The synthesis and evaluation of trimeric X-ray contrast agents

Article abstract of DOI:10.1016/j.tetlet.2011.04.010

Novel trimeric iodinated contrast agents with low osmolality have been prepared and evaluated with the aim of improving the already good safety profile of such agents. While the aim of low osmolality was achieved, the viscosity of the trimeric agents was found to be generally higher than current dimeric agents in clinical use.

Full text of DOI:10.1016/j.tetlet.2011.04.010

Tetrahedron Letters 52 (2011) 3065–3067
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis and evaluation of trimeric X-ray contrast agents
Ian M. Newington a, , Gareth Humphries a, Nicolas Lasbistes a, Véronique Morisson-Iveson a, James Nairne a,
⇑
Joanna Passmore a, Mikkel Thanning b, Lars-Göran Wistrand b, Duncan Wynn a
a GE Healthcare, The Grove Centre, White Lion Road, Amersham, Bucks HP9 7LL, UK
b GE Healthcare AS, Nycoveien 1-2 Postboks 4220 Nydalen, Oslo 0401, Norway
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel trimeric iodinated contrast agents with low osmolality have been prepared and evaluated with the
aim of improving the already good safety profile of such agents. While the aim of low osmolality was
achieved, the viscosity of the trimeric agents was found to be generally higher than current dimeric
agents in clinical use.
Received 5 January 2011
Revised 17 March 2011
Accepted 1 April 2011
Available online 9 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
X-ray
Contrast agent
Osmolality
Viscosity
Synthesis
Of the approximately 600 million X-ray scans given annually,
some 80 million involve the use of iodinated contrast media
(ICM). The use of ICM to enhance the differences between normal
body structures and lesions in soft tissue has radically changed
the practice of radiology.1 ICM are highly concentrated aqueous for-
mulations of iodinated contrast agent and they have a very good
safety profile.2 However, for patients with pre-existing reduced re-
nal function, contrast induced nephrotoxicity (CIN) can occur in a
small number of cases, which is a leading cause of acute renal fail-
ure.3,4 Improvements in the safety of ICM have reduced the inci-
dence of CIN and, to a large extent, this has been associated with
reduced osmolality of the agent.5,6 This reduction in osmolality of
the contrast agent, which allows beneficial addition of salts to the
formulation of the ICM, is an accepted methodology for reducing
CIN incidence.7,8 The primary source of the iodine atoms used to
attenuate the X-rays is a 5-amino-2,4,6-triiodoisophthalic acid
unit.9 Reduction in osmolality has been achieved over time by mov-
ing from ionic to nonionic monomers to nonionic dimeric species
containing this moiety. In order to reduce the incidence of CIN even
further, a reasonable approach would, therefore, be to prepare
agents based on trimers of the triiodoisophthalic acid moiety.
Figure 1 shows the general structure of trimeric X-ray contrast
agents 1 illustrating the range of options for linking three triiodoi-
sophthalic acid groups, where L is a linker attached via linking
groups X, Y and Z, and the groups R1–R6 are polyhydroxylated
nonionic solubilising groups.
A virtual library of several million compounds was constructed
based on a variety of linking chemistries, such as amide, sulfon-
amide and urea, with a wide variety of side-chain and linker vari-
ation, which are all described by general structure 1.
A subset of this library based on more readily available building
blocks with symmetrical linking chemistry, some typical examples
of which are shown in Figure 2, was enumerated and prioritised for
synthesis based on an in-house quantitative structure–activity
relationship (QSAR) model.
Scheme 1 shows an illustrative synthesis. 5-Amino-2,4,6-triio-
doisophthalic acid (2) was converted into the diacid chloride,
R4
R2
I
I
I
I
I
Z
X
R3
R1
L
I
I
O
Y
O
R6
I
I
R5
O
1
Figure 1. General structure of trimeric X-ray contrast agents where R1–R6 are
polyhydroxylated nonionic solubilising groups attached via linking groups X, Y and
Z, where X, Y and Z may be the same or different and selected from C@O, SO2, and
NHC@O, and L is a triamine linker.
⇑
Corresponding author. Tel.: +44 1494 544082; fax: +44 1494 543284.
E-mail address: ian.newington@ge.com (I.M. Newington).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.010

