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WO1992016520A1 - Ligands macrocycliques de thioether et leur utilisation en tant qu'intermediaires pour lier les ions aux substrats - Google Patents

Ligands macrocycliques de thioether et leur utilisation en tant qu'intermediaires pour lier les ions aux substrats Download PDF

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Publication number
WO1992016520A1
WO1992016520A1 PCT/GB1992/000492 GB9200492W WO9216520A1 WO 1992016520 A1 WO1992016520 A1 WO 1992016520A1 GB 9200492 W GB9200492 W GB 9200492W WO 9216520 A1 WO9216520 A1 WO 9216520A1
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WO
WIPO (PCT)
Prior art keywords
ligand
group
ligands
substituted
extended
Prior art date
Application number
PCT/GB1992/000492
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English (en)
Inventor
Philip John Blower
Adrian Peter Richardson
Raymond John Smith
Original Assignee
British Technology Group Ltd
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
Priority claimed from GB919105898A external-priority patent/GB9105898D0/en
Priority claimed from GB919125882A external-priority patent/GB9125882D0/en
Application filed by British Technology Group Ltd filed Critical British Technology Group Ltd
Priority to JP4506056A priority Critical patent/JPH06505975A/ja
Publication of WO1992016520A1 publication Critical patent/WO1992016520A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D341/00—Heterocyclic compounds containing rings having three or more sulfur atoms as the only ring hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6578—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and sulfur atoms with or without oxygen atoms, as ring hetero atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • This invention relates to certain macrocyclic thioether ligands and their use as intermediates for binding ions to substrates, especially the attachment of radionuclides to biologically active substrates such as immunoglobulins.
  • bifunctional chelates which would trap metallic radionuclides and themselves be capable of reaction to covalently bond to the biologically active molecule of interest e.g. an immunoglobulin or be reactable with functions on proteins (e.g. lysine residues) or with an anti-tumour monoclonal antibody.
  • radiolabelled antibodies for in vivo localisation of tumours has been recognised since the discovery of the hybridoma technique for raising monoclonal antibodies in 1976.
  • Methods using radioiodine as the labelling nuclide (1-123 for gamma camera imaging, and 1-131 for both imaging and radioimmunotherapy) have more recently been augmented by the use of chelate-conjugated antibodies labelled with radiometals.
  • the most widely investigated example of this method for imaging purposes employs indium-Ill chelated to a derivative of diethylenetriaminepentaacetic acid (DTPA). These procedures have been the subject of considerable clinical evaluation and pharmacokinetic analysis.
  • DTPA diethylenetriaminepentaacetic acid
  • radioiodine labelled antibodies are known to lose a large portion of their label (as free iodide) in vivo. This results in the need for blocking of the thyroid gland, leads to image degradation and causes dosimetric problems when therapeutic doses are being considered.
  • a characteristic of indium-111 and yttrium-90 labelled antibodies is high non-specific uptake of radioactivity in the liver, spleen and bone marrow. This leads to excessive radiation doses to these organs if beta-emitting nuclides such as yttrium-90 are administered for radiotherapy, and restricts the diagnostic usefulness of indium-labelled antibodies in cases where liver metastates may be present.
  • the half-lives are such that the radiation dose need not be excessive, while the gamma-emission energies are within the range suitable for detection by gamma-cameras.
  • Gamma emitters with suitable emission energies may be used for diagnostic imaging.
  • Copper-64 and copper-62 are positron emitters of potential value in positron emission tomography.
  • Several of the ⁇ -emitters are currently available at specific activities sufficiently high to administer therapeutic doses with reasonable amounts of antibody (e.g. lmCi/mg antibody).
  • some pairs of isotopes of the same element are available, e.g. gold-193 and gold-199, of which one could be used for imaging and the other for therapy using the same antibody-chelate conjugate.
  • the target specificity of the therapeutic dose could be reliably predicted by imaging.
  • the combination of technetium-99m and rhenium-188 or rhenium 186 (both of which metals, in their lower oxidation states, may be described as "soft") may also offer this advantage because of the close chemical similarity between the two elements.
  • Beta emitters and those gamma emitters which also emit cell-killing secondary radiation (e.g. Auger electrons) may be used in cancer therapy.
  • the 9S3 complexes have unusual and useful properties such as high stability (thioethers are typically relatively weakly
  • the present invention provides ligands of formula I
