The synthesis and evaluation of unsymmetrical dimeric X-ray contrast agents

Article abstract of DOI:10.1016/j.tetlet.2011.04.009

Novel dimeric iodinated contrast agents with low osmolality have been prepared and evaluated with the aim of improving the already good safety profile of such agents. The aim of low osmolality was achieved, and the viscosity of these dimeric agents was also found to be beneficially lower than current dimeric agents in clinical use.

Full text of DOI:10.1016/j.tetlet.2011.04.009

Tetrahedron Letters 52 (2011) 3068–3071
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
The synthesis and evaluation of unsymmetrical dimeric X-ray contrast agents
Duncan G. Wynn a, , Gareth Humphries a, Véronique Morisson-Iveson a, James Nairne a, Ian M. Newington a,
⇑
Joanna Passmore a, Lars-Göran Wistrand b
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:
Available online 9 April 2011
Novel dimeric iodinated contrast agents with low osmolality have been prepared and evaluated with the
aim of improving the already good safety profile of such agents. The aim of low osmolality was achieved,
and the viscosity of these dimeric agents was also found to be beneficially lower than current dimeric
agents in clinical use.
Keywords:
X-ray
Contrast agent
Osmolality
Viscosity
Ó 2011 Elsevier Ltd. All rights reserved.
Synthesis
Iodinated contrast agents are widely used in X-ray diagnostic
procedures such as angiography, urography and computed tomog-
raphy. The clinical safety of iodinated X-ray contrast media has
continuously been improved over recent decades through develop-
ment of new agents; from ionic monomers, such as Isopaque™, to
non-ionic monomers, such as Omnipaque™ (1), (iohexol), and
non-ionic dimers, e.g. Visipaque™ (2) (iodixanol) ( Fig. 1). This
improvement in safety has, to a large extent, been associated with
a decrease in osmolality of the agent, going from the highly hyper-
tonic ionic agents to isotonic agents.1 In the case of Visipaque™,
the low osmolality of the agent even allows the addition of sodium
and calcium ions, making the electrolyte composition of the agent
more physiological and blood-like than all other X-ray contrast
media hitherto developed. However, among patients with pre-
existing renal impairment, some can develop contrast media in-
duced nephrotoxicity (CIN).2–5 The incidence of CIN accounts for
OH
HO
HN
O
I
I
O
OH
O
N
OH
HO
I
HN
HO
O
O
N
N
I
HO
HO
I
I
OH
OH
HO
HO
I
I
OH
OH
OH
H
N
H
N
H
N
H
N
O
I
O
O
O
1
2
Figure 1. The structures of iohexol (1) and iodixanol (2).
⇑
Corresponding author. Tel.: +44 1494 545189; fax: +44 1494 543284.
E-mail address: duncan.wynn@ge.com (D.G. Wynn).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.04.009

D. G. Wynn et al. / Tetrahedron Letters 52 (2011) 3068–3071
3069
more than 12% of hospital-acquired renal failures and is a leading
cause of acute renal failure.6 Reduction in renal function increases
morbidity, mortality, length of hospitalisation and acceleration to-
wards end-stage renal disease. Consequently, there is a need for
new contrast agents with improved clinical safety with regard to
nephrotoxicity, especially in at risk individuals. It is thought, in
high-risk patients, that there is a link between the osmolality of
the contrast medium and the incidence of CIN.7,8
Our focus was to synthesise novel unsymmetrical dimeric
iodinated agents with the aim of lowering the viscosity and
achieving low osmolality. The reason for this is that, as discussed
earlier, the physicochemical properties of the agents are thought
to play a key role in CIN.
groups and across one of the aromatic groups. It was hoped that
this asymmetry would, in the first instance, reduce the ability of
the compounds to readily form crystals, leading to highly water
soluble compounds. For compounds with high water solubility,
the viscosity, osmolality and log P were determined.
Scheme 1 shows an illustrative synthesis of a typical dimer 9.
Compound 4 was synthesised by reaction of sodium azide with
epibromohydrin. (Caution: due to the relative explosive nature
of azides only 73 mg of the crude material was isolated to aid char-
acterisation). Azide 4 was exposed to the iodixanol intermediate 3
in MeOH/water with sodium hydroxide buffered with boric acid to
give crude 5. This was then peracetylated with acetic anhydride to
enable purification by silica gel chromatography, hydrolysed, then
persilylated to give 6 in 62% yield over three steps. The exchange of
protecting groups was necessary to avoid aziridine formation
The asymmetry of the dimers is defined with respect to the
attachment points of the linker to the two triiodoaromatic core
N3
O
HO
N3
4
O
HN
N
O
I
a
I
I
I
O
O
O
O
OH
OH
OH
OH
HO
NH
I
HN
OH
HO
NH
I
HN
OH
5
3
N3
N
O
I
Si
O
b,c,d
O
I
e
Si
Si
O
O
O
O
O
NH
I
HN
Si
Si
6
O
NH2
N
O
O
I
Si
O
O
I
NH
I
O
H
O
I
O
Cl
N
O
I
O
8
Si
O
Si
O
O
f
O
NH
I
HN
O
Si
Si
7
I
O
I
H
N
OH
N
H
HO
O
OH
I
HN
O
HO
I
N
O
I
O
O
OH
OH
OH
HO
NH
I
HN
9
Scheme 1. Synthesis of 9: (a) NaOH, H3BO3, MeOH/H2O (2:1), 40 °C, 6 h, 70%; (b) Ac2O, pyridine, 20 °C, 24 h, 90%; (c) NaOH, MeOH/H2O (2.5:1), 18 h, 20 °C, 90%; (d) TMSCl,
CH2Cl2, Et3N, 20 °C, 20 h, 77%; (e) DPPE, CH2Cl2, 20 °C, 24 h, 87%; (f) 8, DMF, Et3N, 20 °C, 18 h, then HCl, MeOH (48% over 2 steps).

