Synthesis of new cyclic and acyclic 5-halouridine derivatives as potential antiviral agents

Article abstract of DOI:10.1055/s-0028-1083369

The synthesis of new cyclic and acyclic nucleoside analogues was achieved by alkylation of 5-halogenated 6-(2,4-dichlo-rophenoxymethyl)pyrimidine-2,4- dione following the Vorbrueggen coupling procedure. Nucleoside analogues of the 1-[(2-hydroxy-ethoxy)met

Full text of DOI:10.1055/s-0028-1083369

PAPER
841
Synthesis of New Cyclic and Acyclic 5-Halouridine Derivatives as Potential
Antiviral Agents
N
ew 5-Halouridine De
o
rivatives as
P
h
otential
A
nt
a
ivira
l
A
ge
n
m
ts ed F. Elshehry,a,b Jan Balzarini,c Chris Meier*a
a
Organic Chemistry, Department of Chemistry, Faculty of Sciences, University of Hamburg,
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Fax +49(40)428385592; E-mail: chris.meier@chemie.uni-hamburg.de
Pesticides Department, National Research Centre, 12622 Dokki, Cairo, Egypt
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Minderbroedersstraat 10, 3000 Leuven, Belgium
b
c
Received 4 September 2008; revised 25 November 2008
O
N
O
N
Abstract: The synthesis of new cyclic and acyclic nucleoside ana-
logues was achieved by alkylation of 5-halogenated 6-(2,4-dichlo-
rophenoxymethyl)pyrimidine-2,4-dione following the Vorbrüggen
coupling procedure. Nucleoside analogues of the 1-[(2-hydroxy-
ethoxy)methyl]-6-(phenylthio)thymine (HEPT)-type were obtained
as well as analogues of ganciclovir, acyclovir, and ribonucleosides.
All compounds were tested against a variety of viruses. Three of the
new compounds were potent and selective anti-HIV-1 inhibitors.
N
N
NH
NH
O
HO
HO
O
O
N3
AZT (1)
ddI (2)
Key words: bioorganic chemistry, drugs, antiviral agents, nucleo-
sides, glycosylation
NH2
NH
N
N
N
N
N
Nucleoside analogues are an important class of chemo-
therapeutics that are used as antiviral or antitumor agents
in the clinic. The main mechanism of action of these com-
pounds is an inhibition of DNA-replicating enzymes.
However, to exert their biological activity, these com-
pounds have to be converted into their corresponding nu-
cleoside triphosphates by cellular enzymes such as
kinases. Despite their toxic side effects1,2 and the risk of
developing resistance after prolonged treatment,3 eight
nucleoside analogues like 3¢-azido-3¢-deoxythymidine
(AZT) (1), 2¢,3¢-dideoxyinosine (ddI) (2), L-3¢-thiacyti-
dine (3TC) (3), and abacavir (ABC) (4) are nowadays
used as anti-HIV agents to improve the quality of life of
AIDS patients. Nucleoside analogues may be modified in
the glycone as in 1–3 or in the glycone and the aglycone
part as in 4 compared to naturally occurring nucleosides
(Figure 1).
N
O
S
NH2
OH
HO
O
3TC (3)
ABC (4)
O
O
O
Br
NH
F
NH
NH
N
O
O
HO
S
N
O
N
H
O
HO
O
OH
BVDU (5)
5-FU (6)
HEPT (7)
Figure 1 Structural formulas of clinically used nucleoside ana-
logues 1–5 as well as 5-fluorouracil (6) and HEPT (7)
louracil derivatives are of current interest in nucleoside
chemistry.
In addition, at least one nucleoside analogue is always in-
cluded in multiple-drug therapies as in the highly active
antiretroviral therapy (HAART) strategy. However, the
alarming expectations concerning the spread and the in-
creasing number of people infected by this disease dem-
onstrate the need for further and more potent drugs. 5-
Substituted cyclic and acyclic nucleosides, for example,
(5E)-bromovinyl-2¢-deoxyuridine (BVDU) (5) or even 5-
halogenated heterocycles like 5-fluorouracil (5-FU) (6)
have been shown to exhibit interesting chemotherapeutic,
biochemical, and biophysical properties (Figure 1).4
Thus, new methods for the convenient synthesis of 5-ha-
Another very interesting class of antiviral active deriva-
tives are the 1-[(2-hydroxyethoxy)methyl]-6-(phenyl-
thio)thymine (HEPT) compounds 7, which showed
selective anti-HIV-1 activity (Figure 1).5 Here we report
on new nucleobase and nucleoside analogues bearing
halogen atom at C-5 and an aryloxymethyl residue in the
6-position of the uracil pyrimidine ring system.
