP0851770A2/fr
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    • 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]
    • 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
    • A61K51/0497—Organic compounds conjugates with a carrier being an 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
    • A61K51/08—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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • 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
    • C07B59/008—Peptides; 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
    • C07C323/64—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 sulfur atoms, not being part of thio groups, bound to the same carbon skeleton
    • C07C323/67—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 sulfur atoms, not being part of thio groups, bound to the same carbon skeleton containing sulfur atoms of sulfonamide groups, bound to the carbon skeleton
    • 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
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H21/00—Compounds containing two or more mononucleotide units having separate phosphate or polyphosphate groups linked by saccharide radicals of nucleoside groups, e.g. nucleic acids
    • 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
    • C07K7/14—Angiotensins: Related peptides
    • 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 new chelating agents containing sulfonamide groups, pharmaceutical compositions containing these compounds, their use in radiodiagnostics and radiotherapy, processes for the preparation of these compounds and compositions, and conjugates of these compounds with substances which accumulate selectively in diseased tissue, in particular peptides.
  • radiopharmaceuticals are used to represent certain structures such as the skeleton, organs or tissues.
  • the diagnostic application presupposes the use of such radioactive agents, which are specific to those after application
  • suitable detectors such as, for example, imaging 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 be the presence of abnormalities in structure and function, pathological
  • 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.
  • radio-labeled compounds the metal can be in free form as an ion or in the form of a metal complex with one or more ligands.
  • metallic radionuclides that can form complexes are technetium-99m and the various rhenium isotopes. The first is used in diagnostics and the second in therapy.
  • the radiopharmaceuticals contain suitable carriers and additives which allow injection, inhalation or ingestion by the patient, as well as physiological buffers, salts etc.
  • 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 good 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.
  • radiopharmaceuticals first requires the synthesis of a suitable ligand. Then the complex with the radionuclide is shown separately (marking).
  • the ligand produced always in the form of a lyophilized kit, is mixed with a solution containing the radionuclide Complex formation conditions implemented. If, for example, the production of a technetium-99m radiopharmaceutical is desired, 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. These complexes are then suitably administered to the patient by injection, inhalation or ingestion.
  • the solutions containing the radionuclide can be obtained from an available Mo-99 / Tc-99m nuclide generator, as in the case of technetium-99m, or from a manufacturer, as in the case of rhenium-186.
  • the complex formation reaction is carried out at suitable temperatures (e.g. 20 ° -100 ° C) within a few minutes to several hours. In order to ensure complete complex formation, a large excess (more than 100-fold excess to the metal radionuclide) of the ligand produced and a sufficient amount of reducing agent are required for a complete reduction of the radionuclide used.
  • Radiopharmaceuticals are made by combining the radionuclide complex, in an amount sufficient for diagnostic or therapeutic use, 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.
  • examples of such carriers are HSA, aqueous buffer solutions, for example tris (hydroxymethyl) aminoethane (or their salts), phosphate, citrate, bicarbonate etc., sterile water, physiological saline, isotonic chloride or dicarbonate Ion solutions or normal plasma ions such as Ca 2+ , Na + , K + and Mg2 + .
  • radiopharmaceutical agents can contain additional agents known as stabilizers. These keep the radionuclide in a stable form until it has reacted with the ligand.
  • stabilizers can include agents known as transfer or auxiliary ligands that are particularly useful in stabilizing and complexing the metal in a well-defined oxidation state until the target ligand complexes the metal via ligand exchange. Examples of this type of auxiliary ligand are
  • gluconheptonic acid (including their salts) gluconheptonic acid, tartaric acid, citric acid, or other common ligands, as detailed below.
  • Radionuclide is the standard
  • Radiopharmaceuticals are shown by first synthesizing the ligand and then reacting it with the metal radionuclide in a suitable manner in order to form a corresponding complex in which the ligand must necessarily be present unchanged after complexation, with the exception of the splitting off of any protective groups or hydrogen ions that may be present. Removal of these groups facilitates coordination of the ligand to the metal ion and thus leads to rapid complexation.
  • pertechnetate is first obtained from a nuclide generator and converted to a lower oxidation level by using suitable reducing agents (eg SnCl2, S2O4 2 " etc.), which is then converted by a suitable one
  • suitable reducing agents eg SnCl2, S2O4 2 " etc.
