WO1997003994A1 - Tungsten clusters - Google Patents

Tungsten clusters Download PDF

Info

Publication number
WO1997003994A1
WO1997003994A1 PCT/US1996/010914 US9610914W WO9703994A1 WO 1997003994 A1 WO1997003994 A1 WO 1997003994A1 US 9610914 W US9610914 W US 9610914W WO 9703994 A1 WO9703994 A1 WO 9703994A1
Authority
WO
WIPO (PCT)
Prior art keywords
och
oxotritungsten
triangulo
molecule
compound
Prior art date
Application number
PCT/US1996/010914
Other languages
French (fr)
Inventor
Ella Y. Fung
Stephen R. Cooper
Original Assignee
Mallinckrodt Medical, Inc.
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 Mallinckrodt Medical, Inc. filed Critical Mallinckrodt Medical, Inc.
Priority to EP96921784A priority Critical patent/EP0871637A4/en
Publication of WO1997003994A1 publication Critical patent/WO1997003994A1/en

Links

Classifications

    • 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
    • C07F11/00—Compounds containing elements of Groups 6 or 16 of the Periodic Table
    • C07F11/005—Compounds containing elements of Groups 6 or 16 of the Periodic Table compounds without a metal-carbon linkage
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/24—Nuclear magnetic resonance, electron spin resonance or other spin effects or mass spectrometry

Definitions

  • the invention is in the field of imaging.
  • the invention is in the field of X-ray imaging.
  • Each metal-metal bond is bridged by two carboxylate groups, leaving the equatorial position, L, at each metal atom occupied by either water, carboxylate or solvent group.
  • These compounds are mainly prepared from refluxing M(CO) 6 in carboxylic acid/anhydride mixtures or reducing MO 4 2- under similar reaction conditions. In cases with bulky carboxylate ligands, the assembly of these compounds usually requires high temperature and pressure to yield enough material for characterization. Since the discovery of this class of cluster compounds, these compounds usually requires high temperature and pressure to yield enough material for characterization. Since the discovery of this class of cluster compounds, most efforts have been directed to the synthesis and characterization of various trinuclear cluster types (see review in Muller, A.; Jostes, R.; Cotton, F.
  • the present invention describes a new process that incorporates functionalized ligands onto tri-tungsten clusters to form new compounds. These new clusters possess desirable properties such as radiopacity and solubility, and they can also be modified with heavy elements to form highly radiopaque materials for use in diagnostic X-ray imaging.
  • the present invention provides new tri-tungsten compounds of the general structure:
  • R 1 is -C k H l Z m or - (C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • R 2 is
  • R 3 is -C k H l Z m or
  • R 4 is - (C k H l Z m or - (C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • R 5 is -C k H l Z m or (C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • R 6 is -C k H l Z m or - (C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • Z is a functional group attachable on aliphatic chains or aromatic rings;
  • R 7 is an anionic molecule, neutral molecule, -C k H l Z m or -(C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • R 8 is an anionic molecule, neutral molecule, -C k H l Z m or - (C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • R 9 is an anionic molecule, neutral molecule, -C k H l Z m , or -(C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • k is about 0-20;
  • l is about 0-50;
  • m is about 1-50;
  • n is about 0-50;
  • p is about
  • R 1 is -C k H l Z m or - (C k H l Z n )(C 6 H (5-q) Z q ) p ;
  • R 2 is
  • R 3 is -C k H l Z m or - (C k H l Z m ) (C 6 H (5-q) Z q ) p ;
  • R 4 is - (C k H l Z m or - (C k H l Z n (C 6 H (5-q) Z q ) p ;
  • R 5 is -C k H l Z m or -(C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • R 6 is -C k H l Z m or - (C k H l Z n ) (C 6 H (5-q) Z q ) p ;
  • Z is a functional group attachable on aliphatic chains or aromatic rings;
  • R 7 is an anionic molecule, neutral
  • tungsten clusters are prepared from refluxing tungsten hexacarbonyl or sodium tungstate/zinc in carboxylic acid/anhydride mixtures.
  • carboxylic acid/anhydride mixtures typically requires high temperature or high boiling solvents and high pressure to yield enough material for characterization.
  • no functionalized carboxylate groups have been used to successfully assemble the W 3 (U 3 -O) 2 (O 2 CR) 6 unit, due to the lack of commercially available anhydrides and to intractable side reactions during the course of cluster assembly.
  • ligand exchange in this system offers a facile synthetic route to new W 3 clusters that cannot be prepared by prior art.
  • the process of the invention comprises heating a parent tri-tungsten cluster in the presence of a desired ligand, and a new tri-tungsten cluster substituted with desired ligand is obtained. Heating temperatures typically range from about
  • Suitable ligands for use in the process of the invention include bidentate ligands and multidentate ligands, such as carboxylate ligands, oxylate ligands, phosphate ligands, and sulfonate ligands. The process of the invention provides high yields.
  • Yields from the process of the invention are especially high in view of yields obtained for known compounds with prior art processes that require heating W(W)6 or [WO 4 ] 2+ /Z n in desired carboxylic acid anhydride at high temperatures (137°C - 160°C) and high pressure. High temperatures and pressure may contribute to decomposition of the cluster and give intractable side products that lead to corresponding lower yield.
  • Functional groups for use with the invention include acids, acyl halides, alcohols, aldehydes, alkoxides, alkenes, alkynes, amides, amines, amino acids, aryl halides, carbohydrates, carboxylates, esters, ethers, ketones, isocyanates, hydroxides, phosphates, phosphonates, sulfates, sulfonates and halogens (F, Cl, Br, I).
  • Functional groups also include any iodinated substituents that improve the overall radio-opacity of the compound. Any unit of two or more atoms that are joined together to give a net charge of zero can serve as the neutral molecule.
  • Neutral molecule groups for use with the invention include water, carbohydrates, organic solvents, and alcohols.
  • Neutral molecules and anionic species are generally used to alter the overall charge of the tungsten cluster.
  • Anionic species such as alkoxides, carboxylates, halides, hydroxides, isocyanates, phosphates, phosphonates, sulfates and sulfonates can also be used in the neutral molecule position to alter the overall charge.
  • Alcohols include branched and unbranched such as methanol, ethanol, propanol and isopropanol.
  • Halogens include fluorine, chlorine, bromine, and iodine.
  • Aldehydes include methyl aldehyde, benzyl aldehyde, and phenyl acetaldehyde.
  • Alkenes include ethene, propene, butene and acrylic.
  • Alkoxides include methoxide, ethoxide, phenoxide and glycerides.
  • Alkynes include ethyne, propyne, butyne and pentyne.
  • Amides include acetamide and benzamide. Amines include primary, secondary, and tertiary amines.
  • Aryl halides include fluorine, chlorine, bromine and iodine substituted aromatic rings.
  • Carbohydrates include glucose and fructose.
  • Esters include alkyl, phenyl and benzyl esters.
  • Ketones include alkyl, phenyl and benzyl ketones.
  • Organic polar or non-polar solvents include acetone, acetonitrile, benzene, dichloromethane, diethyl ether, diglyme, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, nitromethane, nitrobenzene, pyridine, tetrahydrofuran, and toluene.
  • Carboxylates include acetate, acrylate, butyrate, propionate, benzoate, and phenyl acetate.
  • Counter ions include Group I, II and VII ions, typically sodium, potassium, cesium, magnesium, calcium, barium, chloride, bromide and iodide ions. Counter ions also include any other cationic or anionic species such as ammoniums, arsoniums, carbonates, carboxylates, nitrates, phosphates, phosphoniums, polytungstates, sulphates. The overall charge of the molecule ranges from -6 to +6, typically -1 to about +2. Examples of compounds of the invention include:
  • compositions of the invention can be formulated into diagnostic compositions for enteral or parenteral administration.
  • These compositions contain an effective amount of the radiopaque ion complex along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated.
  • parenteral formulations advantageously contain a sterile aqueous solution or suspension of from about 0.05 to about 1.0M of a complex according to this invention.
  • Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration.
  • Preferred parenteral formulations have a concentration of complex of about 0.1 M to about 0.5M.
  • Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride.
  • compositions may advantageously contain a slight excess (e.g., from about 0.01 to about 15.0 mole % of excess) of a complexing agent or its complex with a physiologically acceptable, non-toxic cation.
  • physiologically acceptable, non-toxic cations include calcium ions, magnesium ions, copper ions, zinc ions, salts of n-methylglucamine and diethalanolamine, and the like.
  • Formulations for enteral administration may vary widely, as is well-known in the art. In general, such formulations are liquids which include an effective amount of the complex in aqueous solution or suspension. Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like. Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.
  • the diagnostic compositions are administered in doses effective to achieve the desired enhancement of the image.
  • parenteral dosages will range from about 0.001 to about 1.0 mmol of complex per kg of patient body weight.
  • Preferred parenteral dosages range from about 0.01 to about 0.5 mmol of complex per kg of patient body weight.
  • Enteral dosages generally range from about 0.5 to about 100 mmol, preferably from about 1.0 to about 20 mmol, more preferably from about 1.0 to about 10.0 mmol of complex per kg of patient body weight.
  • compositions of the invention are used in the conventional manner.
  • the compositions may be administered to a patient, typically a warm-blooded animal, either systematically or locally to the organ or tissue to be imaged, and the patient then subjected to the imaging procedure.
  • EXAMPLE 7 Na[W 3 ( ⁇ 3 -O) 2 (O 2 CCH 2 C 6 H 5 ) 9 ] (8).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention provides new tri-tungsten compounds of general structure (I) wherein R1 is -C¿k?H1Zm or -(CkH1Zn) (C6H(5-q) Zq)p; R?2¿ is -C¿k?H1Zm or -(CkH1Zn) (C6H(5-q) Zq)p; R?3¿ is -C¿k?H1Zm or -(CkH1Zn) (C6H(5-q) Zq)p; R?4¿ is -C¿k?H1Zm or -(CkH1Zn) (C6H(5-q) Zq)p; R?5¿ is -C¿k?H1Zm or -(CkH1Zn) (C6H(5-q) Zq)p; R?6¿ is -C¿k?H1Zm or -(CkH1Zn) (C6H(5-q) Zq)p; Z is a functional group attachable on aliphatic chains or aromatic rings; R?7¿ is an anionic molecule, neutral molecule, -C¿k?H1Zm ou -(CkH1Zn) (C6H(5-q) Zq)p; R?8¿ is an anionic molecule, neutral molecule, -C¿k?H1Zm or -(CkH1Zn) (C6H(5-q) Zq)p; R?9¿ is an anionic molecule, neutral molecule, -C¿k?H1Zm or -(CkH1Zn) (C6H(5-q) Zq)p; k is about 0-20; 1 is about 0-50; m is about 1-50; n is about 0-50; p is about 1-10; q is about 1-5; M is a counter positive or negative ion; and a is about -6 - +6. W in the structure is the generally accepted one letter symbol for tungsten. Methods of imaging using compounds of the invention and processes for producing compounds of the invention are also disclosed.

