Chelating compounds, their complexes with paramagnetic metals

Details Chelating compounds, their complexes with paramagnetic metals Chelating compounds, their complexes with paramagnetic metals

2001-09-24

2003-01-21

Richter, Johann (Department: 1623)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Phosphorus containing other than solely as part of an...

C514S107000, C514S114000, C562S011000, C562S012000, C562S014000, C562S015000

Reexamination Certificate

active

06509324

ABSTRACT:

This application is a 371 of PCT/EP00/12977 filed Dec. 20, 2000.
This invention refers to new compounds which can chelate paramagnetic bi- and trivalent metal ions, their chelates with said metal ions and their use as contrast agents in magnetic resonance imaging (M.R.I.).
From a radiologist's point of view, an improvement in the radiographic image, which means a better contrast enhancement between healthy and diseased tissues, is seen as an aid to the diagnosis which can be obtained through previous administration of suitable exogenous substances.
These substances cause a significant alteration of a specific characteristic, known as relaxivity, of the water protons belonging to the tissue under examination, when such protons are submitted to an external magnetic field.
These substances are known as contrast agents for M.R.I. A number of chelated complexes of linear and cyclic polyaminopolycarboxylic ligands with paramagnetic metals are known to be useful as M.R.I. contrast agents.
Said compounds generally derive from the two basic polyaminopolycarboxylic structures, namely diethylenetriaminopentaacetic acid (DTPA) and 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA).
The compounds of the present invention are novel polyamino derivatives comprising at least one phosphonic residue as one of the binding site in the chelating agent structure.
Relaxivity (r
1p
) is an intrinsic property of paramagnetic complexes which characterizes their ability to increase the nuclear magnetic relaxation rate of vicinal protons. In the case of Gd(III) chelates with q≧1, wherein q is the number of coordinated water molecules, a remarkable contribution to the increase in relaxation observed for water protons of the solvent derives from the exchange between the molecule(s) of bound water and the molecules of the remaining solvent (S. Aime et al., Chem. Soc. Rev., 1998, 27, 19).
This contribution (r
1p
is
) is related to the relaxation time (T
1M
) and to the residence time (&tgr;
M
) of the protons of the water molecule(s) which are coordinated in the inner coordination sphere according to the following equation:
r
1
⁢
p
is
=
1.8
·
10
-
5
⁢
 