  • Chelator is stabilized. Because technetium in a row of oxidation levels (+7 to -1), which can change the pharmacological properties by changing the charge of a complex, it is necessary to provide chelators or complex ligands for technetium-99m, which technetium safely, firmly and stably in a defined Can bind oxidation level in order to prevent undesired biodistribution taking place due to redox processes or technetium releases from the corresponding radio diagnostics, which complicates the reliable diagnosis of corresponding diseases.
  • the efficiency of 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. Likewise, direct
  • Protein labeling 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 Patent 4,479,930 and Fritzberg, AR et al. Nucl. Med. 1986, 27, 957) with technetium-99m.
  • donor groups amino, amide, thiol, etc.
  • complexing agents US Patent 4,479,930 and Fritzberg, AR et al. Nucl. Med. 1986, 27, 957
  • Suitable complexing agents for technetium and rhenium isotopes are, for example, cyclic amines as described by Volkert et al. (Appl. Radiol.
  • N2 ⁇ 2 systems (Pillai, MRA, Troutner, DE et al.; Inorg. Chem. 1990, 29; 1850) are in clinical use.
  • a major disadvantage of non-cyclic N 4 systems such as HMPAO is their low complex stability. Tc-99m-HMPAO must because of its instability (Ballinger, JR et al., Appl. Radiat. Isot. 1991, 42; 315), Billinghurst, MW et al.
  • N 2 S2 chelators such as, for example, 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> 9 radio diagnostics with a purity of greater than 69% from a pH value of the complexing medium.
  • N3S systems (Fritzburg, A.; EP-0173424 and EP-0250013) form stable technetium-99m complexes, but have to be heated to temperatures of approx. 100 ° C 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, or to design complexing agents in such a way that they are only selectively coupled to one enriching substance the desired complexing agent structure is formed and thus a weakening of the complex stability is excluded.
  • Such ligands enable a specific, chemically defined binding of technetium or rhenium isotopes to various biological materials, even if so-called prelabeling is carried out.
  • Some chelating agents coupled to monoclonal antibodies eg EP-0247866 and EP-0188256
  • fatty acids EP-0200492
  • N2S2 systems are used as chelating agents, which are not very suitable due to their low stability. Because both the selectively enriching substances in their properties, as well as the Mechanisms according to which they are enriched are very different, it is still necessary to vary the coupling-capable chelating agent and to be able to adapt it to the physiological requirements of the coupling partner with regard to its lipophilicity, membrane permeability, etc.
  • the invention is therefore based on the object of providing stable complex compounds which are coupled or capable of coupling to different selectively enriching compounds without their specificity and selectivity being significantly affected.
  • the requirements for the use of these compounds in humans with regard to the absorbed radiation dose, stability and solubility of the compounds must be fulfilled.
  • this object is achieved in that new chelating agents containing bifunctional sulfonamide groups and their coupling products with specifically enriching compounds are made available.
  • the invention relates to compounds of the general formula (I)
  • R 1 represents a hydrogen atom, a branched or unbranched C ] __g alkyl radical or a sulfur protecting group
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 - R 8 and R 9 are the same or different and each represents a hydrogen atom and / or a branched or unbranched C ] __g alkyl radical,
  • R a is a hydrogen atom, a branched or straight-chain, cyclic or polycyclic c 1-30 alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or
  • Arylalkyl radical which is optionally substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally with one or more heteroatoms from the O series , N, S, P, As, Se is interrupted and / or substituted.
  • Preferred compounds of the general formula (I) are characterized in that n and m each represent 1 and that R 1 , R 2 , R 5 , R 6 , R 7 and R 9 are hydrogen atoms.
  • Particularly preferred compounds of the general formula (I) are characterized in that n and m each represent 1 and that R 1 , R 2 , R 5 , R 6 , R 7 and R 9 are hydrogen atoms.
  • (I) are characterized in that n and m each represent 1 and that R 1 , R 2 , R 5 , R 6 , R 7 and R 9 are hydrogen atoms and B represents a hydroxyl group or a radical -NHR a , wherein
  • R a is a hydrogen atom, a branched or straight-chain cyclic or polycyclic C ] __3 Q - alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl or arylalkyl radical, optionally with hydroxy, oxy, oxo -, Carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally interrupted by one or more heteroatoms from the series 0, N, S, P, As, Se and / or is substituted.
  • the invention further relates to the new bifunctional sulfur-atom-interrupted sulfonamide ligands of the general formula (II)
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 'R 7 , R 8 , R 9 , n, m and B each have the meaning given above.
  • Preferred compounds of the general formula (II) are distinguished in that n and m each represent 1 and in that R 1 , R 2 , R 5 , R 6 , R 7 and R 9 are hydrogen atoms.
  • Particularly preferred compounds of the general formula (I) are characterized in that 1 for each of n and m is and that R 1 , R 2 , R 5 , R 6 , R 7 and R 9 are hydrogen atoms and B is a hydroxyl group or a radical -NHR a , wherein
  • R a is a hydrogen atom, a branched or straight-chain cyclic or polycyclic C ] __3 Q - alkyl, alkenyl, polyalkenyl, alkynyl, polyalkynyl, aryl, alkylaryl, arylalkyl radical, optionally with hydroxy, oxy, oxo -, Carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups with up to 20 carbon atoms and / or optionally interrupted by one or more heteroatoms from the series O, N, S, P, As, Se and / or is substituted.
