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WO1999052861A1 - NOUVEAUX DERIVES DE BENZYLGUANIDINE POUR LA THERAPIE ET LE DIAGNOSTIC IN VIVO ET $i(IN VITRO) - Google Patents

NOUVEAUX DERIVES DE BENZYLGUANIDINE POUR LA THERAPIE ET LE DIAGNOSTIC IN VIVO ET $i(IN VITRO) Download PDF

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Publication number
WO1999052861A1
WO1999052861A1 PCT/DE1999/000377 DE9900377W WO9952861A1 WO 1999052861 A1 WO1999052861 A1 WO 1999052861A1 DE 9900377 W DE9900377 W DE 9900377W WO 9952861 A1 WO9952861 A1 WO 9952861A1
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Prior art keywords
compounds according
acid
compounds
molecule
diagnostics
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PCT/DE1999/000377
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German (de)
English (en)
Inventor
Kai Licha
Wolfgang Wrasidlo
Original Assignee
Institut für Diagnostikforschung GmbH an der Freien Universität Berlin
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Priority claimed from DE19817517A external-priority patent/DE19817517A1/de
Application filed by Institut für Diagnostikforschung GmbH an der Freien Universität Berlin filed Critical Institut für Diagnostikforschung GmbH an der Freien Universität Berlin
Priority to AU34065/99A priority Critical patent/AU3406599A/en
Publication of WO1999052861A1 publication Critical patent/WO1999052861A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/54—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic compound
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/12—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by nitrogen atoms not being part of nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C279/00—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C279/04—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton
    • C07C279/14—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to acyclic carbon atoms of a carbon skeleton being further substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D475/00—Heterocyclic compounds containing pteridine ring systems
    • C07D475/06—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4
    • C07D475/08—Heterocyclic compounds containing pteridine ring systems with a nitrogen atom directly attached in position 4 with a nitrogen atom directly attached in position 2
    • 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

