Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2002-08-27
2004-10-12
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009364, C424S009365, C514S172000, C540S003000, C552S549000, C552S551000
Reexamination Certificate
active
06803030
ABSTRACT:
The present invention relates to novel compounds able to chelate paramagnetic metal ions and to the use thereof as contrast agents in the technique known as “Magnetic Resonance Imaging” (M.R.I.). In particular, the present invention relates to compounds resulting from the conjugation of a carrier consisting of a bile acid residue with molecules endowed with a chelating capacity, as well as their complex chelates with bi- and trivalent paramagnetic metal ions, the salts thereof and the use thereof as contrast agents for M.R.I.
Patent literature reports a number of patents and patent applications concerning chelates of straight and cyclic polyaminopolycarboxylic ligands with paramagnetic metals as contrast agents for M.R.I. Some of these compounds are already in clinical use (Gd-DTPA, N-methylglucamine salt of the gadolinium complex with diethylenetriaminopentaacetic acid, MAGNEVIST®, Schering; Gd-DOTA, N-methylglucamine salt of the gadolinium/1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid complex, DOTAREM®, Guerbet; Gd-HPDO3A, gadolinium complex with 10-(2-hydroxypropyl)-1,4,7,10-tetraazacyclododecane-1,4,7-triacetic acid, PROHANCE®, BRACCO). These contrast agents are designed for a wholly general use, as they are mainly distributed in the extracellular spaces after administration.
On the contrary, a contrast agent capable of providing diagnostically useful information even in case of small lesions such as liver tissue metastasis, should selectively accumulate in the intracellular spaces of the parenchyma of said organ. Intracellular hepatobiliary agents are capable of entering hepatocytes through the sinusoid membrane and are mainly excreted through the bile. The lipophilic nature of their chelating units is considered responsible for the preferential uptake by hepatocytes (Lauffer, R. B.; Chem. Rev. 87, 901-927, 1987; Lauffer, R. B. et al.; Magn. Reson. Med. 4, 582-590, 1987).
Cholic acid is one of the bile acids resulting from cholesterol catabolism; it is excreted by hepatocytes into bile (Elliot, W. H.;
Sterols and bile acids
; H. Danielsson and J. Sjövall, Eds.; pp 231-278, Elsevier, N.Y., 1985).
M.R.I. contrast agents comprising a residue of a chelating agent conjugated by a spacing chain to a bile acid residue are disclosed in WO95/01958. Said agents are stated to be particularly useful in the imaging of liver and bile ducts.
It has also been found that the bile acid residue makes the chelanting agents including it capable of interacting with plasma proteins thus forming non-covalent bonds with them. Therefore the contrast agents comprising a bile acid residue are also particularly useful in the N.M.R. imaging of the vasal system, as disclosed in Italian patent application MI98A002802, which is herein incorporated by reference in its entirety.
EP 279,307 (Abbott) discloses other polyaminopolycarboxylic chelants, capable of complexing metal ions, conjugated with different substrates, inter alia bile acids, as contrast agents. The only compound disclosed in this patent application is a
111
In complex of a conjugate in which a functionalized derivative of EDTA is linked, through an amido bond, to the carboxylic function of a cholic acid. The possibility of chelating paramagnetic metal ions for use in M.R.I. is not referred to in any way.
Betebenner David A. et al. in Bioconjugate Chem. 2; 117-123, 1991 disclose the preparation and characterization of an EDTA derivative conjugated with a cholic acid and of the corresponding chelated complex with
111
In. The conjugation takes place through the terminal amino group of a functional derivative of EDTA with a cholic acid ester, by means of a reaction already used for linking chelating units to proteins (Westerberg, D. A. et al., J. Med. Chem. 32, 236-243, 1989; Brechbiel, M. W. Et al., Inorg. Chem. 25, 2772-2781, 1986). Biodistribution and scintigraphic imaging studies carried out with this compound show that, after uptake by the liver, it rapidly passes into the intestine.
