EP0473764A1 - Complexes metalliques - Google Patents

Complexes metalliques

Info

Publication number
EP0473764A1
EP0473764A1 EP91906773A EP91906773A EP0473764A1 EP 0473764 A1 EP0473764 A1 EP 0473764A1 EP 91906773 A EP91906773 A EP 91906773A EP 91906773 A EP91906773 A EP 91906773A EP 0473764 A1 EP0473764 A1 EP 0473764A1
Authority
EP
European Patent Office
Prior art keywords
hydroxy
pyrone
methyl
carbon atoms
aliphatic hydrocarbon
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP91906773A
Other languages
German (de)
English (en)
Inventor
Robert Charles Hider
Ernst Reinhard Huehns
John Brooke Porter
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Hider Robert Charles
HUEHNS Ernst Reinhard
Original Assignee
Hider Robert Charles
HUEHNS Ernst Reinhard
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 Hider Robert Charles, HUEHNS Ernst Reinhard filed Critical Hider Robert Charles
Publication of EP0473764A1 publication Critical patent/EP0473764A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/34—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D309/36—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with oxygen atoms directly attached to ring carbon atoms
    • C07D309/40—Oxygen atoms attached in positions 3 and 4, e.g. maltol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • METAL COMPLEXES This invention relates to novel radioactive metal complexes and to their use in therapy and particularly diagnosis, especially in the context of cell labelling.
  • Radioactive indium and gallium when labelled to blood cells have been extensively used in diagnostic methods in the clinical setting.
  • the labelling of red cells has been used as a method of splenic imaging or determination of red cell mass
  • platelet labelling has been used for studies on platelet survival and platelet kinetics
  • white cell labelling has been used to localise inflammatory foci in a variety of clinical conditions.
  • the efficient labelling of blood cells has wide implications in the diagnosis of any disorder where haemagglutination may occur, e.g. atherosclerosis, thrombocytopenia, focal sepsis and in the location of tumour and metastatic tissues.
  • Radioactive indium and gallium are generally used in the form of metal complexes.
  • a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by an aliphatic hydrocarbon group of one to six carbon atoms or such a group substituted by one or more groups selected from fluoro, hydroxy and aliphatic hydrocarbyloxy groups but excluding 3-hydroxy-2-methyl-4-pyrone; or (2) 3-hydroxypyridin-2-one or a 3-hydroxypyridin-2-one in which the hydrogen atom attached to the nitrogen.atom is replaced by an aliphatic acyl group, by an aliphatic hydrocarbon group of 1 to 6 carbon atoms, or by an aliphatic hydrocarbon group substituted by one or more substituents selected from aliphatic acyl, alkoxy, cycloalkoxy, aliphatic amide, aliphatic ester, halogen and hydroxy groups and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by one of said substituents, by an alipha
  • the suitability of a ligand for complexing with one metal to provide a complex for use in one therapeutic context is no indication of its value for complexing with a different metal to provide a complex for use in a different therapeutic or diagnostic context.
  • the problem to be solved in the present application is entirely different from that with the iron complexes.
  • the ligands With the iron complexes the ligands are required to release iron which then reassociates with apotransferrin.
  • the complexes are required to bind to the cell and emit a signal .
  • 3-hydroxy-2-methyl-4-pyrone (maltol) is one of the preferred ligands for use in the iron complexes of U.K. Patent No. 2,128,998 it is inferior to other substituted 3-hydroxy-4-pyrones for use in indium and gallium complexes as will be illustrated hereinafter.
  • Preferred radioactive isotopes are the isotopes which emit X-rays or positrons.
  • Specific isotopes which are preferred, are for example the indium radioactive isotopes 111 and 113, particularly 111, and the gallium isotopes 66, 67, 68 and 72, particularly 67 and 68.
  • Indium 111 is particularly suitable for use in the present invention as it decays by emitting ⁇ radiation of 171 and 245 keV and has a half life of 67.2 hours.
  • Ga 67 is particularly suitable as it decays by emitting ⁇ radiation of 185 and 300 keV and has a half life of 78.26 hours.
  • Gallium 66 and 68 are suitable positron emitters.
  • the etal(III) complexes of use in the present invention contain indium and gallium in the trivalent form.
  • the metal(III) complexes are neutral, i.e.
  • ligands there being an internal balance of charges between the metal(III) cation and the ligand(s) bound covalently thereto without the necessity for the presence of a non-covalently bound ion or ions to achieve such balance.