Definitions

  • the invention relates to new benzylguanidine derivatives for therapy, in vivo and in vitro diagnostics, the use of these compounds as therapeutic agents and diagnostic agents and diagnostic agents containing these compounds.
  • the neuroblastoma is a tumor of the sympathetic nervous system that is found in 75% of all patients in the metastatic form and has a poor prognosis. Numerous new therapeutic approaches, such as the
  • MIBG meta-iodobenzylguanidine
  • the neuroblastoma can be treated chemotherapy.
  • Substances suitable for therapy are primarily cytostatic and antibiotic structures (see B. A. Chabner, Anticancer Drugs. In: Cancer - Principles & Practice of Oncology, 4th edition, Lippincott).
  • Applied chemotherapy drugs are e.g. B. cyclophosphamide, cisplatin, epipodophyllotoxins,
  • the object of the invention is therefore to provide new compounds which overcome the disadvantages of the prior art.
  • benzylguanidine structure is coupled with substances or structures which themselves (i) have a therapeutic activity and (ii) are suitable as a signaling molecule for imaging diagnostics.
  • R 1 or R 2 stand for a therapeutic agent, for a therapeutically activatable agent, for a signal molecule for radio diagnostics or for a signal molecule for fluorescence diagnostics with at least one absorption maximum between 400 and 1000 nm,
  • L stands for -NH-, -0-, -S-, -CH 2 - or for a stable, acid-labile and / or enzymatically cleavable linker structure
  • n each represent 0 to 1
  • R to R 7 independently of one another for hydrogen, fluorine, chlorine, bromine, iodine, hydroxyl, carboxy, amino, nitro, C ⁇ -C ⁇ o-alkyl, C ⁇ -C ⁇ 0 -alkoxy, C ⁇ -C ⁇ o-alkoxycarbonyl, C ⁇ -C ⁇ o- Alkylamino, Ci-Cio- (dialkyl) amino, the alkyl radicals being interrupted independently of one another by up to 5 oxygen atoms and / or with 0-2 fluorine, 0-2 chloro, 0-5 hydroxy, 0-3 carboxy, 0-3 esters and / or 0-3 amino groups are substituted,
  • R 2 has the meaning given under a) and the sum of m and n is at least 1,
  • R 1 and R 3 to R 7 have the meaning given under b)
  • n 0 and n is 1 if R 1 is hydrogen and
  • n 1 and n is 0 when R 2 is hydrogen
  • R to R are hydrogen are preferred.
  • the compounds according to the invention are suitable for imaging in vivo diagnostics, in vitro diagnostics and the therapy of neuroblastomas.
  • therapeutically active molecules are coupled to the basic benzylguanidine structure.
  • Therapeutic active ingredients in the general formula (I) are, for example, cytostatic or antibiotic molecules, in particular the compounds listed below:
  • Antibiotics aclacinomycin, actinomycin Fi, anthramycin, azaserine, bleomycins, cactinomycin, Carubicin, Carzino- philin, chromomycins, dactinomycin, daunorubicin, Doxoru- bicine, epirubicin, Mtiomycine, mycophenolic acid, Nogalamy- cin, olivomycins, peplomycin, plicamycin, porfiromycin, puromycin , Streptonigrin, tubercidin, zorubicin and derivatives of the compounds mentioned.
  • Folic acid analogues denopterin, methotrexate, pteropterin, trimetrexate,
  • Pyrimidine analogs ancitabine, azacitidine, 6-azauridine, Carmofur, cytarabine, doxifluridine, enocitabine, floxuridine, 5-fluoro-uracil, purine analogs: fludarabine, 6-mercaptopurine, thiamiprine, thioguanine and derivatives of the compounds mentioned, alkylating Substances: alkylsulfonates, aziridines, ethyleneimines, methylmelamines, nitroureas and nitrogen-leach compounds, such as chlorambucil, chloronaphazine, cyclophosphamide, estramustine, ifosfamide, mechlorethamine, mel ⁇ phalan, novembichin, phenesterols, prednimustine, troferenfamide, des shimmerers substances having hormone activity, such as androgens, antiadrenals, antiandrogens, antiestrogens, estrogens, LH-
  • Compounds of the general formula I which can be activated therapeutically are compounds which contain elements with a high neutron capture cross section and photodynamically active compounds.
  • Photodynamically active molecules are compounds from the class of porphyrins, expanded porphyrins, chlorines, benzochlorines, bacteriochlorins, phthalocyanines, naphthalocyanines or bacteriochlorophylls. After excitation with light, these molecules have the ability to develop a cytotoxic effect through the generation of singlet oxygen or radical reactive molecules.
  • the compounds according to the invention can be used in photodynamic therapy.