The key reaction in our strategy for the synthesis of new
nucleoside analogues is based on the alkylation of silyl-
ated heterocycles following the Vorbrüggen procedure.6
However, first 6-[(2,4-dichlorophenoxy)methyl]pyrimi-
dine-2,4(1H,3H)-dione (8) was synthesized in high yield
by condensation of ethyl-4-(2,4-dichlorophenoxy)-3-oxo-
butanoate (9) with thiourea in the presence of sodium
SYNTHESIS 2009, No. 5, pp 0841–0847
x
x
.
x
x
.2
0
0
9
Advanced online publication: 11.02.2009
DOI: 10.1055/s-0028-1083369; Art ID: T15608SS
© Georg Thieme Verlag Stuttgart · New York

842
M. F. Elshehry et al.
PAPER
ethoxide to give 6-(2,4-dichlorophenoxymethyl)-2- (acetoxymethoxy)propanediyl-1,3-dibenzoate, and ben-
thioxo-2,3-dihydropyrimidin-4(1H)-one (10),7 and then zyloxymethyl acetate.11 These reactions were carried out
desulfurization with (10%) aqueous chloroacetic acid in anhydrous acetonitrile with tin(IV) chloride as a cata-
yielding the target molecule 8.8 The same compound was lyst.
available in poor yield by condensation of 9 with urea in
the presence of concentrated hydrochloric acid in absolute
The same procedure was applied to 2,3,5-tri-O-benzoate-
b-D-ribofuranose-1-acetate leading to the protected b-ri-
bofuranosyl nucleoside 18a–c (Scheme 2). Finally, the
ethanol to give 11 and cyclization with 2 N sodium hy-
droxide to yield 8 (Scheme 1).9
deprotected compounds 15a–c, 17a–c and 19a–c were ob-
tained by cleavage of the ester blocking group with meth-
anolic ammonia. The products were purified by silica gel
O
Cl
O
O
i
column chromatography. All new nucleoside analogues
and pyrimidine analogues were fully characterized by an-
HN
O
Cl
90%
OAryl
OEt
S
N
H
10
1
13
alytical methods like H NMR, C NMR, and elemental
analysis.
Aryl
9
iii
10%
80%
ii
12a–c
HMDS
O
(NH4)2SO4
O
HN
iv
65%
OSi(Me)3
R1
H2N
O
N
O
OAryl
X
O
N
Aryl
Cl
N
OEt
H
11
O
8
(Me)3SiO
OAc
N
Scheme 1 Synthesis of 8. Reagents and conditions: (i) 1. thiourea,
NaOEt, reflux, 24 h, 2. aq 30% HCl; (ii) 10% ClCH2CO2H in H2O,
reflux, 24 h; (iii) urea, EtOH–HCl, r.t., 5–7 d; (iv) 1. aq 2 N NaOH,
95 °C, 1 h, 2. concd HCl.
