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WO1998007730A1 - Dendrimeres stanniques, leur utilisation comme agents de contraste radiographiques et procedes permettant de les preparer - Google Patents

Dendrimeres stanniques, leur utilisation comme agents de contraste radiographiques et procedes permettant de les preparer Download PDF

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Publication number
WO1998007730A1
WO1998007730A1 PCT/DE1997/001821 DE9701821W WO9807730A1 WO 1998007730 A1 WO1998007730 A1 WO 1998007730A1 DE 9701821 W DE9701821 W DE 9701821W WO 9807730 A1 WO9807730 A1 WO 9807730A1
Authority
WO
WIPO (PCT)
Prior art keywords
group
zero
substituted
compounds according
hydroxy
Prior art date
Application number
PCT/DE1997/001821
Other languages
German (de)
English (en)
Inventor
Werner Krause
Herbert Schumann
Original Assignee
Schering Aktiengesellschaft
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 Schering Aktiengesellschaft filed Critical Schering Aktiengesellschaft
Priority to CA002263738A priority Critical patent/CA2263738A1/fr
Priority to JP10510277A priority patent/JP2000516623A/ja
Priority to EP97938794A priority patent/EP0920433A1/fr
Priority to AU41119/97A priority patent/AU4111997A/en
Publication of WO1998007730A1 publication Critical patent/WO1998007730A1/fr
Priority to NO990705A priority patent/NO990705D0/no

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Classifications

    • 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
    • A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
    • 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
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/22—Tin compounds
    • C07F7/2208—Compounds having tin linked only to carbon, hydrogen and/or halogen

