Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Magnetic imaging agent
Reexamination Certificate
2000-09-25
2002-01-08
Powers, Fiona T. (Department: 1626)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Magnetic imaging agent
C424S009365, C548S403000, C548S455000, C556S050000, C562S445000, C562S447000, C562S500000
Reexamination Certificate
active
06337064
ABSTRACT:
The present invention relates to novel chelating agents and the manganese chelated complex salts thereof, the physiologically compatible salts thereof and the use of these compounds in magnetic resonance imaging (MRI).
A valuable M.R.I. contrast agent should recognizedly have, in addition to low administration dosages, very good relaxivity, so as to provide a suitable increase in the contrast between lesions and healthy tissue and among the different organs and tissues; high thermodynamic stability; slow transmetallation kinetic, in particular with ions of endogenous metals such as magnesium and calcium; low toxicity and very good tolerability. The gadolinium chelated complexes are at present the preferred contrast agents, due to the properties of Gd
3+
ion which has seven discoupled electrons and the highest magnetic moment. At the present time, commercially available contrast agents containing gadolinium chelated complexes are: Magnevist
(R)
(Gd-DTPA meglumine double salt), Dotarem
(R)
(Gd-DOTA meglumine salt), Omniscan
(R)
(Gd-DTPA-BMA) and ProHance
(R)
(Gd-HP-DO3A).
The more recent searches aim at founding contrast agents which, besides having the above cited characteristics, are also specific for a definite tissue or body region. Manganese has been suggested as an alternative to gadolinium in these tissue-specific contrast agents (Investigative Radiology 1995, 30(10), 611-620).
The potential usefulness of the Mn
2+
ion as an M.R.I. contrast agent has been taken in consideration since 1978 for myocardium imaging. Manganese complexes with porphyrines and derivatives thereof (for example Mn(III)-meso-tetra-(4-sulfonatophenyl)porphyrine, Mn-TPPS
4
) were proposed as contrast agents specific for tumors (Investigative Radiology, cited ref.). In Magnetic Resonance in Medicine 1988, 8, 293-313, the longitudinal proton relaxation times in rabbit tissues have been studied after intravenous administration of MnCl
2
and of Mn-PDTA (1,3-propylenediamino-N,N′,N″,N′″-tetraacetate). In a recent study, M.R.I. contrast agents were evaluated consisting of Mn-EDTA lipohilic derivatives (for example, manganese-EDTA-bis(hydroxypropyldecylamine), Mn-EDTA-DDP) bound to the membranes of small unilamellar liposomes (“memsomes”) , which are potentially valuable for hepatic and cardiac perfusion imaging (Journal of Liposome Research 1994, 4(2), 811-834). The same compounds are object of International Patent Application WO 92/21017 and of U.S. Pat. No. 5,312,617, which disclose M.R.I. contrast agents based on manganese chelates (II) consisting of EDTA bis-amides where the amide nitrogens are substituted with long chain alkyl residues (C
7
-C
30
). These chelates per se or, more preferably, in combination with lipids or liposomes, are reportedly particularly useful for imaging of liver and as blood-pool agents.
M.R.I. contrast agents comprising manganese chelated complexes are also described in U.S. Pat. Nos. 4,980,148 and 5,246,696. Said complexes, in which the ligand is an alkylenediaminotetraacetic acid in which the alkylene chain is interrupted by one or more substituents selected from O, S, CHOH, CHSH, are stated to be particularly useful for imaging of liver, kidneys, pancreas and gastrointestinal tract.
Recently, Teslascan
(R)
(manganese complex of N,N′-1,2-ethanediylbis[N-[[3-hydroxy-2-methyl-5-[(phosphono-oxy)methyl]-4-pyridinyl]-methyl]glycine salified with Na
+
(1:3), mangafodipir trisodium, was marketed in Europe and in the U.S.A. for use in M.R.I. of the liver. This compound was considered useful for M.R.I. diagnosis of pancreas adenocarcinoma and pancreatitis (Investigative Radiology 1995, 30(10), 611-620).
Ions of paramagnetic metals are known to be highly toxic. The same applies for Mn
2+
ion at the doses commonly used for diagnostic imaging, although this is an essential oligoelement, present in all mammal cells.
