Metal complexes, suitable for use in diagnosis and therapy

Details Metal complexes, suitable for use in diagnosis and therapy Metal complexes, suitable for use in diagnosis and therapy

2000-01-10

2001-07-03

Hartley, Michael G. (Department: 1619)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S009364, C424S009365, C534S016000, C562S443000, C562S446000, C562S564000, C562S556000, C562S565000, C556S045000, C556S057000, C556S138000, C556S148000

Reexamination Certificate

active

06254850

ABSTRACT:

The invention relates to the objects characterized in the claims, i.e., DTPA derivatives substituted in a novel way, their metal complexes, pharmaceutical agents containing these complexes, their use in diagnosis and therapy as well as process for the production of complexes and agents.
Contrast media are indispensable additives in modern diagnosis; thus many diseases could not be diagnosed without the use of contrast media. Contrast media are used in all areas of diagnosis, such as, e.g., diagnostic radiology, radiodiagnosis or ultrasound diagnosis or magnetic resonance tomography.
The selection of the method preferred in each case depends, i.a., on the diagnostic problem, but is also determined by the choice of apparatus available in each case to the physician. Thus, because of the considerable technical expenditure and associated high cost, in particular nuclear spin tomography has not yet found the wide use of other methods, such as, e.g., methods of diagnostic radiology.
The selection of the suitable contrast medium also varies on the basis of the respective problem. Thus, the suitability of the contrast medium for a specific object is determined last but not least by its concentration and distribution behavior in the organism.
Although great progress has been achieved both on the equipment side and on the contrast medium side, solutions satisfactory for all problems are not yet available.
Thus, suitable contrast media do not exist for all indications for the various imaging processes. In particular, until now, no suitable x-ray contrast medium for liver diagnosis has been available.
In diagnostic radiology, basically contrast media based on triiodobenzene have been able to gain acceptance, since these compounds exhibit a high x-ray opacity, a low general and local toxicity and are very readily water-soluble.
Such compounds are described, e.g., in EP 0 105 752, EP 0 015 867. But the latter show insufficient concentration in the liver for an imaging.
The radio-opaque effect of an x-ray contrast medium is basically dependent on the size of the mass attenuation coefficient of the elements, contained in the compound, in the diagnostic range of radiation. In addition to iodine-containing compounds, complexes of metals of higher atomic numbers are also suitable as x-ray contrast media. Physiologically compatible complex compounds of these metals are already widely used in the field of NMR diagnosis. In general, these are metal complexes, as they are described, e.g., in EP 0 071 564.
Wo 93/16375 describes metal complexes, which are linked by amide bonds to iodine-substituted aromatic compounds. These compounds are to allow both NMR and x-ray investigations to be performed with only one administration of contrast medium. A combination of the two imaging processes is advantageous in many cases for a differentiated visualization and a reliable determination of certain diseases. These compounds are to be suitable especially for angiography. As the reprocessing of the production samples revealed, however, the compounds show insufficient concentration in the area of the liver for x-ray investigations.
Liver-specific NMR contrast media are described in EP 0 405 704. These should also be suitable in principle for diagnostic radiology because of the metal content in the complexes. A reprocessing of the experimental samples showed insufficient contrasting of the liver in the x-ray picture in the animal experiment itself with administration of a high dose (conc.: 1 mol/l, dose: 0.5 mmol of Gd/kg intravenously). A sufficient imaging effect in diagnostic radiology is only achieved with a dose in which the safety margin is reduced to a measurement that is no longer justifiable.
The object of this invention was therefore to make available very well-tolerated and water-soluble contrast media, as well as a process for their production that is as simple as possible, which are suitable for NMR diagnosis, diagnostic radiology and radiodiagnosis or radiotherapy—especially for diagnostic radiology of the liver.
This object is achieved by the substances, agents, production processes and uses characterized in the claims. It has been found that metal complexes of general formula I
in which
X
1
independently of one another, stand for a hydrogen atom or a metal ion equivalent of an element of atomic numbers 20-32, 39-51 or 57-83,
X
2
independently of one another, stand for a group O—X
1
with X
1
in the above-indicated meaning or N(R′)R
2
in which
R
1
, R
2
independently of one another, stand for a hydrogen atom or for a saturated or unsaturated, branched or straight-chain C
1
-C
20
chain, in which the chain or parts of the chain can form a cyclic or bicyclic unit, which is interrupted by zero to three oxygen and/or sulfur atoms and/or zero to three sulfoxyl and/or sulfono groups and is substituted by zero to six phenyl, pyridyl, R
3
S, R
3
OOC and/or R
3
O groups, which further contains zero to three
carbonyl and/or thiocarbonyl groups, and optionally present aromatic groups can be substituted one to three times, independently of one another, by R
3
O
2
C,
and/or R
4
groups
or R
1
and R
2
together, with inclusion of the common amide nitrogen atom, form a four- to eight-membered ring, which can contain two additional oxygen atoms and/or two carbonyl groups in which at least two of the radicals referred to with X
1
stand for a metal ion equivalent of the above-mentioned metals,
Z
1
stands for a saturated or unsaturated, branched or straight-chain C
1
-C
20
chain, in which the chain or parts of the chain can form a cyclic or bicyclic unit, which is interrupted by zero to three oxygen and/or sulfur atoms and/or zero to three sulfoxy and/or sulfono groups and is substituted by zero to six phenyl, pyridyl, R
3
S, R
3
OOC and/or R
3
O groups, which further contains zero to three
carbonyl and/or thiocarbonyl groups, and optionally present aromatic groups can be substituted singly or repeatedly, independently of one another, by R
3
O
2
C
and/or R
4
groups,
Z
2
stands for a hydrogen atom or for a saturated or unsaturated, branched or straight-chain C
1
-C
20
chain, in which the chain or parts of the chain can form a cyclic or bicyclic unit, which is interrupted by zero to three oxygen and/or sulfur atoms and/or zero to three sulfoxy and/or sulfono groups, and is substituted by zero to six phenyl, pyridyl, R
3
S, R
3
OOC and/or R
3
O groups, which further contains zero to three
carbonyl and/or thiocarbonyl groups, and optionally present aromatic groups can be substituted one to three times, independently of one another, by R
3
O
2
C,
and/or R
3
groups,
R
3
independently of one another, stand for a hydrogen atom, a phenyl radical or a straight-chain, branched or cyclic C
1
-C
6
radical, which is interrupted by zero to two oxygen atoms and/or zero to two phenylene groups and is substituted with zero to three HO, HOOC radical and/or zero to two phenyl radicals,
R
4
independently of one another, stand for a phenyl radical or a straight-chain, branched or cyclic C
1
-C
6
radical, which is interrupted by zero to two oxygen atoms and/or zero to two phenylene groups and is substituted with zero to three HO, HOOC radicals and/or zero to two phenyl radicals,
and if Z
2
stands for a hydrogen atom, radical Z
1
does not stand for an unsubstituted C
6
-C
10
aryl radical
or Z
1
and Z
2
together with inclusion of the common &agr;-carbon atom form a three- to eight-membered ring or a bicyclic compound with seven to 15 carbon atoms,
in which free carboxylic acid groups, not used for complexing, of the compounds of general formula I according to the invention can also be present in the form of their salts with physiologically compatible inorganic and/or organic cations,
are excellently suited for the production of contrast media for diagnostic radiology and/or NMR diagnosis, preferably of contrast media for diagnostic radiology, especially for diagnostic radiology of the liver, the bile ducts and the gallbladder.
The invention therefore relates to the compounds of general formula I.
Compounds of

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