  • these ligands are monobasic and bidentate, being formed through the loss of a proton from the hydroxy group of the ligand forming compound (OH —_ 0 " ).
  • Metal(III) complexes containing a 3:1 proportion of monobasic, bidentate ligand:metal(III) are therefore neutral .
  • the complexes according to the present invention may contain various different combinations of three ligands of the types (1) and (2).
  • all three ligands within the complex may be chosen from type (1), or all three from type (2), although optionally differing from within these types.
  • the three ligands may be chosen from both types in a 2:1 ratio, i.e. either two ligands derived from the same or two different 3-hydroxy-4-pyrones with one 3-hydroxypyridin-2-one ligand or two ligands derived from the same or two different 3-hydroxypyridin-2-ones with one 3-hydroxy-4-pyrone ligand.
  • complexes of particular interest are those containing three ligands of type (2) or particularly of type (1), these ligands conveniently being identical.
  • these 3-hydroxy-4-pyrones may carry more than one type of substituent group but substitution by one rather than two or three groups is preferred except that substitution by two groups is of interest when at least one of them is an aliphatic hydrocarbon group.
  • the term aliphatic hydrocarbon group is used herein to include both acyclic and cyclic groups which may be unsaturated or saturated, the acyclic groups having a branched chain or especially a straight chain. Groups of from 2 to 6 carbon atoms and particularly 3 to 5 carbon atoms are of most interest except that methyl groups can be of interest when an additional substituent is also present.
  • Saturated aliphatic hydrocarbon groups are preferred, these being either cyclic groups such as the cycloalkyl groups cyclopropyl and cyclohexyl or, more particularly, acyclic groups such as the alkyl groups methyl and ethyl and especially propyl , butyl and pentyl (and their branched chain analogues).
  • cyclic groups such as the cycloalkyl groups cyclopropyl and cyclohexyl or, more particularly, acyclic groups such as the alkyl groups methyl and ethyl and especially propyl , butyl and pentyl (and their branched chain analogues).
  • Similar observations and preferences apply to the aliphatic hydrocarbyl groups present in substituents which are aliphatic hydrocarbon groups substituted by aliphatic hydrocarbyloxy groups with the exception that the latter may sometimes be a methoxy group.
  • alkyl includes both straight and branched chain groups but references to individual alkyl groups such as "propyl” are specific for the straight chain group only.
  • An analogous convention applies to other generic terms.
  • 3-hydroxy-4-pyrone contains a substituted aliphatic hydrocarbon group that group preferably contains only one type of substituent among fluoro, hydroxy and aliphatic hydrocarbyloxy groups.
  • fluoro substituted aliphatic hydrocarbon groups may be used, for example any of the general types of or specific aliphatic hydrocarbon groups as described hereinbefore but substituted by one or more fluoro groups, for example up to five, nine or ten of such groups.
  • Fluoro substituted aliphatic hydrocarbon groups preferably contain one, three or five fluoro atoms, specific examples of such groups being a 1 ,1 ,2,2,2-pentafluoroethyl and 3,3,3-trifluoropropyl group.
  • each R separately (subject to the exclusion of the compound 3-hydroxy-2-methyl-4-pyrone,) is an alkyl or cycloalkyl group, or such a group substituted by three or five fluoro groups, by an alkoxy group or by a hydroxy group, for example ethyl, propyl, isopropyl, butyl or pentyl, or a fluoro substituted derivative thereof containing three or five fluorine atoms, particularly 1 ,1 ,2,2,2-pentafluoroethyl or 3,3,3-trifluoropropyl, or a C ⁇ _4 alkoxy substituted derivative thereof, particularly methoxymethyl , ethoxymethyl , propoxymethyl or butoxymethyl , and n is 1, 2 or 3.
  • Preferred compounds are those which are 2-alkyl, 2,6-dialkyl, 2-fluoroalkyl, 2-alkoxyalkyl, 2-hydroxyalkyl or 6-alkyl-2-hydroxy- alkyl substituted.
  • R is an alkoxymethyl group
  • the compounds of formula (IV) in which the group R at the 6-position is an alkyl group and that at the 2-position is an alkyl or 1-hydroxyalkyl group for example the compounds 3-hydroxy-6-methoxymethyl-4-pyrone, 6-ethoxymethyl-3-hydroxy-4-pyrone, 3-hydroxy-6-propoxymethyl-4- pyrone, 6-butoxymethyl-3-hydroxy-4-pyrone, 2-ethyl-3-hydroxy- 6-methyl-4-pyrone, 3-hydroxy-6-methyl-2-propyl-4-pyrone, 2-butyl-3-hydroxy-6-methyl-4-pyrone, 3-hydroxy-2-hydroxymethyl-6- methyl-4-pyrone ' , 3-hydroxy-2-(l-hydroxyethyl)-6-methyl-4-pyrone, 3-hydroxy-2-(l-hydroxypropyl)-6-methyl-4-pyrone and 3-hydroxy-2-(l-hydroxybutyl)-6-methyl-4-pyrone.
  • 3-hydroxypyridin-2-one ligands of type (2) these may be derived from hydroxypyridinones of the type described in UK Patent No. 2,117,766 (corresponding to US Patent No. 4,550,101 and Japanese Patent Application No. 83/049677) or of the type described in UK Patent No. 2,136,806 (corresponding to US Patent No. 4,810,491 and Japanese Patent Application No. 84/057186).
