Drug – bio-affecting and body treating compositions – Radionuclide or intended radionuclide containing; adjuvant... – In an organic compound
Patent
1995-05-09
1999-11-30
Dees, Jose' G.
Drug, bio-affecting and body treating compositions
Radionuclide or intended radionuclide containing; adjuvant...
In an organic compound
424 111, 424 169, 534 14, 534 10, A61K 5100, A61M 3614
Patent
active
059937742
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB93/02088 filed Oct. 8, 1993.
This invention concerns metal-chelating compounds which are intended mainly for radio-pharmaceutical use. The compounds comprise a metal-chelating moiety, and either a biological targeting group or a protein reactive functionality. Targeting groups of particular interest are bioreductive groups, which may provide compounds useful as hypoxia agents. Prior art relating to ligand systems.
The tetradentate diaminedioxime ligands shown, and their metal complexes, were first described by R K Murmann et al. ##STR2##
J Am Chem Soc. 84, 1349 (1962)
Inorg Chem, 6 2043 (1967)
EP 0123504 B describes the technetium complexes of such ligands, and substituted versions thereof and their use as radiopharmaceuticals.
EP 0179608 B describes the unsymmetrical diaminedioxime ligands shown and their technetium complexes: ##STR3## where R.sub.1-9 are independently H or C.sub.1-4 alkyl,
EP 0380016 A describes the d1 isomers of the following ligands, and their technetium complexes: ##STR4## where R is bivalent radical completing a 4-5 membered ring.
U.S. Pat. No. 5,116,598 describes technetium complexes of tetradentate N.sub.4 ligands bearing at least one pendant CO .sub.2 H group. ##STR5##
R.sub.4 and R.sub.5 or R.sub.8 and R.sub.9 may be combined to form an oxygen atom. Hydroxylamine (C--N--O) ligands are shown rather than oximes (C.dbd.N--O). The text gives no further clarification. No examples are given.
PRIOR ART RELATING TO HYPOXIA AGENTS
It is known that certain molecules, known as bioreductive moieties, are capable of diffusing into and becoming immobilised in hypoxic cells. (See Mason, P. "Free Radicals in Biology" Academic Press 1982). Thus for example nitroimidazoles, and in particular, misonidazole (3-methoxy-1-(2-nitromidazol-1-yl)propan-2-ol) are used against anaerobic bacteria and as radiosensitising agents for hypoxic tumours. It is known that anaerobic metabolism leads to free radical formation and subsequent covalent binding of the nitroimidazole (or degradation product) within the hypoxic cell. In the presence of oxygen (aerobic cells), re-oxidation of the free radicals occurs continuously in a `futile cycle`. Thus it is only under anaerobic conditions that the free radicals can exist long enough for combination with cellular components to occur, i.e. trapping in hypoxic tumours or in ischaemic, but viable myocardium.
Chelated metal atoms may, in certain circumstances, be incorporated into bioreductive molecules without destroying the ability of the bioreductive molecules to discriminate between oxic and hypoxic cells. Radioactive metals can be used.
EPA 502595 claims compounds of the following general formula ##STR6## where B may be a substituted nitrosomethyl group, A is a targeting or functional group and R.sup.1 to R.sup.5 are as defined. These compounds are said to form complexes with radioactive metal ions which are suitable for diagnosis and tumor therapy. No compound is described in which B is nitrosomethyl or substituted nitrosomethyl.
EPA 417870 describes similar compounds for similar uses, but in which the two CO amide groups are replaced by CH.sub.2 groups.
WO 91/18008 describes .sup.99m Tc-cyciopentadienyl carbonyl complexes of general formula (I) in which --X--R can have various meanings including ##STR7##
U.S. Pat. No. 4,193,979 describes sodium 3-(((2-(2-methyl-5-nitro-1H-imidazole-1-yl)ethyl)-amino)carbonyl)-2-pyridi ne-carboxylic and related compounds which are labelled with .sup.99m Tc. The agents are said to be useful as gall bladder and liver imaging agents. No 2-nitroimidazole derivatives are described.
EP 0 441 491 A1 claims boronic acid adducts of .sup.99m Tc dioxime or rhenium dioxime complexes which are linked through alkyl or alkenyl linkers to a biochemically reactive group. The said biochemically reactive group may be a hypoxia-mediated nitroheterocyclic group, in which case, the agents are said to provide a method for diagnostic imaging or radiotherapy of hypoxic tissue.
In KE Linder et al J Nucl Med 33, 5, (1992) Pr
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Archer Colin Mill
Canning Lewis Reuben
Gill Harjit Kaur
Riley Anthony Leonard Mark
Amersham International plc
Dees Jos,e G.
Jones Dameron
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