  • the invention further relates to conjugates containing a compound of the general formula (I and / or II) and nucleotides of the DNA and RNA type, and also selectively accumulating in diseased tissue
  • conjugates are characterized in that the substances accumulating in the diseased tissue are peptides such as endotheline, partial sequences of endothelin, endothelin analogues, endothelin derivatives,
  • Endothelin antagonists or angiotensins partial sequences of angiotensins, angiotensin analogs, angiotensin derivatives and angiotensin antagonists as well as chemotactic peptides.
  • the peptides have the following sequences
  • the present invention furthermore further relates to compounds of the general formula (II)
  • R 1 represents a hydrogen atom, a branched or unbranched C 1-6 alkyl radical or a sulfur protecting group
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 - R 8 and R 9 are the same or different and each represents a hydrogen atom and / or a branched or unbranched C ⁇ _g alkyl radical,
  • R a is a hydrogen atom, a branched or straight-chain, cyclic or polycyclic C ] __3 Q - alkyl, alkenyl, polyalkenyl, alkynyl, Polyalkynyl, aryl, alkylaryl or arylalkyl, which is optionally substituted with hydroxy, oxy, oxo, carboxy, aminocarbonyl, alkoxycarbonyl, amino, aldehyde or alkoxy groups having up to 20 carbon atoms and / or optionally is interrupted and / or substituted by one or more heteroatoms from the series 0, N, S, P, As, Se,
  • Oligonucleotides in which the abbeu is prevented or made more difficult by naturally occurring nucleases, peptides, proteins, antibodies or their fragments are amidic or, in the case of substances containing hydroxyl groups, such as fatty alcohols, ester-like or, in the case of substances containing aldehyde groups, imidic
  • the compounds of the general formula (II) according to the invention are prepared by reacting 2-chloroethanesulfonic acid chloride optionally substituted with R 3 and R 4 in a manner known per se in an aprotic solvent with addition of a suitable base with compounds of the general formula (III)
  • auxiliary bases can, for example, tertiary amines, alkali and
  • Alkaline earth hydroxides, alkali and alkaline earth carbonates are Alkaline earth hydroxides, alkali and alkaline earth carbonates.
  • R 1 , R 2 , R 3 , R 4 , n and B have the meaning given above,
  • kits which are used to produce radiopharmaceuticals, consisting of a compound of the general formula (II) or a conjugate according to the invention containing compounds of the general formula (I and / or II) and substances which accumulate selectively in tissues, a Reducing agents and optionally an auxiliary ligand, which are in the dry state or in solution, as well as instructions for use with a reaction instruction for reacting the described compounds with technetium-99m or Re in the form of a pertechnetate solution or perrhenate solution.
  • the invention also relates to a radiopharmaceutical composition for the non-invasive in vivo presentation of organs, receptors and receptor-containing tissue and / or of atherosclerotic plaques, which contain a compound of the general formula (I) or a conjugate according to the invention containing compounds of the general formula (I and / or II) and contains substances which accumulate selectively in tissues, optionally with the additives customary in galenicals, the compound being prepared in a kit with technetium-99m or Re in the form of a pertechnetate or perrhenate solution.
  • the radiopharmaceutical composition is administered to a patient in an amount of 0.1 to 30 mCi, preferably 0.5 to 10 mCi per 70 kg of body weight, and the radiation emitted by the patient is recorded.
  • many of the chelates synthesized and labeled with technetium-99m or Re show a higher stability than comparable N2S2 and N3S systems which are described in the literature.
  • Example 2 which was coupled to a partial endothelin sequence, no decomposition products could be observed after 24 hours.
  • Tissue-enriching substances also take place according to methods known per se to the person skilled in the art (for example Fritzberg et al .; J. Nucl.Med. 26, 7 (1987)), for example by reacting electrophilic groups of the complex ligand with nucleophilic centers of the selectively in diseased tissues enriching substances or by reaction of nucleophilic groups of the chelator with electrophilic groups of the substances which selectively accumulate in diseased tissues.
  • the coupling partners include different biomolecules used. So e.g. Ligands that bind to specific receptors and thus show changes in receptor density, these include Peptides, steroid hormones, growth factors and neurotransmitters. Coupling products with steroid hormone receptor-affine substances enable improved diagnosis of breast and prostate carcinomas (S.J. Brandes and J.A. Katzenellenbogen, Nucl .Med.Biol. 15, 53, 1988). Variously, tumor cells have an altered density of receptors for peptide hormones or growth factors, e.g. the "epidermal growth factor" (EgF). The concentration differences can be used for the selective enrichment of cytostatics in tumor cells (E. Abound-Pirak et al.;
  • biomolecules are metabolites that can be introduced into the metabolism of the cells and indicate a changed metabolism; these include e.g. Fatty acids, saccharides, peptides and amino acids. Fatty acids coupled to the less stable N2S2 systems have been described in EP-0200492. Other metabolic products such as saccharides, deoxyglucose, lactate and amino acids (leucine, methyl methionine, glycine) were modified with the help of the PET technique for imaging