  • the former consist of a 3-hydroxypyridin-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are also replaced by the same or a different aliphatic hydrocarbon group of 1 to 6 carbon atoms, whilst the latter include 3-hydroxypyridin-2-ones substituted as defined under (2) hereinbefore but excluding those compounds in which the replacement of hydrogen atoms is effected only by aliphatic hydrocarbon groups, these compounds being the substituted hydroxypyridinones of the former patent.
  • the 3-hydroxypyridin-2-ones may contain alkoxy and cycloalkoxy groups and that, as compared with the compounds of U.K. Patent No. 2,136,806, an aliphatic hydrocarbon group on a carbon atom of the ring, as well as one on the nitrogen atom of the ring, can be substituted by one or more halogen groups.
  • Hydroxypyridinones providing ligands which may be used in complexes according to the present invention have the formula (V)
  • X and Y are substituents as defined hereinbefore as substituents on the nitrogen and carbon atoms of a 3-hydroxypyridin-2-one and n is 0, 1, 2 or 3.
  • substituted aliphatic hydrocarbon groups present in the hydroxypyridinones may conveniently contain 1 to 8 and particularly 3 to 6 carbon atoms and, as indicated, may carry more than one substituent group, although it is preferred that only one substituent group is present.
  • a preferred type of compound is a 3-hydroxypyridin-2-one in which the hydrogen atom attached to the nitrogen atom is replaced by an aliphatic hydrocarbon group of 1 to 6 carbon atoms and, optionally, in which one or more of the hydrogen atoms attached to ring carbon atoms are replaced by the same or a different aliphatic hydrocarbon group of 1 to 6 carbon atoms.
  • aliphatic hydrocarbon groups present in these hydroxypyridinones correspond largely to those expressed hereinbefore in relation to the hydroxypyrones, with methyl groups conveniently being used for substitution on ring carbon atoms but larger alkyl and cycloalkyl groups, particularly as described for the hydroxypyrones, being of particular interest for substitution on the ring nitrogen atoms.
  • halogen substituted aliphatic hydrocarbon groups those in which the aliphatic hydrocarbon group is substituted by one or more halogen groups, particularly fluoro groups, are of especial interest.
  • the preferences for such halogen substituted aliphatic hydrocarbon groups are largely as expressed hereinbefore in relation to the fluoro substituted aliphatic hydrocarbon groups of the hydroxypyrones.
  • there is a greater possibility of both an aliphatic hydrocarbon group and a halogen substituted hydrocarbon group being present in the compound, with one, for example the aliphatic hydrocarbon group, being on a carbon atom and the other, for example the halogen substituted hydrocarbon group, on the nitrogen atom.
  • Specific hydroxypyridinones of particular interest have formula (VI),
  • R is an alkyl or cycloalkyl group, or such a group substituted by one, three or five fluoro groups, for example ethyl, n-propyl, isopropyl, butyl, pentyl or hexyl, or a fluoro substituted derivative thereof containing three or five fluorine atoms, particularly 1 ,1 ,2,2,2-pentafluoroethyl or 3,3,3-trifluoropropyl.
  • ligands or combinations of ligands will be of particular value and some indication of these has already been given.
  • One measure of the value of the preferred complexes is provided by the value of their partition coefficient (K par t) between n-octanol and Tris hydrochloride (20 mM, pH 7.4, Tris representing 2-amino-2- hydroxymethylpropane 1,3-diol) at 20°C, this being expressed as the ratio (concentration in organic phass)/(concentration in aqueous phase).
  • Preferred complexes show a value of K par t for each ligand providing compound from 2 to 50, especially from 8 to 40, together with a value of K par t for the 3:1 indium(III) complex from 5 to 100, especially from 30 to 70.
  • the corresponding ranges for the 3:1 gallium(III) complexes are from 5 to 100 and 20 to 50, respectively. Whilst these ranges of K par t are given as a guide to preferred complexes, ligands and/or complexes that have a K par t value outside these ranges can still be suitable for use.
  • the radioactive metal(III) complexes are conveniently prepared by the reaction of the hydroxypyrone and/or hydroxypyridinone ligand-providing compounds and radioactive metal ions, the latter conveniently being derived from a etal(III) salt, particularly the chloride salt.
  • the reaction is conveniently effected in a suitable mutual solvent, usually an aqueous medium. If desired, however, an aqueous/solvent mixture may be used or an organic solvent, for example ethanol, methanol or chloroform and mixtures of these solvents together and/or with water where appropriate.
