Nycomed Imaging as

Nycomed Salutar, Inc.

Daiichi Pharmaceutical Co., Ltd.

Ge Healthcare as

Nycomed as

Arne Berg

Jo Klaveness

Torsten Almen

Harald Dugstad

Pal Rongved

Klaes Golman

Klaus D Krautwurst

Pangl Rongved

Michael Droege

Sook-Hui Kim

Per Strande

Ib Leunbach

Lars-Goran Wistrand

Alan D Watson

Sven Goran Andersson

Unni Nordby Wiggen

Tomas Klingstedt

Goran Pettersson

Peter Leander

Terje Thomassen

Rune Fossheim

Scott M Rocklage

Lars Stubberud

Hakan Wikstrom

Jere D Fellman

Brent Segal

Ib Luenbach

Oyvind Antonsen

Torsten Alm En

Hiroshi Kikuchi

John Varadarajan

Thorfinn Ege

Trygve Gulbrandsen

Kiyoto Yachi

Wolfgang H Gunther

Shi-bao Yu

Hangkan Wikstrom

Michel Gacek

C Allen Chang

Trond Vegard Jacobsen

S B Yu

O Slashedyvind Antonsen

This invention relates generally to non-ionic X-ray contrast agents. It further relates to the synthesis of iodixanol. In particular, it relates to alternative dimerisation reagents in the conversion of 5-acetamido-N,N'-bis(2,3-dihydroxypropyl)-2,4,6-triiodoisophthalamide ('Compound A') to iodixanol.

Alternative dimerisation reagents for synthesis of iodixanol

The invention provides low viscosity iodinated aryl compounds, useful as X-ray contrast agents, of formula C,R,wherein three non-adjacent R groups are iodine and the remaining R groups are non-ionic, hydrophilic moieties, said compound being water soluble at 20&deg; C. to a concentration of at least 350 mgl/ml and which in aqueous solution at 20&deg; C. at a concentration of 350 mgl/ml has a viscosity no greater than 13.8 mPas.

Iodinated x-ray contrast media

The use in diagnostic imaging, in particular X-ray, MRI, ultrasound and scintigraphy, of contrast agents comprising bismuth clusters and/or organic bismuth compounds, and contrast media containing such bismuth compounds. The bismuth compounds are also useful in therapy, in particular as antimicrobial agents and antiulcer agents. Novel bismuth compounds are also disclosed.

Bismuth compounds

The invention provides low viscosity iodinated aryl compounds, useful as X-ray contrast agents, of formula I ##STR1## (wherein n is 0 or 1, and where n is 1 each C.sub.6 R.sub.5 moeity may be the same or different; each group R is a hydrogen atom, an iodine atom or a hydrophilic moiety M or M.sub.1, two or three non-adjacent R groups in each C.sub.6 R.sub.5 moiety being iodine and at least one, and preferably two or three, R groups in each C.sub.6 R.sub.5 moiety being M or M.sub.1 moieties; X denotes a bond or a group providing a 1 to 7 atom chain linking two C.sub.6 R.sub.5 moieties or, where n is 0, X denotes a group R; each M independently is a non-ionic hydrophilic moiety; and each M.sub.1 independently represents a C.sub.1-4 alkyl group substituted by at least one hydroxyl group and optionally linked to the phenyl ring via a carbonyl, sulphone or sulphoxide group, at least one R group being an M.sub.1 moiety; with the proviso that where n is zero either at least one M.sub.1 group other than a hydroxymethyl or 1,2-dihydroxyethyl group is present or then if one hydroxymethyl or 1,2-dihydroxyethyl M.sub.1 group is present at least one nitrogen-attached or hydroxylated-C.sub.3-4 alkyl moiety-containing M group is also present) and isomers thereof.

Contrast media

There is provided a contrast medium composition comprising: (a) a first contrast agent comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group, or salt thereof, having a manganese concentration of at least 0.3 mM or being in a dosage unit form containing at least 300 .mu.mol manganese, together with (b) a second contrast agent. Such compositions have been found to be particularly suited to imaging of the liver.

Contrast agents for MRI using a manganese compound and kojic acid

An x-ray contrast medium containing a multinuclear complex of the formula (M.sub.6 (.mu..sub.3 B).sub.8 A.sub.v).sub.x L.sub.w, wherein M is Mo, W, Re Tc, V, Nb, Ta, Ru, or Fe; .mu..sub.3 B represent a tridentate bridging atom; A is a non-bridging atom; L is a ligand coordinately bonded to at least one M atom; x is a positive integer; and v and w are independently zero or positive integers.

Multinuclear complexes for X-ray imaging

There is provided a contrast medium composition comprising: (a) a first contrast agent comprising a physiologically tolerable manganese compound together with an uptake promoter, having a manganese concentration of at least 0.3 mM or being in a dosage unit form containing at least 300 .mu.mol manganese, wherein the uptake promoter comprises a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group or a physiologically tolerable acid containing .alpha.- and/or .beta.- hydroxy or amino groups, or a salt thereof, and/or vitamin D; together with (b) a second contrast agent. Such compositions are particularly suitable for imaging of the liver.

Composition and method of MRI using both a positive and a negative

Non-cluster type bismuth compounds

Chelant moieties linked to an aryl moiety by an interrupted alkylene

Ultrasound contrast agents comprising a microbubble-generating suspension of a microparticulate X-ray contrast agent in a liquid carrier medium.

Method of ultrasound imaging using microbubble-forming, solid X-ray

There is provided a contrast medium composition for magnetic resonance imaging comprising a physiologically tolerable manganese compound, a physiologically tolerable reducing compound containing an .alpha.-hydroxy ketone group, or salt thereof and a physiologically tolerable carrier or excipient, having a manganese concentration of at least 0.3 mM or being in a dosage unit form containing at least 300 .mu.mol manganese. Such compositions are particularly suitable for imaging of the liver.

Contrast medium for magnetic resonance imaging using physiologically

The invention provides a diagnostic composition for administration to human or animal subjects, the composition containing multilamellar liposomes, optionally together with unilamellar liposomes, the liposomes containing at least one imaging agent and being suspended in an aqueous medium containing said imaging agent, wherein the liposomes comprise a neutral phospholipid and a charged phospholipid, the average particle diameter of the liposomes is 50-3000 nm and the concentration of imaging agent in any aqueous phase filling the interior of the liposomes is substantially the same as that in the aqueous medium in which the liposomes are suspended. The contrast agents concerned are typically X-ray, MRI or ultrasound contrast agents.

Liposomes

The invention relates to the use as contrast enhancing agents in medical imaging, especially X-ray imaging, of multinuclear complexes, i.e. complexes, such as those of W202 (U20) 2, in which the complexed entity comprises at least two contrast enhancing atoms.

Aggregates of x-ray microparticles for ultrasound imaging

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Blommenholm, Norway

Arne Berg