Cascade polymer bound complexing compounds, their complexes...

Details Cascade polymer bound complexing compounds, their complexes... Cascade polymer bound complexing compounds, their complexes...

1998-09-17

2001-02-06

Hollinden, Gary E. (Department: 1616)

Drug, bio-affecting and body treating compositions

In vivo diagnosis or in vivo testing

Magnetic imaging agent

C424S009363, C424S009364, C514S492000, C514S502000, C514S836000, 53, C540S465000, C540S474000

Reexamination Certificate

active

06183724

ABSTRACT:

BACKGROUND OF THE INVENTION
The invention relates to novel cascade polymer complexing compounds and complexes, agents containing these compounds, the use of the complexes in diagnostics and therapy, as well as processes for the production of these compounds and agents.
“Magnevist” (GdDTPA/dimeglumine) is the first recorded contrast medium for nuclear spin tomography (MRI=magnetic resonance imaging). It is particularly well suited for the diagnosis of pathological areas (e.g., inflammations, tumors, etc.). The compound is eliminated, upon intravenous injection, by way of the kidneys; extrarenal elimination is practically not at all observed.
One disadvantage of “Magnevist” resides in that it is distributed after intravenous administration uniformly between the vasal and interstitial spaces. Accordingly, contrasting of the vessels with respect to the surrounding interstitial space is impossible with the use of “Magnevist”.
Especially for the imaging of vessels, a contrast medium would be desirable which is distributed exclusively in the vasal space (vascular space). Such a blood pool agent is to make it possible, with the aid of nuclear spin tomography, to demarcate tissue with good circulation from tissue with poor circulation, and thus to diagnose an ischemia. Also infarcted tissue could be distinguished, on account of its anemia, from surrounding healthy or ischemic tissue with the use of a vasal contrast medium. This is of special importance in case the objective is, for example, to distinguish a cardiac infarction from an ischemia.
Heretofore, most of those patients suspected of harboring a cardiovascular disease (this disease being the most frequent cause of death in Western industrial countries) had to undergo invasive diagnostic tests. In angiography, X-ray diagnostics is presently used, above all, with the aid of iodine-containing contrast media. These tests are burdened by various drawbacks: they bring the risk of radiation stress, as well as discomfort and strain stemming, above all, from the fact that the iodine-containing contrast media must be utilized in a very much higher concentration as compared with NMR contrast media.
Therefore, there is a need for NMR contrast media which can mark the vasal space (blood pool agent). These compounds are to be distinguished by good compatibility and by high efficacy (great increase in signal intensity during MRI).
The premise of solving at least part of these problems by the use of complexing agents bound to macro- or biomolecules has thus far been successful to only a very limited extent.
Thus, for example, the number of paramagnetic centers in the complexes described in European Patent Applications No. 88,695 and No. 150,884 is inadequate for satisfactory imaging.
When increasing the number of required metal ions by repeated introduction of complexing units into a macromolecule, the result is an intolerable impairment of the affinity and/or specificity of this macromolecule [J. Nucli. Med. 24: 1158 (1983)].
Macromolecules are generally suited as contrast media for angiography. Albumin-GdDTPA (Radiology 1987; 162: 205), for example, shows, however, an accumulation in liver tissue to an extent of almost 30% of the dose 24 hours after intravenous injection in rats. Besides, only 20% of the dose is eliminated within 24 hours.
The macromolecule polylysine-GdDTPA (European Patent Application, Publication No. 0,233,619) likewise proved to be suitable as a blood pool agent. However, this compound, on account of its production, consists of a mixture of molecules of various sizes. In elimination tests on rats, it could be demonstrated that this macromolecule is eliminated unchanged by glomerular filtration via the kidneys. Due to its synthesis, however, polylysine-GdDTPA can also contain macromolecules which are so large that they cannot pass through the renal capillaries during glomerular filtration and therefore remain in the body.