  • T is S or Se or Te
  • another T is S or Se or Te
  • the third T is S, Se, Te, >PX or >AsX
  • X being a univalent atom or group, and where A 1 is -C 2 H 4 - or or -C 3 H 6 -,
  • a 2 is -C 2 H 4 - or
  • a 3 is -C 2 H 3 R- or or except when A 1 is -C 3 H 6 -, -C 3 H 5 R-,
  • R is alkyl or substituted alkyl and is preferably selected from hydroxyalkyl, alkoxyalkyl, aryloxyalkyl and arylalkoxyalkyl groups which groups may be substituted, or, if the third T contains P or As, R may also be H.
  • each T is S or two T's are S and the third is the group Preferably A 1 and A 2 are -C 2 H 4 -.
  • X may suitably be a hydrogen atom or an alkyl or phenyl group, which groups may be substituted.
  • R is preferably a group capable of further
  • derivatisation is preferably hydroxyalkyl, alkoxyalkyl, aryloxyalkyl or arylalkoxyalkyl optionally further substituted, for example by halo-, carboxy- or cyano-.
  • 9S3 ligands may derive (at least in part) from their predisposition to facial coordination as a result of their preferred endodentate conformation.
  • the inventors have conceived the notion of further improving these ligands by substituting (9-10)S3 compounds in the thia crown in such a way as to provide (i) a phosphine donor in place of a thioether donor and/or (ii) a further co-ordinating group to satisfy the vacant co-ordination site of four-co-ordinate metal ions or a further tridentate crown to satisfy six-co-ordinate metal ions.
  • One aspect of the invention therefore comprises ligands of formula I above in which one T is where X is preferably a
  • phenyl which may be further derivatised by the introduction of at least one substituent, preferably an ortho substituent, which is a donor group or atom or second macrocycle so as to extend the co-ordination.
  • substituents preferably an ortho substituent, which is a donor group or atom or second macrocycle so as to extend the co-ordination.
  • compounds such as the 1 ,4-dithia,7-phospha(P-mono-orthosubstituted-phenyl)cyclononanes, which have the ortho substituent "pointing towards" the sulphur atoms, are postulated as being useful because a ligand substituted onto that ortho site will assist a tetrahedral complexation of a metal in co-operation with the S, S and P.
  • Such extended ligands may be bound to a protein or other biologically active molecule or moiety, enabling the latter to be tracked through the body, or enabling tumours to be located and/or treated, by radioimmunolocalisation.
  • Metal complexes of such macrocyclic thiaphosphines which have been found to exhibit surprisingly high stability, are also included within the invention. Synthesis of such metal complexes and single crystal X-ray structure determination of the cyclic ligand shows that it is capable of facial tridentate coordination and suggests that it will ligate more strongly than 9S3, in that the phosphine donor of the non-facially coordinating ligand binds to the metal in preference to the thioethers.
  • the invention further includes extended ligands in which at least one uni valent atom or group of a ligand of formula I has been replaced by a moiety extending the co-ordinating
  • Preferred extended ligands according to the invention may be represented by replacing that atom or group by (i) a moiety derived from formula I as set forth above, or (ii) a linker group which can bind to a substrate, the linker group optionally additionally falling within the definition of said moiety and/or having
  • co-ordinating functionality such as carboxyl or amine or more preferably phosphine or even more preferably thiol or thioether.
  • l i nker groups are :
  • T is >PX or >AsX
  • X may suitably incorporate additionally a donor group or atom or a second macrocycle so as to extend the co-ordinating functionality of the ligand.
  • the ligands and extended ligands according to the invention may find application as chelators for reaction with other reagents at the point of use or as intermediates in the preparation of
  • the molecules set forth above can find application as chelators, which may be sold and used to bind metals such as radionuclides to substrates, e.g. in kits for labelling
  • the molecules may be sold as chelates, i.e. as ready-made metal complexes, which the user may then optionally attach to a substrate.
  • the molecules may be sold bound to a substrate, ready for the user then optionally to complex a metal therein.
  • the molecule according to the invention can lastly be a metal complex bound to a substrate.
  • the invention therefore includes ligands and extended ligands as defined above when complexed with either a radionuclide, a biologically active substrate, such as an immunoglobulin, or both.
  • the invention further includes a kit suitable for use in
  • radiodiagnosis or radiotherapy including a ligand, extended ligand or a complex thereof.
  • reactive linking groups and substrate targets are shown in the following Table 2.
  • Ligand D -CH 2 OCH 2 -parabromophenyl (yield 20%)
  • Ligand E -CH 2 OCH 2 -parabenzoate (yield 8%)
  • reaction scheme may be depicted as