⁢
q
(
T
1
⁢
M
+
τ
M
)
T
1M
receives contributions from the reorientation of the paramagnetic species, &tgr;
R
, through the residence time of the coordinated water protons, &tgr;
M
, and the electronic relaxation time of the metal ion, &tgr;
S
. Moreover, r
1p
is
is the highest when T
1M
>&tgr;
M
(fast exchange conditions) and T
1M
is as short as possible.
A remarkable increase in r
1p
at the magnetic field values conventionally used in clinical practice has been up to now obtained, in different ways, mainly by decreasing molecular tumbling, with a consequent increase in &tgr;
R
. The expected increase in r
1p
has not, however, been observed due to the limiting effect caused by the residence time of water molecules, &tgr;
M
. A fine tuning of this parameter has become the primary object of current research in the M.R.I. field, as only &tgr;
M
values of about 30 ns would make it possible to completely exploit the decrease in T
1M
induced by the increase in &tgr;
R
. For this reason, the exchange rate values of water molecules in lanthanide (III) complexes are of paramount importance in the development of novel M.R.I. contrast agents. In fact, the residence time of the water molecule(s) coordinated to a Gd(III) complex plays a particularly important role, in that it directly contributes to the nucleus-electron dipolar interaction and controls the transfer efficiency of the paramagnetic effect to the water molecules of the solvent.
The above cited prior art contrast agents, generally comprising polyaminopolycarboxylic acid derivatives, have shown &tgr;
M
values generally comprised between 200 and 2500 ns, where such values are significantly higher than the 30 ns optimum one.
Optimization and harmonization of the above parameters are still remarkably important objects for everyone dealing with the development of novel M.R.I. contrast agents.
The present invention relates to polyamino derivatives comprising as the binding site in the structure of the chelating agent at least one phosphonic is residue, capable of causing an increase in the proton exchange rate and therefore advantageously low &tgr;
M
values.
More particularly, the object of the present invention is acyclic polyamino derivative chelating agents of formula (I), both in the racemic and the optically active forms,
wherein
Y is a COOH group or a PO(OH)
2
group, with the proviso that at least one Y group is ═PO(OH)
2
;
R is a hydrogen atom, or —(CH
2
)
m
—O—R
2
, (C
1
-C
5
)-alkyl-(C
6
-C
10
)-aryl or (C
1
-C
5
)-alkyl-heteroaryl whose aryl or heteroaryl moiety comprises 1 or 2 fused rings optionally substituted with one or more halogen atoms, OH groups, alkyl(C
1
-C
5
) groups and/or an OR
3
group, wherein
R
2
is (C
1
-C
5
)-alkyl-(C
6
-C
10
)-aryl, optionally substituted with one or more halogen atoms, OH and (C
1
-C
5
)-alkyl groups;
R
3
is (C
6
-C
10
) aryl optionally substituted with one or more halogen atoms, OH and/or (C
1
-C
5
)-alkyl groups;
m ranges from 1 to 5;
R
1
can have the same meanings as R with the proviso that when Y is PO(OH)
2
, R
1
is selected from H, (CH
2
)
m
NH
2
, (CH
2
)
m
COOH or an amido derivative thereof.
A further object of the invention are the chelates of said compounds of formula (I) with the bi- and trivalent ions of metal elements having atomic number ranging between 20 and 31, 39, 42, 43, 44, 49, or 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 whose cations selected from sodium, potassium, magnesium, calcium or mixtures thereof.
A further object of the present invention is the use of the compounds of formula (I), their complexes with paramagnetic metals and the physiologically compatible salts thereof for the preparation of pharmaceutical formulations for the imaging of organs and/or tissues of the human or animal body, by use of M.R.I.
Examples of (C
1
-C
5
)-alkyl-(C
6
-C
10
)-aryl groups comprise benzyl, phenethyl, naphthylmethyl wherein the aryl moiety is optionally substituted with one or more halogen atoms or OR
3
groups wherein R
3
is as defined above.
Examples of (C
1
-C
5
)-alkyl-heteroaryl groups comprise pyridylmethyl or indolylmethyl.
Examples of (C
6
-C
10
) aryl groups comprise phenyl or naphthyl optionally substituted with one or more halogen atoms, OH and/or (C
1
-C
5
)-alkyl groups.
Examples of (C
1
-C
5
) alkyl groups preferably comprise methyl, ethyl, isopropyl.
Preferred are compounds of formula (II),
wherein 4 side carboxylic groups and a central phosphonic group are present and wherein
R and R have the above defined meanings.
Among compounds of formula (II), particularly preferred are those in which R
1
is an hydrogen atom and R can assume all previously defined meanings.
Also preferred are the compounds of formula (III)
wherein two side phosphonic groups and three carboxylic groups are present, and wherein
R
1
has all the values defined above, as well as the compounds of general formula (IV),
 wherein three phosphonic groups and two carboxylic groups are present and wherein
R has the values defined above.
Particularly preferred are the following compounds:
N,N′-[(Phosphonomethylimino)di-2,1-ethanediyl]bis[N-carboxymethyl-L-phenylalanine];
[[4S-(4R*,12R*)]-4-Carboxy-5,11-bis(carboxymethyl)-1-phenyl-12-[(phenylmethoxy)methyl]-8-(phosphonomethyl)-2-oxa-5,8,11-triazatridecan-13-oic] acid;
N,N′-[(Phosphonomethylimino)di-2,1-ethanediyl]bis[N-carboxymethyl-L-tryptophan];
N,N-Bis[2-[(carboxymethyl)(phosphonomethyl)amino]ethyl]-O-(4-hydroxyphenyl)-3,5-diiodo-L-tyrosine;
N,N′-[(Phosphonomethylimino)di-2,1-ethanediyl]bis[N-(carboxy-methyl)-glycine];
N,N′-[(Phosphonomethylimino)di-2,1-eth

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