  • Other therapeutic agents are substances with a high neutron capture cross section for neutron capture therapy, preferably compounds that contain the element boron. Particularly preferred are BSH and boron phenylalanine as well as molecules that 1 to 12 boron atoms ent ⁇ hold, preferably compounds of the general formula I wherein R 1 and / or R 2 is -B (OH) 2, ortho-carboranyl, para- 7
  • Appropriate signaling molecules are coupled to the benzylguanidine structure for diagnostics using highly sensitive detection methods, such as radio diagnostics and fluorescence diagnostics. This ensures that the resulting conjugates have a binding affinity comparable to that of benzylguanidine or MIBG.
  • Radiodiagnostics is a highly sensitive, imaging method that is widely used in tumor diagnostics. It includes u. a. the detection of ⁇ -radiation-emitting nuclides ( ⁇ -scintigraphy,
  • SPECT positron-emitting nuclides
  • PET positron-emitting nuclides
  • nuclide 9m Tc is widely used diagnostically due to its short half-life (6 h) and easy availability (Tc generators).
  • new agents for scintigraphic diagnostics based on the benzylguanidine structure are made available which are outstandingly suitable for the production of radiodiagnostics and which allow easy handling in the clinic.
  • Signal molecules for radiodiagnostics in the general formula I are therefore preferably nuclide-binding chelators, peptides and complexing agents which complex the above-mentioned nuclides.
  • the invention relates to compounds of the general formula I in which the signal molecule for radiodiagnostics R 1 and / or R 2 for a nuclide-binding chelator which is a mono- or bifunctional chelating N 4 -, N 3 S-, N 2 S 2 -, NOS 2 - or S having 4 structure which forms with 99m Tc and / or 186/188 R ⁇ stable complexes or nuklidbindenden complexing agent which forms a polyvinyl lyamino polycarboxylic acid has Strukur, the stable complexes with In, or a nuclide-binding peptide of the amino acid sequence Cys-Gly-Gly or Cys-Gly-Cys, which forms stable complexes with 99m Tc and / or i86 / i88 Re .
  • chelators are in Bioconjugate Chem. 1997, 8, 407-415, Bioconjugate Chem. 1997, 8, 621-636; Nucl. Med. Biol. 1991, 18, 589-603.
  • the chelators are particularly suitable for labeling with 99m Tc for radiodiagnosis and 186/188 R ⁇ f ur e di radiotherapy.
  • the following structures are preferred: 4-carboxyethylphenylgloxal-bis-N-methylthiosemicarbazone-N-hydroxysuccinimide ester,
  • Thioacetylglycylglycylglycine and thioacetylglycylglycine and derivatives are particularly preferred, the thiol group bearing a suitable protective group.
  • Protected thiol groups are, for example, S-triphenylmethyl (trityl), S-diphenylmethyl (benzhydryl), S-benzyloxycarbonyl, S-tert. Butyloxycarbonyl, S-acetamidomethyl (Acm) and mixed Disulfides (e.g. -SS- tert.butyl).
  • Another subject is nuclide-binding, cysteine-rich amino acid sequences, such as Cys (Acm) GlyCys (Acm), Cys (Acm) GlyGly, CysGlyCys, CysGlyGly.
  • ethylenediaminetetraacetic acid EDTA
  • diethylenediaminepentaacetic acid DTPA
  • trans-1 2-cyclohexanediamine tetraacetic acid
  • 1,4,7, 10-tetraazacyclododecanetetraacetic acid 1,4,7, 10-tetraazacyclododecane triacetic acid
  • 1,4, 7-triazacyclic acid 1,4,8, 11-tetraazatetradecanetetraacetic acid 1, 5, 9-triazacyclododecane triacetic acid, where some of the acetic acid residues may be present as an amide or ester.
  • They are particularly suitable for complexing In In for radio diagnostics , but also for complexing Gd, which has a high neutron capture cross section and is suitable for neutron capture therapy (Jpn. J. Cancer Res. 1993, 84, 841-43) .
  • signaling molecules for radio diagnostics in general formula I are substances for positron emission tomography (PET). Structures containing the isotope F-18 or those which can be labeled with F-18 are particularly preferred.
  • Preferred signal molecules for fluorescence diagnostics are fluorescent dyes with an absorption maximum between 600 and 1000 nm for in-vivo near infrared diagnostics (NIR).
  • NIR diagnostics the high permeability of biological tissue for light of the wavelength 650-1000 nm is used and a fluorescent dye as a contrast medium is detected in vivo based on its absorption or fluorescence. 11
  • fluorescent dyes with an absorption maximum between 400 and 800 nm are preferred.
  • the compounds according to the invention are suitable for the in vitro diagnosis of components to which they have a specific binding (analysis of components from body fluids).
