Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-07-24
1994-09-20
Stoll, Robert L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514227, 5142315, 5142318, 5142355, 514236, 514252, 514255, 514316, 514326, 514327, 514331, 514422, 514425, 544 581, 544 586, 544 86, 544106, 544130, 544141, 544162, 544221, 544306, 544360, 544399, 546188, 546190, 546208, 548556, A61K 3115, C07D21108, C07D24104, C07D27912, C07D26530
Patent
active
053489543
DESCRIPTION:
BRIEF SUMMARY
This application is the U.S. national phase of International Application No. PCT/EP90/00079, filed Jan. 15, 1990.
The present invention relates to certain novel chelating agents, in particular heterocyclic polyamines, and to their uses, especially their medical uses.
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.
Polyamine chelating agents, for example 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. 2,407,645 (Bersworth), U.S. Pat. No. 2,387,735 (Bersworth), EP-A-71564 (Schering), EP-A-130934 (Schering), EP-A-165728 (Nycomed AS), DE-A-2918842 (Rexolin Chemicals AB), DE-A-3401052 (Schering), EP-A-258616 (Salutar), DE-A-3633245 (Schering), EP-A-263059 (Schering), EP-A-277088 (Schering) and DE-A-3633243 (IDF).
Thus, for example, EP-A-71564 describes paramagnetic metal chelates, for which the chelating agent is nitrilotriacetic acid (NTA), N,N,N',N'-ethylenediamine-tetraacetic 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-tetraazacyclododecanetetraacetic acid (DOTA), referred to in DE-A-3401052 (Schering) and in U.S. Pat. No. 4,639,365 (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. More recently, to improve compatibility, stability, solubility and selectivity, in EP-A-250358 Schering have proposed a narrow range of compounds having a DTPA-like structure including a bridging alkylene chain. Thus EP-A-250358 specifically discloses several 2,6-bis-aminomethyl-1-piperidine compounds.
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 such polyamine chelating agents which form metal chelates of reduced toxicity, improved stability or improved water solubility.
Nycomed, in European Patent Application No. EP-A-299795 suggest that the toxicity of certain APCA chelating agents and their chelates may be reduced by introducing at least one hydrophilic moiety as a substituent on one or more of the alkylene bridges between the amine nitrogens.
We now propose a novel class of polyamine chelating agents which incorporate within their structure a 5- or 6-membered saturated heterocyclic ring and carry hydrophilic moieties on or in the ring or on the alkylene bridges between the amine nitrogens.
Thus viewed from one aspect the present invention provides a compound of formula I ##STR3## (wherein X represents a bond, an oxygen or sulphur atom or a group of formula CHR.sup.1 or NR.sup.3 ; a group of formula OR.sup.3 or NR.sup.3 R.sup.3 or a C.sub.1-8 alkyl or (C.sub.1-8 alkoxy)-C.sub.1-8 alkyl group optionally substituted by a hydroxyl group or by a group of formula NR.sup.3 R.sup.3 or CONR.sup.3 R.
REFERENCES:
patent: 2387735 (1945-10-01), Bersworth
patent: 2407645 (1946-09-01), Bersworth
patent: 4639365 (1987-01-01), Sherry
patent: 5130437 (1992-07-01), Rocklage et al.
Krejcarek et al., Biochemical and Biophysical Research Communications, 77, 581-585, 1977.
Hnatowich et al., Science, 220, 613-615, 1983.
Meares et al., Analytical Biochemistry, 142, 68-78, 1984.
Almen Torsten
Berg Arne
Dugstad Harald
Klaveness Jo
Krautwurst Klaus D.
Chapman Lara E.
Nycomed Imaging AS
Stoll Robert L.
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