  • Non-biological substances such as misonidazole and its derivatives, which irreversibly bind to cell components in tissues or tissue parts with a reduced oxygen concentration, can also be used for the specific enrichment of radioactive isotopes and thus for imaging tumors or ischemic regions (ME Shelton, J. Nucl. Med. 30, 351, 1989).
  • Endothelines, endothelin derivatives or with partial sequences of the endotheline or their derivatives for the detection of atherosclerotic vascular diseases were applied to WHHL rabbits, which have high LDL concentrations in the blood due to a genetic defect in the LDL receptor and thus have atherosclerotic lesions. About 1 to 6 h after application of the derivatives in WHHL rabbits, a high accumulation in atherosclerotic plaques could be demonstrated. So far, only very late stages of atherogenesis have been diagnosed with invasive procedures. The compounds according to the invention therefore offer the decisive advantage of diagnosing much earlier stages of atherosclerosis using a non-invasive method.
  • Coupling products of the chelates according to the invention or their complexes with technetium-99m or Re with fatty alcohols, fatty alcohol derivatives or with fatty alcohol amines or their derivatives have proven to be favorable for the detection of atherosclerotic vascular diseases.
  • These derivatives were applied to WHHL rabbits by a genetic defect of the LDL receptor have high LDL concentrations in the blood and thus have atherosclerotic lesions. About 1 to 6 h after application of the derivatives in WHHL rabbits, a high accumulation in atherosclerotic plaques could be demonstrated. So far, only very late stages of atherogenesis have been diagnosed with invasive procedures.
  • the compounds according to the invention therefore offer the decisive advantage of diagnosing much earlier stages of atherosclerosis using a non-invasive method.
  • compositions according to the invention are prepared in a manner known per se by adding the complexing agents according to the invention with the addition of a reducing agent, preferably tin (II) salts such as chloride, pyrophosphate or tartrate, and optionally with the addition of galenics usual additives - dissolves in aqueous medium and then sterile filtered.
  • a reducing agent preferably tin (II) salts such as chloride, pyrophosphate or tartrate
  • galenics usual additives - dissolves in aqueous medium and then sterile filtered.
  • Suitable additives are, for example, physiologically harmless buffers (eg tromethamine), small additions of electrolytes (eg sodium chloride), stabilizers (eg gluconate, phosphates or phosphonates).
  • the pharmaceutical composition according to the invention is in the form of a solution or in lyophilized form and is shortly before application with a solution of Tc-99m pertechnetate, eluted from commercially available Mo / Tc generators, or a perrhenate solution.
  • the pharmaceutical compositions according to the invention are dosed in amounts of 1x10 "5 to 5 ⁇ io 4 nmol / kg body weight, preferably in amounts between lxlO -3 to 5xl0 2 nmol / kg body weight.
  • the amount of radioactivity for diagnostic applications is between 0.05 to 50 mCi, preferably 5 to 30 mCi per 70 kg application, for therapeutic applications between 5 and 500 mCi, preferably 10 to 350 mCi.
  • the application is normally carried out by intravenous, intraarterial, peritoneal or intertumor injection of 0.1 to 2 ml of a solution of the agents according to the invention, intravenous application is preferred.
  • N-vinylsulfonylglycine methyl ester (1) An ice-cooled solution of 8.91 g (100 mmol) of the glycine methyl ester and 17.9 g of chloroethanesulfonyl chloride (110 mmol) in 100 ml of dichloromethane is slowly added with dry pyridine (400 mmol) while cooling with ice. The mixture is allowed to warm to RT and, after the reaction has ended, 200 ml of dilute HCl are added and the dichloromethane phase is separated off.
  • N- (5-chloro-3-thiapentylsulfonyl) ⁇ lycine methyl ester (3) A solution of 2.57 g of glycine derviate 2 (10 mmol) in 50 ml of anhydrous carbon tetrachloride is mixed with 3.14 g of powdered triphenylphosphine (12 mmol) under a nitrogen atmosphere. added and heated under reflux. After cooling, it is diluted with 50 ml of hexane and kept at -20 ° C for some time. The precipitate is suctioned off and the procedure is repeated as above until none
  • N- (5-mercapto-3-thiapentylsulfonyl) glycine (5) 3.52 g (10 mmol) 4. are stirred under protective gas in aqueous methanolic potassium hydroxide solution at 50 ° C. for 3 hours. After cooling, it is diluted with 400 ml of water and the undissolved solution is filtered off. The filtrate is acidified with HCl, extracted with dichloromethane, dried, concentrated and recrystallized. Yield: 64% Analysis:
  • 10 mg of compound 5_ are dissolved in 1.0 ml of ethanol. 50 ul of this ligand solution are mixed with 100 ul ethanol, 150 ul phosphate buffer pH 8.5, 50 ul of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul of a deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 ⁇ l of a pertechnetate solution (400-1000 ⁇ Ci) are added.
  • a deoxygenated tin (II) chloride solution 50 mg / ml 0.1 N HCl
  • a pertechnetate solution 400-1000 ⁇ Ci
  • the reaction mixture is examined for the purity of the Tc complex formed by means of HPLC: LiChrospher RP-18 Column, 5 ⁇ , 125 x 4.6mm; Gradient elution from 100% A to 100% B within 15 min (eluent A: acetonitrile / sodium phosphate 5 mM, pH 2.0 (10/90); eluent B: acetonitrile / sodium phosphate 5 mM, pH 2.0 (75/25); 1 ml / min.
  • the radiochemical purity is> 92%.
  • reaction mixture 150 ul phosphate buffer pH 8, 5, 50 ul of a deoxygenated aqueous citrate solution (50 mg / ml), 2.5 ul of a deoxygenated tin (II) chloride solution (5 mg / ml 0.1 N HCl) and 100 ul of a pertechnetate Solution (400-1000 ⁇ Ci) added.
  • the reaction mixture is after a

