EP0923588A1 - Bismuth dendrimers, processes for their preparation, and their use as x-ray contrast agents - Google Patents

Bismuth dendrimers, processes for their preparation, and their use as x-ray contrast agents

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Publication number
EP0923588A1
EP0923588A1 EP97938795A EP97938795A EP0923588A1 EP 0923588 A1 EP0923588 A1 EP 0923588A1 EP 97938795 A EP97938795 A EP 97938795A EP 97938795 A EP97938795 A EP 97938795A EP 0923588 A1 EP0923588 A1 EP 0923588A1
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Prior art keywords
group
compounds according
zero
hydroxy
substituted
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German (de)
French (fr)
Inventor
Werner Krause
Herbert Schumann
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Bayer Pharma AG
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Schering AG
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    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/50—Organo-phosphines
    • C07F9/5004—Acyclic saturated phosphines
    • C07F9/5009—Acyclic saturated phosphines substituted by B, Si, P or a metal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A61K49/04—X-ray contrast preparations
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/94—Bismuth compounds

Definitions

  • the invention relates to dendrimeric organometallic bismuth compounds (bismuth dendrimers) which can advantageously be used as X-ray contrast media and to processes for their preparation.
  • the contrast media currently used in X-ray diagnostics contain either barium or iodine as the contrasting element. All currently approved parenterally administered contrast agents contain iodine, either with three or six iodine atoms per molecule (DP Swanson, HM Chilton, JH Thrall, "Pharmaceuticals in Medical Imaging", 1990, McMillan). In these compounds, the iodine atoms are always covalently coupled to the "carrier molecule" and enable the representation of such vessels, organs and tissues that are reached by the iodine-containing contrast media. The presence of the contrast medium increases the x-ray density of these tissues relative to their surroundings, so that they become visible in the x-ray image and allow diagnoses regarding their shape or pathological changes. With these contrast media, a number of different diagnostic methods can be used, such as for the Water-soluble, iodine-containing compounds include angiography, urography, myelography and cholecystography.
  • Barium is used in the form of the water-insoluble barium sulfate as an orally administered formulation exclusively for the presentation of the gastrointestinal tract.
  • Contrast agents without iodine lie in avoiding the known side effects of the iodine-containing compounds such as pseudo-allergic reactions, chemotoxic effects and the side effects of released iodide on the thyroid gland.
  • the disadvantage of metal complexes is the usually relatively low metal content or the too low solubility of the metal complexes, which is generally too low for use as an X-ray contrast medium.
  • Bismuth organic compounds are e.g. in EP 0716 091 A1, JP A 4-154622, Vestn. Leningrad Univ., Fisz., Khim. vol. 4, pp. 113-116 (1976), J. Chem. Soc, Chem. Commun., Vol. 16, pp. 1143-4 (1992), J. Coord. Chem., Vol. 12, pp. 53-57 (19982).
  • Bismuth dendrimers have not been described, however.
  • the object of the present invention is to design contrast media for use in X-ray diagnostics that do not contain iodine and therefore cannot cause the side effects induced by this element. It has now surprisingly been found that novel, previously unknown organic bismuth compounds, so-called bismuth dendrimers, can be used as X-ray contrast agents. The structure of these new compounds corresponds to the general formula I.
  • X is the central unit for O, S, N, P, C, Si, Sn, Ge, Bi or stands for an aryl, heteroaryl, alkyl or cycloalkyl group, the heteroatoms, and / or alkyl-hydroxy, polyhydroxyalkyl substituents and / or Can contain ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride and or urea groups, where X has the base multiplicity b,
  • L for one stands which can be zero to ten times hydroxy-substituted and can contain zero to ten aryl or heteroaryl, ether, ester, thioether, thioester, amide, thioamide, sulfonate, sulfonamide, phosphonate or phosphoric acid amide groups;
  • n 1 to 10, preferably 1 to 5,
  • R independently of one another for a branched or unbranched zero to six-fold hydroxy-substituted C ⁇ -C-jo-aryl or benzyl group, one
  • Ether group -OR ester group COOR, thioether group -SR, thioester group -COSR, amide group -CONR R or thioamide group -CSNR R, in which
  • R independently of one another represents a branched or unbranched zero to six times hydroxy-substituted C 1 -C 6 alkyl group, zero to six times hydroxy substituted C 6 -C 10 aryl or benzyl group, 4
  • R independently of one another represents a hydrogen atom or a branched or unbranched zero to six times hydroxy-substituted C 6 -C 18 aryl or benzyl group
  • the invention therefore relates to organism of bismuth of the general formula I as characterized by the claims.
  • dendrimer was defined by Tomalia (D.A. Tomalia, Spectrum of Science, September 1995, pages 42-47). This is understood to mean a polymeric compound in which a central molecule (“initiator core”) is surrounded concentrically by monomer layers. Dendrimers are characterized by an increasing number of branches from the inside out.
  • the branches are caused by bismuth atoms.
  • the bismuth-containing monomer shells applied one after the other are also referred to as generations in this document.
  • the central unit X in the compounds according to the invention is a central atom such as 0, S, N, P, C, Si, Sn, Ge or Bi or an aryl, heteroaryl, alkyl or cycloalkyl group, the heteroatoms and / or alkyl, hydroxy - Or can contain polyhydroxyalkyl substituents.
  • the central unit X can also be referred to as the zero generation.
  • the central unit X can also contain a metabolically cleavable bridge, such as an ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride or urea bond, so that the invention Bismuth dendrimer can be broken down in the human or animal organism.
