Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...
Patent
1994-08-08
1999-02-09
Shah, Mukund J.
Organic compounds -- part of the class 532-570 series
Organic compounds
Unsubstituted hydrocarbyl chain between the ring and the -c-...
540465, 424 9361, 534 15, 534 16, C07D49808, C07F 1502
Patent
active
058696512
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP 92/01598 F.D. Jul. 16, 1992.
The present invention relates to certain novel polyamine chelating agents, in particular to hydroxamate and hydrazide derivatives of 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.A.-2407645 (Bersworth), U.S.A.-2387735 (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 agents are nitrilotriacetic acid (NTA), N,N,N',N'-ethylenediaminetetraacetic acid (EDTA), N-hydroxyethyl-N,N',N'-ethylenediaminetriacetic acid (HEDTA), N,N,N',N",N"-diethylenetriaminepentaacetic 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 GdDTPA, 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.A.-4639365 (Sherry/University of Texas), has also recently received attention in this regard.
More recently, a number of modifications to the basic APCA structures have been proposed to provide chelating agents with improved stability, water solubility, selectivity or toxicity. This includes for example providing hydrophilic substituents as described by Nycomed in EP-A-299795 or altering the structure of bridging chains between the amine nitrogens as described by Schering in EP-A-250358.
In the field of hepatobiliary MRI contrast agents, where lipophilicity is desired, Nycomed (in EP-A-165728) have proposed the use of paramagnetic chelates of certain anilide group-containing iminodiacetic acids and Lauffer in WO-A-86/06605 has suggested the use of paramagnetic chelates of triaza and tetraaza macrocycles which carry a fused aromatic ring but are otherwise unsubstituted.
However, all hitherto known APCA chelating agents and their metal chelates encounter problems of toxicity, stability, selectivity or suppressed relaxivity and there is thus a general and continuing need for such polyamine chelating agents which form metal chelates of reduced toxicity or improved stability, water solubility, selectivity or relaxivity.
We have now found that certain substituted derivatives of aminopolycarboxylic acids and metal chelates thereof are particularly suitable for use as diagnostic and therapeutic agents, for example as radiotherapeutic agents, as detoxification agents and as contrast agents for diagnostic imaging processes. In particular we have found that high relaxivity paramagnetic metal chelates of such substituted APCA derivatives are especially suited for use as MRI contrast agents.
In one aspect the present invention therefore provides a compound of formula I agent hydrogen atom or an alkyl or alkoxy group, optionally carrying one or more substituents selected from hydroxy, alkoxy and aryl groups; group NA; optionally substituted by a group Y; CSZ, PO.sub.2 Z or B; R.sup.2).sub.n X.sup.1 !.sub.p (CR.sup.1 R.sup.2).sub.n X.
REFERENCES:
patent: 5322681 (1994-06-01), Klaveness
Gries et al, Chemical Abstract 109: 6552x for DE 3,625,417 (Feb. 11, 1988).
Gries et al., Chem. Abst 109: 6552x, 1988.
Dugstad Harald
Himmelsbach Richard J.
Klaveness Jo
Rongved P.ang.l
Strande Per
Nycomed Salutar
Shah Mukund J.
Sripada Pavanaram K.
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