Description

TUNGSTEN CLUSTERS
FIELD OF THE INVENTION The invention is in the field of imaging. In particular, the invention is in the field of X-ray imaging.
BACKGROUND OF THE INVENTION Synthesis and characterization of bi-oxo capped trinuclear clusters with the general formula [M3 (M3-O)2 (O2CR)6L3]n± (M =
Mo, W) are well established. See for example Bino, A.; Ardon, M.; Maor, I.; Kaftory, M.; Dori, Z. J im. Chem. Soc. 1976, 98, 7093; Bino, A.; Cotton, F. A.; Dori, Z. J Am. Chem. Soc. 1978, 100, 5252; Bino, A.; Cotton, F. A.; Dori, Z.; Koch, S.; Kueppers, H.; Millar, M.; Sekutowski, J. Inorg. Chem. 1978, 17, 3245; Birnbaum, A.; Cotton, F. A.; Dori, Z.; Reisner, G. M.; Schwotzer, W.; Shaia, M. Inorg. Chem. 1983, 22, 2723; Cotton, F. A.; Dori, Z.; Marler, D. O.; Schwotzer, W. Inorg. Chem. 1983, 22, 3104; Birnbaum, A.; Cotton, F. A.; Dori, Z.; Kapon, M. Inorg. Chem. 1984, 23, 1617; and Cotton, F. A.; Dori, Z.; Marler, D. O.; Schwotzer, W. Inorg. Chem. 1984, 23, 4033. This type of cluster contains two capping oxygen atoms sitting above and below the M3 triangular plane. Each metal-metal bond is bridged by two carboxylate groups, leaving the equatorial position, L, at each metal atom occupied by either water, carboxylate or solvent group. These compounds are mainly prepared from refluxing M(CO)6 in carboxylic acid/anhydride mixtures or reducing MO4 2- under similar reaction conditions. In cases with bulky carboxylate ligands, the assembly of these compounds usually requires high temperature and pressure to yield enough material for characterization. Since the discovery of this class of cluster compounds, these compounds usually requires high temperature and pressure to yield enough material for characterization. Since the discovery of this class of cluster compounds, most efforts have been directed to the synthesis and characterization of various trinuclear cluster types (see review in Muller, A.; Jostes, R.; Cotton, F. A. Angew. Chem. Int. Ed. Engl. 1980, 19, 875; Cotton, F. A. Polyhedron, 1986, 5, 3; Cotton, F. A.; Shang, M.; Sun, Z. S. Inorg. Chim. Acta. 1993, 212, 95 and references therein). These studies have demonstrated a wide range of M3 clusters with various bridging and capping ligands (Bino, A.; Cotton, F. A.; Dori, Z.; Kolthammer, B. W. S. J. Am. Chem. Soc. 1981, 103, 5779; Ardon, M.; Bino, A.; Cotton, F. A.; Dori, Z.; Kaftory, M.; Kolthammer, B. W. S.; Kapon, M.; Reisner, G. M. Inorg. Chem. 1981, 20, 4083; Cotton, F. A.; Dori, Z.; Kapon, M.; Marler, D. O. ; Reisner, G. M.; Schwotzer, W.; Shaia, M. Inorg. Chem.. 1985, 24, 4381; Cotton, F. A.; Felthouse, T. R.; Lay, D. G. Inorg. Chem. 1981, 20, 2219; Cotton, F. A.; Shang, M.; Sun, Z. S. J. Am. Chem. Soc. 1991, 113, 3007; and Cotton, F. A.; Shang, M.; Sun, Z. S. J. Cluster Sci. 1992, 3, 123). Relatively little is known about the reactivity of bi-oxo capped clusters, [M3 (μ3O)2 (OsCR)6L3]n± (M = Mo, W), partly due to their remarkable stability demonstrated by Cotton and co- workers (see Cotton, F. A.; Dori, Z.; Marler, D. O.; Schwotzer, W. Inorg. Chem. 1984, 23, 4033-8). Recently Sasaki and Richens have independently studied the kinetics of terminal water exchange in [M3(μ3-O)2(O2CCH3)6(H2O)3]2+ (M = Mo, W) (Nakata, K.; Nagasawa, A.; Soyama, N. ; Sasaki, Y.; Ito, T. Inorg. Chem. 1991, 30, 1575-9. Powell, G.; Richens, D. T. Inorg. Chem. 1993, 32, 4021). Their results show that the water exchange rate in this system is several orders of magnitude slower than in "M3 (IV) aquo ion", [M3(μ3-O)(μ-O)3(H2O)9]4+ (M = Mo, W), and that the degree of inertness is more profound in tungsten case.
Although exchange of the bridging carboxylates has been performed on reactive molybdenum di- and tri-nuclear systems (Telser, J.; Drago, R. S. Inorg. Chem. 1984, 23, 1978; Nakata, K.; Yamaguchi, T.; Sasak, Y.; Ito, T. Chem. Lett . 1992. 6, 983-6 ), no such direct carboxylate exchange has been successfully performed on the bi-oxo capped W3 system, [W3(μ3-O)2(O2CR)6L3]n±.
SUMMARY OF THE INVENTION
The present invention describes a new process that incorporates functionalized ligands onto tri-tungsten clusters to form new compounds. These new clusters possess desirable properties such as radiopacity and solubility, and they can also be modified with heavy elements to form highly radiopaque materials for use in diagnostic X-ray imaging.
The present invention provides new tri-tungsten compounds of the general structure:
Figure imgf000005_0001
wherein R1 is -CkHlZm or - (CkHlZn) (C6H(5-q) Zq) p; R2 is
-CkHlZm or - (CkHlZm) (C6H(5-q) Zq) p; R3 is -CkHlZm or
(CkHlZn (C6H(5-q) Zq) p; R4 is - (CkHlZm or - (CkHlZn) (C6H(5-q) Zq) p; R5 is -CkHlZm or (CkHlZn) (C6H(5-q) Zq) p; R6 is -CkHlZm or - (CkHlZn) (C6H(5-q) Zq) p; Z is a functional group attachable on aliphatic chains or aromatic rings; R7 is an anionic molecule, neutral molecule, -CkHlZm or -(CkHlZn) (C6H(5-q) Zq)p;
R8 is an anionic molecule, neutral molecule, -CkHlZm or - (CkHlZn) (C6H(5-q) Zq)p; R9 is an anionic molecule, neutral molecule, -CkHlZm, or -(CkHlZn) (C6H(5-q)Zq)p; k is about 0-20; l is about 0-50; m is about 1-50; n is about 0-50; p is about
1-10; q is about 1-5; M is a counter positive or negative ion; and a is about -6 - +6. W in the structure is the generally accepted one letter symbol for tungsten. A process for producing compounds of the general formula:
Figure imgf000006_0001
wherein R1 is -CkHlZm or - (CkHlZn)(C6H(5-q) Zq)p; R2 is
-CkHlZm or -(CkHlZn) (C6H(5.q) 2^)p; R3 is -CkHlZm or - (CkHlZm) (C6H(5-q)Zq)p; R4 is - (CkHlZm or - (CkHlZn (C6H(5-q)Zq)p; R5 is -CkHlZm or -(CkHlZn) (C6H(5-q) Zq)p; R6 is -CkHlZm or - (CkHlZn) (C6H(5-q) Zq)p; Z is a functional group attachable on aliphatic chains or aromatic rings; R7 is an anionic molecule, neutral molecule, -CkHlZm or -(CkHlZn (C6H(5-q) Zq)p; R8 is an anionic molecule, neutral molecule, -CkHlZm or - (CkHlZm) (C6H(5-q) Zq)p; R9 is an anionic molecule, neutral molecule, -CkHlZm or -(CkHlZn) (C6H(5-q)Zq)p; k is about 0-20; 1 is about 0-50; m is about 1-50; n is about 0-50; p is about