  • a metabolically cleavable bridge such as an ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride or urea bond
  • a bismuth atom preferably serves as the central unit of the dendrimer.
  • the variable b stands for the base multiplicity of the central unit, that is to say for the number of reactive positions of the central unit which can be linked to the first generation of bismuth-containing monomers.
  • the base multiplicity b of oxygen and sulfur is, for example, 2, of bismuth, nitrogen and phosphorus 3, of silicon, germanium and tin 4. If the central unit is formed by organic groups, the base multiplicity can be between 1 and 12.
  • Group L is a link between two generations. Starting from the central unit (0th generation), the first generation of bismuth-containing organyls is connected by means of group L.
  • Group L can also contain a metabolically cleavable bridge, such as an ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride or urea linkage, so that the bismuth dendrimer according to the invention can be broken down in the human or animal organism.
  • a metabolically cleavable bridge such as an ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride or urea linkage, so that the bismuth dendrimer according to the invention can be broken down in the human or animal organism.
  • a C ß -C ⁇ alkylene group can also be used as the connecting member L.
  • This group can be zero to ten times hydroxy-substituted. It may also contain zero to ten aryl or heteroaryl, ether, ester, thioether, thioester, amide, thioamide, sulfonate, sulfonamide, phosphonate or phosphoric acid amide groups.
  • L is preferably an ethylene or a propylene group.
  • the groups R and R can either for a further generation of bismuth-containing monomers of the formula la
  • the groups R optionally contained in the groups R and R represent branched or unbranched zero to six times hydroxy-substituted C 1-6 alkyl groups or zero to six times hydroxy-substituted C 6 -C 10 aryl or benzyl groups.
  • the groups R optionally contained in the groups R and R stand for hydrogen atoms or for branched or unbranched zero to six times hydroxy-substituted CjC ß- alkyl groups or for zero to six times hydroxy-substituted C ⁇ -Cio-Aiy'- or benzyl groups.
  • the groups L, R and R can be different in each generation.
  • hydrophilic groups such as hydroxyl, carboxy, amido, ether, thioether, ester or thioester groups, are preferred.
  • the hydrophilic dendrimers according to the invention generally contain at least as many hydrophilic groups as bismuth atoms of the last generation are present.
  • the invention preferably relates to those dendrimers in which all groups R 1 , R 2 of the last generation contain hydrophilic substituents.
  • the groups R and R in the last generation preferably represent a branched or unbranched zero to six times hydroxy-substituted Ci-Ce alkyl group, particularly preferably the 2,3-dihydroxypropyl radical. Examples of connections with bismuth as the central unit of the base multiplicity three and one or two generations are shown below:
  • X represents a central unit shark represents a halogen atom
  • M is a metal atom, e.g. Mg represents, b corresponds to the base multiplicity of the central unit, m corresponds to the charge number of M reduced by 1, Y is a direct bond or a group L, where L stands for a Cj-Cio-alkylene group which may be zero to ten times hydroxy-substituted and may contain from zero to ten aryl or heteroaryl, ether, ester, thioether, thioester, amide, thioamide, sulfonate, sulfonamide, phosphonate or phosphoric acid amide groups
  • R independently of one another for a branched or unbranched zero to six times hydroxy-substituted Ce-C-jo aryl or benzyl group
  • R independently of one another represents a branched or unbranched zero to six times hydroxy-substituted Ci-Cg-alkyl group, zero to six times hydroxy-substituted Ce-C-io-aryl or benzyl group,
  • R independently of one another represents a hydrogen atom or a branched or unbranched zero to six times hydroxy-substituted C 6 -C 18 aryl or benzyl group
  • the new compounds meet the requirements for contrast media, especially for X-ray contrast media. They are particularly suitable for computed tomography.
  • the compounds according to the invention with molecular weights greater than 10,000 are suitable for the representation of the intravascular space.
  • the compounds according to the invention are also suitable for displaying tumors, infarcted tissue or inflammation.
  • the compounds according to the invention can also be used as contrast agents in MRI, ultrasound and radio diagnostics. They are also used in therapy.

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Abstract

The invention concerns dendrimeric organometallic bismuth compounds (bismuth dendrimers) which can advantageously be used as X-ray contrast agents. The invention also concerns processes for their preparation.

Description

Wismutdendrimere, Bismuth dendrimers,
Verfahren zu ihrer Herstellung und ihre Verwendung als RöntgenkontrastmittelProcess for their preparation and their use as X-ray contrast media
Die Erfindung betrifft dendrimere metallorganische Wismutverbindungen (Wismut- dendrimere), die vorteilhaft als Röntgenkontrastmittel eingesetzt werden können sowie Verfahren zu ihrer Herstellung.The invention relates to dendrimeric organometallic bismuth compounds (bismuth dendrimers) which can advantageously be used as X-ray contrast media and to processes for their preparation.
