EP2178856A1 - Ligands bispidone et leurs complexes métalliques - Google Patents

Ligands bispidone et leurs complexes métalliques

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Publication number
EP2178856A1
EP2178856A1 EP08759052A EP08759052A EP2178856A1 EP 2178856 A1 EP2178856 A1 EP 2178856A1 EP 08759052 A EP08759052 A EP 08759052A EP 08759052 A EP08759052 A EP 08759052A EP 2178856 A1 EP2178856 A1 EP 2178856A1
Authority
EP
European Patent Office
Prior art keywords
radicals
formula
chain
hydrogen
aryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP08759052A
Other languages
German (de)
English (en)
Inventor
Peter Comba
Christina Haaf
Marion Kerscher
Achim Lienke
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Universitaet Heidelberg
Original Assignee
Universitaet Heidelberg
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Universitaet Heidelberg filed Critical Universitaet Heidelberg
Publication of EP2178856A1 publication Critical patent/EP2178856A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • C07F1/00—Compounds containing elements of Groups 1 or 11 of the Periodic Table
    • C07F1/005—Compounds containing elements of Groups 1 or 11 of the Periodic Table without C-Metal linkages

Definitions

  • the present invention relates to novel bispidone ligands, processes for their preparation and their use as ligands in metal complexes and the selective separation of metals, metal complexes containing these ligands, processes for their preparation and the use of such metal complexes in organic synthesis, in the bleaching technique and in the radiopharmaceutical Area.
  • Multi-dentate ligands are a compound of great interest because of their versatility in both technical and medical fields.
  • such ligands are used for the selective separation of metal ions or in metal complexes for the catalytic oxidation of unsaturated compounds or for bleaching.
  • stable and biocompatible metal complexes find application as contrast agents or in the diagnosis and treatment of cancer.
  • radical R A is selected from a group according to one of the formulas (2a) to (2d)
  • E is selected from N or P, x is an integer from 0 to 5, the radical R 1 is hydrogen, straight-chain or branched-chain (C 1 -C 12) -alkyl radicals, (C 3-8 ) cycloalkyl radicals, (C 5 - I 2) aryl or heteroaryl, (C 6- I 2) alkaryl or Alkheteroarylresten or a composition as defined above group of formula (2a) to (2d), wherein e are defined and x are as above, both radicals R 2 each independently selected from hydrogen, straight or branched chain (C 1-12) alkyl, (C 3-8) cycloalkyl, and (C 6-12) aryl or (C 5-12) heteroaryl, both radicals are selected, R 3 are each independently selected from hydrogen, straight or branched (Ci -12) alkyl, (C 3-8) cycloalkyl, (C 6 -I 2) aryl or (C 5 - I2) heteroaryl and carboxylic acid groups or
  • aryl group as used herein is not particularly limited and includes all chemical groups having an aromatic skeleton such as a phenyl group. In accordance with the present invention, the term “aryl” includes both unsubstituted and substituted aromatic groups.
  • heteroaryl radical as used herein is not subject to any particular restriction and includes all aromatic groups whose skeleton contains one or more heteroatoms, such as a pyridyl radical.
  • groups may be, inter alia, derivatives of 5-rings, such as pyrroles, furans, thiophenes or imidazoles, or derivatives of 6-rings, such as pyrazines, pyridines or pyrimidines.
  • alkaryl group as used in the present invention includes all those compounds substituted with at least one alkyl group, such as benzyl or ethylphenyl groups.
  • the “alkaryryl” may be both unsubstituted and substituted on one or more alkyl groups and / or the aromatic skeleton.
  • alkheteroaryl as used herein is not particularly limited and includes all compounds containing an aromatic skeleton having at least one heteroatom and at least one alkyl group.
  • alkheteroaryl radicals are, for example, picolinyl radicals.
  • carboxylic acid group or derivatives derived therefrom, selected from esters, amides and peptides means a corresponding -CO 2 H, -CO 2 " , -CONH 2 , -CONHR x group in which R x then represents a corresponding amide or peptide residue.
  • x is an integer value from 0 to 5. If x is, for example, in the formula (2a)
  • a preferred embodiment of the present invention relates to a bispidone ligand according to formula (1) as defined above, in which the radical R A is a group of the formula (2a):