  • methanol or especially ethanol may be used where it is desired to effect the separation of at least one major part of a by-product such as sodium chloride by precipitation whilst the indium or gallium complex is retained in solution. Reaction is generally rapid and will usually have proceeded substantially to completion at 20°C in a few minutes.
  • the complexes of the present invention are often used in solution but, where desired, may be prepared in solid form by evaporation of the reaction mixture and freeze drying, followed by crystallization from a suitable solvent if further purification is required.
  • the nature of the metal complex obtained by the reaction of the ligand-providing compound(s) and metal ions will depend both on the proportion of these reactants and upon the pH of the reaction mixture.
  • the hydroxypyrone and/or hydroxypyridinone ligand-providing compound(s) and the metal salt are conveniently mixed in solution in at least a 3:1 molar proportion and the pH adjusted to a value in the range 6-9, for example 7 or 8.
  • ligand-providing compound:metal(III) ratio may conveniently be greater than 3:1, for example being 100:1 or up to 1000:1.
  • the product will consist essentially of the 3:1 ligand:metal(III) complex.
  • it will be preferable to incorporate some "cold" non-radioactive metal with the radioactive metal when forming the ligand:metal complex the amount of ligand-providing compound(s) being adjusted accordingly. This will result in some non-radioactive complex being administered in combination with radioactive complex.
  • the ligand-providing compounds will conveniently be used in a 2:1 or 1:1 ratio, as desired, although with complexes in which the ligands are heterogeneous a mixture of different 3:1 complexes will always result even when a 2:1 ratio is employed. For this reason complexes in which the ligands are homogeneous are preferred.
  • the radioactive indium or gallium cation is preferably obtained from its chloride salt.
  • the amount of radioactivity required in the complex is often within the range 10 to 60 mCi/yg, but will ultimately depend on the proposed use of the complex as described hereinafter.
  • the present invention thus further includes a process for the preparation of a neutral 3:1 ligand:metal(III) complex of a substituted 3-hydroxy-4-pyrone or 3-hydroxypyridin-2-one as defined hereinbefore which comprises reacting the ligand providing compound or compounds with the trivalent cation of the indium or gallium radioactive isotope.
  • 3-hydroxy-4-pyrones including 2-trifluoromethyl-3-hydroxy-4-pyrone
  • one convenient starting material consists of 3-hydroxy-4-pyrone which is readily obtainable by decarboxylation of 2,6-dicarboxy-3-hydroxy-4-pyrone ( econic acid).
  • 3-hydroxy-4-pyrone may be reacted with an aldehyde to insert a 1-hydroxyalkyl group at the 2-position, which group may then be reduced to produce a 2-alkyl-3-hydroxy-4-pyrone.
  • the preparation of 2-ethyl-3- hydroxy-4-pyrone, etc., by this route is described in the published US Application Serial No. 310,141 (series of 1960) referred to in U.S. Patent No. 3,376,317.
  • the preparation of other substituted 3-hydroxy-4-pyrones may be exemplified as follows.
  • the hydrocarbyloxyalkyl substituted 3-hydroxy-4-pyrones may be prepared from 3-hydroxy-6-hydroxymethyl- 4-pyrone (kojic acid) by protecting the 3-hydroxy group, for example as a benzyloxy group, and reacting the protected compound with the corresponding alkyl halide, for example in dimethylformamide using sodium hydride. Deprotection is then effected, for example a benzyloxy group being converted to hydroxy using concentrated hydrochloric acid, and the end product isolated.
  • 3-hydroxy-6- methoxy ethy1-4-pyrone, 6-ethoxymethy1-3-hydroxy-4-pyrone, 3-hydroxy-6-propoxymethyl-4-pyrone and 6-butoxymethyl-3-hydroxy-4- pyrone have been prepared.
  • 3-hydroxy-4-pyrones wherein two of the hydrogen atoms attached to the ring carbon atoms have been substituted may also be prepared from kojic acid. For example, kojic acid is converted to the chloro analogue using thionyl chloride. This is then reacted with zinc dust and hydrochloric acid to form 3-hydroxy-6-methyl-4-pyrone.
  • the present invention thus includes a process for the preparation of a 3-hydroxy-4-pyrone in which one or more of the hydrogen atoms attached to the ring carbon atoms is replaced by an aliphatic hydrocarbon group of one to six carbon atoms substituted by an aliphatic hydrocarbyloxy group of one to six carbon atoms, and one or more other hydrogen atoms are optionally replaced by an aliphatic hydrocarbon group of one to six carbon atoms, which comprises reacting an intermediate, in which the 3-hydroxy group is protected and the or each aliphatic hydrocarbon group substituted by an aliphatic hydrocarbyloxy group is replaced by the corresponding hydroxy substituted aliphatic hydrocarbon group, with an aliphatic hydrocarbyl halide containing the corresponding aliphatic hydrocarbyl group and then deprotecting the 3-hydroxy group.
