Iodinated x-ray contrast media

Details Iodinated x-ray contrast media Iodinated x-ray contrast media

1998-12-22

2001-10-30

Kumar, Shailendra (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C424S009452, C514S546000, C514S751000, C514S754000, C560S130000, C560S141000, C560S142000

Reexamination Certificate

active

06310243

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to improvements in and relating to contrast media, and in particular iodinated X-ray contrast media.
BACKGROUND OF THE INVENTION
Contrast media may be administered in medical imaging procedures, for example X-ray, magnetic resonance and ultrasound imaging, to enhance the image contrast in images of a subject, generally a human or non-human animal body. The resulting enhanced contrast enables different organs, tissue types or body compartments to be more clearly observed or identified. In X-ray imaging, the contrast media function by modifying the X-ray absorption characteristics of the body sites into which they distribute.
Clearly however the utility of a material as a contrast medium is governed largely by its toxicity, by its diagnostic efficacy, by other adverse effects it may have on the subject to which it is administered, and by its ease of storage and ease of administration.
Since such media are conventionally used for diagnostic purposes rather than to achieve a direct therapeutic effect, when developing new contrast media there is a general desire to develop media having as little as possible an effect on the various biological mechanisms of the cells or the body as this will generally lead to lower animal toxicity and lower adverse clinical effects.
The toxicity and adverse biological effects of a contrast medium are contributed to by the components of the medium, e.g. the solvent or carrier as well as the contrast agent and its components (e.g. ions where it is ionic) and metabolites.
The following major contributing factors to contrast media toxicity and adverse effects have been identified:
the chemotoxicity of the contrast agent.
the osmolality of the contrast medium, and
the ionic composition (or lack thereof) of the contrast medium.
In coronary angiography, for example, injection into the circulatory system of contrast media has been associated with several serious effects on cardiac function. These effects are sufficiently severe as to place limitations on the use in angiography of certain contrast media.
In this procedure, for a short period of time a bolus of contrast medium rather than blood flows through the circulatory system and differences in the chemical and physicochemical nature of the contrast medium and the blood that it temporarily replaces can give rise to undesirable effects, e.g. arrhythmias, QT-prolongation, and, especially, reduction in cardiac contractile force and occurrence of ventricular fibrillation. There have been many investigations into these negative effects on cardiac function of infusion of contrast media into the circulatory system, e.g. during angiography, and means for reducing or eliminating these effects have been widely sought.
Early injectable ionic X-ray contrast agents, based on triiodophenylcarboxylate salts, were particularly associated with osmotoxic effects deriving from the hypertonicity of the contrast media injected.
This hypertonicity causes osmotic effects such as the draining out of water from red-blood cells, endothelial cells, and heart and blood vessel muscle cells. Loss of water makes red blood cells stiff and hypertonicity, chemotoxicity and non-optimal ionic make-up separately or together reduce the contractile force of the muscle cells and cause dilation of small blood vessels and a resultant decrease in blood pressure.
The osmotoxicity problem was addressed by the development of the non-ionic triiodophenyl monomers, such as iohexol, which allowed the same contrast effective iodine concentrations to be attained with greatly reduced attendant osmotoxicity effects.
The drive towards reduced osmotoxicity led in due course to the development of the non-ionic bis(triiodophenyl) dimers, such as iodixanol, which reduce osmotoxicity associated problems still further allowing contrast effective iodine concentrations to be achieved with hypotonic solutions.
This ability to achieve contrast effective iodine concentrations without taking solution osmolality up to isotonic levels (about 300 mOsm/kg H
2
O) further enabled the contribution to toxicity of ionic imbalance to be addressed by the inclusion of various plasma cations, as discussed for example in WO-90/01194 and WO-91/13636 of Nycomed Imaging AS.
However X-ray contrast media, at commercial high iodine concentrations of about 300 mgI/mL have relatively high viscosities, ranging from about 15 to about 60 mPas at ambient temperature with the dimeric media generally being more viscous than the monomeric media. Such viscosities pose problems to the administrator of the contrast medium, requiring relatively large bore needles or high applied pressure, and are particularly pronounced in paediatric radiography and in radiographic techniques which require rapid, bolus administration, e.g. in angiography.
In practice, viscosities in excess of 30 mPas at body temperature (37° C.) are unacceptably high for routine X-ray investigations, and especially for paediatric investigations. Accordingly, the maximum practical iodine concentration achievable with available non-ionic iodinated X-ray contrast agents is generally about 300-350 mgI/mL. Higher iodine concentrations, if accessible at acceptable viscosities, would increase the diagnostic efficacy of contrast enhanced images. Alternatively viewed, lower contrast medium viscosities for any given iodine concentration would increase ease of administration and the range of investigations and patients for which the contrast media could be used.
SUMMARY OF THE INVENTION
The present invention addresses the viscosity problem encountered with the prior art materials and thus viewed from one aspect the invention provides iodinated aryl compounds, useful as X-ray contrast agents, of formula I
(wherein n is 0 or 1, and where n is 1 each C
6
R
5
moiety may be the same or different; each group R is a hydrogen atom, an iodine atom or a hydrophilic moiety M or M
1
, two or three non-adjacent R groups in each C
6
R
5
moiety being iodine and at least one, and preferably two or three, R groups in each C
6
R
5
moiety being M or M
1
moieties; X denotes a bond or a group providing a 1 to 7, for example 1, 2, 3 or 4 atom chain linking two C
6
R
5
moieties or, where n is 0, X denotes a group R; each M independently is a non-ionic hydrophilic moiety; and each M
1
independently represents a C
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, preferably at least two R groups and especially preferably at least one R group in each C
6
R
5
moiety, being an M
1
moiety; with the proviso that where n is zero either at least one M
1
group other than a hydroxymethyl or 1,2-dihydroxyethyl (and optionally other than any hydroxyethyl) group is present or then if one hydroxymethyl or 1,2-dihydroxyethyl M
1
group (and optionally any hydroxyethyl group) is present at least one nitrogen-attached hydroxylated alkyl (preferably C
1-4
-alkyl) moiety-containing M group is also present) and isomers, especially stereoisomers and rotamers, thereof.
In a further aspect the invention provides a compound of formula C
6
R
6
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° C. to a concentration of at least 350 mgI/ml and which in aqueous solution at 20° C. at a concentration of 350 mgI/ml has a viscosity no greater than 13.8 mPas.
In a yet further aspect, the invention provides a compound of formula C
6
R
6
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° C. to a concentration of at least 400 mgI/ml and which in aqueous solution at 20° C. at a concentration of 400 mgI/ml has a viscosity no greater than 30.0 mPas.
DETAILED DESCRIPTION OF THE INVENTION
It is found that the compounds of the invention exhibit advantageously low viscosity in aqueous solution; this is thought to derive from the presence of

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