Stand der TechnikState of the art
Die in der Röntgendiagnostik derzeit gebräuchlichen Kontrastmittel enthalten als kontrastgebendes Element entweder Barium oder Jod. Alle derzeit zugelassenen parenteral applizierten Kontrastmittel sind jodhaltig, entweder mit drei oder mit sechs Jodatomen pro Molekül (D.P. Swanson, H.M. Chilton, J.H. Thrall, "Pharmaceuticals in Medical Imaging", 1990, McMillan). Die Jodatome sind in diesen Verbindungen immer kovalent an das "Trägermolekül" gekoppelt und ermöglichen die Darstellung von solchen Gefäßen, Organen und Geweben, die von den jodhaltigen Kontrastmitteln erreicht werden. Durch die Anwesenheit des Kontrastmittels erhöht sich die Röntgendichte dieser Gewebe relativ zu ihrer Umgebung, so daß sie im Röntgenbild sichtbar werden und Diagnosen bezüglich ihrer Form bzw. krankhafter Veränderungen erlauben. Mit diesen Kontrastmitteln können eine Reihe verschiedener Diagnoseverfahren Anwendung finden, wie z.B. für die wasserlöslichen, jodhaltigen Verbindungen die Angiographie, Urographie, Myelographie und Cholezystographie.The contrast media currently used in X-ray diagnostics contain either barium or iodine as the contrasting element. All currently approved parenterally administered contrast agents contain iodine, either with three or six iodine atoms per molecule (DP Swanson, HM Chilton, JH Thrall, "Pharmaceuticals in Medical Imaging", 1990, McMillan). In these compounds, the iodine atoms are always covalently coupled to the "carrier molecule" and enable the representation of such vessels, organs and tissues that are reached by the iodine-containing contrast media. The presence of the contrast medium increases the x-ray density of these tissues relative to their surroundings, so that they become visible in the x-ray image and allow diagnoses regarding their shape or pathological changes. With these contrast media, a number of different diagnostic methods can be used, such as for the Water-soluble, iodine-containing compounds include angiography, urography, myelography and cholecystography.
Barium wird in Form des nicht wasserlöslichen Bariumsulfats als oral zu verabreichende Formulierung ausschließlich für die Darstellung des Magen- /Darmtraktes eingesetzt.Barium is used in the form of the water-insoluble barium sulfate as an orally administered formulation exclusively for the presentation of the gastrointestinal tract.
In der Vergangenheit wurden jedoch auch eine Reihe von neuartigen Typen von Kontrastmitteln vorgeschlagen oder untersucht, die in der Mehrzahl der Fälle Metallkomplexe darstellen (z.B. R.M. Nalbandian, W.T. Rice, W.O. Nickels, Annais of NY Acad. Sc, 1959, 79, 779-792; WO 90/03804; US 4,310,507, US 4,478,816, US 4,647,447, US 4, 176, 173, US 5,417,958). Das Ziel bei der Suche nachIn the past, however, a number of novel types of contrast agents have been proposed or investigated, which in the majority of cases represent metal complexes (e.g. RM Nalbandian, WT Rice, WO Nickels, Annais of NY Acad. Sc, 1959, 79, 779-792 ; WO 90/03804; US 4,310,507, US 4,478,816, US 4,647,447, US 4, 176, 173, US 5,417,958). The goal in finding
Kontrastmitteln ohne Jod liegt darin, die bekannten Nebenwirkungen der jodhaltigen Verbindungen wie pseudoallergische Reaktionen, chemotoxische Effekte sowie die Nebenwirkungen von freigesetztem Jodid an der Schilddrüse zu vermeiden. Der Nachteil von Metallkomplexen liegt in dem gewöhnlich relativ niedrigen Metallgehalt bzw. der zu niedrigen Löslichkeit der Metallkomplexe, der in der Regel für die Verwendung als Röntgenkontrastmittel zu niedrig ist.Contrast agents without iodine lie in avoiding the known side effects of the iodine-containing compounds such as pseudo-allergic reactions, chemotoxic effects and the side effects of released iodide on the thyroid gland. The disadvantage of metal complexes is the usually relatively low metal content or the too low solubility of the metal complexes, which is generally too low for use as an X-ray contrast medium.
Wismutorganische Verbindungen, zum Teil auch verwendbar als Röntgenkontrastmittel, sind z.B. in EP 0716 091 A1, JP A 4-154622, Vestn. Leningrad Univ., Fisz., Khim. vol. 4, S. 113-116 (1976), J. Chem. Soc, Chem. Commun., vol. 16, S. 1143-4 (1992), J. Coord. Chem., vol. 12, S. 53-57 (19982) beschrieben worden. Wismutdendrimere sind jedoch bislang nicht beschrieben worden.Bismuth organic compounds, some of which can also be used as X-ray contrast agents, are e.g. in EP 0716 091 A1, JP A 4-154622, Vestn. Leningrad Univ., Fisz., Khim. vol. 4, pp. 113-116 (1976), J. Chem. Soc, Chem. Commun., Vol. 16, pp. 1143-4 (1992), J. Coord. Chem., Vol. 12, pp. 53-57 (19982). Bismuth dendrimers have not been described, however.
Die Aufgabe der vorliegenden Erfindung besteht nun darin, Kontrastmittel für die Anwendung in der Röntgendiagnostik zu konzipieren, die kein Jod enthalten und damit die durch dieses Element induzierten Nebenwirkungen nicht hervorrufen können. Es wurde nun überraschend gefunden, daß neuartige, bisher noch nicht bekannte wismutorganische Verbindungen, sogenannte Wismutdendrimere, als Röntgenkontrastmittel verwendet werden können. Die Struktur dieser neuen Verbindungen entspricht der allgemeinen Formel IThe object of the present invention is to design contrast media for use in X-ray diagnostics that do not contain iodine and therefore cannot cause the side effects induced by this element. It has now surprisingly been found that novel, previously unknown organic bismuth compounds, so-called bismuth dendrimers, can be used as X-ray contrast agents. The structure of these new compounds corresponds to the general formula I.