  • R 1 is a straight or branched (Ci -6) alkyl, (C 6-12) Alkheteroarylrest or a group of the above defined formula (2a), both R 2 are each independently selected from hydrogen or (C 6 - 12 ) aryl or (C 5 -I2 ) heteroaryl are selected, both R 3 are each independently selected from (Ci -6 ) aryl or heteroaryl groups or carboxylic acid groups or derivatives derived therefrom, selected from esters, amides and peptides are the radical R 4 is selected from hydrogen, straight or branched (C 1-I2) alkyl or (C 3-8) cycloalkyl is selected, and both of R 5 and R 6 are each independently selected from hydrogen, straight or branched (C M2 Aikylresten or (C 3-8 ) cycloalkyl radicals are selected, and wherein E is selected from N or P, preferably from N, and x is an integer from 0 to 5.
  • R 1 is methyl, picolinyl or a group of the formula (3):
  • E is selected from N or P and x is an integer from 0 to 5
  • the radical R 4 is hydrogen, straight or branched chain (C 1 -I 2 ) alkyl radicals, (C 3-8 ) cycloalkyl radicals, (C6-1 2) aryl or (C 5 I 2) heteroaryl is selected, and, if appropriate, two radicals R 5 and R 6 are each independently selected from hydrogen, straight or branched (Ci -I2) alkyl, (C 3-8) cycloalkyl, ( C 6 -I2 ) aryl or (C 5 -I2 ) heteroaryl radicals are selected, with formaldehyde and an acetone derivative of the formula (5):
  • each of R 3 is independently selected from hydrogen, straight or branched chain (C 1 -12 ) alkyl, (C 3-8 ) cycloalkyl, (C 6-12 ) aryl, or (C 5-12 ) heteroaryl and carboxylic acid or derived derivatives selected from esters, amides and peptides, to form a piperidone intermediate of formula (6):
  • Formula (6)
  • radicals R A and R 3 are as defined above, and (b) reacting the piperidone intermediate of the formula (6) with formaldehyde and an amine of the general formula H 2 NR 1 , wherein the radical R 1 is hydrogen straight or branched chain (Ci -I2) alkyl, (C 3-8) cyclo alkyl, (C6 -I 2) aryl or (C 5 I 2) heteroaryl, (C 6- I 2) or Alkyaryl- Alkhe- teroaryl groups or a group of the formula (2a) to (2d) as defined above, wherein E and x are as defined above, and wherein the radicals R 3 to R 6 are as defined above.
  • the radicals R 1 is hydrogen straight or branched chain (Ci -I2) alkyl, (C 3-8) cyclo alkyl, (C6 -I 2) aryl or (C 5 I 2) heteroaryl, (C 6- I 2) or Alkyaryl- Alkhe- teroaryl groups or a group of
  • a further embodiment relates to a process for the preparation of one of the above-defined bispidone ligands according to formula (1), in which the radical R 1 is a group of the formula (2a):
  • R 4 is selected from hydrogen, straight or branched chain (C 1-I2) alkyl, (C 3-8) cycloalkyl, (C 6- I 2) aryl or (C 5 - I 2 ) heteroaryl radicals is selected, and if appropriate both radicals R 5 and R 6 are each independently hydrogen, straight-chain or branched-chain (C M2 ) alkyl radicals, (C 3-8 ) cycloalkyl radicals, (C 6 -i 2) aryl radicals or (C 5 -I2 ) heteroaryl radicals are selected, with formaldehyde and a compound of the formula (7): Formula (7)
  • radical R 1 consists of hydrogen, straight-chain or branched-chain (Ci-I 2 ) alkyl radicals, (C 3 -8) cycloalkyl radicals, (C5-12) aryl or heteroaryl radicals, (C6-12) alkaryl or Alkheteroaryl phenomenon or a as defined above group of formula (2a) to (2d), wherein e and x are as previously defined, both R 2 are each independently selected from hydrogen, straight or branched (C1-1 2) alkyl, (C 3- 8) cycloalkyl, (C 6- I 2) aryl or (C5-I2) heteroaryl are selected, both radicals R 3 are each independently selected from hydrogen, straight or branched (C1-12) alkyl, (C 3-8) Cycloalkyl radicals, (C 6 -I 2) aryl or (C 5 -12 ) heteroaryl radicals or carboxylic acid groups or derivatives derived therefrom, selected from esters, amides and peptides,
  • the present invention furthermore relates to the use of the above bispi- nite ligands for the selective separation of metal ions, for the preparation of metal complexes for the catalytic oxidation of unsaturated compounds, for the catalytic bleaching or for the diagnosis and / or therapy of tumor diseases.
  • selective separation of metals is not particularly limited and refers to all applications in which there are at least two metals, one or more of which are to be enriched and / or removed.
  • catalytic oxidation includes all those reactions which introduce an oxygen atom or oxygen molecule into a target compound and / or increase or decrease the oxidation numbers of the participating reactants.
  • tumor disease includes all such diseases of a mammal that are related to a direct cancer or are in some way associated with a cancer.
  • Another aspect of the present invention relates to a metal complex comprising one of the bispidone ligands defined above, wherein the metal is selected from Mn, Cu, Fe, Co, Ti, V, Mo, W, Tc, In, Ga, Y, Re, or the Selective earth metals is selected.
  • metal as used herein is not particularly limited and includes the metal as such and its ions in all known oxidation states.
  • the metal in such a metal complex according to the invention is a radioactive nuc-Nd.
  • nuclide includes all isotopes of the aforementioned metals useful in the invention.