13a–c
Cl
AcO
O
SnCl4
31–57%
BnOCH2OAc
SnCl4
O
52–60%
X
Next, three halogenated pyrimidine analogues were pre-
pared by halogenation of uracil derivative 8 using differ-
ent halogen sources and ceric ammonium nitrate (CAN) at
70 °C or 80 °C. Iodination of 6-modified uracil derivative
8 takes place in the presence of CAN and elemental iodine
in methanol at 70 °C to give 5-iodouracil 12a. In addition,
chlorination of uracil derivative 8 by LiCl/CAN in aceto-
nitrile–AcOH as solvent at 80 °C for 24 hours gave 5-
chlorouracil 12b. Bromination took place by treatment of
pyrimidine 8 with LiBr/CAN in methanol at 70 °C to yield
5-bromouracil 12c (Table 1).10
HN
BzO
R1
O
OAc
OBz
O
N
R2O
O
BzO
SnCl4
O
14a–c: R2 = Ac
15a–c: R2 = H
NH3–MeOH
41–63%
X
HN
R1
O
O
N
20a–c
BzO
O
OAc
OBz
SnCl4
32–41%
20–30%
Table 1 5-Halogenation of 6-(2,4-Dichlorophenyloxymethyl)uracil
(8)
O
O
N
X
X
O
O
HN
HN
O
CAN
halogen
source
Cl
Cl
X
R1
HN
R1
HN
O
N
R3O
O
Cl
O
Cl
O
R2O
O
N
H
O
N
H
O
solvent
OR3
8
12a–c
16a–c: R3 = Bz
17a–c: R3 = H
NH3–MeOH
42–54%
R2O
R2O
12
a
X
I
Solvent
MeOH
Halogen source Yield
18a–c: R = Bz
19a–c: R = H
NH3–MeOH
26–52%
I2
72%
65%
46%
a: X = I, b: X = Cl, c: X = Br
b
Cl
Br
MeCN–AcOH
MeOH
LiCl
LiBr
Scheme 2 Synthesis of acyclic 5-halogenated uracil nucleoside ana-
logues 15–20
c
The newly prepared compounds were tested for their bio-
logical activity against various viruses. All compounds
failed to exhibit any antiviral effect against feline corona
virus (FIPV), feline herpes virus, para-influenza-3-virus,
reovirus, sindbis virus, cocksackie virus B4, punta toro vi-
The bis(trimethylsilyl) derivatives 13a–c, obtained from
the silylation of 12a–c with hexamethyldisilazane
(HMDS) and a catalytic amount of ammonium sulfate,
were reacted with 2-acetoxyethyl acetoxymethyl ether, 2-
Synthesis 2009, No. 5, 841–847 © Thieme Stuttgart · New York

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New 5-Halouridine Derivatives as Potential Antiviral Agents
843
1H NMR (DMSO-d6/TMS): d = 1.21 (t, J = 7.1 Hz, 3 H, CH2CH3),
4.13 (q, J = 7.1 Hz, 2 H, CH2CH3), 5.22 (s, 2 H, CH2), 5.32 (s, 2 H,
CH2Oaryl), 6.94–7.60 (m, 3 Haryl), 10.13 (s, 2 H, NH).
13C NMR (DMSO-d6/TMS): d = 14.10, 33.86, 61.20, 67.10, 116.67,
121.02, 126.01, 127.68, 129.29, 149.96, 154.26, 166.07, 166.94.
rus, herpes virus type-1 (KOS), herpes virus-type-2 (G),
herpes simplex virus-1 TK– KOS ACVr, vaccinia virus,
vesicular stomatitis virus, respiratory syncytial virus, in-
fluenza A H1N1 subtype, influenza A H3N2 subtype, and
influenza B. Most compounds also proved to be inactive
against HIV-1 and HIV-2 in T-lymphocytes (CEM/0-
cells). However, compounds 20a–c showed significant
and highly selective inhibitory potency against HIV-1
while they proved to be inactive against HIV-2.12 The ac-
tivity found was in the low- and submicromolar range, re-
spectively (20a: EC50 = 0.16 mM, 20b: EC50 = 5.6 mM and
20c: EC50 = 0.83 mM). Maybe this selective HIV-1 activ-
ity can be explained by the resemblance of compounds
20a–c with the HEPT structure. Interestingly, compounds
20a and 20c were found to be 10-fold more active as com-
pared to HEPT (7) (EC50 = 7.5 mM).13
MS(ESI–): m/z = 333.0 [M]+.
Anal. Calcd for C13H14Cl2N2O4 (333.17): C, 46.87; H, 4.24; N, 8.41.
Found: C, 46.94; H, 4.18; N, 8.49.
6-[(2,4-Dichlorophenoxy)methyl]pyrimidine-2,4(1H,3H)-dione
(8)
Method A: A mixture of 10 (1.95 g, 6.48 mmol) and chloroacetic
acid (3.10 g, 32.81 mmol) in H2O (30 mL) was refluxed for 24 h and
cooled to r.t. The formed precipitate was collected by filtration,
washed with H2O (2 × 20 mL), dried, and recrystallized from a mix-
ture of DMF and H2O (5:1); yield: 1.50 g (80%); fine colorless crys-
tals; mp 278–280 °C.
1H NMR (DMSO-d6/TMS): d = 4.80 (s, 2 H, CH2Oaryl), 5.55 (s, 1
H, CH), 7.10–7.70 (m, 3 Haryl), 11.11 (br s, 2 H, 2 NH).