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  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Vascular Medicine (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)
  • Toxicology (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne de nouveaux composés de formule générale (I) M -L, dans laquelle M représente un radio-isotope de Tc ou de Re, et L un ligand de formule générale (II) R?1S-CR2R3-(CR4R5)¿n=1,2-S-CHR?6-CHR7-SO¿2-NH-(CR8R9)m=1,2-CO-B dans laquelle R?1, R2, R3, R4, R5, R6, R7, R8, et R9¿ peuvent avoir différentes notations et où B représente un autre groupe, qui d'une part convient pour la liaison dative d'ions métal et d'autre part pour le couplage avec des composés à concentration sélective. Ces nouveaux composés permettent la complexation du technétium et du rhénium et sont utilisés dans le domaine médical pour le diagnostic et la thérapeutique.
EP96945141A 1995-09-21 1996-09-19 Agents de chelation amidosulfoniques sulfures bifonctionnels du type s 2?ny pour isotopes radioactifs Withdrawn EP0851770A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE1995136785 DE19536785A1 (de) 1995-09-21 1995-09-21 Bifunktionelle sulfidhaltige Sulfonamid-Chelatbildner vom Typ S¶2¶NY für radioaktive Isotope
DE19536785 1995-09-21
PCT/DE1996/001825 WO1997012636A2 (fr) 1995-09-21 1996-09-19 Agents de chelation amidosulfoniques sulfures bifonctionnels du type s2ny pour isotopes radioactifs