3066
I. M. Newington et al. / Tetrahedron Letters 52 (2011) 3065–3067
All the compounds were purified by preparative reverse phase
HPLC to ensure high purity and removal of salts, which could ad-
versely affect the physicochemical characterisation. An alternative
synthesis was employed for later examples using polyhydroxy-
amines, such as 3-aminopropan-1,2-diol, in the first step to avoid
the dihydroxylation chemistry. This avoided repetitive treatments
with metal capture resins to remove residual osmium from the fi-
nal products 1, resulting in loss of material.
A library of some 50 trimeric contrast agents was synthesised in
this way.10 The physicochemical properties of some of these are
shown in Table 1. All the compounds listed have at least four
hydroxy groups per triiodoaromatic unit and were highly water-
soluble. The compounds were evaluated as mixtures of diastereoi-
somers, which could clearly be seen in the HPLC chromatograms
but were too close in retention time to separate. Compounds with
lower hydroxy count were generally less soluble and, in some
cases, not soluble enough to achieve the required iodine concentra-
tion of 320 mgImLÀ1. What can be seen from the results is that the
concept of obtaining very low osmolality by using trimeric agents
has, indeed, been achieved.
The current low osmolar contrast agent iodixanol (Fig. 3) has an
osmolality of approximately 210 mOsmkgÀ1 and is formulated to
iso-osmolality at 290 mOsmkgÀ1 with added electrolyte in the
ICM Visipaque™. This has the benefit of improving the cardiologi-
cal safety profile of the agent. A reduction in osmolality of the
agent itself to below 100 mOsmkgÀ1 can thus be expected to en-
hance the safety profile of the contrast medium by reducing both
renal and cardiological impact.
As can also be seen in Table 1, the viscosity of the agents 1 var-
ies significantly and is higher than that of iodixanol at the same
concentration of iodine.11 This is undesirable, since the rapid intra-
venous administration of the large volumes of ICM required for a
computed tomography (CT) scan is made both slower and more
painful for the patient. This result is, perhaps, not surprising in
Figure 2. Some examples of readily available linkers (A–F) and side-chains (P and Q
for R1, R3, R5; R–T for R2, R4, R6).
which was treated with N-methylprop-2-en-1-amine to generate
selectively the monoamide. Treatment with a protected polyhydr-
oxylated acyl chloride resulted in the acyl chloride 3. This was
attached to a triamine linker by heating in a 1:3 molar ratio in
N,N-dimethyl acetamide to give a trimeric compound that was
tris-‘dihydroxylated’ with osmium tetroxide and then deprotected
to give the final compound 1e.
OAc
OAc
NH2
a, b, c
I
I
O
I
NH
I
HO
OH
Cl
N
O
I
O
O
I
O
2
3
OH
HO
HN
OH
HO
HN
O
I
I
O
I
OH
H
N
OH
I
N
d, e, f
OH
H
N
N
O
O
O
HO
I
O
I
O
HN
I
I
O
OH
HO
HO
N
OH
N
H
I
O
1e
Scheme 1. Synthesis of 1e. Reagents and conditions: (a) SOCl2, 1,2-DCE, 85 °C, 6 h, 97%; (b) N-methylprop-2-en-1-amine, dry THF, 50 °C, 18 h, 59%; (c) 3-chloro-3-oxopropan-
1,2-diyl diacetate, DMAc, 18 h, 20 °C, 56%; (d) 3-(2-aminoethyl)pentane-1,5-diamine (0.33 equiv), DMAc, Et3N, 60 °C, 24 h, 67%; (e) OsO4, NMO, t-BuOOH, acetone, H2O; (f)
MeOH, NH3, 20 °C, 18 h (25% over 2 steps).