1-10; q is about 1-5; M is a counter positive or negative ion; and a is about -6 - +6; comprising heating bi-oxo capped tri-tungsten clusters in the presence of a ligand, provided the ligand is in excess of the tri-tungsten cluster, and recovering a fully or partially substituted tri-tungsten cluster.
Also, methods of imaging using compounds of the invention are disclosed. DETAILED DESCRIPTION OF THE INVENTION
General procedures for preparing tri-nuclear tungsten clusters include Cotton, F. A.; Wilkinson, G. Advance Inorganic Chemistry; 4th Ed. ; John Wiley & Son: New York, 1980, pp. 868-871; Cotton, F. A. Polyhedron, 1986, 5,5; Bino, A.; Ardon, M.; Maor, I.; Kaforty, M.; Dori, Z. J. Am. Chem. Soc. 1976, 98, 7093; Bino, A.; Cotton, F. A.; Dori, Z. J Am. Chem. Soc. 1978, 100, 5252. Bino, A.; Cotton, F. A.; Dori, Z.; Koch, S.; Kueppers, H.; Millar, M.; Sekutowski, J. Inorg. Chem. 1978, 17, 3245. Birnbaum, A.; Cotton, F. A.; Dori, Z.; Reisner, G. M.; Schwotzer, W.; Shaia, M. Inorg. Chem. 1983, 22, 2723. Cotton, F. A.; Dori, Z.; Marler, D. O.; Schwotzer, W. Inorg. Chem. 1983, 22, 3104 and Cotton, F. A.; Dori, Z.; Marler, D. O.; Schwotzer, W. Inorg. Chem. 1984, 23, 4033. Typically tungsten clusters are prepared from refluxing tungsten hexacarbonyl or sodium tungstate/zinc in carboxylic acid/anhydride mixtures. In cases with bulky carboxylate ligands, it usually requires high temperature or high boiling solvents and high pressure to yield enough material for characterization. To date, however, no functionalized carboxylate groups have been used to successfully assemble the W3(U3-O)2 (O2CR)6 unit, due to the lack of commercially available anhydrides and to intractable side reactions during the course of cluster assembly. By using the assembled W3 (μ3-O)2 unit in the parent cluster as a template, ligand exchange in this system offers a facile synthetic route to new W3 clusters that cannot be prepared by prior art. Compounds of the invention are therefore prepared after the parent tungsten cluster is obtained and the process of the invention is applied. The process of the invention comprises heating a parent tri-tungsten cluster in the presence of a desired ligand, and a new tri-tungsten cluster substituted with desired ligand is obtained. Heating temperatures typically range from about
80°C to about 160°C. Generally the heating time is from about 2 to 5 hours, mostly depending on the ligand. Recovery of desired cluster is obtained by conventional chromatographic methods. As long as there is excess ligand over the tungsten cluster, there will be fully or partially substituted clusters obtained. Preferably, 10% or more excess ligand is used. Any bi-oxo capped tri-tungsten cluster can be used in the process of the invention. Suitable ligands for use in the process of the invention include bidentate ligands and multidentate ligands, such as carboxylate ligands, oxylate ligands, phosphate ligands, and sulfonate ligands. The process of the invention provides high yields. Yields from the process of the invention are especially high in view of yields obtained for known compounds with prior art processes that require heating W(W)6 or [WO4] 2+/Zn in desired carboxylic acid anhydride at high temperatures (137°C - 160°C) and high pressure. High temperatures and pressure may contribute to decomposition of the cluster and give intractable side products that lead to corresponding lower yield.
Functional groups for use with the invention include acids, acyl halides, alcohols, aldehydes, alkoxides, alkenes, alkynes, amides, amines, amino acids, aryl halides, carbohydrates, carboxylates, esters, ethers, ketones, isocyanates, hydroxides, phosphates, phosphonates, sulfates, sulfonates and halogens (F, Cl, Br, I). Functional groups also include any iodinated substituents that improve the overall radio-opacity of the compound. Any unit of two or more atoms that are joined together to give a net charge of zero can serve as the neutral molecule. Neutral molecule groups for use with the invention include water, carbohydrates, organic solvents, and alcohols. Neutral molecules and anionic species are generally used to alter the overall charge of the tungsten cluster. Anionic species such as alkoxides, carboxylates, halides, hydroxides, isocyanates, phosphates, phosphonates, sulfates and sulfonates can also be used in the neutral molecule position to alter the overall charge. Alcohols include branched and unbranched such as methanol, ethanol, propanol and isopropanol. Halogens include fluorine, chlorine, bromine, and iodine. Aldehydes include methyl aldehyde, benzyl aldehyde, and phenyl acetaldehyde. Alkenes include ethene, propene, butene and acrylic. Alkoxides include methoxide, ethoxide, phenoxide and glycerides. Alkynes include ethyne, propyne, butyne and pentyne. Amides include acetamide and benzamide. Amines include primary, secondary, and tertiary amines. Aryl halides include fluorine, chlorine, bromine and iodine substituted aromatic rings. Carbohydrates include glucose and fructose. Esters include alkyl, phenyl and benzyl esters. Ketones include alkyl, phenyl and benzyl ketones. Organic polar or non-polar solvents include acetone, acetonitrile, benzene, dichloromethane, diethyl ether, diglyme, dimethyl acetamide, dimethyl formamide, dimethyl sulfoxide, nitromethane, nitrobenzene, pyridine, tetrahydrofuran, and toluene. Carboxylates include acetate, acrylate, butyrate, propionate, benzoate, and phenyl acetate. Counter ions include Group I, II and VII ions, typically sodium, potassium, cesium, magnesium, calcium, barium, chloride, bromide and iodide ions. Counter ions also include any other cationic or anionic species such as ammoniums, arsoniums, carbonates, carboxylates, nitrates, phosphates, phosphoniums, polytungstates, sulphates. The overall charge of the molecule ranges from -6 to +6, typically -1 to about +2. Examples of compounds of the invention include:
Sodiumtriangulohexakis [μ-(acetato-O:OÕ)]tris(acetato-O)di-μ3-oxotritungsten (IV) ;