  • nuclide encompasses those metal isotopes which are preferably used in radiopharmaceutical compounds, such as, for example, 99m Tc, 64 Cu (for example for positron emission tomography), 67 Cu (for use in therapy, for example), 86 Y, 90 Y and 188 Re.
  • Another aspect of the present invention relates to a method for the manufacture of a lung of the foregoing metal complexes, wherein the Bispidonligand as defined above with a metal salt solution of the corresponding metal is reacted at a temperature in the range of 20 to 100 0 C.
  • the present invention relates to use the metal complex as defined above in the catalytic oxidation of unsaturated compounds, the catalytic bleaching and the diagnosis and / or treatment of tumor diseases.
  • Another object of the present invention relates to a compound having the formula (6):
  • radical R A is selected from a group according to one of the formulas (2a) to (2d):
  • E is selected from N or P and x is an integer from 0 to 5
  • the two radicals R 3 are each independently selected from hydrogen, straight or branched (Ci - I 2) alkyl, (C 3- 8) cycloalkyl, (C 6- i2) aryl or (C 5-12) heteroaryl or carboxylic acid groups or derivatives derived therefrom, selected from esters, amides and peptides, are selected
  • the radical R 4 selected from hydrogen, straight or branched chain (C 1-I2) Alkyl radicals, (C 3 - 8 ) cycloalkyl radicals, (C 6 -I2 ) aryl or (C 5 I 2 ) heteroaryl radicals is selected
  • both R 5 and R 6 are each independently selected from hydrogen, straight or branched chain (C1 -12) alkyl radicals, (C 3-S ) cycloalkyl radicals, (C 6-12 ) aryl or (C 5 - I 2 ) heteroaryl radicals are selected
  • the bispidone ligands of the present invention are advantageously characterized by the fact that, due to their variable structure, a large number of highly efficient metal complexes can be tapped, for example for olefin oxidation, in applications as bleaching agents or in the diagnosis and / or therapy of tumor cancers.
  • the property of the particular metal complex can already be specifically influenced by the synthesis of the bispidone ligands according to the invention.
  • the present invention provides surprisingly diverse synthetic routes, which advantageously allow the preparation of bispidone ligands.
  • Copper tetrafluoroborate is introduced into 5 ml acetonitrile in a 250 ml three-necked flask and the bispidone is dissolved in 17 ml acetonitrile and added to the dissolved copper tetrafluoroborate, the dark blue solution is heated to 82 ° C. for 5 min Room temperature is initiated by Etherdiffusion the crystallization. The purification was carried out by repeated recrystallization from acetonitrile.
  • Copper tetrafluoroborate is introduced into 5 ml acetonitrile in a 100 ml three-necked flask. Likewise, the bispidone is dissolved in 5 ml of acetonitrile and added to the dissolved copper tetrafluoroborate. The now dark blue solution is for 5 min. heated to 82 ° C. After cooling to room temperature, crystallization is initiated by Etherdiffusion. The purification is carried out by recrystallization from acetonitrile. Yield: 54.8 mg (0.07 mmol, 58.3%).
  • amine A1 and formalin in 5 ml of THF are added at 0 ° C.
  • P2 is then added at room temperature in 5 ml of THF. It is stirred at room temperature for 30 h. It is evaporated to dryness, the oily residue is recrystallized from methanol.
  • N-tosyliminophenyliodinane (1 eq, 0.4 mmol, 150 mg), the copper catalyst (5 mol%, 0.02 mmol) and columned degassed styrene (22 eq, 8.7 mmol, 1 mL) were degassed in dry, de-gassed Acetonitrile was stirred under nitrogen at 25 ° C until the reaction mixture cleared (7 h max.). The solution was filtered through a short neutral Alox column, the column rinsed with ethyl acetate (20 ml).
  • Cobalt (II) tetrafluoroborate is placed in 2 ml acetonitrile in a 50 ml flask. Then B3, also dissolved in 2 ml of acetonitrile, is added and heated briefly. The pink colored solution is stirred overnight. Etheriffusion produces pinkish crystals. Purification takes place by recrystallization from acetonitrile.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne de nouveaux ligands bispidone, des procédés de fabrication de ceux-ci et leur utilisation en tant que ligands dans des complexes métalliques et dans la séparation sélective de métaux. L'invention concerne également des complexes métalliques contenant ces ligands, des procédés de fabrication de ces complexes métalliques et l'utilisation de ces derniers dans la synthèse organique, dans le blanchiment et dans le domaine radiopharmaceutique.
EP08759052A 2007-07-16 2008-06-05 Ligands bispidone et leurs complexes métalliques Withdrawn EP2178856A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102007033020A DE102007033020A1 (de) 2007-07-16 2007-07-16 Bispidonliganden und deren Metallkomplexe
PCT/EP2008/004506 WO2009010129A1 (fr) 2007-07-16 2008-06-05 Ligands bispidone et leurs complexes métalliques