  • the present invention further includes a process for the preparation of a 3-hydroxy-6-methyl-4-pyrone substituted at the 2-position by a C-
  • 3-hydroxy-4-pyrone intermediates are novel compounds and fall within the scope of the present invention.
  • the 3-hydroxypyridin-2-ones may be prepared by procedures described in U.K. Patents Nos. 2,117,766 and 2,136,806, and by variants thereon.
  • radiolabelled metal(III) complexes of the present invention can with advantage be used to label granulocytes, platelets, red cells and lymphocytes.
  • Radiolabelled leucocytes can be used clinically to detect sites of abscess and inflammation.
  • Radiolabelled platelets may be used diagnostically to measure platelet survival and distribution. Furthermore they may be used to visualize venous and arterial accumulation of platelets in atherosclerotic lesions, venous rhombi and thrombophlebitis.
  • An additional use of radiolabelled platelets is to provide an early indication of renal transplant rejection and to assess the thrombogenicity of arterial grafts.
  • the circulation and distribution of radiolabelled autologous lymphocytes can be visualized and analysed using the complexes of the present invention.
  • Labelling of red blood cells is of diagnostic benefit in the following instances: cardiovascular imaging, gated wall motion studies, measurement of ejection function of the left ventricle, measurement of blood volume, gastro-intestinal bleeding studies and for the labelling of heat denatured red blood cells for splenic imaging.
  • lymphocytes labelled with radioactive indium complexes for example of In 114, and potentially also gallium complexes, may be used in therapy, principally in the treatment of ly phomas.
  • the complexes of the present invention are therefore also of interest in a therapeutic context.
  • the dosage of radiolabelled metal(III) complex labelled blood cell administered to the patient is dependent upon the radioactive isotope, the species of blood cell, the diagnostic purpose it is being employed for and the method of detection to be used. The following information may, however, be provided by way of guidance.
  • the normal adult dose of indium 111 labelled leucocytes for location of sites of infection is 500-1000 yCi (18.5 -9- 37 MBq).
  • dosages within the range 300 to 1000 yCi, particularly 600 yCi should generally be suitable.
  • gallium(III) complexes of the present invention dosages within the range 300 to 1000, 2000 or 2500 vCi, particularly 500, 1000 or 1500 yCi should generally be suitable.
  • the normal adult dosage of radioactive gallium 67 is 1000-2000 yCi (37-74 MBq) for detecting tumours in the lymphatic system.
  • a dosage of 1500-2500 yCi (55.5-92.5 MBq) is recommended.
  • dosages used for indium 111 and gallium 67 complexes in other labelling contexts will be similar to those given above subject to any variations generally recognised in the literature as being suitable in that context.
  • dosages for other radioactive isotopes will be similar in terms of yCi although not necessarily in terms of the amount of the complex.
  • indium(III) or gallium(III) complexes are to be used in vivo either diagnostically or therapeutically, then these are best formulated into pharmaceutical compositions with a suitable diluent or carrier as described in UK Patents Nos. 2,117,766, 2,128,998 or 2,136,806.
  • the invention is illustrated by the following Examples, Examples 1 to 3 of which relate to intermediates for the preparation of the complexes. Certain of these intermediates are novel p_e ⁇ se_ and are included within the scope of the present invention.
  • the nmr signals have been attributed to the protons to which they are believed to relate.
  • 3-Benzyl-6-methoxymethyl-4-pyrone (8 g, 0.032 mol) was refluxed in 100 ml hydrochloric acid for 2 hours. After cooling, the pH of the mixture was adjusted to pH 11, followed by extraction into dichloromethane (2 x 50 ml). The aqueous layer was treated with concentrated hydrochloric acid to pH 2 and further extracted into dichloromethane (3 x 100 ml). The extracts were combined, dried over anhydrous sodium sulphate and evaporated to dryness.
  • step (1) Yield 8.2 g (73.3%) in step (1) and 4.2 g (80%) in step (2);
  • step (1) Yield 8.3 g (83%) in step (1) and 5.4 g (78.6%) in step (2);
  • Ethyl maltol is prepared as described in Example 1 of U.S. Patent Application 310,141 referred to in U.S. Patent No. 3,376,317.
  • the ethyl maltol is made up in stock solutions at a concentration of 0.01M in 20 M HEPES/0.8.% NaCl , pH 7.4-7.5.
  • the more concentrated stock solution of ethyl-maltol is added dropwise to an acidic solution of 67 Ga-(GaCl 3 ) in 0.04 N HC1.
  • the resulting solution is neutralized to pH 7.0.
  • the synthesis of l-ethyl-3-hydroxypyridin-2-one is described in Example 1 of European Patent No. 094149.