Publications (1)

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EP0851770A2 true EP0851770A2 (fr) 1998-07-08

Family

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Application Number Title Priority Date Filing Date
EP96945141A Withdrawn EP0851770A2 (fr) 1995-09-21 1996-09-19 Agents de chelation amidosulfoniques sulfures bifonctionnels du type s 2?ny pour isotopes radioactifs

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Country Link
EP (1) EP0851770A2 (fr)
AU (1) AU1436197A (fr)
CA (1) CA2232315A1 (fr)
DE (1) DE19536785A1 (fr)
WO (1) WO1997012636A2 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0946202B1 (fr) * 1996-10-28 2003-09-10 Amersham Health AS Agents de contraste
US6537520B1 (en) 1998-03-31 2003-03-25 Bristol-Myers Squibb Pharma Company Pharmaceuticals for the imaging of angiogenic disorders
US6524553B2 (en) 1998-03-31 2003-02-25 Bristol-Myers Squibb Pharma Company Quinolone vitronectin receptor antagonist pharmaceuticals
US6548663B1 (en) 1998-03-31 2003-04-15 Bristol-Myers Squibb Pharma Company Benzodiazepine vitronectin receptor antagonist pharmaceuticals
BR9909420A (pt) 1998-03-31 2001-09-25 Du Pont Pharm Co Composto, kit, composição metalofarmacêutica de diagnóstico ou terapêutica, composição de agente de contraste de ultrassom, composição radiofarmacêutica terapêutica e composição radiofarmacêutica de diagnóstico
EP1140864A2 (fr) 1998-12-18 2001-10-10 Du Pont Pharmaceuticals Company Medicaments antagonistes du recepteur de la vitronectine
US6794518B1 (en) 1998-12-18 2004-09-21 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
JP2002532440A (ja) 1998-12-18 2002-10-02 デュポン ファーマシューティカルズ カンパニー ビトロネクチン受容体拮抗剤薬剤
US6569402B1 (en) 1998-12-18 2003-05-27 Bristol-Myers Squibb Pharma Company Vitronectin receptor antagonist pharmaceuticals
US6511649B1 (en) 1998-12-18 2003-01-28 Thomas D. Harris Vitronectin receptor antagonist pharmaceuticals

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4310999C2 (de) * 1993-03-31 1996-07-18 Diagnostikforschung Inst Bifunktionelle chalkogenatom-unterbrochene Chelatbildner vom Typ XN¶1¶S¶1¶X' für radioaktive Isotope und deren Metallkomplexe, Verfahren zu ihrer Herstellung sowie diese enthaltende pharmazeutische Mittel
DK0710228T3 (da) * 1993-07-19 1998-09-21 Resolution Pharm Inc Hydraziner med N3S-konfiguration som radionuclidchelatorer
EP0724601A4 (fr) * 1993-08-17 1999-02-03 Neorx Corp Composes chelatants de s 3n servant au radiomarquage de ligands, d'antiligands ou d'autres proteines

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9712636A3 *

Also Published As

Publication number Publication date
WO1997012636A2 (fr) 1997-04-10
DE19536785A1 (de) 1997-03-27
WO1997012636A3 (fr) 1997-09-12
AU1436197A (en) 1997-04-28
CA2232315A1 (fr) 1997-04-10

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