Definitions

  • Tin dendrimers their use as X-ray contrast media and process for their preparation
  • the invention relates to dendrimeric organometallic tin compounds (tin 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 applicable 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).
  • the iodine atoms in these compounds are always covalently coupled to the "carrier molecule" and enable the display of such vessels, organs and tissues that are reached by the iodine-containing contrast agents.
  • contrast agent increases the x-ray density of these tissues relative to their environment, So that they are visible in the X-ray image and allow diagnoses regarding their shape or pathological changes.
  • These contrast media can be used for a number of different diagnostic methods, such as angiography, urography, myelography and cholecystography for the water-soluble, iodine-containing compounds in the form of the water-insoluble barium sulfate as oral administering formulation used exclusively for the representation of the gastrointestinal tract.
  • 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 tin compounds, so-called tin dendrimers, can be used as X-ray contrast agents.
  • Organotin compounds with more than one metal atom per molecule have been described in the literature.
  • the polynuclear organotin complexes of samarium and ytterbium [(CH3Sn) 3] 2Ln (THF) 4 with Ln Sm and Yb from Bochkarev et al. (J. Organomet. Chem. 1993; 443: C26-28) or the Perstanna [1.1.1] propellane from Sita and Kinoshita (J. Am. Chem. Soc. 1992; 114: 7024-9) or the alkyltin compounds from Mitchell et al. (J. Organomet. Chem. (1983), 259: pp. 157-164; J. Organomet. Chem. (1984), 269: pp. 249-254).
  • Hydrophilic tin dendrimers within the meaning of the present invention have, however, hitherto not been known.
  • 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 or stands for an aryl, heteroaryl, alkyl or cycloalkyl group, the heteroatoms and / or alkyl, hydroxy, polyhydric oxyalkyl substituents and / or may contain ester, amide, thioester, thioamide, acetal, ketal, thioacetal, thioketal, disulfide, anhydride and / or urea groups, where X has the base multiplicity b,
  • R 1 , R 2 , R 3 independently of one another for a branched or unbranched zero to six times hydroxy-substituted C 1 -C 6 -alkyl group, for a zero to six times hydroxy-substituted C 6 -C 10 aryl or
  • R 4 independently of one another for a branched or unbranched zero to six times hydroxy-substituted d-C ⁇ -alkyl group, for a zero to six times hydroxy-substituted C 6 -C 10 aryl or
  • R 5 independently of one another for a hydrogen atom or a branched or unbranched zero to six times hydroxy-substituted CrC ⁇ -alkyl group, for a zero to six times hydroxy-substituted C 6 -C 10 aryl or
  • n stands for the numbers 1 -10
  • the molecule contains at least one hydroxyl, carboxy, amido, ether, thioether, ester or thioester group.
  • the invention therefore relates to organotin compounds 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 a polymeric compound in which a central molecule ("initiator core") concentrically
  • Dendrimers are characterized by an increasing number of branches from the inside out.
  • the branches are caused by tin atoms.
  • the tin-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 O, S, N, P, C, Si, Sn, Ge or an aryl, heteroaryl, alkyl or cycloalkyl group, the heteroatoms and / or alkyl, hydroxy or may contain polyhydroxyalkyl substituents.
  • the central unit X can also be referred to as the zero generation.
  • the central unit X can also be a metabolically cleavable bridge, such as an ester, amide, thioester, thioamide, acetal, ketal, thioacetal, Contain thioketal, disulfide, anhydride or urea bond, so that the tin dendrimer according to the invention can be broken down in the human or animal organism.
  • a tin or silicon atom is preferably used 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 tin-containing monomers.
  • the base multiplicity b of oxygen and sulfur is, for example, 2, of 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 (zero generation), the first generation of tin-containing organyls is connected by means of a group L.
  • a d-C-io-alkylene group can 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.
  • n stands for the number of links between L and the tin-containing residues of the next generation.
  • the size of n depends on the number of functional residues in L.
  • n can stand for the numbers 1-10.
  • Preferably n stands for!
  • the groups R 1 , R 2 and R 3 can either for a further generation of tin-containing monomers of the formula la
  • the groups R 1 , R 2 and R 3 in the last generation preferably represent a branched or unbranched zero to six-fold hydroxy-substituted C 6 alkyl group, particularly preferably the 2,3-dihydroxypropyl radical.
  • R 4 contained stand for branched or unbranched zero to six hydroxy-d-C ⁇ - Alkylgr uppen or zero to six hydroxy-substituted C 6 -C ⁇ 0 aryl or benzyl groups.
  • R 1 and R 2 groups contained are hydrogen atoms or branched or unbranched zero to six hydroxy-C ⁇ -C 6 -alkyl or zero to six hydroxy-substituted C 6 -C ⁇ 0 aryl or Benzyl groups.
  • the compounds according to the invention must be hydrophilic for in vivo use. This is achieved through hydrophilic substituents.
  • the compounds thus contain at least one hydroxyl, carboxy, amido, ether or thioether, ester or thioester group in the molecule, hydroxyl groups being particularly suitable for the purpose according to the invention.
  • the groups R 1 , R 2 , R 3 in the last generation of the dendrimer preferably carry at least one hydroxyl group.
  • Dendrimers which carry 2,3-dihydroxypropyl groups in the last generation are very particularly preferred.
  • the dendrimers according to the invention generally contain at least as many hydrophilic groups as tin atoms of the last generation.
  • the invention preferably relates to those dendrimers in which all groups R 1 , R 2 , R 3 of the last generation contain hydrophilic substituents.
  • the compounds according to the invention are suitable for the following uses: as a contrast medium for X-ray, MRI, ultrasound or radio diagnostic technology, as a contrast medium for computer tomography, as a contrast medium for displaying the extracellular space, as a contrast medium for displaying the intravascular space, as a contrast medium for the display of tumors, infarcted tissue or inflammation, as a therapeutic agent.
  • R -CH2 (CHOH) CH2 ⁇ H the empirical formula is SnsC 4H ⁇ o ⁇ 24.
  • the molecular weight is 1605, the relative tin content of the molecule is 37%.
  • the molecule is non-ionic.
  • X represents a central unit
  • R 1 , R 2 , R 3 independently of one another for a branched or unbranched zero to six times hydroxy-substituted C 1 -C 6 -alkyl group, for a zero to six times hydroxy-substituted C ⁇ -C-io-aryl or
  • R 4 independently of one another represents a branched or unbranched zero to six times hydroxy-substituted C 1 -C 6 -alkyl group, represents a zero to six times hydroxy-substituted C 6 -C 10 aryl or benzyl group,
  • R 5 independently of one another represents a hydrogen atom or a branched or unbranched zero to six times hydroxy-substituted Cj-C ⁇ -alkyl group, stands for a zero to six times hydroxy-substituted C 6 -C ⁇ o-aryl or benzyl group.
  • X represents a central unit
  • b corresponds to the base multiplicity of the central unit, Y is a direct bond or a group L; with L has the meaning defined above
  • R 1 , R 2 , R 3 independently of one another for a branched or unbranched zero to six times hydroxy-substituted C ⁇ C 6 alkyl group, for a zero to six times hydroxy-substituted C 6 -C *) 0 aryl or benzyl group, an ether group -OR 4 , ester group -COOR 4 , thioether group
  • R 4 independently of one another for a branched or unbranched zero to six times hydroxy-substituted d-C ⁇ -alkyl group, for a zero to six times hydroxy-substituted C 6 -C 10 aryl or
  • R 5 independently of one another for a hydrogen atom or a branched or unbranched zero to six times hydroxy-substituted C 1 -C 6 -alkyl group, for a zero to six times hydroxy-substituted C 6 -C 10 aryl or
  • Z is halogen or another leaving group.
  • Triphenyltin hydride (26.3 g, 75.0 mmol, manufactured according to HG Kuivila, OF Beumel, J. Am. Chem. Soc. 83 (1961) 1246; or FD Greene, NN Lowry, J. Org. Chem. 32 (1967) 883) with tetravinylsilane (2.04 g, 15.0 mmol, Aldrich) and a catalytic amount of hexachloroplatinic (IV) acid (5 drops of a 0.1 M solution in i-propanol, Aldrich) were added and the reaction mixture was stirred vigorously for 24 h.
  • Example 2 Si (CH 2 -CH 2 -Sn (pC 6 H 4 O-CH 3 ) 3 ) 4