Publications (1)

Publication Number Publication Date
EP2178856A1 true EP2178856A1 (fr) 2010-04-28

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EP08759052A Withdrawn EP2178856A1 (fr) 2007-07-16 2008-06-05 Ligands bispidone et leurs complexes métalliques

Country Status (4)

Country Link
US (1) US20110003984A1 (fr)
EP (1) EP2178856A1 (fr)
DE (1) DE102007033020A1 (fr)
WO (1) WO2009010129A1 (fr)

Families Citing this family (5)

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Publication number Priority date Publication date Assignee Title
ES2349082T3 (es) 2006-07-07 2010-12-27 Unilever Plc Endurecimiento de un líquido.
DE102010007058A1 (de) * 2010-02-06 2011-08-11 Clariant International Limited Verfahren zur Herstellung von 3,7-Diaza-bicyclo[3.3.1]nonan-Metallkomplex-Lösungen
EP2474578A1 (fr) 2011-01-06 2012-07-11 Rahu Catalytics Limited Compositions antipeaux
EP3024898B1 (fr) 2013-07-25 2017-11-08 OMG UK Technology Limited Catalyseurs encapsulés
EP3818116A1 (fr) 2018-07-05 2021-05-12 Catexel Technologies Limited Composition de revêtement durcissable par oxydation

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Publication number Priority date Publication date Assignee Title
GB0325432D0 (en) * 2003-10-31 2003-12-03 Unilever Plc Ligand and complex for catalytically bleaching a substrate
DE102004062568B3 (de) * 2004-12-24 2006-02-23 Forschungszentrum Rossendorf E.V. Radioaktive Metallkomplexe von Chelatbildnern und deren Verwendung für die nuklearmedizinische Diagnostik und Therapie sowie Verfahren zur Herstellung radioaktiver Metallkomplexe

Non-Patent Citations (1)

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Title
See references of WO2009010129A1 *

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WO2009010129A1 (fr) 2009-01-22
DE102007033020A1 (de) 2009-01-22
WO2009010129A8 (fr) 2009-03-26
US20110003984A1 (en) 2011-01-06

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