All known agents comprising the residue of a bile acid are characterized by the presence of a single chelating unit and, therefore, of a single metal ion coordinated per each molecule of the agent itself.
The present invention relates to compounds capable of chelating at least two metal ions. Said compounds are obtained by conjugation of a carrier consisting of a bile acid residue with two chelating molecules, said conjugation taking place through a central reactive polyfunctional substrate or central synton. In particular, the bonds between the central syntons of the invention and the chelating units are obtained by means of functional residues suitably selected so that said chelating units can keep unaltered their capability to coordinate the metal ion and the stability of the resulting chelates does not decrease.
More particularly, the present invention relates to compounds of general formula (I)
wherein:
A is a polyfunctional reactive substrate containing at least three functional groups deriving from any polyvalent organic residue which can be aliphatic with open chain, optionally branched, or alicyclic, or heterocyclic containing N, O and/or S, or aromatic or heteroaromatic;
Z is a bile acid residue;
Y
1
and Y
2
, which can be the same or different, are the residue of a chelating agent of the bi-trivalent metal ions having atomic numbers ranging between 20 and 31, 39, 42, 43, 44, 49, and between 57 and 83;
L
1
, L
2
and L
3
, which can be the same or different, are a single bond between the functional groups Y1and A, Y2 and A and/or Z and A, or a spacer comprising at most 20 carbon atoms.
Bile acid herein means all bile acids obtained by bioconversion or synthetic modification of cholesterol, particularly cholic, deoxycholic, chenodeoxycholic, ursodeoxycholic, lithocholic acids and the derivatives thereof, including those with taurine and glycine. Said residues are linked to the L
3
group through covalent bonds involving the hydroxy group, optionally converted to an amino group, at the 3-position or the carboxy group at the 24-position of the cholane skeleton.
Preferred compounds are those in which L
1
and L
2
, which can be the same or different, are a spacer chain of formula (II)
wherein:
Q is a C
1
-C
8
alkyl chain optionally substituted with 1 to 3 OH groups;
s is an integer 0 to 5;
R
1
is an H atom, or a C
1
-C
5
alkyl group;
X is
L
3
is a group of formula (III)
in which: X and s have the above defined meanings (with the proviso that when s is different from 0 then CO and X are present).
Particularly preferred are the compounds in which L
1
and L
2
are selected from those of formula (IV), (V), (VI)
L
3
is a single bond between the Z and A functional groups or a group
in which:
n is an integer 1 to 8, and
R
1
has the above defined meanings.
The invention also relates to the complex chelates of said compounds of formula (I) with the bi- and trivalent ions of the metal elements having atomic numbers ranging between 20 and 31, 39, 42, 43, 44, 49, and between 57 and 83, as well as the salts thereof with physiologically compatible 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, for example, from acetate, succinate, citrate, fumarate, maleate, oxalate, or with anions of inorganic acids such as ions of halo acids, i.e. chlorides, bromides, iodides.
The invention also relates to the preparation of the compounds of general formula (I) as well as the complex salts thereof and the use thereof for the preparation of pharmaceutical formulations for the diagnostic use, in particular for M.R.I. contrast formulations.
Furthermore, the compounds of the invention can optionally be chemically conjugated with suitable macromolecules or englobated in suitable carriers.
Preferred compounds are those in which Z is a residue deriving from the following bile acids or derivatives thereof with taurine and glycine:
A is a polyfunctio
Beltrami Andrea
Cappelletti Enrico
De Haen Christoph
Lattuada Luciano
Virtuani Mario
Bracco Imaging S.p.A.
Nixon & Vanderhye P.C.
Tucker Zachary C.
LandOfFree
Bile acids conjugates with metal ion chelates and the use... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Bile acids conjugates with metal ion chelates and the use..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Bile acids conjugates with metal ion chelates and the use... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3328732