Organic compounds -- part of the class 532-570 series – Organic compounds – Rare earth containing
Patent
1995-05-12
1998-10-06
Hollinden, Gary E.
Organic compounds -- part of the class 532-570 series
Organic compounds
Rare earth containing
534 16, 424 91, 424 93, C07F 500
Patent
active
058177779
DESCRIPTION:
BRIEF SUMMARY
This invention concerns new substituted cyclopentane compounds which are expected to be useful as chelating agents for alkaline earth, transition, lanthanide and actinide metal ions. Calcium plays a central role in physiological regulatory systems which engenders a need for chelating agents to sequester Ca(II) or to serve as the basis for Ca(II) assays (in, e.g. ion-selective electrodes). Sequestration of other alkaline earths is important for removal of, e.g. .sup.90 Sr. Lanthanide metal ions, especially gadolinium (III), are finding growing use as contrast enhancement agents in magnetic resonance imaging in medicine, for which purpose they must be chelated (e.g. by diethylenetriaminepentaacetic acid, DTPA) to reduce their toxicity. Requirements for actinide chelators arise from fuel reprocessing, actinide decorporation, and effluent treatment.
The compound cis,cis,cis-1,2,3,4-cyclopentanetetracarboxylic acid.sup.(1) has been known for many years. Tetraamides of this acid, and some tetraamines formed by reduction of the corresponding tetraamide, are described in U.S. Pat. Nos. 3,723,526.sup.(2), 3,641,149 and 3,507,894.sup.(3) and in French Patent 1447835.sup.(4). U.S. Pat. No. 4,493,909.sup.(5) describes tetraamides of this acid where each amide nitrogen has 2 mono- or bis-(hydroxyl)alkyl substituents as cell-opening components for polyurethane foams.
The compounds all-cis cyclopentane tetra.sup.(6) - and penta-methanol.sup.(7) and their corresponding mesylate.sup.(8) or tosylate.sup.(6,9) esters have been described.
The invention concerns new tetrapodal preferably octadentate ligands uniquely suited stereochemically for co-ordination to alkaline earths, transition metals, lanthanides and actinides. The ligands are based upon a cis,cis,cis-1,2,3,4-tetrasubstituted cyclopentane framework. ##STR2## The invention provides substituted cyclopentane compounds of the formula ##STR3## wherein the groups X.sup.1, X.sup.2, X.sup.3 and X.sup.4 may be the same or different and each is --CONRR.sup.1, --CH.sub.2 NHCOR, --CH.sub.2 OCOR, --CH.sub.2 OR.sup.1, --CH.sub.2 SR.sup.1, --CH.sub.2 SOR, --CH.sub.2 SO.sub.2 R or --CH.sub.2 SO.sub.2 NRR.sup.1, which may optionally be substituted with a potential ligand donor group or a group which may permit attachment to a biologically active molecule or insoluble support a group which may permit attachment to a biologically active molecule or insoluble support CH.sub.2 OR.sup.1, then R.sup.1 includes a potential ligand donor group, --CONRR.sup.1, then R and R' are not both mono- or di-hydroxyalkyl and Z is not H.
The stereochemistry of z is undefined. The invention includes such compounds which are attached through Z or a group R to a biologically active molecule or insoluble support. The invention also includes complexes of such compounds with alkaline earth or transition or lanthanide or actinide metal ions.
Groups which may permit attachment to a biologically active molecule or insoluble support include alkyl or aryl amine, carboxyl, isothiocyanate, active ester and others well known in the art.
Potential ligand donor groups include those derived from O--, N--, or S-containing heterocycles, thiols, thioethers, ethers, amines, alcohols, ketones, nitrites or carboxylic, phosphonic, phosphinic, boronic, sulphonic, arsonic or arsinic acids, and their amides and esters, .beta.-diketones, Schiff bases of either ketones, .alpha.-diketones or aldehydes, .alpha.-hydroxycarboxylic acids, .alpha.-ketocarboxylic acids and hydroxamic acids.
One class of ligands results from reaction of esters of cis,cis,cis-1,2,3,4-cyclopentanetetracarboxylic acid (X.dbd.COOH) with primary or secondary amines RR--NH where R.dbd.H or alkyl, and R includes another potential ligand donor group.
Another class results from reaction of cis,cis,cis-1,2,3,4-tetrakis-(aminomethyl) cyclopentane. (X.dbd.CH.sub.2 NH.sub.2) or cis,cis,cis-1,2,3,4-tetrakis(hydroxymethyl)cyclopentane (X.dbd.CH.sub.2 OH) with electrophiles derived from alkyl or aryl groups (which may or may not themselves contain another potential ligand
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Seitz et al., Arch. Pharm., vol. 309 (11), pp. 930-932, 1976.
Cooper Stephen Randolph
Orchard Pamela Joan
Amersham International plc
Hollinden Gary E.
Jones Dameron
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