  • the l-ethyl-3-hydroxypyridin-2-one is made up into stock solutions in 20 mM HEPES/0.8 NaCl pH 7.4-7.5 at a final concentration of 0.01M.
  • the l-ethyl-3-hydroxypyridin-2-one solution is added dropwise to an acidic solution of in 0.04 N HC1.
  • the resulting solution is neutralized to pH 7.0.
  • Comp exes of other 3-hydroxypyridin-2-ones are prepared in a similar manner.
  • the ligands are preferably added in large excess as compared with the metal salt, for example a 100:1 or 1000:1 rather than a 3:1 molar proportion of ligand providing compound:salt, in order to ensure that all the radioactive metal cations combine with the ligand providing compound in the form of the 3:1 complex.
  • Partition coefficients of complexes were determined by addition of 1 ml of a solution of the 67 Ga-(III) and 111 In-(III) 3:1 complex prepared as described in Example 1 using a 3:1 molar proportion to 1 ml of water-saturated octan-1-ol in a glass test tube. The system was allowed to equilibrate at ambient temperature for 15 minutes on a gently rotating mixer. The tubes were spun at 3000 rpm (1500 g) for 10 minutes after which time 200 microliter samples of each phase were taken, weighed using an analytical balance and counted for radioactivity. Partition coefficients were calculated using the following equation:
  • Solutions of the ligands were produced by dissolving the ligand in aqueous tris hydrochloride of pH 7.4. Acid washed glassware was used throughout and, following mixing of 5 ml of the 10 ⁇ 4 M aqueous solution with 5 ml of n-octanol for 1 minute, the aqueous n-octanol mixture was centrifuged at 1,000 g for 30seconds. The two resulting phases were separated for a concentration determination by spectrophotometry on each. Values typical of those obtained are shown in Table 2.
  • Example 6 Red cell labelling with r 67 Ga(III)-(3-hydro ⁇ y-4- pyrone ⁇ l complexes
  • Figure 1 represents the data for 67 Ga(III)-(maltol) 3 for comparative purposes
  • Figure 2 represents the data for ⁇ 7Ga(III)-(ethyl-maltol) 3
  • Figure 3 for 67 Ga(III)-(isopropyl-maltol) 3
  • Figure 4 for 67 Ga(III)-(butyl-maltol) 3 .
  • the complexes containing the larger alkyl groups allow for more rapid uptake of & 7 Ga into the red cells and achieve a higher absolute incorporation.
  • Figure 5 shows the effect of ligand concentration on uptake of 6 g a into erythrocytes at 15 minutes for various complexes.
  • the graphs labelled 1 to 4 represent, respectively, the results for the maltol, ethyl-maltol, isopropyl-maltol and butyl-maltol 67 Ga complexes (the first for comparative purposes). Again this indicates that the complexes containing the larger alkyl groups give increased incorporation of 67 Ga into red cells.
  • Example 7 Leucocyte labelling with [ ⁇ In(III)- (3-hydroxy-4-pyrones)31
  • the effect of ligand concentration on white cell labelling with T ⁇ T In(III) 3:1 3-hydroxy-4-pyrone complexes prepared as described in Example 1 using a 100:1 to 1000:1 molar proportion was performed using mixed whited cell populations suspended in buffer.
  • the white cells were harvested from 60 ml of whole blood obtained from normal human volunteers. The blood was drawn into a 60 ml syringe, anticoagulated using heparin (100 Units/10 ml whole blood) and the red cells allowed to sediment by standing the syringe upright using a ring-stand for 1 hour.
  • the majority of the white cells were found in the supernatant plasma.
  • the supernatant was expressed into a sterile plastic tube using a 19 g bufferfly set.
  • the cells were washed twice using 20 mM HEPES-saline (0.8%) and resuspended in 5 ml buffer.
  • a cell count and differential was performed using a coulter-counter device and the cell suspension concentration was adjusted to 9 x 10 6 white cells/0.9 ml.
  • Labelling was performed by adding 0.1 ml of a solution of the appropriate min(III) 3:1 complex and incubating for 15 minutes. After 15 minutes incubation the cells were washed twice with 2 ml of buffer.
  • the cells and separate washes were counted using an automatic gamma counter with energy windows set for " ⁇ Un.
  • Example 3 The effect of white cell concentration was studied using radiolabelled 111 In-(III)-(2-butyl-3-hydroxypyridin-2-one)3 complex. Cells were labelled, separated and counted using the procedures of Example 4. The effect of red cell volume was investigated using the butyl-maltol 3:1 Ga(III) complex. 0.5 ml of the complex prepared as in Example 1 using a 100:1 to 1000:1 molar proportion was added to heparinised glass blood collection tubes containing 1, 2, 3, 4 or 5 ml of washed, packed red cells obtained as in Example 3.
  • Figure 7 shows the effect of leucocyte concentration on indium labelled complex incorporation at 0.0001 M concentration of the butyl-maltol 3:1 11 In(III) complex, incubation being for 15 minutes. Cell concentration had no significant effect on percentage uptake of the radiolabelled complex.