wobeiin which
X als Zentraleinheit für O, S, N, P, C, Si, Sn, Ge, Bi steht oder für eine Aryl, Heteroaryl, Alkyl- oder Cycloalkylgruppe steht, die Heteroatome, und/oder Alkyl- Hydroxy-, Polyhydroxyalkylsubstituenten und/oder Ester-, Amid-, Thioester-, Thioamid-, Acetal-, Ketal-, Thioacetal-, Thioketal, Disulfid-, Anhydrid- und oder Harnstoffgruppen enthalten kann, wobei X die Basismultiplizität b aufweist,X is the central unit for O, S, N, P, C, Si, Sn, Ge, Bi or stands for an aryl, heteroaryl, alkyl or cycloalkyl group, the heteroatoms, and / or alkyl-hydroxy, polyhydroxyalkyl substituents and / or Can contain ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride and or urea groups, where X has the base multiplicity b,
L für eine steht, die null bis zehnfach hydroxysubstituiert sein kann und null bis zehn Aryl- oder Heteroaryl-, Ether-, Ester-, Thioether-, Thioester-, Amid-, Thioamid-, Sulfonat-, Sulfonamid-, Phosphonat- oder Phosphorsäureamidgruppen enthalten kann;L for one stands which can be zero to ten times hydroxy-substituted and can contain zero to ten aryl or heteroaryl, ether, ester, thioether, thioester, amide, thioamide, sulfonate, sulfonamide, phosphonate or phosphoric acid amide groups;
n 1 bis 10, bevorzugt 1 bis 5 ist,n is 1 to 10, preferably 1 to 5,
1 21 2
R , R unabhängig voneinander für eine weitere Einheit der Formel laR, R independently of one another for a further unit of the formula la
L-BiR1R2 (la)L-BiR 1 R 2 (la)
oderor
1 21 2
R , R unabhänig voneinander für eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte Cß-C-jo-Aryl- oder Benzylgruppe, eineR, R independently of one another for a branched or unbranched zero to six-fold hydroxy-substituted Cβ-C-jo-aryl or benzyl group, one
Ethergruppe -OR , Estergruppe COOR , Thioethergruppe -SR , Thioestergruppe -COSR , Amidgruppe -CONR R oder Thioamidgruppe -CSNR R steht , worinEther group -OR, ester group COOR, thioether group -SR, thioester group -COSR, amide group -CONR R or thioamide group -CSNR R, in which
33
R unabhängig voneinander für eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte C1-C6-Alkylgruppe, null bis sechsfach hydroxysubstituierte C6-C10-Aryl- oder Benzylgruppe steht, 4R independently of one another represents a branched or unbranched zero to six times hydroxy-substituted C 1 -C 6 alkyl group, zero to six times hydroxy substituted C 6 -C 10 aryl or benzyl group, 4
R unabhängig voneinander für ein Wasserstoffatom oder eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte C6-Cιo-Aryl- oder Benzylgruppe steht,R independently of one another represents a hydrogen atom or a branched or unbranched zero to six times hydroxy-substituted C 6 -C 18 aryl or benzyl group,
Die Erfindung betrifft daher wismutorganische Verbindungen der allgemeinen Formel I, wie sie durch die Patentansprüche gekennzeichnet sind.The invention therefore relates to organism of bismuth of the general formula I as characterized by the claims.
Der Begriff Dendrimer wurde von Tomalia definiert (D.A. Tomalia, Spektrum der Wissenschaft, September 1995, Seite 42-47). Man versteht darunter eine polymere Verbindung, in der ein zentrales Molekül ("Initiator-Kern") konzentrisch von Monomer-Schichten umgeben ist. Kennzeichnend für Dendrimere ist eine von innen nach außen steigende Anzahl von Verzweigungen.The term dendrimer was defined by Tomalia (D.A. Tomalia, Spectrum of Science, September 1995, pages 42-47). This is understood to mean a polymeric compound in which a central molecule (“initiator core”) is surrounded concentrically by monomer layers. Dendrimers are characterized by an increasing number of branches from the inside out.
Bei den erfindungsgemäßen Verbindungen werden die Verzweigungen durch Wismutatome bewirkt. Die nacheinander aufgebrachten wismuthaltigen Monomer- Schalen werden in diesem Dokument auch als Generationen bezeichnet.In the compounds according to the invention, the branches are caused by bismuth atoms. The bismuth-containing monomer shells applied one after the other are also referred to as generations in this document.
Als Zentraleinheit X dient in den erfindungsgemäßen Verbindungen ein Zentralatom wie 0, S, N, P, C, Si, Sn, Ge oder Bi oder eine Aryl-, Heteroaryl-, Alkyl- oder Cycloalkylgruppe, die Heteroatome und/oder Alkyl-, Hydroxy- oder Polyhydroxyalkylsubstituenten enthalten kann. Die Zentraleinheit X kann auch als nullte Generation bezeichnet werden.The central unit X in the compounds according to the invention is a central atom such as 0, S, N, P, C, Si, Sn, Ge or Bi or an aryl, heteroaryl, alkyl or cycloalkyl group, the heteroatoms and / or alkyl, hydroxy - Or can contain polyhydroxyalkyl substituents. The central unit X can also be referred to as the zero generation.
Die Zentraleinheit X kann aber auch eine metabolisch spaltbare Brücke, wie beispielsweise eine Ester-, Amid-, Thioester, Thioamid-, Acetal-, Ketal-, Thioacetal-, Thioketal-, Disulfid-, Anhydrid- oder Harnstoffbindung enthalten, so daß das erfindungsgemäße Wismutdendrimer im menschlichen oder tierischen Organismus abgebaut werden kann.The central unit X can also contain a metabolically cleavable bridge, such as an ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride or urea bond, so that the invention Bismuth dendrimer can be broken down in the human or animal organism.