  • Ligands were synthesised in detail as follows:- Preparation of Lloand B. viz 9S3-CH 2 OH
  • This compound was prepared by a method analogous to that for B (9S3-CH 2 OH), substituting 1,2-dibromo-3-(4'-bromobenzyloxy) propane for 2,3-dibromopropane. It was purified by silica gel chromatography as described for C (later). Yield 20%.
  • This compound was prepared by a method analogous to that for B (9S3-CH 2 OH), substituting 1,2-dibromo-3-(4'-carboxybenzyloxy)propane for 2,3-dibromopropane. It was purified as follows. The DMSO reaction solution was diluted with water (200 ml) and the mixture extracted with chloroform. The chloroform extracts were washed with water, dried over MgSO 4 and evaporated to dryness. The residue was extracted into 10% sodium hydroxide solution, the extract washed with chloroform and acidified with concentrated hydrochloric acid, resulting in precipitation of a solid.
  • R 1 may be as follows:
  • Ligand F -CH 2 -paracyanophenyl (yield 43%)
  • Ligand G -CH 2 -meta-monobromo-phenyl (yield 57%)
  • Ligand B (1 mmol) was reacted with sodium hydride (1 mmol) in dry dimethylformamide (5 ml) followed by addition of benzyl
  • This compound was prepared by a method analogous to that for C, substituting 4-cyanobenzyl chloride for benzyl chloride.
  • the product was purified by silica gel chromatography also as described for C. Yield 43%.
  • This compound was prepared by a method analogous to that for C, substituting 3-bromobenzyl chloride for benzyl chloride.
  • the product was purified by silica gel chromatography as described for C. Yield 57%
  • IR (mull, cm -1 ) 1095(s), 1080(s), 930(s), 875, 830, 820, 810, 765, 745, 725, 700, 695, 635.
  • Nickel (II) tetrafluoroborate hexahydrate (0.0357g
  • the mixture was centrifuged, and the supernatant decanted off.
  • the red solid was shaken with ether (12ml) and again centrifuged.
  • the solvent was poured off and the product dried under high vacuum.
  • IR (mull, cm -1) 1410, 840(s), 745(s), 695, 550, 480.
  • the ligand structure was determined by single crystal X-ray to confirm the structure Cu(9PhPS2) 2 + as having tetrahedral
  • Ligand E (see Example 1) (51mg, 0.15 mmol), dicyclohexylcarbodiimide (31mg, 0.16 mmol), and N-hydroxysulphosuccinimide, sodium salt (32.5mg, 0.15 mmol) were stirred in dry dimethylformamide (1ml) under dry dinitrogen at room temperature for 48h. A white solid was precipitated (dicyclohexylurea) and was removed by filtration. The filtrate was diluted with 15ml diethylether, resulting in formation of a gummy solid which was collected and freed of solvent under high vacuum.
  • Infra red absorption (cm -1 ): 3500 (br), 2900, 2840, 1760, 1730, 1655, 1615, 1600, 1405, 1355, 1225 (br), 1095, 1070, 1035, 985.
  • the product was dissolved in dimethyl sulphoxide (DMSO) to a concentration of lOmg/ml for use in protein labelling, and stored below 0°C. (Hereafter the product is identified as "bifunctional chelator solution").
  • DMSO dimethyl sulphoxide
  • Ligand E (0.103g, 0.3 mmol), dicyclohexylcarbodiimide (0.062g, 0.3 mmol), and N-hydroxysuccimide (0.062g, 0.3 mmol) were stirred at 4°C in dry tetrahydrofuran (3ml) under dry dinitrogen for 3h.
  • Figure 2 gives the results for gel filtration of rabbit IgG incubated with 197 Hg pre-chelated with the bifunctional chelator (9S3-activated ester): radioactivity and absorbance elution profi 1e;
  • Figure 3 shows gel filtration of rabbit IgG incubated with 1 97 Hg pre-chelated with intermediate E (9S3-carboxylate):
  • Figures 4 and 5 show gel filtration of 197 Hg-labelled rabbit IgG incubated with whole human serum for 24h: radioactivity and absorbance elution profiles respectively;
  • Figures 6 and 7 show gel filtration of 197 Hg-labelled rabbit IgG in PBS: radioactivity and absorbance profiles respectively.
  • Example 5-1) (3.62 ⁇ l) was diluted to 46 ⁇ l with DMSO and the solution added to 2 ⁇ l aqueous carrier-free 197 HgCl 2 (37 MBq/ml , Medgenix pic). After 2 minutes this solution was added to
  • rabbit IgG (Sigma, 2mg in 1ml phosphate buffered saline, PBS). After incubation at room temperature for lh, the sample was chromatographed on a sephadex G25M gel filtration column
  • radioactive mercuric chloride was incubated with protein in the absence of any chelator; in this case 32% of the activity was eluted with protein, indicating significant non-specific binding.
  • the chelating moiety binds mercury sufficiently strongly to suppress non-specific binding, while the activated ester
  • the conjugate was incubated with human serum, and with bovine serum albumin which is known to be capable of binding class b metals (e.g. copper).
  • class b metals e.g. copper
  • Rabbit IgG labelled with 197 Hg by the procedure described above (O.Tml) was added to human serum (2ml) obtained by clotting whole blood, and incubated for 24h at 37°C under sterile conditions. A sample of the serum was then loaded onto a 300 x 8mm gel filtration column (LKB GlasPak, TSK G3000SW) and eluted with phosphate buffered saline. Absorbance at 280nm was monitored and 0.5ml fractions were collected and counted. Results are shown in

