Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1995-06-20
1998-04-21
Kight, John
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
536 179, 536 181, 536 182, 536 184, 549403, 564442, 568306, 568329, 424 185, A61K 5104, C07H 1500, C07D31104, C07C21100
Patent
active
057414769
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/US93/12272 filed Dec. 16, 1993.
The present invention relates to polyhydric phenol compounds, to a method of preparing these compounds, to a pharmaceutical composition comprising these compounds and to the use of this composition for diagnosis and therapy.
It is shown in literature, e.g. by LeFevre et al. (J. Biol. Chem., 1959, 234, 3022-3026), that phloretin is an inhibitor of glucose transport processes. It is also known from literature (e.g Ogawara et al., J. Antibiotics, 1986, 39, 606-608; Akiyama et al., J. Biol. Chem., 1987, 262, 5592-5593; and Linassier et al.,m Biochem. Pharmacol., 1990, 39, 187-193), that genistein inhibits the tyrosine kinase activity.
It is well-known in the art (see e.g. Berry et al., J. Nucl. Med., 1991, 32, 1518-1525), that fluorodeoxyglucose (FDG) accurately traces glucose transport. In this connection .sup.18 F-FDG has been developed as an imaging agent for detecting and locating various diseases and disorders where glucose transport plays a part. Although .sup.18 F-FDG is generally considered as a useful PET imaging agent, the PET technique is usually not the technique of choice for diagnosing purposes. As correctly stated by Lutz et al. (J. Label. Comp. Radiopharm., 1991, 29, 535-545), "there is no question that more patients would benefit if a glucose analogue could be labelled with a single photon emitting radionuclide such as .sup.123 I". Such a radioactive-iodine labelled glucose analogue would allow the use of simple gamma detection devices and, if desired, the application of the more advanced SPECT technique.
Lutz et al. indeed have succeeded in labelling glucose analogues with .sup.123 I, viz. by synthetizing the various isomers of 123-iodobenzyl-deoxyglucose. The test results obtained by these authors, however, were disappointing, because biodistribution studies showed, that the overall tissue uptake was too low for these glucose analogues to offer perspectives for use as imaging agents. Apparently, the introduction of radioactive iodine in the deoxyglucose molecule has an adverse influence on the in vivo stability of this compound, so that transport of radioactivity into the relevant tissues is virtually prevented.
It is the main objective of the present invention to provide a diagnostic agent for pathologies, related to a disturbed--generally increased--glucose metabolism, and/or for tumour cells, which agent is labelled with a suitable isotope to allow its detection by gamma detection devices.
This objective can be achieved by new polyhydric phenol compounds which, according to the present invention, have the general formula ##STR2## wherein R is a hydrogen atom or a saccharide moiety; N-(carboxymethyl)carbamoyl group;
Surprisingly it has been found, that the radiohalogenated polyhydric phenol compounds of the present invention, in particular labelled with radioisotopes of Br and I, are easily transported by plasma proteins to the relevant tissues, and consequently show an identical behaviour to the acceptor sites in the tissues as the corresponding unlabelled compounds, for example, unlabelled phloretin, the properties of which are described by LeFevre et al. (see above).
Examples of radiohalogenated polyhydric phenol compounds of the invention are: well as their analogues, wherein the 4-hydroxy group (Z) is replaced by:
In connection with the chemical stability and the synthetic accessibility, compounds are preferred which have the general formula ##STR3## wherein R, R.sub.1, R.sub.2, Z, A and B have the meanings given above; and .sup.125, .sup.131 I, .sup.75 Br, .sup.76 Br .sup.77 Br and .sup.82 Br.
As will be described hereinafter, compounds of the above general formula II, wherein Y* is selected from .sup.124 I, .sup.125 I, and .sup.131 I, are in particular useful for tumour therapy.
Pre-eminently suitable compounds of the invention are radiolabelled phloretin and its carbohydrates, which can be represented by the general formula ##STR4## wherein R, Z and Y* have the meanings given above.
The new radiohalogenated polyhydric
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Boone Jeffrey S.
Kelley Lara C.
Kight John
Mallinckrodt Medical Inc.
McBride Thomas P.
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