Landscapes

  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pyridine Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

Complexes ligand:métal (III) neutres 3:1 dans lesquels le cation métallique trivalent est un isotope radioactif d'indium ou de galium et chaque ligand consiste séparément en un composé de: (1) 3-hydroxy-4-pyrone dans lequel un des atomes d'hydrogène, ou davantage, fixé à des atomes de carbone cycliques est remplacé par un groupe hydrocarbure aliphatique constitué de un à six atomes de carbone ou un groupe semblable substitué par un groupe, ou davantage, sélectionné(s) à partir de groupes fluoro, hydroxy et hydrocarbyloxy aliphatique mais excluant 3-hydroxy-2-méthyle-4-pyrone; ou (2) un 3-hydroxypyridine-2-one ou un 3-hydroxypyridine-2-one dans lequel l'atome d'hydrogène fixé à l'atome d'azote est remplacé par un groupe acyle aliphatique, par un groupe hydrocarbure aliphatique constitué de 1 à 6 atomes de carbone ou par un groupe hydrocarbure aliphatique substitué par un substituant, ou davantage, sélectionné(s) à partir de groupes d'acyle aliphatique, alkoxy, cycloalkoxy, amide aliphatique, ester aliphatique, halogène et hydroxy et, éventuellement, dans lequel un, ou davantage, des atomes d'hydrogène fixé(s) aux atomes de carbone cyclique est (sont) remplacé(s) par l'un desdits substituents, par un groupe hydrocarbure aliphatique constitué de 1 à 6 atomes de carbone ou par un groupe hydrocarbure aliphatique substitué par un groupe alkoxy, cycloalkoxy, ester aliphatique ou hydroxy ou par un groupe halogène, ou davantage; s'adressant à la thérapie et, particulièrement, au diagnostic basé sur la désignation cellulaire.
EP91906773A 1990-03-23 1991-03-22 Complexes metalliques Withdrawn EP0473764A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9006522 1990-03-23
GB909006522A GB9006522D0 (en) 1990-03-23 1990-03-23 Metal complexes

Publications (1)

Publication Number Publication Date
EP0473764A1 true EP0473764A1 (fr) 1992-03-11

Family

ID=10673114

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91906773A Withdrawn EP0473764A1 (fr) 1990-03-23 1991-03-22 Complexes metalliques

Country Status (5)

Country Link
EP (1) EP0473764A1 (fr)
JP (1) JPH04506672A (fr)
CA (1) CA2058288A1 (fr)
GB (2) GB9006522D0 (fr)
WO (1) WO1991014664A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6004951A (en) * 1989-11-22 1999-12-21 Bernstein; Lawrence Richard Administration of gallium complexes of 3-hydroxy-4-pyrones to provide physiologically active gallium levels in a mammalian individual
US5574027A (en) * 1989-11-22 1996-11-12 Bernstein; Lawrence R. Pharmaceutical compositions of gallium complexes of 3-hydroxy-4-pyrones
US5258376A (en) * 1989-11-22 1993-11-02 Bernstein Lawrence R Pharmaceutical compositions of gallium complexes of 3-hydroxy-4-pyrones
ATE195868T1 (de) * 1991-11-12 2000-09-15 Lawrence Richard Bernstein Pharmazeutische zusammensetzungen von gallium- komplexen von 3-hydroxy-4-pyronen
US5336482A (en) * 1991-12-05 1994-08-09 The Du Pont Merck Pharmaceutical Company Technetium-99m complexes with N-substituted 3-hydroxy-4-pyridinones
US5298525A (en) * 1992-11-23 1994-03-29 University Technologies International, Inc. Diabetes prevention and treatment
US6448273B1 (en) 1997-05-29 2002-09-10 Btg International Limited Orally active iron (III) chelators
GB9711093D0 (en) * 1997-05-29 1997-07-23 British Tech Group Novel orally active iron (III) chelators
CA2560544C (fr) 2004-01-16 2015-05-19 Carnegie Mellon University Marquage cellulaire pour des techniques de resonance magnetiques nucleaires
EP2010646A2 (fr) 2006-04-14 2009-01-07 Carnegie Mellon University Marquage des cellules et quantification pour les techniques de résonance magnétique nucléaire
JP5645658B2 (ja) 2007-07-10 2014-12-24 カーネギー メロン ユニバーシティー 核磁気共鳴技術のための細胞標識を製造するための組成物及び方法