13C NMR (DMSO-d6/TMS): d = 65.5, 98.0, 115.3, 122.6, 125.4,
128.1, 129.4, 150.6, 151.2, 151.8, 163.8.
In summary, we have prepared efficiently new 6-alkylated
5-halogenated uracil nucleobases and nucleoside ana-
logues. Some of these compounds showed promising se-
lective anti-HIV-1 activity. Further work focusing on
analogues of 20 is currently under investigation in our lab-
oratories.
MS (ESI–): m/z = 286.0 [M]+.
Anal. Calcd for C11H8Cl2N2O3 (287.10): C, 46.02; H, 2.81; N, 9.76.
Found: C, 46.10; H, 2.76; N, 9.85.
Method B: The crude product 11 was added to a solution of aq 2 N
NaOH (30 mL) at 95 °C with stirring. The clear solution was cooled
to 65 °C and carefully acidified while stirring by slow addition of
concd HCl. The product precipitated immediately, collected by fil-
tration, and dried. Compound 8 was obtained as colorless powder of
a high degree of purity in 65% yield.
Melting points were taken on an Apotec apparatus and are uncor-
rected. IR spectra were recorded on an Avatar 370 FT- IR spectrom-
eter. NMR spectra were recorded with Bruker AMX400 and Bruker
and Bruker DRX 500 Fourier-transform spectrometers. All 1H and
13C NMR chemical shifts (d) are quoted in ppm and calibrated with
respect to solvent signals. ESI mass spectra were taken on a Finni-
gan Thermo Quest MAT 95XL spectrometer. Merck precoated 60
F254 plates with a 0.2 mm layer of silica gel were used for TLC. For
column chromatography, Merck silica gel 60 (230–400) mesh was
used. All reactions were carried out under dry N2, except for the
synthesis of 8 and 12a–c. Petroleum ether (PE) refers to the fraction
boiling in the range 40–60 °C.
6-(2,4-Dichlorophenoxymethyl)-5-iodo-2-oxo-2,3-dihydro-1H-
pyrimidinon-4-one (12a)
A mixture of uracil derivative 8 (0.38 g, 1.34 mmol), I2 (0.20 g, 0.80
mmol), CAN (0.37 g, 0.67 mmol), and MeOH (8 mL) was stirred at
70 °C for 24 h. The product precipitated and was filtered from the
hot solvent, washed with Et2O (10 mL), dried, and crystallized from
MeOH; yield: 0.40 g (72%); colorless solid; mp 255–257 °C.
1H NMR (DMSO-d6/TMS): d = 5.03 (s, 2 H, CH2Oaryl), 7.30–7.70
(m, 3 Haryl), 11.10 (br s, 2 H, 2 NH).
13C NMR (DMSO-d6/TMS): d = 71.4, 74.9, 116.2, 123.3, 126.1,
128.6, 129.8, 150.5, 151.0, 152.6, 162.0.
6-(2,4-Dichlorophenoxymethyl)-2-thioxo-2,3-dihydropyrimi-
din-4(1H)-one (10)
Thiourea (8.90 g, 117 mmol) and ethyl 4-(2,4-dichlorophenoxy)-3-
oxobutanoate (9; 13.4 g, 45.95 mmol) were added to a solution of
Na (2.70 g, 117 mmol) in EtOH (100 mL) and refluxed under anhyd
conditions for 24 h. The reaction product was evaporated in vacuum
and the residue was dissolved in H2O (200 mL), acidified with aq
30% HCl and the precipitate was collected by filtration, dried at 60–
70 °C, and recrystallized from a mixture of DMF and H2O (5:1);
yield: 12.5 g (90%); crystalline, colorless solid; mp 318–320 °C.
MS (ESI–): m/z = 412.0 [M – 1].
Anal. Calcd for C11H7Cl2IN2O3 (412.99): C, 31.99; H, 1.71; N, 6.78.
Found: C, 32.06; H, 1.66; N, 6.87.
1H NMR (DMSO-d6/TMS): d = 5.00 (s, 2 H, CH2Oaryl), 6.01 (s, 1
H, CH), 7.20–7.80 (m, 3 Haryl), 11.03 (br s, 2 H, 2 NH).