I. M. Newington et al. / Tetrahedron Letters 52 (2011) 3065–3067
3067
Table 1
The QSAR developed for these compounds did not allow a ready
correlation of structure with physicochemical properties, although
some general trends were indicated. The best compounds in this
trimeric series, considering viscosity as well as osmolality, were,
therefore, 1f and 1l.
Physicochemical properties of some representative trimeric X-ray contrast agents
measured at 320 mgImLÀ1
.
Product
L
R1,3,5 R2,4,6 Osmolality
(mOsmkgÀ1
Viscosity
(mPas)
Log P
)
Iodixanol
1a
1b
1c
1d
1e
1f
1g
1h
1i
1j
1k
1l
1m
1n
210
82
25
48
41
256
82
94
31
68
86
À4.0
À5.0
À5.0
À4.4
À5.0
À2.9
À6.0
À4.5
À3.4
À4.0
À3.4
À3.0
À3.9
À3.2
À3.4
In conclusion, we have shown that it is possible to achieve ex-
tremely low osmolality with trimeric X-ray contrast agents, but
it has proved more difficult to simultaneously achieve low enough
viscosity for clinical application. As a result, the search for very low
osmolar X-ray contrast agents has continued with dimeric
structures.12
A
A
A
B
C
C
C
C
C
D
D
E
E
F
P
P
Q
P
P
P
Q
Q
Q
P
P
P
P
P
S
T
R
S
S
T
R
S
R
S
T
S
T
T
189
121
93
120
172
87
280
959
521
575
76
Acknowledgements
64
51.8
422
36
79
47
Analytical support was provided by Gunnar Hagelin and Astri
Rogstad; preparative HPLC was carried out by Gry Olausen and in
silico predictions by Hanno Priebe, all of the GE Healthcare re-
search laboratories in Nycoveien, Oslo.
297
249
References and notes
OH
OH
H
N
H
1. McClennan, B. L. Am. J. Roentgenol. 1990, 155, 225–233.
2. Thomson, K. R.; Varma, D. K. Aust. Prescr. 2010, 33, 19–22.
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Med. 1997, 103, 368–375.
4. Briguiori, C.; Tavano, D.; Colombo, A. Prog. Cardiovasc. Dis. 2003, 45, 493–503.
5. Aspelin, P.; Aubry, P.; Fransson, S. G.; Strasser, R.; Willenbrock, R.; Berg, K. J. N.
Engl. J. Med. 2003, 348, 491–499.
6. Thomsen, H. S.; Morcos, S. K. Br. J. Radiol. 2003, 76, 513–518.
7. Barrett, B.; Carlisle, E. J. Radiology 1993, 188, 171–178.
8. Solomon, R. Kidney Int. 2005, 68, 2256–2263.
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10. Wynn, D.; Nairne, R. J. D.; Axelsson, O.; Thaning, M.; Lasbistes, N. P.C.T. Int.
Appl. WO2007094683A1, 2007; Chem. Abstr. 2007, 147, 277286.
11. Eivindvik, K.; Sjogren, C. E. Acta Radiol. 1995, 36, S32–38.
12. Wynn, D. G.; Humphries, G.; Morisson-Iveson, V.; Nairne, J.; Newington, I. M.;
Passmore, J.; Wistrand, L.-G. Tetrahedron Lett. 2011, 52, 3068–3071.
HO
OH
O
O
N
OH
OH
I
I
I
I
H
N
H
N
HO
OH
N
O
N
O
I
OH
I
O
O
Figure 3. Structure of iodixanol.
view of the size of these trimeric compounds with molecular
weight in the 2100–2500 range and with 12 hydroxy groups or
more per molecule. In comparison, dimeric contrast agents will
generally give solutions having a lower viscosity but, until re-
cently,12 have typically been found to possess higher osmolality.