Organic compounds -- part of the class 532-570 series – Organic compounds – Heavy metal containing
Patent
1999-12-27
2000-11-28
Nazario-Gonzalez, Porfirio
Organic compounds -- part of the class 532-570 series
Organic compounds
Heavy metal containing
534 15, 534 16, 562 14, 562 17, 562553, 562565, 562571, C07F 500, C07C22900
Patent
active
061537756
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to novel ligands for complexing metal ions, especially lanthanide metals such as gadolinium, samarium or ytterbium, as well as metals known to exhibit similar chemistry such as yttrium, plus the main group metals indium and gallium.
.alpha.-Imine carboxylic acids which comprise an imine and a carboxylate donor of formula: ##STR1## are known to function as bidentate ligands for metal ions forming 5-membered chelate rings at a single metal centre, i.e. mononuclear metal complexes. Metal complexes have been prepared with the transition metals molybdenum, iron, ruthenium, cobalt, rhodium, iridium, copper, palladium and platinum, plus the main group metals aluminium and zinc [M. Yamaguchi et al, Inorg.Chem., 35, 143(1996)].
Tetradentate N.sub.2 O.sub.2 diiminedicarboxylic acid analogues have been prepared and shown to bridge two transition metal centres forming binuclear metal complexes of cobalt or iridium [K. Severin et al., Z.Naturforsch.B, 50, 265,(1995)] as opposed to chelating a single metal centre: ##STR2##
Polydentate Schiff base ligands and their complexation with lanthanide metals are known. Thus Orvig et al [Inorg.Chem.,27, 3929(1988)] prepared potentially heptadentate N.sub.4 O.sub.3 ligands and studied their metal complexation with lanthanide metals: ##STR3##
The lanthanide (Ln) complexes of H.sub.3 hatren, H.sub.3 datren and H.sub.3 trac of formula Ln(ligand) in which the ligand functions as an N.sub.4 O.sub.3 heptadentate donor were found to be unstable, undergoing facile decomposition via hydrolysis or solvent displacement of coordinated donor atoms. Orvig et al later reported [(J.Am.Chem.Soc., 113, 2528(1991)] the X-ray crystal structure of the neutral ytterbium complex Yb(trac). This heptadentate complex could only be unambiguously characterised under rigorously anhydrous conditions. The rapid hydrolysis of these complexes in the presence of water led Orvig et al to conclude that this class of lanthanide complexes was too unstable to be useful as MRI contrast agents. Subsequent work focused on developing analogous ligand systems with saturated CH--NH bonds in place of the C.dbd.N imine bond, since the ease of solvolysis was ascribed to the presence of the imine bond.
The possibility of a radiometal (.sup.99m Tc) coordinated imine undergoing hydrolytic cleavage both in vitro and in vivo has previously been noted [G. F. Morgan et al, J.Nucl.Med., 32, 500(1991)]. The ligand studied was the tetradentate N.sub.3 O ligand MRP20: ##STR4##
It has now been found that a novel class of tripodal chelating agents incorporating imine C.dbd.N bonds form lanthanide and other metal complexes which are relatively stable in the presence of water at neutral pH.
The present invention provides, in a first aspect, a ligand of formula: ##STR5## where:
A is N, CR.sup.1, P, P.dbd.O, cis,cis,cis-1,3,5-trisubstituted-cyclohexane or an N,N',N"-trisubstituted-triaza 9 to 14 membered macrocyclic ring;
L.sup.1, L.sup.2, L.sup.3 are linker groups which are independently chosen from C.sub.1-4 alkylene, C.sub.4-6 cycloalkylene or C.sub.4-6 o-arylene;
Y.sup.1, Y.sup.2, Y.sup.3 are independently chosen from --NH.sub.2, --B(.dbd.O)OZ, --N.dbd.CR--B(.dbd.O)OZ, --NR--CR.sub.2 --B(.dbd.O)OZ, --N[CR.sub.2 --B(.dbd.O)Q].sub.2 and --O--CR.sub.2 --B(.dbd.O)OZ where B is C or PR.sup.2, each Q is independently --OZ or --NR.sub.2 and Z is H or a counter-ion;
each R and R.sup.1 group is independently chosen from H, C.sub.1-5 alkyl, C.sub.1-5 alkoxyalkyl, C.sub.1-5 hydroxyalkyl, C.sub.1-5 aminoalkyl, C.sub.5-10 aryl or C.sub.1-6 fluoroalkyl;
R.sup.2 is OH, C.sub.1-6 alkyl, C.sub.1-6 alkoxyalkyl, C.sub.1-6 fluoroalkyl, C.sub.1-10 alkoxy or C.sub.5-10 aryl;
with the proviso that at least one of Y.sup.1, Y.sup.2 and Y.sup.3 is --N.dbd.CR--B(.dbd.O)OZ.
A is preferably N or CR.sup.1, L.sup.1, L.sup.2 and L.sup.3 are preferably C.sub.1-3 alkylene, most preferably C.sub.1-2 alkylene. The N,N',N"-trisubstituted-triaza 9 to 14 membered macrocyclic ring has preferably 9-12 members, and is most preferably 1,4,7-trisubstitut
REFERENCES:
patent: 5071965 (1991-12-01), Dunn et al.
patent: 5405601 (1995-04-01), Dunn et al.
Orvig et al., Inorganic Chemistry, vol. 27, No. 22, pp. 3929-3934, 1988.
Doble Daniel Martin John
Schroder Martin
Nazario-Gonzalez Porfirio
NYCOMED Amersham PLC.
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