Sodiumtriangulo hexakis [μ-(propinato-O:OÕ)]tris(propionato-O)di-μ3-oxotritungsten (IV);
Sodium triangulo hexakis [μ -(methoxyacetato-O:OÕ)]tris(methoxyacetato -O)di-μ3-oxotritungsten (IV) ;
Sodium triangulo hexakis [μ - (acrylato-O:OÕ)]tris(acrylato-O)di-μ3-oxotritungsten (IV) ; Sodium triangulo hexakis [μ-(benzoato-O:OÕ)]tris(benzoato -O) di-μ3-oxotritungsten (IV) ;
Sodium triangulo hexakis [μ-(phenylacetato-O:OÕ)]tris(phenylacetato -O)di-μ3-oxotritungsten (IV) ;
Sodium triangulo hexakis [μ-(p-hydoxyphenylacetato-O:OÕ )]tris(p-hydoxyphenylacetato -O)di-μ3- oxotritungsten (IV); Sodium triangulo hexakis [μ-(4-acetoxyglycolamido-3,5-diiodophenylacetato-O:OÕ)]tris(4-acetoxyglycolamido-3,5-diiodophenylacetato-O) di-μ3-oxotritungsten (IV);
Sodium triangulo hexakis [μ-(pyruvato-O:OÕ)]tris(pyruvato - O)di-μ3-oxotritungsten ( IV);
Sodiumtriangulo hexakis[μ-(DL-lactato-O:OÕ)]tris(DL-lactato-O)di-μ3-oxotritungsten (IV);
Sodium triangulo hexakis[μ-(glycolato-O:OÕ)]tris(glycolato-O)di-μ3-oxotritungsten (IV);
Sodium triangulo hexakis[μ-(glycerato-O:OÕ)]tris(glycerato-O)di-μ3-oxotritungsten ( IV);
Triangulo monoaquohexakis[μ-(acetato-O:OÕ)](dihydroxy-O)di-μ3-oxotritungsten (IV); Triangulo monoaquohexakis[μ-(propionato-O:OÕ)](dihydroxy-O)di-u3-oxotritungsten (IV);
Triangulo monoaquohexakis [μ-(methoxyacetato-O:OÕ)] (dihydroxy-O)di-μ3-oxotritungsten (IV);
Triangulo monoaquohexakis[μ-(acrylato-O:OÕ)](dihydroxy-O)di-μ3-oxotritungsten (IV);
Triangulo monoaquohexakis[μ-(benzoato-O:OÕ)](dihydroxy-O)di-μ3-oxotritungsten (IV); Triangulomonoaquohexakis[μ-(phenylacetato-O:OÕ)](dihydroxy-O)di-μ3-oxotritungsten (IV); Triangulo monoaquohexakis[μ-(p-hydroxyphenylacetato-O:OÕ)](dihydroxy-O)di-μ3-oxotritungsten (IV);
Triangulo monoaquohexakis[μ-(4-acetoxyglycolamido-3,5-diiodophenylacetatato-O:OÕ )] (dihydroxy-O)di-μ3-oxotritungsten (IV);
Triangulo monoaquohexakis[μ-(pyruvato-O:OÕ)](dihydroxy-O)di-μ3-oxotritungsten ( IV) ;
Triangulo monoaquohexakis [μ-(DL-lactato-O:OÕ)](dihydroxy-O) di-μ3-oxotritungsten (IV) ;
Triangulo monoaquohexakis[μ-(glycolato-O:OÕ)](dihydroxy-O) di-μ3-oxotritungsten (IV) ;
Triangulo monoaquohexakis[μ-(glycerato-O:OÕ)](dihydroxy-O) di-μ3-oxotritungsten (IV) ; Triangulo diaquohexakis[μ-(acetato-O:OÕ)] (hydroxy-O) di-μ3-oxotritungsten (IV) chloride;
Triangulo diaquohexakis [μ- (propinato-O:OÕ)] (hydroxy-O) di-μ3-oxotritungsten(IV) chloride;
Triangulo diaquohexakis[μ-(methoxyacetato-O:OÕ)] (hydroxy-O)di-μ3-oxotritungsten(IV) chloride;
Triangulo diaquohexakis[μ-(acrylato-O:OÕ)] (hydroxy-O) di- μ3-oxotritungsten (IV) chloride;
Triangulo diaquohexakis[μ-(benzoato-O:OÕ)] (hydroxy-O) di-μ3-oxotritungsten (IV) chloride;
Triangulo diaquohexakis[μ-(phenylacetato-O:OÕ)] (hydroxy-O)di-μ3-oxotritungsten (IV) chloride;
Triangulo diaquohexakis[μ-(4-acetoxyglycolamido-3,5-diiodophenylacetato-O:OÕ )] (hydroxy-O)di-μ3-oxotritungsten (IV) chloride;
Triangulo diaquohexakis[μ-(p-hydroxyphenylacetato-O:OÕ)] (hydroxy-O) di-μ3-oxotritungsten (IV) chloride;
Triangulo diaquohexakis[μ-(pyruvato-O:OÕ)] (hydroxy-O) di-μ3-oxotritungsten (IV) chloride;
Triangulo diaquohexakis[μ-(DL-lactato-O:OÕ)] (hydroxy-O) di-μ3-oxotritungsten (IV) chloride;
Triangulo diaquohexakis [μ-(glycolato-O:OÕ)] (hydroxy-O) di-μ3-oxotritungsten (IV) chloride; Triangulo diaquohexakis [μ -(glycerato-O:OÕ)] (hydroxy-O) di-μ3-oxotritungsten (IV) chloride .
Triangulo triaquohexakis[μ-(acetato-O:OÕ)]di-μ3-oxotritungsten (IV) dichloride; Triangulo triaquohexakis[μ-(propionato-O:OÕ)]di-μ3-oxotritungsten (IV) dichloride;
Triangulo triaquohexakis[μ-(methoxyacetato-O:OÕ)]di-μ3-oxotritungsten(IV) dichloride;
Triangulo triaquohexakis[μ-(acrylato-O:OÕ)]di-μ3-oxotritungsten(IV) dichloride; Triangulo triaquohexakis[μ-(benzoato-O:OÕ)]di-μ3-oxotritungsten (IV) dichloride;
Triangulo triaquohexakis[μ-(phenylacetato-O:OÕ)]di-μ3-oxotritungsten(IV) dichloride;
Triangulo triaquohexakis[μ-(p-hydroxyphenylacetato-O:OÕ)]di-μ3-oxotritungsten (IV) dichloride;
Triangulo triaquohexakis[μ-(4-acetoxyglycolamido-3,5-diiodophenylacetato-O:OÕ)]di-μ3-oxotritungsten (IV) dichloride;
Triangulo triaquohexakis[μ-(pyruvato-O:OÕ)]di-μ3-oxotritungsten(IV) dichloride;
Triangulo triaquohexakis[μ-(DL-lactato-O:OÕ)]di-μ3-oxotritungsten (IV) dichloride;
Triangulo triaquohexakis[μ-(glycolato-O:OÕ)]di-μ3-oxotritungsten(IV) dichloride; and Triangulo triaquohexakis[μ -(glycerato-O:OÕ)]di-μ3-oxotritungsten (IV) dichloride.
The compositions of the invention can be formulated into diagnostic compositions for enteral or parenteral administration. These compositions contain an effective amount of the radiopaque ion complex along with conventional pharmaceutical carriers and excipients appropriate for the type of administration contemplated. For example, parenteral formulations advantageously contain a sterile aqueous solution or suspension of from about 0.05 to about 1.0M of a complex according to this invention. Parenteral compositions may be injected directly or mixed with a large volume parenteral composition for systemic administration. Preferred parenteral formulations have a concentration of complex of about 0.1 M to about 0.5M. Such solutions also may contain pharmaceutically acceptable buffers and, optionally, electrolytes such as sodium chloride. The compositions may advantageously contain a slight excess (e.g., from about 0.01 to about 15.0 mole % of excess) of a complexing agent or its complex with a physiologically acceptable, non-toxic cation. Such physiologically acceptable, non-toxic cations include calcium ions, magnesium ions, copper ions, zinc ions, salts of n-methylglucamine and diethalanolamine, and the like.
Formulations for enteral administration may vary widely, as is well-known in the art. In general, such formulations are liquids which include an effective amount of the complex in aqueous solution or suspension. Such enteral compositions may optionally include buffers, surfactants, thixotropic agents, and the like. Compositions for oral administration may also contain flavoring agents and other ingredients for enhancing their organoleptic qualities.