Bevorzugt dient ein Wismutatom als Zentraleinheit des Dendrimers.A bismuth atom preferably serves as the central unit of the dendrimer.
Die Variable b steht für die Basismultiplizität der Zentraleinheit, das heißt für die Anzahl der reaktiven Positionen der Zentraleinheit, die mit der ersten Generation von wismuthaltigen Monomeren verknüpft werden kann. Die Basismultiplizität b von Sauerstoff und Schwefel ist beispielsweise 2, von Wismut, Stickstoff und Phosphor 3, von Silicium, Germanium und Zinn 4. Wird die Zentraleinheit von organischen Gruppen gebildet, kann die Basismultiplizität zwischen 1 und 12 liegen.The variable b stands for the base multiplicity of the central unit, that is to say for the number of reactive positions of the central unit which can be linked to the first generation of bismuth-containing monomers. The base multiplicity b of oxygen and sulfur is, for example, 2, of bismuth, nitrogen and phosphorus 3, of silicon, germanium and tin 4. If the central unit is formed by organic groups, the base multiplicity can be between 1 and 12.
Die Gruppe L ist ein Verbindungsglied zwischen zwei Generationen. Ausgehend von der Zentraleinheit (nullte Generation) wird die erste Generation von wismuthaltigen Organylen mittels der Gruppe L verbunden.Group L is a link between two generations. Starting from the central unit (0th generation), the first generation of bismuth-containing organyls is connected by means of group L.
Die Gruppe L kann auch eine metabolisch spaltbare Brücke, wie beispielsweise eine Ester-, Amid-, Thioester, Thioamid-, Acetal-, Ketal-, Thioacetal-, Thioketal-, Disulfid-, Anhydrid- oder Harnstoffbindung enthalten, so daß das erfindungsgemäße Wismutdendrimer im menschlichen oder tierischen Organismus abgebaut werden kann.Group L can also contain a metabolically cleavable bridge, such as an ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride or urea linkage, so that the bismuth dendrimer according to the invention can be broken down in the human or animal organism.
Als Verbindungsglied L kann ferner eine Cß-C^-Alkylengruppe stehen. Diese Gruppe kann null bis zehnfach hydroxysubstituiert sein. Sie kann ferner null bis zehn Aryl- oder Heteroaryl-, Ether-, Ester-, Thioether-, Thioester-, Amid-, Thioamid-, Sulfonat-, Sulfonamid-, Phosphonat- oder Phosphorsäureamidgruppen enthalten.A C ß -C ^ alkylene group can also be used as the connecting member L. This group can be zero to ten times hydroxy-substituted. It may also contain zero to ten aryl or heteroaryl, ether, ester, thioether, thioester, amide, thioamide, sulfonate, sulfonamide, phosphonate or phosphoric acid amide groups.
Bevorzugt steht L für eine Ethylen- oder eine Propylengruppe.L is preferably an ethylene or a propylene group.
1 21 2
Die Gruppen R und R können entweder für eine weitere Generation von wismuthaltigen Monomeren der Formel laThe groups R and R can either for a further generation of bismuth-containing monomers of the formula la
L-BiR1R2 (la)L-BiR 1 R 2 (la)
oder in der letzten Generation für eine organische Gruppe, wie z.B.or in the last generation for an organic group, e.g.
• eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte C^-A branched or unbranched zero to six times hydroxy-substituted C ^ -
C6-Alkylgruppe oderC 6 alkyl group or
• eine null bis sechsfach hydroxysubstituierte Cß-Cio-Aryl- oder Benzylgruppe,A zero to six-fold hydroxy-substituted C ß -io-aryl or benzyl group,
33
• eine Ethergruppe -OR• an ether group -OR
33
• eine Estergruppe COOR• an ester group COOR
3 • eine Thioethergruppe -SR3 • a thioether group -SR
33
• eine Thioestergruppe -COSR• a thioester group -COSR
3 43 4
• eine Amidgruppe -CONR R• an amide group -CONR R
3 43 4
• eine Thioamidgruppe -CSNR R Die in den Gruppen R und R gegebenfalls enthaltenen Gruppen R stehen für verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte C-|-Cg- Alkylgruppen oder für null bis sechsfach hydroxysubstituierte C6-C10-Aryl- oder Benzylgruppen.• a thioamide group -CSNR R The groups R optionally contained in the groups R and R represent branched or unbranched zero to six times hydroxy-substituted C 1-6 alkyl groups or zero to six times hydroxy-substituted C 6 -C 10 aryl or benzyl groups.
1 2 4 Die in den Gruppen R und R gegebenfalls enthaltenen Gruppen R stehen für Wasserstoffatome oder für verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte C-j-Cß-Alkylgruppen oder für null bis sechsfach hydroxysubstituierte Cβ-Cio-Aiy'- oder Benzylgruppen.1 2 4 The groups R optionally contained in the groups R and R stand for hydrogen atoms or for branched or unbranched zero to six times hydroxy-substituted CjC ß- alkyl groups or for zero to six times hydroxy-substituted Cβ-Cio-Aiy'- or benzyl groups.
Für die erfindungsgemäßen Verbindungen, gilt daß die Gruppen L, R und R in jeder Generation verschieden sein können.For the compounds according to the invention, the groups L, R and R can be different in each generation.
Bevorzugt sind Verbindungen, die hydrophile Gruppen, wie Hydroxy-, Carboxy-, Amido-, Ether-, Thioether-, Ester- oder Thioestergruppen enthalten.Compounds which contain hydrophilic groups, such as hydroxyl, carboxy, amido, ether, thioether, ester or thioester groups, are preferred.