It is therefore important also in the case of manganese, for this to be administered as stable complex, thereby preventing any toxicity due to the free metal. Conversely, some compounds of the above cited literature, for example Mn-DPDP, show some instability in vivo: a recent biodistribution study proved that this complex dissociates, releasing manganese which accumulates in liver, pancreas and kidneys, whereas the undissociated chelate is removed through glomerular filtration. The M.R.I. properties of Mn-DPDP would therefore be ascribable mainly to the manganese ion released by the complex, which accumulates in liver and pancreas (Investigative Radiology 1994, 29(2), S249-S250). Another recent study gave evidence of the dissociation of Mn-DPDP in liver homogenate, in the presence of calcium and magnesium ions (MRM 1996, 35, 14-19).
The present invention relates to stable manganese chelated complex salts in which said ion is in the oxidation state +2 (Mn(II)). Said compounds are ethylenediaminotetraacetic acid (EDTA) derivatives, characterized in having a substituent containing at least one cyclic unit in &agr; position to the carboxyl of one or two of the four acetic groups. Contrary to the manganese chelated complexes of the prior art, which, as mentioned above, are generally considered particularly useful in imaging of liver, pancreas and gastrointestinal tract, the chelates of the present invention have a good stability as well as surprising relaxivity values in human serum.
More particularly, the invention relates to compounds of formula (I), both in the racemic and optically active forms:
wherein:
R
1
, R
2
are independently a hydrogen atom, or a straight or branched (C
1
-C
20
) alkyl chain, saturated or unsaturated, being said chain optionally interrupted by one or, more nitrogen or sulfur atoms, as well as by —CO—, —CONH—, —NHCO—, —SO—, —SO
2
—, —SO
2
NH— groups, or optionally substituted by one or more NH
2
, OH, halogen, COOH groups and the respective ester or amide derivatives, said chain being in any case interrupted or substituted by one or more R
3
cyclic residues, which are the same or different, non-fused or fused, with the proviso that, when some of the R
3
residues are fused together, the maximum number of rings forming the corresponding polycyclic unit is three, wherein
R
3
is a 5- or 6-membered cyclic unit, carbocyclic or heterocyclic, saturated, unsaturated or aromatic, being said cyclic units unsubstituted or substituted with one or more R
4
groups, which are the same or different, wherein
R
4
is OH, halogen, NHR
5
, N(R
5
)
2
, —O—R
5
, —S—R
5
, or —CO—R
51
wherein the R
5
groups, which are the same or different, are a straight or branched (C
1
-C
5
) alkyl, unsubstituted or substituted with one or more hydroxy and/or alkoxy and/or carboxy groups, or R
4
is a COOH group, or an ester or amido derivative thereof, or a —SO
3
H group or an amido derivative thereof,
or R
4
is a —O—R
6
group, wherein R
6
is a 5- or 6-membered cyclic unit, carbocyclic or heterocyclic, saturated, unsaturated or aromatic, being said cyclic unit optionally substituted by one or more OH, halogen, —NHR
5
, —N(R
5
)
2
, —O—R
5
, —S—R
5
, —CO—R
5
groups, wherein R
5
has the meanings defined above, or by one or more —COOH groups, or the ester or amido derivatives thereof, or —SO
3
H or amido derivatives thereof,
with the proviso that R
1
and R
2
are not at the same time hydrogen;
as well as the chelates thereof with the manganese ion in the oxidation state +2 (Mn(II)) and the salts thereof with physiologically compatible organic bases selected from primary, secondary, tertiary amines or basic amino acids, or with inorganic bases whose cations are sodium, potassium, magnesium, calcium, or mixtures thereof.
In case the chelated complex has a total charge, this is preferably neutralized with a physiologically compatible counter-ion. Suitable substances for salifying the compounds of the invention and/or the chelates thereof, are, for example:
cations of inorganic bases such as alkali or alkaline-earth metals ions selected from sodium, potassium, magnesium, calcium,
Brocchetta Marino
Calabi Luisella
Palano Daniela
Paleari Lino
Uggeri Fulvio
Dibra S.p.A.
Nixon & Vanderhye
Powers Fiona T.
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