Organic compounds -- part of the class 532-570 series – Organic compounds – Rare earth containing
Patent
1997-12-29
1999-03-23
Dees, Jose' G.
Organic compounds -- part of the class 532-570 series
Organic compounds
Rare earth containing
534 10, 424 93, 424 94, 424 165, C07F 500
Patent
active
058861580
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to metal complexes of polyamino acids, to a process for their preparation and to their use in diagnostic imaging.
These compounds are branched derivatives of gadoteric acid, which is sold in the form of the meglumine salt under the brand name Dotarem.RTM. as a contrast agent for magnetic resonance imaging. Meglumine gadoterate is a stable complex whose spin-lattice relaxivity at 37.degree. C. and 20 MHz is about 3.5 mM.sup.-1 s.sup.-1 which is of the same order of magnitude as that of the other commercial contrast agents.
The gadolinium complexes according to the invention have relaxivities R.sub.1 greater than 20 mM.sup.-1 s.sup.-1 ; this makes it possible to administer to an individual, in order to obtain the same signal intensity, a diagnostic, composition whose molar concentration of complexed Gd.sup.3+, and thus of compound according to the invention, is 6 times and even 10 times as low as the concentrations currently used clinically.
Since the osmolality of the complex solutions of the invention, for the same relaxivity, is markedly lower than that of Dotarem.RTM. and even than that of nonionic compounds such as gadodiamide, it may be envisaged to use solutions whose weight content of active ingredient is greater than those which are known in order to obtain higher-quality images, without reaching an unacceptable level of side effects.
Besides the heavy metal ion Gd.sup.3+, these complexes contain bromine or iodine atoms and are opaque to X-rays and they are sufficiently soluble, in particular owing to the presence of hydrophilic groups around the aromatic rings, to be used in conventional radiology or in dichromography.
The compounds of the invention have the formula: ##STR4## in which R represents a group ##STR5## in which X is Br or I, R.sub.1 is H, (C.sub.1 -C.sub.3)alkyl or (C.sub.2 -C.sub.8)mono- or polyhydroxyalkyl and ##STR6## X being as defined above, and R'.sub.1 and R'.sub.2 taking, independently of each other, any one of the meanings given for R.sub.1 and R.sub.2, with the exception of A, provided that --CO--NR.sub.1 R.sub.2 or --CO--NR'.sub.1 R'.sub.2 comprises at least 2 hydroxyl groups, and M represents H or an organic or inorganic cation. Among the pharmaceutically acceptable cations, mention may be made of Na.sup.+ or those derived from lysine, arginine, N-methylglucamine or diethanolamine.
The alkyl groups can be linear or branched.
Compounds in which --CONR.sub.1 R.sub.2 or --CONR'.sub.1 R'.sub.2 comprise at least 6 hydroxyl groups and more particularly represent CON(CH.sub.2 (CHOH).sub.4 CH.sub.2 OH).sub.2 are preferred.
The compounds of formula I can be prepared by the action of the amine of formula II ##STR7## in which X, R.sub.1 and R.sub.2 are as defined above, on the gadolinium complex of formula III corresponding to the structural formula I in which R=--(CH.sub.2).sub.2 COOH, in the presence of a coupling agent, in particular one of those used in peptide synthesis, such as a carbodiimide, for example in aqueous solution.
The amines of formula II for which R.sub.2 is different from A can be obtained by reacting HNR.sub.1 R.sub.2 with the diacid dichloride of formula IV: ##STR8## in which the NH.sub.2 function is protected in the form of phthalimide, followed by a hydrazinolysis.
The amino alcohols HNR.sub.1 R.sub.2 are known or can be prepared by methods similar to those described in the literature. Mention may be made, in particular, of commercial amino alcohols, defined by: --(CHOH).sub.2 --CH.sub.2 OH; CH.sub.2 CH.sub.2 OH or R.sub.1 ; EP-A-33,426.
The amines of formula II for which R.sub.2 represents A and R.sub.1 represents H are simply obtained by reacting an amine of formula H.sub.2 NA with the diacid dichloride of formula IV which has been N-protected beforehand. It will be noted that the amine H.sub.2 NA, which corresponds to an amine of formula II in which R.sub.2 is different from A, can be prepared in accordance with the process proposed above.
The contrast agent compositions for magnetic resonance imaging which comprise a compound of
REFERENCES:
patent: 5324504 (1994-06-01), Roger, Jr. et al.
patent: 5346690 (1994-09-01), Gundersen et al.
patent: 5403576 (1995-04-01), Lin et al.
Meyer Dominique
Rousseaux Olivier
Schaefer Michel
Simonot Christian
Dees Jos,e G.
Guerbet S.A.
Jomes Dameron
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