The diagnostic compositions are administered in doses effective to achieve the desired enhancement of the image.
Such doses may vary widely, depending upon the particular complex employed, the organs or tissues which are the subject of the imaging procedure, the imaging equipment being used, and the like. In general, parenteral dosages will range from about 0.001 to about 1.0 mmol of complex per kg of patient body weight. Preferred parenteral dosages range from about 0.01 to about 0.5 mmol of complex per kg of patient body weight. Enteral dosages generally range from about 0.5 to about 100 mmol, preferably from about 1.0 to about 20 mmol, more preferably from about 1.0 to about 10.0 mmol of complex per kg of patient body weight.
The diagnostic compositions of the invention are used in the conventional manner. The compositions may be administered to a patient, typically a warm-blooded animal, either systematically or locally to the organ or tissue to be imaged, and the patient then subjected to the imaging procedure.
X-ray contrast Imaging Procedures are found in Albert A. Moss, M.D., Gordon Gamsu, M.D., and Harry K. Genant, M.D., Computed Tomography of the Body, (W.B. Saunders Company, Philadelphia, Pennsylvania 1992) and M. Sovak, Editor, Radiocontrast Agents, (Springer-Verlag, Berlin 1984). General procedures for ligand synthesis and metal complexing are well known and exemplified in such texts as Watson, A.D., Rocklage, S.C., Carvlin, M.J. In Magnetic Resonance Imaging, 2nd ed.; Stark, D.D., Bradley, W.G., Eds.; Mosby Year Book: St. Louis, MO 1992, Chapter 14 and Gaughan, G. In Enhanced Magnetic Resonance Imaging, Runge, V.M., Ed.; Mosby Year Book: St. Louis, MO, 1989, Chapter 9.
The following examples illustrate the specific embodiments of the invention described in this document. As would be apparent to skilled artisans, various changes and modifications are possible and are contemplated within the scope of the invention described. EXAMPLES
Synthesis of Na[W3(μ3-O)2 (Q2CCH3)9] (1)
Na[W3(μ3-O)2(O2CCH3)9] (1). A mixture of 5.0 g of Na2WO4 (15 mmol) and 6.0 g W(CO)6 (17 mmol) was heated in acetic anhydride/acetic acid (1:10, 250 mL) at 140°C for 10 h. After the reaction mixture had cooled to 70 °C, yellow percipitates were filtered and washed successively with acetic anhydride and diethyl ether. It was recrystallized by dissolution in methanol (10 mL/g) and precipitation from acetonitrile (30 mL/g); yield 7.65 g (63%): 1H NMR (300 MHz, DMSO-d6)_δ 1.98 (s, 9H), 2.24 ppm (s, 18H); UV-vis (H2O)_λmax (ε, mol-1 dm3 cm-1) 378 (1530), 454 (1620) nm;
ESI-MS m/z for [W3 (μ3-O)2 (O2CCH3)9] is 1114; Analysis calc'd for Na[W3(μ3-O)2(O2CCH3)9], C18H27NaO20W3: C, 19.0; H, 2.4; Na,
2.0; W, 48.5; found: C, 18.8; H, 2.7; Na, 2.1; W, 49.8.
EXAMPLE 1
Na[W3(μ3-O)2(O2CCH2CH3)9] (2). A solution of Na[W3(μ3- O)2(O2CCH3)9] (108 mg, 0.095 mmol) in propionic acid (10 mL) was heated to 80°C for 2 h. The resulting yellow solution was evaporated to dryness to leave a yellow-brown residue. It was disssolved in methanol and purified by passing through a basic alumina column; yield 42 mg (35 %): 1H NMR (300 MHz, DMSO-d6)_δ 1.03 (m, 27H), 2.27 (q, 6H), 2.46 (q, 12H); 13C NMR (75.6 MHz, DMSO-d6)_δ 11.3, 11.4, 30.0, 32.2, 177.8, 186.2; IR (KBr)_V 2979, 2938, 2881, 1643, 1555, 1470, 1446, 1378, 1235, 1077, 901, 810, 675, 638, 605, 546 cm-1; UV-vis
(DMSO)_λmax (ε,mol-1 dm3 cm-1) 386 (2500), 461 (2300) nm; ESI -MS m/z for [W3 (μ3-O)2 (O2CCH2CH3)9] - is 1240; Analysis calc'd for Na[W3(μ3-O)2(O2CCH2CH3)9] .3H2O, C27H51NaO23W3: C, 24.6; H, 3.9; Na, 1.7; found: C, 24.3; H, 3.6; Na, 2.0.
EXAMPLE 2
Na[W3(μ3-O)2(O2CCH2CH2CH3)9] (3). This compound was prepared similarly to Na[W3 (μ3-O)2 (O2CCH2CH3)9] using excess butyric acid (CAUTION! STENCH!) in place of propionic acid. Pure product was isolated as yellow-brown oil; yield 55.1 mg (45 %) : 1H NMR (CD3OD) δ 0.92 (m, 27H), 1.64 (m, 18H), 2.48 (m, 18H) ppm; 13C NMR (CD3OD)_δ 13.18, 13.79, 19.61, 19.83, 37.91, 41.04, 180.72, 186.34 ppm; IR (KBr)_V 2958, 2926, 2874, 1700, 1642, 1611, 1558, 1447, 1353, 1321, 1211, 1095, 937, 895, 805, 642, 600, 437 cm-1; UV-vis (methanol)_λmax (ε,mol-1 dm3 cm-1) 381 (2100), 458 (2300) nm; ESI-MS m/z for [W3(μ3-O)2(O2CCH2CH2CH3)9]- is 1368.
EXAMPLE 3 Na[W3(μ-O)2(O2C(CH3)3)6(OCH3)3] (4). Na [W3(μ3-O)2(O2CH3)9] (100 mg, 0.088 mmol) was added to 10 mL (87.0 mmol) of molten trimethyl acetic acid and slowly heated to 80°C for 4 h. The resulting yellow-brown material was dissolved in methyl alcohol and passed through a basic alumina column. A yellow band was collected, concentrated, and passed through a second column of basic alumina. On rotary evaporation a yellow crystalline product was obtained; yield 22.8 mg (18 %) : 1H NMR (300 MHz, CD3OD)_δ 1.15 (s, 54H), 3.34 (s, 9H) ppm; 13C NMR (CD3OD)_δ 27.7 ppm (resonances for the quaternary carbons and coordinated methoxide groups were obscured); IR (KBr)_V 2963, 2928, 2875, 2806, 1555, 1485, 1428, 1381, 1361, 1233, 1069, 909, 809, 780, 627, 599, 465 and 452 cm-1; UV-vis (methanol)_λmax (ε,mol-1 dm3 cm-1) 384 (1700), 458 (2000) nm; ESI-MS m/z for [W3(μ2-O)2(O2CC(CH3)3)6(OCH3)3]- is 1284; Analysis calc'd for Na[W3(μ3-O)2(O2CC(CH3)3)6(OCH3)3]. 5 CH3OH, C38H83NaO22W3 : C, 31.1; H, 5.70; Na, 1.57; found: C, 31.1; H, 5.05; Na, 1.08.
EXAMPLE 4 Na[W3(μ3-O)2(O2CCH=CH2)7(O2CCH2CH2CH=CHCOOH)2] (5).
A solution of Na[W3(μ3-O)2(O2CCH3)9] (1) (500 mg, 0.11 mmol) in 50 mL (729 mmol) of acrylic acid was slowly heated to 80° C for 6 hours. Initial color of the reaction mixture was yellow-brown. After heating to 80°C, color changed to orange with orange precipitate. The orange solution was filtered and orange insoluble material was isolated. Excess acrylic acid in the orange solution was removed by evaporation, from which a crude product was obtained. The pure orange crystalline product was isolated from a chromatotron plate using 10%, 15% and 25% of methanol in ethyl acetate as an eluate; yield 32.3 mg (5.5%): 1H NMR (300 MHz, CD3OD)_δ centered at 2.82 (t), 4.52 (t), 5.84 (m) and 6.27 (m) ppm; 13C NMR (75.6 MHz, CD3OD)_δ 128.5, 128.9, 130.7, 32.2, 176.3, 178.4 ppm; IR (KBr)_V 1723, 1636, 1541,