  • Preferred compounds of the general formula I according to the invention are therefore characterized in that R 1 and / or R 2 for a xanthine, fluorescein, rhodamine, oxazine or phenoxazine, thiazine or phenothiazine, cyanine, oxonol, Merocyanine, styryl, Squarilium or Croconium dye is available.
  • L stands for -NH-, -0-, -S-, -CH 2 - or for one
  • Carbon linker structure the esters, ethers, amides, secondary or tertiary amines, ketones, thiourea. May contain urea, carbamate or maleimido groups.
  • the invention further relates to compounds of the general formula (I) in which the
  • Benzylguanidine structure are linked via a physiologically cleavable bond to the radicals R 1 and / or R 2 .
  • the chemical bond which is contained in the linker structure L according to the general formula I is structurally such that it is split at certain physiological parameters by which diseased tissue (tumors) are characterized and which differ from normal tissue areas.
  • Preferred compounds are those in which R 1 and / or R 2 is a therapeutically active molecule.
  • L stands for a linker structure which has an acid-labile bond, preferably an alkylhydrazone, acylhydrazone, arylhydrazone, sulfonylhydrazone, imine, oxime, acetal, ketal, orthoester corresponding to the fragments
  • the compounds according to the invention can also be cleaved by enzymes with which neuroblastomas are endowed in an increased concentration. 13
  • the invention therefore furthermore relates to compounds having linker structures L which are cleaved enzymatically.
  • Enzymatically cleavable linker structures are, for example, those which are cathepsins, peptidases, carboxypeptidases, ⁇ - and ⁇ -glucosidases, lipases, oxidases, phospholipases, phosphatases, phosphodiesterases, proteases, elastases, sulfatases, reductases, transferases and bacterial enzymes, for example Penicillin amidases, ß-lactamases, are cleaved.
  • Preferred enzymatically cleavable structures are short-chain peptide sequences, such as, for example, sequences which contain the amino acid sequence Val-Leu-Lys.
  • the compounds are preferably synthesized by deliberately representing the radicals in the general formula I for R 1 and R 2 and coupling them to benzylguanidine.
  • the structure L is optionally coupled either to the benzylguanidine structure or R 1 or R 2 .
  • the compounds are particularly advantageously synthesized from 3- or 4-aminobenzylguanidine or N, N-di-Boc-3- or NN-di-Boc-4-aminobenzylguanidine.
  • the invention therefore also relates to a method for producing
  • R 1 or R 2 stand for a therapeutic agent, for a therapeutically activatable agent, for a signal molecule for radio diagnostics or for a signal molecule for fluorescence diagnostics with at least one absorption maximum between 400 and 1000 nm,
  • L stands for -NH-, -0-, -S-, -CH 2 - or for a stable, acid-labile and / or enzymatically cleavable linker structure
  • n each represent 0 to 1
  • R 2 has the meaning given under a) and the sum of m and n is at least 1,
  • R 1 and R 3 to R 7 have the meaning given under b)
  • n 0 and n is 1 if R 1 is hydrogen and
  • n 1 and n is 0 when R 2 is hydrogen
  • the aromatic structure of the general formula I together with at least one of the radicals R 1 to R 2, includes a partial structure of a therapeutic active substance, a partial structure of a therapeutically activatable active substance, a partial structure for a signaling molecule for radiodiagnostics or a partial structure of a signaling molecule for fluorescence diagnosis the aforementioned absorption maximum means
  • the therapeutic agents are synthesized according to the methods known to the person skilled in the art.
  • the dyes are synthesized by the processes known to the person skilled in the art.
  • Acid-labile bonds are generated based on the following literature examples.
  • Another object of the invention is the use of the compounds containing the therapeutic agents for the therapy of neuroblastomas.
  • the subject is also the use of the radioactive compounds described as in vivo radio diagnostics and in vivo radiotherapeutics.
  • the use of the dye-containing compounds for the in vivo diagnosis of diseased tissue by means of near infrared (NIR) radiation by detection of the unabsorbed radiation and / or the fluorescent radiation, and for the in vitro diagnosis of constituents from body fluids, such as Blood, urine, cerebrospinal fluid, lymph by detection of the non-absorbed radiation and / or the fluorescent radiation (inter alia by means of FACS "fluorescence activated cell sorting").