5-Chloro-6-(2,4-dichlorophenoxymethyl)-2-oxo-2,3-dihydro-
1H-pyrimidinon-4-one (12b)
A mixture of the uracil derivative 8 (0.31 g, 1.07 mmol), LiCl (0.54
g, 1.28 mmol), CAN (1.17 g, 2.14 mmol), and MeCN–AcOH (1:1.8
mL) was stirred at 80 °C for 18 h. The solvent was evaporated. After
coevaporation with EtOH–H2O (2:1, 3 × 10 mL) gave a colorless
powder that was crystallized from EtOH; yield: 0.20 g (65%); col-
orless solid; mp 266–268 °C.
13C NMR (DMSO-d6/TMS): d = 65.5, 103.1, 115.7, 122.9, 125.9,
128.6, 129.8, 151.3, 152.1, 161.1, 176.3.
MS (ESI–): m/z = 302.0 [M]+.
Anal. Calcd for C11H8Cl2N2O2S (301.97): C, 43.58; H, 2.66; N,
9.24. Found: C, 43.66; H, 2.59; N, 9.30.
1H NMR (DMSO-d6/TMS): d = 4.81 (s, 2 H, CH2Oaryl), 7.11–7.48
Ethyl 4-(2,4-Dichlorophenoxy)-3-ureidobutanoate (11)
Finely powdered urea (8.00 g, 133 mmol) was added to a mixture of
9 (35.8 g, 123 mmol) dissolved in absolute EtOH (2.5 mL) contain-
ing concd HCl (0.5 mL). The mixture was stored in a desiccator
over concd H2SO4 under a membrane pump vacuum for 7 d to ob-
tain a dry product 11, which was recrystallized from EtOH; yield:
4.30 g (10%); white crystals; mp 150–152 °C.
(m, 3 Haryl), 11.00 (br s, 2 H, 2 NH).
13C NMR (DMSO-d6/TMS): d = 65.6, 107.2, 115.4, 124.3, 126.2,
128.4, 129.8, 145.8, 150.2, 152.6, 160.1
MS (ESI–): m/z = 320.0 [M – 1].
Anal. Calcd for C11H7Cl3N2O3 (321.54): C, 41.09; H, 2.19; N, 8.71.
Found: C, 41.17; H, 2.11; N, 8.81.
Synthesis 2009, No. 5, 841–847 © Thieme Stuttgart · New York

844
M. F. Elshehry et al.
PAPER
1-[(2-Acetoxyethoxy)methyl]-5-bromo-6-(2,4-dichlorophen-
5-Bromo-6-(2,4-dichlorophenoxymethyl)-2-oxo-2,3-dihydro-
1H-pyrimidinon-4-one (12c)
oxymethyl)uracil (14c)
A mixture of uracil derivative 8 (0.38 g, 1.34 mmol), LiBr (0.14 g,
1.61 mmol), CAN (1.47 g, 2.68 mmol), and MeOH (8 mL) was
stirred at 70 °C for 24 h. Workup as for 12b gave a colorless powder
that was recrystallized from EtOH; yield: 0.23 g (46%); white solid;
mp 247–249 °C.
1H NMR (DMSO-d6/TMS): d = 4.90 (s, 2 H, CH2Oaryl), 7.10–7.50
(m, 3 Haryl), 11.11 (br s, 2 H, 2 NH).
13C NMR (DMSO-d6/TMS): d = 67.7, 97.7, 116.3, 123.3, 126.2,
128.3, 129.8, 147.6, 150.5, 152.6, 160.4.
MS (ESI–): m/z = 366.0 [M – 1].
Yield: 1.50 g (31%); mp 148–150 °C.
1H NMR (DMSO-d6/TMS): d = 2.00 (s, 3 H, COCH3), 3.81 (t,
J = 3.7 Hz, 2 H, HOCH2), 4.20 (t, J = 3.7 Hz, 2 H, CH2O), 5.35 (s,
2 H, CH2Oaryl), 5.60 (s, 2 H, OCH2N), 7.10–7.51 (m, 3 Haryl), 11.95
(br s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 21.2, 63.4, 67.5, 68.4, 74.5, 104.4,
117.4, 125.5, 128.4, 129.0, 130.9, 147.3, 151.1, 152.1, 158.9, 171.2.
MS (ESI–): m/z = 482.0 [M – 1].