1444, 1405, 1376, 1344, 1278, 1190, 1058, 984, 812, 694,
667, 635, 601 cm-1; UV-vis (methanol)_λmax (ε,mol-1 dm3 cm-1)
333 (11,000), 367 (6100) and 481 (4000) nm; ESI-MS m/z for
[W3(μ3-O)2(O2CCH=CH2)7(O2CCH2CH2CH=CHCOOH)2]- is 1368 ; Analysis calc'd for Na[W3(μ3-O)2(O2CCH=CH2)7(O2CCH2CH2CH=CHCOOH)2],
C33H35NaO24W3 : C, 28.51; H, 2.54; Na, 1.65; found: C, 28.12; H, 2.64; Na, 1.35.
EXAMPLE 5
[W3(μ3-O)2(O2CCH=CH2)6(H2O)3]Cl2 (6). Hydrolysis of crude W3-acrylate cluster (5) (456 mg) by heating in 36% HCl at room temperature for three days yielded orange solution and unreacted starting material. The orange solution was filtered and slow evaporation yielded orange crystals, yield 170 mg (44.8%) : 1H NMR (300 MHz, CD3OD)_δ centered at 5.85 (d), 6.26 (m), 6.48 (d) ppm; 13C NMR (75.6 MHz, CD3OD)_δ 128.6, 132.6, 178.6 ppm; IR (KBr)_V 2953, 1642, 1526, 1447, 1379, 1279, 1068, 984, 816, 700, 647, 605, 437 cm-1 ; UV-vis ( methanol)_λmax (ε,mol-1 dm3 cm-1) 324 (11,000), 362 (shoulder, 6500), 473 (5400) nm; ESI-MS m/z for [W3(μ3-O)2(O2CCH=CH2)6(H2O)3]2+ is 532.
EXAMPLE 6
Na[W3(μ3-O)2(O2CCH2OCH3)9] (7). A solution of 2.28 g (2 mmol) of Na[W3(μ3O)2(O2CCH3)9] (1) in 3.6 g (40 mmol) of methoxyacetic acid containing a few drops of methoxyacetic anhydride was heated at 130°C for 3 hours under nitrogen. Any volatiles were removed by gradual application of vacuum at 100 - 130 °C. The residue was treated with another 3.6 g portion of methoxyacetic acid, and the same procedure was repeated. After thorough removal of all volatiles under high vacuum at 130 °C, the residue was cooled and dissolved in 10 mL of acetonitrile. Upon standing, yellow-brown crystals of the product was separated, yield 1.97 g (70%) :1H NMR (300 MHz, CD3OD)_δ 3.40 (s, 18H), 3.43 (s, 9H), 4.20
(s, 6H), 4.34 (s, 12H); UV-vis (H2O)_λmax (ε,mol-1 dm3 cm-1) 380 (1550) and 454 (1660) nm; ESI-MS m/z for [W3(μ3-O)2(O2CCH2OCH3)9]- is 1383; Analysis calc'd for Na[W3(μ3-O)2(O2CCH2OCH3)9] .1.5 MeCN, C30H49.5N1.5NaO29W3 : C, 24.5; H 3.4; N, 1.4; Na, 1.6; W, 37.5; found: C, 24.3; H, 3.5; N, 1.3; Na, 1.6; W, 32.1. EXAMPLE 7 Na[W3(μ3-O)2(O2CCH2C6H5) 9] (8). A mixture of Na[W3(μ3-O)2(O2CCH3)9] (1 g, 0.9 mmol) and phenylacetic acid (10 g, 73 mmol) was stirred at 100°C for 5 h. It was then subjected to column chromatography (0-25% acetonitrile in methylene chloride) over silica gel to give a yellow product yield 0.61 g (38%): 1H NMR (300 MHz, DMSO-d6)_δ 3.18 (s, 6H), 3.70 (s, 12H), 7.0-7.2 (m, 45H) ppm; 13C NMR (75.6 MHz, DMSO-d6)_δ 41.5, 44.6, 125.6, 126.8, 127.8, 128.4, 129.1, 129.9, 135.1, 138.2, 174.0, 182.7; IR (KBr)_V 1625, 1547, 1481, 1425, 1327, 1266 , 1198, 1145, 711, 677, 648 , 612, 581 cm-1; UV-vis (methanol)_λmax (ε, mol-1dm3cm-1) 284 (16,400), 382
(2030), 459 (2045) nm; ESI-MS m/z for [W3(μ3-O)2(O2CCH2C6H5)9]- is 1799; Analysis calc'd for Na[W3(μ3-O)2(O2CCH2 H5)9],
C72H53NaO20W3 : C, 47.4; H 3.48; Na, 1.26; found: C, 49.71; H, 4.51; Na, 1.17.
Example 8
[W3(μ3-O)2(O2CCH2C6H5OH)6(MeOH)3]Cl2 (9). A mixture of Na[W3(μ3-O)2 (O2CCH3)9] (5 g, 4.3 mmol) and p-hydroxyphenylacetic acid
(18 g, 118 mmol) was stirred at 165 °C for 5 h. The solid mass, obtained after cooling to room temperature, was triturated with diethyl ether to extract excess p- hydroxyphenylacetic acid. The residue was dissolved in methanol (500 mL), bubbled with HCl, and stirred at ambient temperature for three days. The resulting solution was then evaporated to dryness and the residue was purified by column chromatography (cone.HCl (aq) :MeOH:MeCN, 0:25:75 to
0.5:99.5:0) to give a yellow solid; yield 1.2 g (16%) : 1H NMR (300 MHz, DMSO-d6)_δ 3.69 (m, 12H), 6.7 (m, 12H), 6.9 (m, 12H) ppm; 13C NMR (75.6 MHz, DMSO-d6)_δ 40.9, 115.4,
124.6, 130.1, 156.7, 185.4 ppm; IR (KBr)_V 3432, 2960, 2925,
1615, 1552, 1516, 1437, 1239, 1174, 803, 741, 704, 647 cm-1;
UV-vis (methanol)_λmax (ε, mor1dm3cm-1) 278 (6200), 378 (550), 460 (664) nm; ESI-MS m/z for [M-H]+, where [M-H]+ =
[W3(μ3-O)2(O2CCH2C6H4OH)6(MeOH)2(OMe)]+, is 1586 and signals observed at 1555 and 1523 are due to successive loss of methanol; Analysis calc'd for [W3(ju3-
O)2(O2CCH2C6H4OH)6(MeOH)3]Cl2, C51H54Cl2O23W3 : C, 36.96; H, 3.28; Cl, 4.28; found: C, 35.76; H, 3.39; Cl, 4.21.
Example 9
[W3(μ3-O)2(O2CCHOHCH3)6(H2O)3]Cl2 (10). A mixture of Na [W3 (μ3- O)2(O2CCH3)9] (5 g, 4.3 mmol) in 109 mL of DL-lactic acid
(85% in H2O) was heated at 130°C for 20 h. Excess lactic acid and side products were removed by vacuum distillation at 110 °C. The resulting crude product was recrystallized from methanol/ethyl ether. This material was further treated with another portion of DL-lactic acid, and the same procedure was repeated. After thorough removal of all volatiles under high vacuum at 110 °C, Na[W3(μ3-O)2(O2CCHOHCH3)9] was purified by dissolution in methanol and precipitation from ethyl ether, yield 7.5 g. A solution of 1.0 g( 0.71 mmol) of Na[W3(μ3-O)2(O2CCHOHCH3)9] was stirred in
40 mL of 1 M HCl at room temperature for 2 d. The resulting reaction solution was evaporated down to ~2 mL and precipitated from acetone. A 350 mg portion of this material was purified by ion-exchange column chromatography (Dowex 50×2-200), yield 200 mg (64.5% based on W3) : Η NMR (300 MHz, CD3OD) δ 1.39 (m,18H), 4.60 (q, 6H) ; ESI-MS m/z for [W3(μ3-O)2(O2CCHOHCH3)6(H-O)3]2+ is 586; Analysis calc' d for [W3(μ3-O)2(O2CCHOHCH3)6(H2O)3]Cl2, C18H36Cl2O23W3 : C, 17.30; H 2.92; Cl, 5.70; W, 44.38; found: C, 17.55; H, 3.39; Cl, 6.52; W, 46.61.
Although the invention has been described with respect to specific modifications, the details thereof are not to be construed as limitations, for it will be apparent that various equivalents, changes and modifications may be resorted to without departing from the spirit and scope thereof, and it is understood that such equivalent embodiments are to be included therein.