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D. G. Wynn et al. / Tetrahedron Letters 52 (2011) 3068–3071
OH
OH
I
O
H
N
O
I
H
N
OH
N
HO
HO
N
H
O
HO
O
I
OH
HO
I
I
I
HN
N
O
HN
N
O
HO
I
HO
I
O
I
O
I
O
O
O
O
OH
OH
OH
OH
OH
HO
NH
I
HN
HO
HO
NH
I
HN
OH
11
10
OH
OH
I
O
I
I
O
I
H
N
H
N
OH
HO
N
N
H
O
OH
O
OH
HO
I
I
HN
O
HN
O
HO
I
HO
N
O
I
N
O
I
I
O
O
O
O
OH
OH
OH
OH
OH
HO
NH
I
HN
OH
HO
NH
I
HN
13
12
Figure 2. Structures of the products 10–13.
during the treatment of 6 with 1,2-bis(diphenylphosphino)ethane
(DPPE) to form the amine 7, of which 87% was the desired material.
Amine 7 was mixed with the acid chloride 8 in DMF with triethyl-
amine present to give the corresponding product in approximately
80% purity.9 This was deprotected with 2 M HCl at reflux in meth-
anol, treated with ion exchange resins (AmberliteÒ 200C resin and
AmberliteÒ IRA-67 resin) to remove any salts, and purified by pre-
parative HPLC to yield the final compound 9. The synthesis of 9 as
described was unoptimised. Nevertheless, it was possible to pre-
pare 25 g of 9 using this route.
Using analogous chemistry it was possible to synthesise four
other compounds, 10, 11, 12, and 13, which are shown in Figure
2. All compounds were purified by preparative reversed phase
HPLC to ensure high purity, after removal of salts by the use of
an ion exchange resin, which could adversely affect the physico-
chemical characterisation.
The physicochemical properties of the five products are shown
in Table 1. All the compounds listed have at least four hydroxy
groups per triiodoaromatic unit and were highly water-soluble. It
can be seen from the results that the concept of obtaining low
osmolality and low viscosity by using unsymmetric dimeric agents
has, indeed, been achieved.
The five compounds prepared all displayed good water solubil-
ity (Table 1). The viscosity of the agents was consistently lower
than that of iodixanol (25 mPas) at the same concentration of io-
dide. This lower viscosity would allow the rapid intravenous
administration of the large volumes of Iodinated Contrast Media
(ICM) required for a Computerised Tomography (CT) scan to be less
painful for the patient. There was a range of osmolalities from 216
to 422 mOsm/kg. This demonstrated that relatively small changes
to the structures of the compounds led to significant differences
in osmolality.
Table 1
Physicochemical properties of the unsymmetrical dimeric X-ray contrast agents
measured at ꢀ320 mgImLÀ1
Compound Aqueous
solubility (mgI/
Osmolality
(mOsm/kg)
Viscosity
(mPas@320 mgI/
mL)
Log P
mL)
9
10
11
12
13
Iodixanol
319
307
320
296
322
320
216
255
270
422
278
210
17
22
16
20
20
25
À3.0
À2.8
À2.9
À3.6
À3.4
À2.6
In conclusion, we have shown that it is possible to achieve low
osmolality with unsymmetric dimeric X-ray contrast agents and it
has proved equally successful to simultaneously achieve low
viscosities.
Acknowledgements
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 GE Healthcare research
laboratories in Nycoveien, Oslo.
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