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne des composés stanniques organo-métalliques dendrimères (dendrimères stanniques) pouvant s'utiliser avantageusement comme agents de contraste radiographiques, ainsi que des procédés permettant de les préparer.
PCT/DE1997/001821 1996-08-16 1997-08-18 Dendrimeres stanniques, leur utilisation comme agents de contraste radiographiques et procedes permettant de les preparer WO1998007730A1 (fr)

Priority Applications (5)

Application Number Priority Date Filing Date Title
CA002263738A CA2263738A1 (fr) 1996-08-16 1997-08-18 Dendrimeres stanniques, leur utilisation comme agents de contraste radiographiques et procedes permettant de les preparer
JP10510277A JP2000516623A (ja) 1996-08-16 1997-08-18 錫デンドリマー、そのレントゲン造影剤としての使用及びその製法
EP97938794A EP0920433A1 (fr) 1996-08-16 1997-08-18 Dendrimeres stanniques, leur utilisation comme agents de contraste radiographiques et procedes permettant de les preparer
AU41119/97A AU4111997A (en) 1996-08-16 1997-08-18 Tin dendrimers, their use as x-ray contrast agents and processes for their preparation
NO990705A NO990705D0 (no) 1996-08-16 1999-02-15 Tinndendrimerer, deres anvendelse som r°ntgenkontrastmidler og fremgangsmÕter for deres fremstilling

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19633869 1996-08-16
DE19633869.7 1996-08-16

Publications (1)

Publication Number Publication Date
WO1998007730A1 true WO1998007730A1 (fr) 1998-02-26

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PCT/DE1997/001821 WO1998007730A1 (fr) 1996-08-16 1997-08-18 Dendrimeres stanniques, leur utilisation comme agents de contraste radiographiques et procedes permettant de les preparer

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EP (1) EP0920433A1 (fr)
JP (1) JP2000516623A (fr)
AU (1) AU4111997A (fr)
CA (1) CA2263738A1 (fr)
DE (1) DE19726340C2 (fr)
NO (1) NO990705D0 (fr)
WO (1) WO1998007730A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2554790A1 (de) * 1974-12-26 1976-07-01 Uniroyal Inc Tetrasubstituierte zinnorganische verbindungen
WO1993010824A1 (fr) * 1991-12-04 1993-06-10 Guerbet S.A. Nouveau compose macromoleculaire polyamine iode, son procede de preparation et son utilisation comme agent de contraste

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5714166A (en) * 1986-08-18 1998-02-03 The Dow Chemical Company Bioactive and/or targeted dendrimer conjugates
DE4344460A1 (de) * 1993-12-22 1995-06-29 Schering Ag Metallkomplexe von dendrimeren Makromolekülen, diese enthaltende diagnostische Mittel sowie Verfahren zur Herstellung der Komplexe und Mittel
NL9401886A (nl) * 1994-05-27 1996-01-02 Dsm Nv Samenstelling bestaande uit een dendrimeer en een in het dendrimeer opgesloten actieve stof, een werkwijze voor de bereiding van een dergelijke samenstelling en een werkwijze voor het vrijgeven van de actieve stof.
AUPM623994A0 (en) * 1994-06-15 1994-07-07 Biomolecular Research Institute Limited Antiviral dendrimers

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2554790A1 (de) * 1974-12-26 1976-07-01 Uniroyal Inc Tetrasubstituierte zinnorganische verbindungen
WO1993010824A1 (fr) * 1991-12-04 1993-06-10 Guerbet S.A. Nouveau compose macromoleculaire polyamine iode, son procede de preparation et son utilisation comme agent de contraste

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
MITCHELL T N ET AL: "Long-range tin-tin coupling constants. II. Two-bond coupling via carbon", J. ORGANOMET. CHEM. (JORCAI,0022328X);83; VOL.259 (2); PP.157-64, UNIV. DORTMUND;ABT. CHEM.; DORTMUND; 4600/50; FED. REP. GER. (DE), XP002049170 *
VAN DE HEISTEEG B J J ET AL: "A new type of organometallic spiro compounds: 2,2,6,6-tetracyclopentadienyl-4-sila-2,6-dititanaspiro[3.3]heptane", ORGANOMETALLICS (ORGND7,02767333);86; VOL.5 (8); PP.1749-50, VRIJE UNIV. AMSTERDAM;SCHEIKD. LAB.; AMSTERDAM; 1081 HV; NETH. (NL), XP002049171 *

Also Published As

Publication number Publication date
CA2263738A1 (fr) 1998-02-26
DE19726340A1 (de) 1998-02-19
AU4111997A (en) 1998-03-06
NO990705L (no) 1999-02-15
EP0920433A1 (fr) 1999-06-09
DE19726340C2 (de) 1999-05-06
JP2000516623A (ja) 2000-12-12
NO990705D0 (no) 1999-02-15

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