Aminopolycarboxylic acids and derivatives thereof

Details Aminopolycarboxylic acids and derivatives thereof Aminopolycarboxylic acids and derivatives thereof

1990-03-16

1993-03-30

Stoll, Robert L.

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

424 9, 534 10, 534 12, 534 13, 534 14, 534 15, 534 16, 436173, 1286534, 540465, 540474, 556 45, 556 57, 556138, 562565, 562566, C07C10126, C07D28500, C07D27300, A61K 4900, A61K 31195, A61K 31555

Patent

active

051982080

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to certain chelating agents, in particular aminopoly(carboxylic acid or carboxylic acid derivative) compounds, and to the metal chelates thereof.
The medical use of chelating agents is well established, for example as stabilizers for pharmaceutical preparations, as antidotes for poisonous heavy metal species and as diagnostic agents for the administration of metal species (e.g. ions or atoms) for diagnostic techniques such as X-ray, magnetic resonance imaging (MRI) or ultrasound imaging or scintigraphy.
Aminopoly(carboxylic acid or carboxylic acid derivative) (hereinafter APCA) chelating agents and their metal chelates are well known and are described for example in U.S. Pat. No. 2407645(Bersworth), U.S. Pat. No. 2387735 (Bersworth), EP-A-71564 (Schering), EP-A-130934 (Schering), EP-A-165728 (Nycomed AS), DE-A-2918842 (Rexolin Chemicals AB) and DE-A 3401052 (Schering).
Thus, for example, EP-A-71564 describes paramagnetic metal chelates, for which the chelating agent is nitrilotriacetic acid (NTA), N,N,N',N'-ethylenediaminetetraacetic acid (EDTA), N-hydroxyethyl-N,N',N'-ethylenediamine-triacetic acid (HEDTA), N,N,N',N",N"-diethylenetriamine-pentaacetic acid (DTPA) and N-hydroxyethylimino-diacetic acid, as being suitable as contrast agents for MRI, contrast being achieved by the effect of the magnetic field of the paramagnetic species (e.g. Gd(III)) with the chelating agents serving to reduce the toxicity and to assist administration of that paramagnetic species.
Amongst the particular metal chelates disclosed by EP-A-71564 was Gd DTPA, the use of which as an MRI contrast agent has recently received much attention. The Gd(III) chelate of 1,4,7,10-tetraazacvclododecanetetraacetic acid (DOTA), referred to in DE-A-3401052 (Schering) and in U.S. Pat. No. 4639365 (University of Texas), has also recently received attention in this regard.
To improve stability, water solubility and selectivity, relative to the APCA chelating agents described in EP-A-71564, Schering, in EP-A-130934, have proposed the partial substitution for the N-attached carboxyalkyl groups of alkyl, alkoxyalkyl, alkoxycarbonylalkyl or alkylaminocarbonylalkyl groups, where any amide nitrogens may themselves carry polyhydroxyalkyl groups.
However, all hitherto known APCA chelating agents and their metal chelates encounter problems of toxicity, stability or selectivity and there is thus a general and continuing need for APCA chelating agents which form metal chelates of reduced toxicity or improved stability.
We now propose certain new improved toxicity APCAs, and in particular APCAs which carry hydrophilic groups on the amine nitrogens or on the alkylene chains linking the amine nitrogens.
Viewed from one aspect, the present invention thus provides APCA chelating agents wherein at least one bridging group between amine nitrogens carries a hydrophilic moiety, preferably a hydroxyalkyl or an optionally hydroxylated alkoxy group, and metal chelates and salts thereof.
Viewed from another aspect, the present invention provides compounds of formula I --X (I) together are a group --(CHR.sub.1).sub.q --A'--(CHR.sub.1).sub.r --, where A' is an oxygen or sulphur atom or a group ##STR1## A is a group or A--(CHR.sub.1).sub.m --represents a carbon-nitrogen bond or, when the groups Z together are a group --(CHR.sub.1).sub.q --A'--(CHR.sub.1).sub.r --, A may also represent an oxygen or sulphur atom; each Y, which may be the same or different, is a each X, which may be the same or different, is a carboxyl group or a derivative thereof or a group R.sub.1 ; each R.sub.1, which may be the same or different, is a hydrogen atom, a hydroxyalkyl group or an optionally hydroxylated alkoxy or alkoxyalkyl group; n, m, p, q and r are each 2,3 or 4, preferably 2; with the provisos that at least two nitrogens carry a --CHR.sub.1 X moiety wherein X is a carboxyl group or a derivative thereof, that each --CHR.sub.1 X moiety is other than a methyl group, and that unless A' is oxygen or sulphur or A is N--(CHR.sub.1).sub.p --N(CHR.sub.1 X).sub.2 at le

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patent: 2407645 (1946-09-01), Bersworth
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Gavin et al., Chemical Abstracts, 104:137019y, 1986.
Samoilova et al., Chemical Abstracts, 73:98343u, 1973.

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