  • the compounds according to the invention are also suitable for the diagnosis and therapy of tumors of other types and other origins.
  • Examples are neuroendocrine tumors (e.g. pheochromocytoma; A. Lau et al., Clinical Nuclear Med. 1996, 21, 316-318, "glomus jugulare tumors", E. Nussen, J. Laryngol. Otol. 1996, 110, 373-375), and small intestinal carcinoids (S. Dresel et al., Nuclear Medicine 1994, 35, 53-58), tumors of the adrenal cortex
  • the particular advantage of therapy and diagnostics with the compounds according to the invention is that they are taken up into the diseased cells with simultaneous rapid elimination from the healthy residual body due to the hydrophilicity and the low molecular weight of the compounds.
  • the systemic toxicity is reduced in particular in comparison to antibodies as carrier molecules (eg EP 282057) which have very long circulation times.
  • agents are prepared by methods known to those skilled in the art, optionally using customary auxiliaries and / or carriers as well as diluents and the like. These include physiologically tolerable electrolytes, buffers, detergents and substances for adaptation of Os olartician and to improve the Stabili ⁇ ty and solubility.
  • the measures used in pharmacy are responsible for the sterility of the preparations 20th
  • the dye 4 is produced based on methods known from the literature.
  • 0.1 g (0.12 mmol) 4 and 0.05 g (0.18 mmol) 1 are in 3 ml phosphate buffer (50 mM, pH 8) and 3 ml DMF for 5 h at room temp. coupled. After adding diethyl ether, the precipitated crude product is purified by chromatography (RP-18, Europrep., Mobile phase H 2 0 + 1% CH 3 COOH /
  • the compound is a structural mixture of the therapeutically active, alkylating part of the melphalan and the benzylguanidine.
  • 0.74 g (1.5 mmol) 8 are in 7 ml CH 2 C1 2 and 0.5 ml trifluoroacetic acid for 20 h at room temperature. touched. After evaporation of the solvent, chromatographic purification is carried out (Kieselgel 60, Merck, eluent CH 2 Cl 2 / methanol 9: 1). 0.45 g (74%) 9 is obtained as a white powder, mp. 120-123 ° C (dec.).
  • the compound combines the benzylguanidine structure and the camptothecin structure.
  • the synthesis takes place from 9-aminomethylcamptothecin 13 (J. Med. Chem. 34 (1991) 98-107).
  • the synthesis is carried out by reacting 4- (N- [2,4-diamino-6-pteridinylmethyl] -N-methylamino) benzoic acid 15 with HD-Lys (Boc) -OtBu (based on Biochem. 30 (1991) 5674), the ⁇ -amino group of which is released by cleavage of the protective group to give 16.
  • the coupling then takes place to this amino group by reaction with N, N '-di-Boc-p-isothiocyanatobenzylguanidine 17, which is obtained from 10, to give product 18.
  • the synthesis is carried out by linking N, N '-di-Boc-p-isothiocyanatobenzylguanidin 17 with 4- (aminomethyl) - benzoic acid hydrazide 18 to the intermediate 20 and reaction of the hydrazide group with the keto group of 3'-deamino-3' - (4- morpholinyl) doxorubicin 21 to product 22 to form an acid labile hydrazone bond.
  • the presentation is analogous to the synthesis of 8 as described in Example 3.
  • the cleaning is carried out chromatographically (Kieselgel 60, Merck, mobile solvent
  • Boc protective groups are cleaved directly by stirring in 5 ml of CH 2 C1 2 / 2.5 ml of trifluoroacetic acid for 12 h. After evaporation of the solvents in vacuo and stirring with diethyl ether, a brown-yellow powder is obtained which is purified by chromatography (RP-18 Europrep, eluent H 2 0 + 2% CH 3 COOH / 5% MeOH), yield 0.4 g (40% , calculated as diacetate) 25 as a yellowish lyophilisate.
  • the synthesis is carried out analogously to the synthesis described in Example 8 using N, N'-bis (S-benzoylthioacetyl) -3, 4-diaminobutyric acid 28.
  • the last step is carried out starting from 0.1 g (0.22 mmol) 28 and 0.08 g (0.22 mmol) 25. 29 is obtained as a yellowish powder.
  • 0.5 mg 27 and 29 are dissolved in 0.5 ml phosphate buffer (100 mM Na 2 HP0 4 , pH 9.5) and with 50 ⁇ l trisodium citrate dihydrate solution (150 mM) and 2.5 ⁇ l tin (II ) chloride dihydrate (200 mM in 0.05 N HCl) was added. Then 100 ⁇ l pertechnetate solution (from a 99 Mo / 99m Tc generator, 400 - 900 ⁇ Ci) is added, 15 min at room temperature. incubated and filtered (0.2 ⁇ filter).