Claims

CLAIMS What is claimed is:
1. A compound of the general formula:
Figure imgf000026_0001
wherein R1 is -CkHlZm or -(CkHlZn) (C6H(5-q)Zq)p; R2 is
-CkHlZn or -(CkHlZn) (C6H(5-q) Zq)p; R3 is -CkHlZm or (CkHlZn)(C6H(5-q)Zq)p; R4 is -(CkHlZn) or -(CkHlZn) (C6H(5-q) Zq) p; R5 is -CkHlZm or -(CkHlZn) (C6H(5-q) Zq)p; R6 is -CkHlZm or - (CkHlZn) (C6H(5-q) Zq)p; Z is a functional group attachable on aliphatic chains or aromatic rings; R7 is an anionic molecule, neutral molecule, -CkHlZm or -(CkHlZn) (C6H(5-q) Zq)p; R8 is an anionic molecule, neutral molecule, -CkHlZm or - (CkHlZn)(C6H(5-q) Zq)p; R9 is an anionic molecule, neutral molecule, -CkHlZm or - (CkHlZn) (C6H(5-q)Zq)p; k is about 0-20; 1 is about 0-50; m is about 1-50; n is about 0-50; p is about
1-10; q is about 1-5; M is a counter positive or negative ion; and a is about -6 - +6.
2 . The compound of claim 1 wherein R1 is -CH2OCH3 ; R2 is - CH2OCH3; R3 is -CH2OCH3; R4 is -CH2OCH3; R5 is -CH2OCH3; R6 is -CH2OCH3; R7 is -CH2OCH3; R8 is -CH2OCH3; R9 is -CH2OCH3; M is sodium; and a is -1.
3. The compound of claim 1 wherein R1 is -CH2OCH3; R2 is -CH2OCH3; R3 is -CH2OCH3; R4 is -CH2OCH3; R5 is -CH2OCH3; R6 is - CH2OCH3; R7 is H2O; R8 is OH-; R9 is OH-; and a is 0.
4. The compound of claim 1 wherein R1 is -CH2OCH3; R2 is - CH2OCH3; R3 is -CH2OCH3; R4 is -CH2OCH3; R5 is -CH2OCH3; R6 is - CH2OCH3; R7 is H2O; R8 is H2O; R9 is OH-; M is Cl-; and a is
+1.
5. The compound of claim 1 wherein R1 is -CH2OCH3; R2 is - CH2OCH3; R3 is -CH2OCH3; R4 is -CH2OCH3; R5 is -CH2OCH3; R6 is - CH2OCH3; R7 is H2O; R8 is H2O; R9 is H2O; M is Cl-; and a is +2.
6. The compound of claim 1 wherein R1 is -CH=CH2; R2 is -CH=CH2; R3 is -CH=CH2; R4 is -CH=CH2; R5 is -CH=CH2; R6 is -CH=CH2; R7 is-CH=CH2; R8 is-CH=CH2; R9 is-CH=CH2; M is Na+; and a is -1.
7. The compound of claim 1 wherein R1 is -CH=CH2; R2 is -CH=CH2; R3 is -CH=CH2; R4 is -CH=CH2; R5 is -CH=CH2; R6 is -
CH=CH2; R7 is H2O; R8 is H2O; R9 is H2O; M is Cl- ; and a is +2.
8. The compound of claim 1 wherein R1 is -CH2C6H4OH; R2 is -CH2C6H4OH; R3 is -CH2C6H4OH; R4 is -CH2C6H4OH; R5 is -CH2C6H4OH;
R6 is -CH2C6H4OH; R7 is -CH2C6H4OH; R8 is -CH2C6H4OH; R9 is -CH2C6H4OH M is sodium; and a is -1.
9. The compound of claim 1 wherein R1 is -CH2C6H4OH; R2 is -CH2C6H4OH; R3 is -CH2C6H4OH; R4 is -CH2C6H4OH; R5 is -CH2C6H4OH; R6 is -CH2C6H4OH; R7 is H2O; R8 is H2O; R9 is H2O; M is Cl-; and a is +2.
10. The compound of claim 1 wherein R1 is -C(O)CH3; R2 is -C(O)CH3; R3 is -C(O)CH3; R4 is -C(O)CH3; R5 is -C(O)CH3; Re is -C(O)CH3; R7 is -C(O)CH3; R8 is -C(O)CH3; R9 is -C(O)CH3; M is sodium; and a is -1.
11. The compound of claim 1 wherein R1 is -CH(OH)CH3; R2 is -CH(OH)CH3; R3 is -CH(OH)CH3; R4 is -CH(OH)CH3; R5 is -CH(OH)CH3; R6 is -CH(OH)CH3; R7 is -CH(OH)CH3; R8 is -CH(OH)CH3; R9 is -CH(OH)CH3; M is sodium; and n is -1.
12. The compound of claim 1 wherein R1 is -CH(OH)CH3; R2 is -CH(OH)CH3; R3 is -CH(OH)CH3; R4 is -CH(OH)CH3; R5 is -CH(OH)CH3; R6 is -CH(OH)CH3; R7 is H2O; R8 is OH-; R9 is OH-; and a is 0.
13. The compound of claim 1 wherein R1 is -CH(OH)CH3; R2 is -CH(OH)CH3; R3 is -CH(OH)CH3; R4 is -CH(OH)CH3; R5 is - CH(OH)CH3; R6 is -CH(OH)CH3; R7 is H2O; R8 is H2O; R9 is OH-; M is Cl-; and a is +1.
14. The compound of claim 1 wherein R1 is -CH(OH)CH3; R2 is -CH(OH)CH3; R3 is -CH(OH)CH3; R4 is -CH(OH)CH3; R5 is - CH(OH)CH3; R6 is -CH(OH)CH3; R7 is H2O; R8 is H2O; R9 is H2O; M is Cl-; and a is +2.
15. A method of imaging comprising the administration of a diagnostically effective amount of a compound of the general formula:
Figure imgf000029_0001
wherein R1 is -CkHlZm or - (CkHlZn) (C6H(5-q)Zq)p; R2 is
-CkHlZn or - (CkHlZm (C6H(5-q) Zq)p; R3 is -CkHlZm or (CkHlZn) (C6H(5-q)Zq)p; R4 is - (CkHlZm) or - (CkHlZn) (C6H(5-q) Zq)p; R5 is -CkHlZm or -(CkHlZn)(C6H(5-q) Zq)p; R6 is -CkHlZm or - (CkHlZn) (C6H(5-q) Zq)p; Z is a functional group attachable on aliphatic chains or aromatic rings; R7 is an anionic molecule, neutral molecule, -CkHlZn or - (CkHlZn) (C6H(5-q) Zq)p;
R8 is an anionic molecule, neutral molecule, -CkHlZm or - (CkHlZn) (C6H(5-q) Zq)p; R9 is an anionic molecule, neutral molecule, -CkHlZm or - (CkHlZn) (C6H(5-q)Zq)p; k is about 0-20; 1 is about 0-50; m is about 1-50; n is about 0-50; p is about 1-10; q is about 1-5; M is a counter positive or negative ion; and a is about -6 - +6.
16 . The method of claim 15 wherein R1 is -CH2OCH3; R2 is - CH2OCH3 ; R3 is -CH2OCH3; R4 is -CH2OCH3; R5 is -CH2OCH3 ; R6 is - CH2OCH3 ; R7 is -CH2OCH3 ; R8 is -CH2OCH3 ; R9 is -CH2OCH3 ; M is sodium; and a is -1 .
17 . The method of claim 15 wherein R1 is -CH2OCH3 ; R2 is - CH2OCH3 ; R3 is -CH2OCH3; R4 is -CH2OCH3; R5 is -CH2OCH3 ; R6 is - CH2OCH3; R7 is H2O; R8 is OH-; R9 is OH-; and a is 0.
18. The method of claim 15 wherein R1 is -CH2OCH3; R2 is -CH2OCH3; R3 is -CH2OCH3; R4 is -CH2OCH3; R5 is -CH2OCH3; R6 is -CH2OCH3; R7 is H2O; R8 is H2O; R9 is OH-; M is Cl- ; and a is
+1.
19. The method of claim 15 wherein R1 is -CH2OCH3; R2 is -CH2OCH3; R3 is -CH2OCH3; R4 is -CH2OCH3; R5 is -CH2OCH3; R6 is -CH2OCH3; R7 is H2O; R8 is H2O; R9 is H2O; M is Cl- ; and a is +2.
20. The method of claim 15 wherein R1 is -CH=CH2; R2 is -CH=CH2; R3 is -CH=CH2; R4 is -CH=CH2; R5 is -CH=CH2; R6 is -CH=CH2; R7 is-CH=CH2; R8 is-CH=CH2; R9 is-CH=CH2; M is sodium and a is -1.
21. The method of claim 15 wherein R1 is -CH=CH2; R2 is -CH=CH2; R3 is -CH=CH2; R4 is -CH=CH2; R5 is -CH=CH2; R6 is -CH=CH2; R7 is H2O; R8 is H2O; R9 is H2O; M is Cl-; and a is +2.
22. The method of claim 15 wherein R1 is -CHAHiOH; R2 is - CH2C6H4OH; R3 is -CH2C6H4OH; R4 is -CH2C6H4OH; R5 is -CH2C6H4OH; R6 is -CH2C6H4OH; R7 is -CH2C6H4CH; R8 is -CH2C6H4OH; R9 is -CH2C6H4OH M is sodium; and a is -1.
23. The method of claim 15 wherein R1 is -CHAHjOH; R2 is -CH2C6H4OH; R3 is -CH2C6H4OH; R4 is -CH2C6H4OH; R5 is -CH2C6H4OH; R6 is -CH2C6H4OH; R7 is H2O; R8 is H2O; R9 is H2O; M is Cl-; and a is +2.
24. The method of claim 15 wherein R1 is -C(O)CH3; R2 is - C(O)CH3; R3 is -C(O)CH3; R4 is -C(O)CH3; R5 is -C(O)CH3; R6 is -C(O)CH3; R7 is -C(O)CH3; R8 is -C(O)CH3; R9 is -C(O)CH3; M is sodium; and a is -1.
25. The method of claim 15 wherein R1 is -CH(OH) CH3; R2 is -CH(OH)CH3; R3 is -CH(OH)CH3; R4 is -CH(OH)CH3; R5 is -CH(OH)CH3; R6 is -CH(OH)CH3; R7 is -CH(OH)CH3; R8 is -CH(OH)CH3; R9 is -CH(OH)CH3; M is sodium; and n is -1.
26. The method of claim 15 wherein R1 is -CH(OH)CH3; R2 is -CH(OH)CH3; R3 is -CH(OH)CH3; R4 is -CH(OH)CH3; R5 is -CH(OH)CH3; R6 is -CH(OH)CH3; R7 is H20; R8 is OH-; R9 is OH-; and a is 0.
27. The method of claim 12 wherein R1 is -CH(OH)CH3; R2 is -CH(OH)CH3; R3 is -CH(OH)CH3; R4 is -CH(OH)CH3; R5 is -CH(OH)CH3; R6 is -CH(OH)CH3; R7 is H2O; R8 is H2O; R9 is OH-; M is Cl-; and a is +1.
28. The method of claim 12 wherein R1 is -CHrøCBj; R2 is -CH(OH)CH3; R3 is -CH(OH)CH3; R4 is -CH(OH)CH3; R5 is -CH(OH)CH3; R6 is -CH(OH)CH3; R7 is H2O; R8 is H2O; R9 is H2O; M is Cl-; and a is +2.
PCT/US1996/010914 1995-07-20 1996-06-26 Tungsten clusters WO1997003994A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP96921784A EP0871637A4 (en) 1995-07-20 1996-06-26 Tungsten clusters