Anal. Calcd for C16H15BrCl2N2O6 (482.11): C, 39.86; H, 3.14; N,
5.81. Found: C, 39.78; H, 3.23; N, 5.90.
Anal. Calcd for C11H7BrCl2N2O3 (365.99): C, 36.10; H, 1.93; N,
7.65. Found: C, 36.19; H, 1.85; N, 7.74.
6-(2,4-Dichlorophenoxymethyl)-1-(2-hydroxyethoxymethyl]-5-
iodouracil (15a)
Nucleosides 14, 16, 18, 20; General Procedure
Yield: 2.00 g (41%); mp 154–156 °C.
A suspension of uracils 12a–c (0.01 mol) and (NH4)2SO4 (10 mg) in
HMDS (40 mL) was stirred under reflux for 4 h. The excess of
HMDS was evaporated under reduced pressure to give bis(trimeth-
ylsilyl) compounds 13a–c. A solution of protected cyclic and acy-
clic aglycone part (0.01 mol) in anhyd MeCN (60 mL) and SnCl4 (2
mL) was added to 13a–c and the mixture was stirred at –30 ° for 24
h. After addition of pyridine (4 mL), the mixture was filtered to re-
move the inorganic materials. The filtrate was diluted with CHCl3
(100 mL). The organic layers were washed with a aq sat. NaHCO3
(150 mL), followed by aq 1 N HCl (150 mL), then brine (100 mL),
and finally H2O (50 mL), dried (Na2SO4), and then the filtrate was
concentrated to dryness under reduced pressure. The products 14a–
c, 16a–c, 18a–c, and 20a–c were separated by silica gel column
chromatography (gradient of EtOAc–PE). Each protected nucleo-
side was dissolved in MeOH saturated with ammonia and stirred for
2 d at r.t. Then, the solution was concentrated to dryness and the res-
idue was recrystallized from MeOH to give nucleosides 15a–c,
17a–c, and 19a–c as colorless solids.
1H NMR (DMSO-d6/TMS): d = 3.70 (t, J = 3.7 Hz, 2 H, HOCH2),
3.60 (t, J = 3.7 Hz, 2 H, CH2O), 4.70 (br s, 1 H, OH), 5.40 (s, 2 H,
CH2Oaryl), 5.50 (s, 2 H, OCH2N), 7.30–7.80 (m, 3 Haryl), 12.00 (br
s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 60.2, 70.9, 70.7, 71.5, 73.9, 82.9,
117.3, 123.6, 126.7, 128.7, 129.9, 149.8, 151.4, 152.4.
MS (ESI–): m/z = 487.0 [M – 1].
Anal. Calcd for C14H13Cl2IN2O5 (487.07): C, 34.52; H, 2.69; N,
5.75. Found: C, 34.60; H, 2.61; N, 5.84.
5-Chloro-6-(2,4-dichlorophenoxymethyl)-1-(2-hydroxy-
ethoxymethyl]uracil (15b)
Yield: 2.50 g (63%); mp 165–167 °C.
1H NMR (DMSO-d6/TMS): d = 3.60 (t, J = 3.7 Hz, 2 H, HOCH2),
3.50 (t, J = 3.7 Hz, 2 H, CH2O), 4.64 (br s, 1 H, OH), 5.29 (s, 2 H,
CH2Oaryl), 5.40 (s, 2 H, OCH2N), 7.32–7.72 (m, 3 Haryl), 12.20 (br
s, 1 H, NH).
1-[(2-Acetoxyethoxy)methyl]-6-(2,4-dichlorophenoxymethyl)-
5-iodouracil (14a)
Yield: 1.80 g (34%); mp 130–132 °C.
1H NMR (DMSO-d6/TMS): d = 2.14 (s, 3 H, COCH3), 4.10 (t,
J = 3.7 Hz, 2 H, HOCH2), 4.35 (t, J = 3.7 Hz, 2 H, CH2O), 5.60 (s,
2 H, CH2Oaryl), 5.75 (s, 2 H, OCH2N), 7.63–7.90 (m, 3 Haryl), 12.12
(br s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 21.0, 63.2, 66.9, 71.4, 73.7, 83.1,
117.2, 123.6, 128.6, 129.9, 149.7, 151.5, 160.9, 170.6.
MS (ESI–): m/z = 528.0 [M – 1].