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3468915A (en) * 1966-04-18 1969-09-23 Pfizer & Co C Novel 2-substituted-6-methylpyromeconic acids
DE2304381C3 (de) * 1973-01-30 1979-06-21 Byk-Mallinckrodt, Chemische Produkte Gmbh, 6057 Dietzenbach Hoch 113m Indium-acetylacetonat enthaltendes Mittel für die szintigraphische Funktionsdiagnostik der Leber auf dessen Herstellung
FR2390408A1 (fr) * 1977-05-11 1978-12-08 Philips France Procede de marquage par un isotope radioactif d'un sel hydrosoluble d'oxine, ou de ses derives halogenes ou sulfones, produits ainsi marques, procede de marquage des elements figures du sang, et medicaments ainsi obtenus
GB2117766B (en) * 1982-03-24 1985-08-29 Nat Res Dev Pharmaceutical compositions
EP0107458B1 (fr) * 1982-10-22 1987-07-29 National Research Development Corporation Compositions pharmaceutiques
GB8308055D0 (en) * 1983-03-24 1983-05-05 Hider R C Pharmaceutical compositions
AU580958B2 (en) * 1983-07-07 1989-02-09 Mallinckrodt, Inc. Sterile radioactive indium-containing aqueous solution

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9114664A1 *

Also Published As

Publication number Publication date
GB9006522D0 (en) 1990-05-23
GB9106137D0 (en) 1991-05-08
CA2058288A1 (fr) 1991-09-24
GB2242191B (en) 1993-12-08
JPH04506672A (ja) 1992-11-19
GB2242191A (en) 1991-09-25
WO1991014664A1 (fr) 1991-10-03

Similar Documents

Publication Publication Date Title
EP0107734B1 (fr) Complexes isonitriles de radionucleides pour agents d'etiquetage et mise en image
EP0473764A1 (fr) Complexes metalliques
JPS62201363A (ja) 放射線標識エーテル置換イソニトリル錯化合物を含有する心筋像形成剤
Benoist et al. A Click procedure with heterogeneous copper to tether technetium-99m chelating agents and rhenium complexes. Evaluation of the chelating properties and biodistribution of the new radiolabelled glucose conjugates
US5071965A (en) Novel tc-99m complexes
EP0213945A2 (fr) Complexes de radionucléide et d'isonitrile substitué par des groupes carboxy, carbalcoxy et carbamide
US5219555A (en) Method for labeling proteins with technetium or rhenium
US4443426A (en) Blood agent
US5741476A (en) Polyhydric phenol compounds
Martin et al. Synthesis and Characterization of 2-Iodo-4-[5′-(4'″-Methylpiperazin-1'″-yl)-2′, 5′-bi-1h-Benzimidazol-2′-Yl] Phenol (iodoHoechst 33258) and 2, 5-Disubstituted Benzimidazole Model Compounds
JPH02304068A (ja) 置換された１，４，７，１０‐テトラアザシクロトリデカン
US4894445A (en) Metal-isonitrile adducts for preparing radionuclide complexes
US5693324A (en) Tris(isonitrile) copper(I) sulfates for preparing radionuclide complexes
FI85859C (fi) Foerfarande foer framstaellning av radionuklidkomplex av metall/isonitriladdukter.
Fairbank et al. Steric effects on the rates of redox reactions involving nickel (II/III) macrocycles
USRE35904E (en) Method and probes for detecting nucleoside transporter and method for producing the probes
WO2007137135A2 (fr) Analogues de roténone, méthode de préparation et d'utilisation
Reimann et al. Some New Co-ordination Compounds of Copper (II) Chloride
Dolphin et al. A convenient and economical preparation of L-methionine-methyl-d3
Chan et al. Synthesis and biodistribution of radioiodinated‐5‐iodonicotine
McPherson et al. Radiolabeling of proteins with radioisotopes of copper using p‐carboxyalkylphenylglyoxal bis‐(4N‐methylthiosemicarbazone)(TSC) bifunctional chelates
US4872561A (en) Carboxy, carboalkoxy and carbamile substituted isonitrile radionuclide complexes
EP0546233B1 (fr) Procédé pour la préparation et marquage avec 99mTc du 2-alkoxyisobutylisonitrile
Saji et al. Synthesis and in vivo behavior of a copper‐64‐labeled dithiosemicarbazone derivative coupled to a dihydropyridine carrier
US4598073A (en) Certain polycyclo-palladium-bipyridine complexes having anti-tumor activity

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19911112

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 19940930