Bedingt durch die Symmetrie des Moleküls enthalten die erfindungsgemäßen hydrophilen Dendrimere in der Regel mindestens so viele hydrophile Gruppen, wie Wismutatome der letzten Generation vorhanden sind. Ein Dendrimer der Basismultiplizität 3 (b=3) mit einer Generation (n=1) trägt beispielsweise 3 Wismutatome in der letzten Generation und enthält in der Regel somit mindestens 3 hydrophile Gruppen. Tragen die Wismutatome der letzten Generation mehrere hydrophile Gruppen, so beträgt die Anzahl der hydrophilen Gruppen des gesamten Moleküls ein vielfaches hiervon. Ein Dendrimer der Basismultiplizität 3 (b=3) mit einer Generation (n=1) kann somit 6 hydrophile Gruppen enthalten. Bevorzugt betrifft die Erfindung solche Dendrimere bei denen alle Gruppen R1, R2 der letzten Generation hydrophile Substituenten enthalten.Due to the symmetry of the molecule, the hydrophilic dendrimers according to the invention generally contain at least as many hydrophilic groups as bismuth atoms of the last generation are present. A dendrimer of base multiplicity 3 (b = 3) with one generation (n = 1) carries, for example, 3 bismuth atoms in the last generation and therefore usually contains at least 3 hydrophilic groups. If the bismuth atoms of the last generation carry several hydrophilic groups, the number of hydrophilic groups in the entire molecule is a multiple thereof. A dendrimer of base multiplicity 3 (b = 3) with one generation (n = 1) can thus contain 6 hydrophilic groups. The invention preferably relates to those dendrimers in which all groups R 1 , R 2 of the last generation contain hydrophilic substituents.
1 21 2
Bevorzugt stehen die Gruppen R und R in der letzten Generation für eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte Ci-Ce- Alkylgruppe, besonders bevorzugt für den 2,3-Dihydroxypropylrest. Beispiele für Verbindungen mit Wismut als Zentraleinheit der Basismultiplizität drei und ein bzw. zwei Generationen sind nachfolgend dargestellt:The groups R and R in the last generation preferably represent a branched or unbranched zero to six times hydroxy-substituted Ci-Ce alkyl group, particularly preferably the 2,3-dihydroxypropyl radical. Examples of connections with bismuth as the central unit of the base multiplicity three and one or two generations are shown below:
Für R = -CH2CONHCH2(CHOH)CH2OH lautet die Summenformel Bi4C36H72N60i8- Das Molekulargewicht beträgt 1712, der relative Wismutgehalt des Moleküls liegt bei 49%. Das Molekül ist nichtionisch.For R = -CH 2 CONHCH 2 (CHOH) CH 2 OH the molecular formula is Bi 4 C3 6 H 72 N 6 0i8- The molecular weight is 1712, the relative bismuth content of the molecule is 49%. The molecule is non-ionic.
Für R = -CH2CONHCH(CH2OH)2 lautet die Summenformel Bi C39H78N60i8- Das Molekulargewicht beträgt 1754, der relative Wismutgehalt des Moleküls liegt bei 48%. Das Molekül ist nichtionisch. For R = -CH 2 CONHCH (CH 2 OH) 2 the molecular formula is Bi C 3 9H 78 N 6 0i8- The molecular weight is 1754, the relative bismuth content of the molecule is 48%. The molecule is non-ionic.
Für R = -CH2CONHCH2(CHOH)CH2OH lautet die Summenformel Bi22CιooH2θθNl2θ36- Das Molekulargewicht beträgt 6742, der relative Wismutgehalt des Moleküls liegt bei 68%. Das Molekül ist nichtionisch.For R = -CH 2 CONHCH 2 (CHOH) CH 2 OH the molecular formula is Bi22Cιoo H 2θθ N l2θ36- The molecular weight is 6742, the relative bismuth content of the molecule is 68%. The molecule is non-ionic.
Methoden zur Herstellung dieser Verbindungen sind dem Fachmann geläufig. Als beispielhaft, jedoch nicht auf diese Verfahren beschränkt, sei die folgende Methode genannt. Methods for the preparation of these compounds are known to the person skilled in the art. The following method is mentioned as an example, but not limited to these methods.