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  • Proteomics, Peptides & Aminoacids (AREA)
  • General Health & Medical Sciences (AREA)
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  • Physics & Mathematics (AREA)
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Abstract

Le 1,4,7-trithiacyclononane (9S3) et les composés associés de formule (I), où l'un des T est S ou Se ou Te, un autre T est S ou Se ou Te et le troisième T est S, Se, Te, >PX ou >AsX, X étant un atome ou un groupe univalent, et où A1 est -C¿2?H4-, ou (a), ou -C3H6-, A?2¿ est -C¿2?H4- ou (a), et A?3¿ est -C¿2?H3R- ou (b), ou, sauf lorsque A?1¿ est -C¿3?H6-, -C3H5R-, où R est alkyle ou alkyle substitué ou, si le troisième T contient P ou As, R peut également être H, peuvent être substitués par un groupe de liaison qui peut se lier à un substrat, par exemple une protéine, et qui lui-même conserve une fonctionnalité de coordination pour chélater un radionuclide pour le diagnostique ou la thérapie.
PCT/GB1992/000492 1991-03-20 1992-03-19 Ligands macrocycliques de thioether et leur utilisation en tant qu'intermediaires pour lier les ions aux substrats WO1992016520A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP4506056A JPH06505975A (ja) 1991-03-20 1992-03-19 環状リガンド

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB9105898.2 1991-03-20
GB919105898A GB9105898D0 (en) 1991-03-20 1991-03-20 Compounds useful as intermediates for binding ions to substrates
GB919125882A GB9125882D0 (en) 1991-12-05 1991-12-05 Cyclic ligands
GB9125882.2 1991-12-05

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WO1992016520A1 true WO1992016520A1 (fr) 1992-10-01

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EP (1) EP0576492A1 (fr)
JP (1) JPH06505975A (fr)
CA (1) CA2105872A1 (fr)
GB (1) GB2253850B (fr)
WO (1) WO1992016520A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5879657A (en) * 1993-03-30 1999-03-09 The Dupont Merck Pharmaceutical Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
US20210228748A1 (en) * 2017-02-08 2021-07-29 Helmholtz-Zentrum Dresden - Rossendorf E.V. In vivo stable hg-197(m) compounds, method for the production thereof and use thereof in nuclear medical diagnostics and endoradionuclide therapy (theranostics)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5892057A (en) * 1997-09-18 1999-04-06 Pierce Chemical Company Preparation of sulfo-N-hydroxysuccinimide salts
WO1999014192A1 (fr) * 1997-09-18 1999-03-25 Pierce Chemical Company Sulfo-n-hydroxysuccinimide et procede d'elaboration

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4782013A (en) * 1987-07-23 1988-11-01 Eastman Kodak Company Photographic element containing a macrocyclic ether compound

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4782013A (en) * 1987-07-23 1988-11-01 Eastman Kodak Company Photographic element containing a macrocyclic ether compound

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ANGEWANDTE CHEMIE, INTERNATIONAL EDITION IN ENGLISH, vol. 23, no. 10, October 1984, (Weinheim, DE), D. SELLMANN et al.: "A facile route to 1,4,7-trithiacyclononane", pages 807-808, see the whole article (cited in the application) *
CHEMICAL ABSTRACTS, vol. 90, no. 25, 18 June 1979, (Columbus, Ohio, US), T. WEISS et al.: "Organometalloidal compounds with o-phenylene substituents, IV. Synthesis of 2,3,7,8,12,13-hexamethoxytribenzo[b,e,h][1,4,7]trithiacyclononatriene", page 626, abstract no. 204069x, & Z. NATURFORSCH., B: ANORG. CHEM., ORG. CHEM. 1979, 34B(3), 448-50 (cited in the application) *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5879657A (en) * 1993-03-30 1999-03-09 The Dupont Merck Pharmaceutical Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
US6022523A (en) * 1993-03-30 2000-02-08 Dupont Pharmaceuticals Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
US20210228748A1 (en) * 2017-02-08 2021-07-29 Helmholtz-Zentrum Dresden - Rossendorf E.V. In vivo stable hg-197(m) compounds, method for the production thereof and use thereof in nuclear medical diagnostics and endoradionuclide therapy (theranostics)

Also Published As

Publication number Publication date
GB9205992D0 (en) 1992-04-29
CA2105872A1 (fr) 1992-09-21
GB2253850A (en) 1992-09-23
GB2253850B (en) 1994-11-09
JPH06505975A (ja) 1994-07-07
EP0576492A1 (fr) 1994-01-05

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