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US08/504,728 US5641472A (en) 1995-07-20 1995-07-20 Tungsten clusters
US08/504,728 1995-07-20

Publications (1)

Publication Number Publication Date
WO1997003994A1 true WO1997003994A1 (en) 1997-02-06

Family

ID=24007484

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1996/010914 WO1997003994A1 (en) 1995-07-20 1996-06-26 Tungsten clusters

Country Status (3)

Country Link
US (1) US5641472A (en)
EP (1) EP0871637A4 (en)
WO (1) WO1997003994A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997026921A2 (en) * 1996-01-23 1997-07-31 Nycomed Salutar Inc. Contrast media
WO2012097801A1 (en) 2011-01-18 2012-07-26 Siemens Aktiengesellschaft Method for generating a contrast medium-assisted x-ray image and x-ray system
EP2540321A1 (en) 2011-06-30 2013-01-02 Bayer Intellectual Property GmbH Bis Tridentate W3O2 Clusters for X-Ray imaging
EP2733148A1 (en) 2012-11-15 2014-05-21 Bayer Pharma Aktiengesellschaft Tungsten complexes with di-dentate ligands

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060199972A1 (en) * 2005-02-09 2006-09-07 State Of Oregon Acting By & Through The State Board Of Higher Edu On Behalf Of The Univ Of Oreg. Methods for producing gallium and other oxo/hydroxo-bridged metal aquo clusters

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992017215A1 (en) * 1990-03-28 1992-10-15 Nycomed Salutar, Inc. Contrast media
US5602268A (en) * 1995-07-20 1997-02-11 Mallinckrodt Medical, Inc. Process for producing tungsten clusters

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
INORGANIC CHEMISTRY, 15 September 1993, Vol. 32, No. 19, POWELL et al., "Complex Formation and Water Exchange on Trinuclear Dioxo-Capped Complexes (M3(mu3-O)2(mu-CH3CO2)6(OH2)3)2+ (M=Mo, W) and Monooxo-Capped Complex (W3(mu3-O)(mu-CH3CO2)6(OH2)3)2+", pages 4021-4029. *
INORGANIC CHEMISTRY, 19 December 1984, Vol. 23, No. 26, COTTON et al., "Synthesis and Structure of New Trinuclear Cluster Compounds (M3(mu3-O)2(O2CC3H7)6(H2O)3)2+ (M= Mo, W), Comparison of Mo and W Bon Radii as a Function of M-M Bond Order", pages 4738-4742. *
INORGANIC CHEMISTRY, 21 November 1984, Vol. 23, No. 24, COTTON et al., "New Preparative Methods, Structure and Nitration of Bio-oxo-capped Trimolybdenum(IV) and Tritungsten(IV) Cluster Cations", pages 4033-4038. *
POLYHEDRON, March 1993, Vol. 12, No. 5, MADDEN et al., "Formation of Isopolyoxometallate(VI) Anions in the Reaction Between M(CO)6(M=W, Mo) and Acetic Acid: X-Ray Crystal Structure of (W3(mu3-O)2(mu2eta2-O2CCH3)6(H2O)3)2(W10O32 ) Solvent", pages 473-477. *
See also references of EP0871637A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997026921A2 (en) * 1996-01-23 1997-07-31 Nycomed Salutar Inc. Contrast media
WO1997026921A3 (en) * 1996-01-23 1997-10-23 Nycomed Salutar Inc Contrast media
WO2012097801A1 (en) 2011-01-18 2012-07-26 Siemens Aktiengesellschaft Method for generating a contrast medium-assisted x-ray image and x-ray system
US9693742B2 (en) 2011-01-18 2017-07-04 Siemens Aktiengesellschaft Method for generating a contrast medium-assisted X-ray image and X-ray system
EP2540321A1 (en) 2011-06-30 2013-01-02 Bayer Intellectual Property GmbH Bis Tridentate W3O2 Clusters for X-Ray imaging
WO2013000970A1 (en) 2011-06-30 2013-01-03 Bayer Intellectual Property Gmbh Bis tridentate w3o2 clusters for x-ray imaging
EP2733148A1 (en) 2012-11-15 2014-05-21 Bayer Pharma Aktiengesellschaft Tungsten complexes with di-dentate ligands

Also Published As

Publication number Publication date
US5641472A (en) 1997-06-24
EP0871637A1 (en) 1998-10-21
EP0871637A4 (en) 2000-01-05

Similar Documents

Publication Publication Date Title
EP0670832B1 (en) Hepatobiliary magnetic resonance contrast agents
US5262532A (en) Paramagnetic metalloporphyrins as contrast agents for magnetic resonance imaging
Farrell et al. The Weak‐Link Approach to the Synthesis of Inorganic Macrocycles
Gust et al. Aqua [1-(2, 6-dichloro-4-hydroxyphenyl)-2-phenylethylenediamine](sulfato) platinum (II) Complexes with Variable Substituents in the 2-Phenyl Ring. 1. Synthesis and Antitumor and Estrogenic Properties
US4442305A (en) Polycatecholamide chelating agents
LT3535B (en) Multinuclear complexes, contrast media containing them and use
Spies et al. Synthesis and reactions of trigonal-bipyramidal rhenium and technetium complexes with a tripodal, tetradentate NS3 ligand
CA1171425A (en) Organic platinum complexes and uses
WO1992017215A1 (en) Contrast media
US5602268A (en) Process for producing tungsten clusters
Siedle et al. Formazanylpalladium compounds. Synthesis and structure of bis (1, 3, 5-tri-p-tolylformazanyl) palladium
US5482699A (en) Multinuclear complexes for x-ray imaging
WO1997003993A9 (en) Process for producing tungsten clusters
US5641472A (en) Tungsten clusters
AU649001B2 (en) MRI image enhancement of bone and related tissue using complexes of paramagnetic cations and polyphosphonate ligands
CA1226295A (en) Glycolic acid type platinum complexes
JP2519205B2 (en) All-cis-1,3,5-triamino-2,4,6-cyclohexanetriol derivative
JP4056088B2 (en) Multidentate imines and their metal complexes
JPH04120066A (en) 10-(2'-hydroxy-3'-polyoxaalkyl)-1,4,7-triscarboxy- methyl-1,4,7,10-tetraazacyclododecane
JP2740240B2 (en) Calixarene derivatives
EP0716091B1 (en) Tris(substituted phenyl)bismuth derivative
Deeming et al. [RhPd 2 (pyS) 4 (η 3-C 4 H 7) 2][BF 4]: synthesis and X-ray structure of a mixed-metal trinuclear complex containing two µ 3-pyridine-2-thionato (pyS) ligands
Gandolfi et al. Metal catecholato complexes: a source for metallo-labeling antigens
Lu et al. Synthesis, characterization and crystal structure of the bis (1, 10-phenanthroline) tri (trans-2, 3-dimethylacrylato) lanthanide (III) dimer
Carmona et al. Substitution reactions in cyclometallated complexes. Crystal and molecular structure of (C5H5N)(Me3P) Ni (CH2CMe2-o-C6H4)

Legal Events

Date Code Title Description
AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1996921784

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1996921784

Country of ref document: EP

WWW Wipo information: withdrawn in national office

Ref document number: 1996921784

Country of ref document: EP