HerstellungsmethodeManufacturing method
Stufenweise (konsekutive) Reaktion von Wismuthalogeniden mit metallorganischen Verbindungen, z.B. Grignardverbindungen dadurch gekennzeichnet, daß Verbindungen der allgemeinen Formel IIGradual (consecutive) reaction of bismuth halides with organometallic compounds, e.g. Grignard compounds, characterized in that compounds of the general formula II
XHalb (II)XHal b (II)
mit metallorganischen Verbindungen der allgemeinen Formel IIIwith organometallic compounds of the general formula III
MHal(Y-CH=CH2)m (III)MHal (Y-CH = CH 2 ) m (III)
zur Reaktion gebracht werden, wobei X eine Zentraleinheit darstellt Hai ein Halogenatom darstellt,are reacted, where X represents a central unit shark represents a halogen atom,
M ein Metallatom, z.B. Mg, darstellt, b der Basismulitplizität der Zentraleinheit entspricht, m der um 1 verminderten Ladungszahl von M entspricht, Y eine direkte Bindung oder eine Gruppe L ist, wobei L für eine C-j-Cio-Alkylengruppe steht, die null bis zehnfach hydroxysubstituiert sein kann und null bis zehn Aryl- oder Heteroaryl-, Ether-, Ester-, Thioether-, Thioester-, Amid-, Thioamid-, Sulfonat-, Sulfonamid-, Phosphonat- oder Phosphorsäureamidgruppen enthalten kannM is a metal atom, e.g. Mg represents, b corresponds to the base multiplicity of the central unit, m corresponds to the charge number of M reduced by 1, Y is a direct bond or a group L, where L stands for a Cj-Cio-alkylene group which may be zero to ten times hydroxy-substituted and may contain from zero to ten aryl or heteroaryl, ether, ester, thioether, thioester, amide, thioamide, sulfonate, sulfonamide, phosphonate or phosphoric acid amide groups
Die erhaltenen Verbindungen der allgemeinen Formel IVThe compounds of general formula IV obtained
X(Y-CH=CH2)b (IV)X (Y-CH = CH 2 ) b (IV)
können anschließend, z.B. mit HHal zu Verbindungen der allgemeinen Formel Vcan then, e.g. with HHal to compounds of general formula V
X(Y-CH2-CH2Hal)b (V)X (Y-CH 2 -CH 2 Hal) b (V)
umgesetzt werden. Daraus werden die entsprechenden metallorganischen Verbindungen der allgemeinen Formel VI hergestelltbe implemented. The corresponding organometallic compounds of the general formula VI are prepared from this
X(Y-CH2-CH2 Hal)b (VI) die entweder mit Verbindungen der allgemeinen Formel VIIX (Y-CH 2 -CH 2 Hal) b (VI) which either with compounds of the general formula VII
BiHal3 (VII)BiHal 3 (VII)
oder - in der letzten Dendrimerengβneration - mit Verbindungen der allgemeinen Formel VIIIor - in the last dendrimer generation - with compounds of the general formula VIII
BiHalRV (VIII)BiHalRV (VIII)
umgesetzt werden, wobeibe implemented, whereby
1 21 2
R , R unabhänig voneinander für eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte Ce-C-jo-Aryl- oder Benzylgruppe,R, R independently of one another for a branched or unbranched zero to six times hydroxy-substituted Ce-C-jo aryl or benzyl group,
3 3 3 eine Ethergruppe -OR , Estergruppe COOR , Thioethergruppe -SR , Thioestergruppe -COSR , Amidgruppe -CONR R oder3 3 3 an ether group -OR, ester group COOR, thioether group -SR, thioester group -COSR, amide group -CONR R or
Thioamidgruppe -CSNR R steht , worinThioamide group -CSNR R, in which
33
R unabhängig voneinander für eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte Ci-Cg-Alkylgruppe, null bis sechsfach hydroxysubstituierte Ce-C-io-Aryl- oder Benzylgruppe steht,R independently of one another represents a branched or unbranched zero to six times hydroxy-substituted Ci-Cg-alkyl group, zero to six times hydroxy-substituted Ce-C-io-aryl or benzyl group,
44
R unabhängig voneinander für ein Wasserstoffatom oder eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte C6-Cιo-Aryl- oder Benzylgruppe steht,R independently of one another represents a hydrogen atom or a branched or unbranched zero to six times hydroxy-substituted C 6 -C 18 aryl or benzyl group,
Die neuen Verbindungen erfüllen die Anforderungen für Kontrastmittel, insbesondere für Röntgenkontrastmittel. Sie sind insbesondere für die Computertomographie geeignet.The new compounds meet the requirements for contrast media, especially for X-ray contrast media. They are particularly suitable for computed tomography.
Diejenigen erfindungsgemäßen Verbindungen mit Molekulargewichten bis ca. 10.000 sind besonders geeignet für die Darstellung des ExtrazellulärraumesThose compounds according to the invention with molecular weights up to approximately 10,000 are particularly suitable for the representation of the extracellular space
Die erfindungsgemäßen Verbindungen mit Molekulargewichten größer als 10.000 sind für die Darstellung des Intravasalraumes geeignet. Die erfindungsgemäßen Verbindungen sind auch geeignet zur Darstellung von Tumoren, infarziertem Gewebe oder von Entzündungen.The compounds according to the invention with molecular weights greater than 10,000 are suitable for the representation of the intravascular space. The compounds according to the invention are also suitable for displaying tumors, infarcted tissue or inflammation.
Die erfindungsgemäßen Verbindungen können auch als Kontrastmittel in der MRI-, der Ultraschall- und der Radiodiagnostik verwendet werden. Darüber hinaus finden sie Anwendung in der Therapie. The compounds according to the invention can also be used as contrast agents in MRI, ultrasound and radio diagnostics. They are also used in therapy.