Macromolecular contrast media based on carbohydrates, for example dextran, have also been described (European Patent Application, Publication No. 0,326,226). The disadvantage of these compounds resides in that they carry normally only 4.6% of the signal-intensifying paramagnetic cation.
SUMMARY OF THE INVENTION
An object, therefore, resides in making available novel diagnostic aids, above all for the recognition and localization of vascular diseases, which aids do not exhibit the aforedescribed disadvantages. This and other objects have been attained by the present invention.
It has been found that complexes comprising nitrogen-containing cascade polymers provided with complexing ligands, ions of an element of atomic numbers 21-29, 39, 42, 44 or 57-83, as well as optionally cations of inorganic and/or organic bases, amino acids or amino acid amides, are surprisingly excellently suitable for the production of NMR and X-ray diagnostic media without exhibiting the afore-mentioned drawbacks.
The polymers according to this invention can be described by general Formula I
wherein
A means a nitrogen-containing cascade nucleus of basis multiplicity b,
S means a reproduction unit,
N means a nitrogen atom,
Z
1
and Z
2
, for the first to penultimate generation, in each case are
but, for the last generation,
Z
1
means a hydrogen atom, a C
1
-C
10
-alkyl, C
2
-C
10
-acyl (e.g., alkanoyl) or C
1
-C
10
-alkylsulfonyl residue, each optionally containing 1-3 carboxy, 1-3 sulfonic acid, 1-5 hydroxy groups and/or 1-3 oxygen atoms (e.g., oxa(—O—) atoms), or it means the residue of a complexing agent or complex K, and
Z
2
means, to an extent of 96-100%, the residue of a complexing agent or complex K and, to an extent of 4-0%, V′ wherein V′ is the residue V exhibiting at the end a functional group or, linked via this functional group, a bio- or macromolecule, V meaning a straight-chain, branched, saturated or unsaturated C
1
-C
20
-alkylene group which optionally contains imino, phenylene, phenylenoxy, phenylenimino, amide, hydrazide, ureido, thioureido, carbonyl, ester. group(s), oxygen, sulfur and/or nitrogen atom(s) and is optionally substituted by hydroxy, mercapto, imino, epoxy, oxo, thioxo, and/or amino group(s),
b means the numbers 1 through 50, and
s means the numbers 1 to 3,
wherein the reproduction units S can be different from generation to generation. Also the complex (forming) residues optionally standing for Z
1
and Z
2
need not be identical. A “generation” is represented by each S group in a chain of S groups.
Examples of alkyl, acyl and alkylsulfonyl residues standing for Z
1
that can be cited are: —CH
2
COOH; —(CH
2
) COOH; —CH(COOH)CH
2
COOH; —CH
2
—CH(COOH)CH
2
OH; —CH
2
SO
3
H; —(CH
2
)
2
SO
3
H; —COCH
3
; —COCH
2
OH; —COCHOHCH
2
OH; —COCH
2
O—CH
2
COOH; —CO(CHOH)
4
CH
2
OH; —COCH
2
COOH; —CO(CH
2
)
2
COOH; —CO(CH
2)
3
COOH; —CO(CH
2
)
4
COOH; —COCHOHCOOH; —CO(CHOH)
2
COOH; —COCH
2
CHOHCH
2
COOH; —SO
2
CH
2
COOH; —SO
2
(CH
2
)COOH; —SO
2
CH
3
.
Suitable as the cascade nucleus A are:
a nitrogen atom,
wherein
R
2
, R
3
and R
4
mean, in each case independently of one another, a covalent bond or
g means the number 2, 3, 4 or 5,
t means the number 1, 2, 3, 4, 5, 6, 7 or 8,
l means the number 0, 1, 2, 3, 4 or 5,
r means the number 0 or 1,
n means the number 0, 1, 2, 3 or 4,
m means the number 0, 1, 2, 3 or 4,
k means the number 1, 2, 3, 4 or 5,
a means the number 2, 3, 4 or 5,
W means CH, CH
2
, NH or a nitrogen atom,
C
1
means
C
2
, C
3
, C
4
and C
5
mean, in each case independently, a hydrogen atom or
f means the number 1, 2, 3, 4 or 5,
j means the number 6, 7 or 8,
Y
1
and Y
2
mean, in each case independently of each other, a hydrogen atom,
and
Y
3
is a nitrogen atom,
a and g are as defined above,
———
means a single or double bond,
with the proviso that, if Y
3
is a nitrogen atom, Y
1
and Y
2
mean hydrogen. C
6
H
4
is phenylene.
The simplest case of a cascade nucleus is represented by the nitrogen atom, the three bonds of which (basis multiplicity b=3) are occupied in a first “inner layer” (generation 1) by three reproduction units S each of which

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