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Abstract

L'invention concerne de nouveaux dérivés de benzylguanidine pour la thérapie et le diagnostic in vivo et in vitro, ainsi que l'utilisation de ces composés comme agents thérapeutiques et agents de diagnostic, notamment pour le traitement et le diagnostic de neuroblastomes. L'invention concerne également des agents de diagnostic contenant lesdits composés.
PCT/DE1999/000377 1998-04-09 1999-02-05 NOUVEAUX DERIVES DE BENZYLGUANIDINE POUR LA THERAPIE ET LE DIAGNOSTIC IN VIVO ET $i(IN VITRO) WO1999052861A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU34065/99A AU3406599A (en) 1998-04-09 1999-02-05 Novel benzyl guanidine derivatives for therapy and (in-vivo) and (in-vitro) diagnosis

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE19817517.5 1998-04-09
DE19817517A DE19817517A1 (de) 1998-04-09 1998-04-09 Neue Benzylguanidinderivate für die Therapie, In-vivo- und In-vitro-Diagnostik
US8170698P 1998-04-15 1998-04-15
US60/081,706 1998-04-15

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WO1999052861A1 true WO1999052861A1 (fr) 1999-10-21

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Cited By (6)

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WO2020061007A1 (fr) * 2018-09-17 2020-03-26 The Children's Hospital Of Philadelphia Promédicaments macromoléculaires à base de polymères
IT201900000202A1 (it) * 2019-01-08 2020-07-08 Univ Degli Studi Roma La Sapienza Radiofarmaco per utilizzo diagnostico terapeutico in medicina nucleare e medicina radio guidata
WO2025101904A1 (fr) * 2023-11-08 2025-05-15 The Children's Hospital Of Philadelphia Promédicaments ciblant le transporteur de norépinéphrine pour thérapie anticancéreuse

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EP2298736A1 (fr) * 2000-03-22 2011-03-23 Solulink, Inc. Réactifs de réticulation bifonctionnels à base d'hydrazine et de carbonyle
WO2001070685A3 (fr) * 2000-03-22 2003-03-27 Solulink Inc Agents de reticulation bifonctionnels a base d'hydrazine et de carbonyle
US10010631B2 (en) 2006-12-26 2018-07-03 Lantheus Medical Imaging, Inc. Ligands for imaging cardiac innervation
US12324845B2 (en) 2006-12-26 2025-06-10 Lantheus Medical Imaging, Inc. Ligands for imaging cardiac innervation
US11241509B2 (en) 2006-12-26 2022-02-08 Lantheus Medical Imaging, Inc. Ligands for imaging cardiac innervation
US11174223B2 (en) 2010-05-11 2021-11-16 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US9388125B2 (en) 2010-05-11 2016-07-12 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
US9682927B2 (en) 2010-05-11 2017-06-20 Lantheus Medical Imaging, Inc. Compositions, methods, and systems for the synthesis and use of imaging agents
WO2020061007A1 (fr) * 2018-09-17 2020-03-26 The Children's Hospital Of Philadelphia Promédicaments macromoléculaires à base de polymères
CN112996533B (zh) * 2018-09-17 2025-01-10 费城儿童医院 基于聚合物的大分子前药
CN112996533A (zh) * 2018-09-17 2021-06-18 费城儿童医院 基于聚合物的大分子前药
JP2022501341A (ja) * 2018-09-17 2022-01-06 ザ・チルドレンズ・ホスピタル・オブ・フィラデルフィアThe Children’S Hospital Of Philadelphia ポリマーベースの高分子プロドラッグ
US12311028B2 (en) 2018-09-17 2025-05-27 The Children's Hospital Of Philadelphia Polymer-based macromolecular prodrugs
US11253603B2 (en) 2018-09-17 2022-02-22 The Children's Hospital Of Philadelphia Polymer-based macromolecular prodrugs
JP7546552B2 (ja) 2018-09-17 2024-09-06 ザ・チルドレンズ・ホスピタル・オブ・フィラデルフィア ポリマーベースの高分子プロドラッグ
US11642414B2 (en) 2018-09-17 2023-05-09 The Children's Hospital Of Philadelphia Polymer-based macromolecular prodrugs
CN113557037B (zh) * 2019-01-08 2024-08-09 罗马大学 用于核医学和放射引导医学的诊断/治疗用途的放射性药物
US20220072165A1 (en) * 2019-01-08 2022-03-10 Università Degli Studi Di Roma "La Sapienza" Radiodrug for diagnostic/therapeutic use in nuclear medicine and radio-guided medicine
CN113557037A (zh) * 2019-01-08 2021-10-26 罗马大学 用于核医学和放射引导医学的诊断/治疗用途的放射性药物
WO2020144586A1 (fr) * 2019-01-08 2020-07-16 Università Degli Studi Di Roma "La Sapienza" Radiomédicament pour une utilisation diagnostique/thérapeutique en médecine nucléaire et en médecine guidée par radio
IT201900000202A1 (it) * 2019-01-08 2020-07-08 Univ Degli Studi Roma La Sapienza Radiofarmaco per utilizzo diagnostico terapeutico in medicina nucleare e medicina radio guidata
WO2025101904A1 (fr) * 2023-11-08 2025-05-15 The Children's Hospital Of Philadelphia Promédicaments ciblant le transporteur de norépinéphrine pour thérapie anticancéreuse

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