Claims

Patentansprüche claims
1. Dendrimere Verbindungen der allgemeinen Formel I1. Dendrimeric compounds of the general formula I
x-rMBiR1R2 b (I)x-rMBiR 1 R 2 b (I)
wobeiin which
X als Zentraleinheit für O, S, N, P, C, Si, Sn, Ge, Bi steht oder für eineX is the central unit for O, S, N, P, C, Si, Sn, Ge, Bi or one
Aryl, Heteroaryl, Alkyl- oder Cycloalkylgruppe steht, die Heteroatome, und/oder Alkyl- Hydroxy-, Polyhydroxyalkylsubstituenten und/oder Ester-, Amid-, Thioester-, Thioamid-, Acetal-, Ketal-, Thioacetal-, Thioketal, Disulfid-, Anhydrid- und oder Harnstoffgruppen enthalten kann, wobei X die Basismultiplizität b aufweist,Aryl, heteroaryl, alkyl or cycloalkyl group, the heteroatoms, and / or alkyl-hydroxy, polyhydroxyalkyl substituents and / or ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide , Anhydride and or urea groups, where X has the base multiplicity b,
L unabhängig voneinander für eine C^Cio-Alkylengruppe steht, die null bis zehnfach hydroxysubstituiert sein kann und null bis zehn Aryl- oder Heteroaryl-, Disulfid-, Anhydrid-, Thioketal-, Thioacetal-, Ketal-, Ether-, Ester-, Thioether-, Thioester-, Amid-, Thioamid-, Harnstoff-, Sulfonat-, Sulfonamid-, Phosphonat- oder Phosphorsäureamidgruppen enthalten kann;L independently of one another represents a C 1-4 alkylene group which can be zero to ten times hydroxy-substituted and zero to ten aryl or heteroaryl, disulfide, anhydride, thioketal, thioacetal, ketal, ether, ester, May contain thioether, thioester, amide, thioamide, urea, sulfonate, sulfonamide, phosphonate or phosphoric acid amide groups;
n 1 bis 10 ist,n is 1 to 10,
b die Basismultiplizität der Zentraleinheit ist,b is the base multiplicity of the central unit,
R , R unabhängig voneinander für eine weitere Einheit der Formel laR, R independently of one another for a further unit of the formula la
L-BiR1R2 (la)L-BiR 1 R 2 (la)
oderor
1 21 2
R , R unabhänig voneinander für eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte Cg-C-jo-Aryl- oder Benzylgruppe, eine Ethergruppe -OR , Estergruppe COOR , Thioethergruppe -SR ,R, R independently of one another for a branched or unbranched zero to six times hydroxy-substituted Cg-C-jo-aryl or benzyl group, an ether group -OR, ester group COOR, thioether group -SR,
3 3 4 Thioestergruppe -COSR , Amidgruppe -CONR R oder3 3 4 thioester group -COSR, amide group -CONR R or
3 43 4
Thioamidgruppe -CSNR R steht , worin R unabhängig voneinander für eine verzweigte oder unverzweigte null bis sechsfach hydroxysubstituierte C^Cß-Alkylgruppe, null bis sechsfach hydroxysubstituierte Cβ-C^-Ar l- oder Benzylgruppe steht,Thioamide group -CSNR R, in which R is independently a branched or unbranched zero to six hydroxy-C ^ C ß alkyl group, zero to six hydroxy-substituted C β -C -Ar l- or benzyl group,
R unabhängig voneinander für ein Wasserstoffatom oder eine verzweigteR independently of one another for a hydrogen atom or a branched one
5 oder unverzweigte null bis sechsfach hydroxysubstituierte C6-Cιo-Aryl- oder Benzylgruppe steht.5 or unbranched zero to six times hydroxy-substituted C 6 -Cιo-aryl or benzyl group.
2. Dendrimere Verbindungen gemäß Anspruch 1 , dadurch gekennzeichnet, daß n eine natürliche Zahl von 1 bis 5 ist.2. Dendrimeric compounds according to claim 1, characterized in that n is a natural number from 1 to 5.
3. Verbindungen gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß ein o Wismutatom die Zentraleinheit X bildet.3. Compounds according to claim 1 or 2, characterized in that an o bismuth atom forms the central unit X.
4. Verbindungen gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß L in mindestens einer Generation für eine Ethylen- oder Propylengruppe steht.4. Compounds according to claim 1 or 2, characterized in that L represents at least one generation for an ethylene or propylene group.
5. Verbindungen gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß sie zwei oder drei Generationen aufweisen.5. Compounds according to claim 1 or 2, characterized in that they have two or three generations.
5 6. Verbindungen gemäß Anspruch 1 oder 2, dadurch gekennzeichnet, daß die5 6. Compounds according to claim 1 or 2, characterized in that the
1 21 2
Gruppen R und R in der letzten Generation für einen 2,3-Dihydroxypropylrest stehen.Groups R and R in the last generation represent a 2,3-dihydroxypropyl radical.
7. Verwendung von Verbindungen nach Anspruch 1 oder 2 zur Herstellung von Diagnostika und/oder Therapeutika.7. Use of compounds according to claim 1 or 2 for the production of diagnostic and / or therapeutic agents.
0 8. Verwendung von Verbindungen nach Anspruch 1 oder 2 zur Herstellung von Kontrastmitteln für die Röntgen-, MRI-, Ultraschall- oder Radiodiagnostika- Technik.8. Use of compounds according to claim 1 or 2 for the production of contrast media for X-ray, MRI, ultrasound or radio diagnostic technology.
9. Verwendung von Verbindungen nach Anspruch 1 oder 2 zur Herstellung von Kontrastmitteln für die Computertomographie.9. Use of compounds according to claim 1 or 2 for the production of contrast media for computer tomography.
5 10. Verwendung von Verbindungen nach Anspruch 1 oder 2 zur Herstellung von Kontrastmitteln für die Darstellung des Extrazellulärraumes oder des Intravasalraumes. 5 10. Use of compounds according to claim 1 or 2 for the production of contrast media for the representation of the extracellular space or the intravascular space.
EP97938795A 1996-08-23 1997-08-18 Bismuth dendrimers, processes for their preparation, and their use as x-ray contrast agents Withdrawn EP0923588A1 (en)

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CA2622021C (en) * 2005-09-14 2014-07-15 Wisconsin Alumni Research Foundation Composition comprising a dendrimer and the use thereof for binding phosphate
US20110064674A1 (en) * 2008-05-21 2011-03-17 Carnegie Mellon University Luminescent multimodal nanoparticle probe system and method of manufacture thereof
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