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US 6,149,890 AGranted
Chelated complexes of paramagnetic metals with low toxicity
AssigneeDibra S.p.A.
InventorsFulvio Uggeri, Franco Fedeli, Alessandro Maiocchi, Maurizio Franzini, Mario Virtuani
Life of this patent
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Abstract
Compounds of formulae (I) and (II) ##STR1## wherein the R, R.sub.1, R.sub.2, R.sub.3 and R.sub.4 groups have the meanings defined in the disclosure, are useful chelants for metal ions. The complexes of compounds (I) and (II) with paramagnetic ions are useful as contrast agents for M.R.I. imaging.
Claims8
A compound of formula (I), in the racemic or in the optically active forms:
- ##STR23## wherein:
- R is ##STR24## and each R.sub.1, which can be the same or different, is a hydrogen atom or a --CH.sub.2 OH group,
- as well as the chelated complexes of said compounds of formula (I) with the di- and trivalent ions of the metallic elements having atomic numbers ranging from 20 to 31, 39, from 42 to 44, 49 and from 57 to 83 and the physiologically acceptable salts thereof with organic bases selected from primary, secondary, tertiary amines or basic amino acids, or with inorganic bases the cations of which are sodium, potassium, magnesium, calcium, or mixtures thereof, or with anions of physiologically acceptable organic acids, selected from acetate, succinate, citrate, fumarate, maleate, oxalate, or with anions of physiologically acceptable inorganic acids selected from the anions of the hydrogen halides or the sulfate ions.
A compound of formula (II), in the racemic or the optically active form:
- ##STR25## wherein:
- R.sub.2 is ##STR26## each R.sub.3, which can be the same or different, is a hydrogen atom or a --CH.sub.2 OH group, and
- each R.sub.4, which can be the same or different, has the same meanings, as described for R.sub.3 or is CH.sub.3 or C.sub.2 H.sub.5,
- as well as the chelated complexes of said compounds of formula (II) with the di- and trivalent ions of the metallic elements having atomic numbers ranging from 20 to 31, 39, from 42 to 44, 49 and from 57 to 83 and the physiologically acceptable salts thereof with organic bases selected from primary, secondary, tertiary amines or basic amino acids, or with inorganic bases the cations of which are sodium, potassium, magnesium, calcium, or mixtures thereof, or with anions of physiologically acceptable organic acids, selected from acetate, succinate, citrate, fumarate, maleate, oxalate, or with anions of physiologically acceptable inorganic acids selected from the anions of the halo acids or the sulfate ions.
1 more element
A compound of formula (III), in the racemic or the optically active form:
- ##STR27## wherein:
- Y is --OH, --NH--CH.sub.2 --CH.sub.2 --O--CH.sub.2 --CH.sub.2 --OH, ##STR28## and each R.sub.3, which can be the same or different, is a hydrogen atom or a --CH.sub.2 OH group;
- as well as the chelated complexes of said compounds of formula (III) with the di- and trivalent ions of the metallic elements having atomic numbers ranging from 20 to 31, 39, from 42 to 44, 49 and from 57 to 83 and the physiologically acceptable salts thereof with organic bases selected from primary, secondary, tertiary amines or basic amino acids, or with inorganic bases the cations of which are sodium, potassium, magnesium, calcium, or mixtures thereof, or with anions of physiologically acceptable organic acids, selected from acetate succinate, citrate, fumarate, maleate, oxalate, or with anions of physiologically acceptable inorganic acids selected from the anions of the halo acids or the sulfate ions.
A paramagnetic chelate, selected from the following group:
- gadolinium complex of 10-[2-[[2-(2-hydroxyethoxy)ethyl]amino]-2-oxoethyl]-.alpha.,.alpha.',.alph a."-tris(hydroxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid;
- gadolinium complex of .alpha.,.alpha.',.alpha."-tris(hydroxymethyl)-10-(2-hydroxypropyl)-1,4,7,1 0-tetraazacyclododecane-1,4,7-triacetic acid;
- gadolinium complex of 2,9-bis(hydroxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid salified with 1-deoxy-1-(methylamino)-D-glucitol (1:1);
- gadolinium complex of [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11-tetra(hydroxymethyl)-1,4,7,10-tetraazacyc lododecane-1,4,7,10-tetraacetic acid sodium salt (1:1);
- gadolinium complex of 1-deoxy-1-[methyl-[1-oxo-2-[4,7,10-tris(1-carboxy-2-hydroxy-eth-1-yl)-1,4, 7,10-tetraazacyclododec-1-yl]ethyl]amino]-D-glucitol;
- gadolinium complex of .alpha.,.alpha.',.alpha."-tris(hydroxymethyl)-10-[2,3-dihydroxy-1-(hydroxy methyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid;
- gadolinium complex of [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11-tetra(hydroxymethyl)-10-[2-[[2-(2-hydroxy ethoxy)ethyl]amino]-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triace tic acid;
- gadolinium complex of [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11-tetra(hydroxymethyl)-10-[2-(4-morpholinyl )-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid;
- dysprosium complex of 10-[2-[[2-(2-hydroxyethoxy)ethyl]amino]-2-oxoethyl]-.alpha.,.alpha.',.alph a."-tris(hydroxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid;
- dysprosium complex of .alpha.,.alpha.',.alpha."-tris(hydroxymethyl)-10-(2-hydroxypropyl)-1,4,7,1 0-tetraazacyclododecane-1,4,7-triacetic acid;
- dysprosium complex of 2,9-bis(hydroxymethyl)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid salified with 1-deoxy-1-(methylamino)-D-glucitol (1:1);
- dysprosium complex of [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11-tetra(hydroxymethyl)-1,4,7,10-tetraazacyc lododecane-1,4,7,10-tetraacetic acid sodium salt (1:1);
- dysprosium complex of 1-deoxy-1-[methyl-[1-oxo-2-[4,7,10-tris(1-carboxy-2-hydroxy-eth-1-yl)-1,4, 7,10-tetraazacyclododec-1-yl]ethyl]amino]-D-glucitol;
- dysprosium complex of .alpha.,.alpha.',.alpha."-tris(hydroxymethyl)-10-[2,3-dihydroxy-1-(hydroxy methyl)propyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid;
- dysprosium complex of [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11-tetra(hydroxymethyl)-10-[2-[[2-(2-hydroxy ethoxy)ethyl]amino]-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triace tic acid;
- dysprosium complex of [2S-(2R*,5R*,8R*,11R*)]-2,5,8,11-tetra(hydroxymethyl)-10-[2-(4-morpholinyl )-2-oxoethyl]-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid.
13 more elements
Dependencies are inferred from the claim text.