13C NMR (DMSO-d6/TMS): d = 60.2, 64.8, 70.9, 73.7, 112.0,
117.4, 123.6, 126.8, 128.7, 129.9, 145.5, 150.7, 152.2, 158.9.
MS (ESI–): m/z = 394.0 [M – 1].
Anal. Calcd for C14H13Cl3N2O5 (395.62): C, 42.50; H, 3.31; N, 7.08.
Found: C, 42.59; H, 3.23; N, 7.17.
5-Bromo-6-(2,4-dichlorophenoxymethyl)-1-(2-hydroxy-
ethoxymethyl]uracil (15c)
Yield: 1.90 g (43%); mp 170–172 °C.
1H NMR (DMSO-d6/TMS): d = 3.67 (t, J = 3.7 Hz, 2 H, HOCH2),
3.55 (t, J = 3.8 Hz, 2 H, CH2O), 4.62 (br s, 1 H, OH), 5.30 (s, 2 H,
CH2Oaryl), 5.45 (s, 2 H, OCH2N), 7.31–7.74 (m, 3 Haryl), 12.11 (br
s, 1 H, NH).
Anal. Calcd for C16H15Cl2IN2O6 (529.11): C, 36.32; H, 2.86; N,
5.29. Found: C, 36.39; H, 2.95; N, 5.36.
1-[(2-Acetoxyethoxy)methyl]-5-chloro-6-(2,4-dichlorophen-
oxymethyl)uracil (14b)
Yield: 2.50 g (57%); mp 144–146 °C.
1H NMR (DMSO-d6/TMS): d = 2.10 (s, 3 H, COCH3), 3.95 (t,
J = 3.8 Hz, 2 H, HOCH2), 4.31 (t, J = 3.8 Hz, 2 H, CH2O), 5.45 (s,
2 H, CH2Oaryl), 5.61 (s, 2 H, OCH2N), 7.61–7.91 (m, 3 Haryl), 12.20
(br s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 20.9, 63.2, 64.7, 67.0, 73.6, 112.2,
117.3, 123.6, 126.7, 128.7, 129.9, 145.4, 150.8, 152.2, 158.9, 170.6.
MS (ESI–): m/z = 437.0 [M – 1].
13C NMR (DMSO-d6/TMS): d = 60.2, 67.3, 70.9, 73.9, 103.6,
117.3, 123.6, 126.7, 128.7, 129.9, 147.1, 151.0, 152.3, 159.2.
MS (ESI–): m/z = 440.0 [M – 1].
Anal. Calcd for C14H13BrCl2N2O5 (440.07): C, 38.21; H, 2.98; N,
6.37. Found: C, 38.30; H, 2.90; N, 6.46.
2-{[6-(2,4-Dichlorophenoxymethyl)-5-iodo-2,4-dioxo-1-pyrim-
idinyl]methoxy}-1,3-propanediyl Dibenzoate (16a)
Yield: 2.40 g (33%); mp 96–98 °C.
1H NMR (DMSO-d6/TMS): d = 4.12–4.42 (m, 5 H, 2 CH2 andCH),
5.11 (s, 2 H, CH2Oaryl), 5.50 (s, 2 H, OCH2N), 7.10–7.82 (m, 13
Anal. Calcd for C16H15Cl3N2O6 (437.66): C, 43.91; H, 3.45; N, 6.40.
Found: C, 43.99; H, 3.53; N, 6.32.
Haryl), 12.20 (br s, 1 H, NH).
Synthesis 2009, No. 5, 841–847 © Thieme Stuttgart · New York

PAPER
New 5-Halouridine Derivatives as Potential Antiviral Agents
845
13C NMR (DMSO-d6/TMS): d = 64.1, 71.4, 73.4, 74.8, 83.4, 117.1,
123.6, 126.7, 128.5, 129.1, 129.4, 129.5, 129.9, 133.8, 149.3, 151.6,
152.2, 160.7, 165.7.
1H NMR (DMSO-d6/TMS): d = 3.39–3.64 (m, 5 H, 2 CH2 and CH),
4.81 (m, 2 H, OH), 5.50 (s, 2 H, CH2Oaryl), 5.62 (s, 2 H, OCH2N),
7.44–7.81 (m, 3 Haryl), 12.30 (br s, 1 H, NH).
MS (ESI–): m/z = 725.0 [M – 1].
13C NMR (DMSO-d6/TMS): d = 61.1, 67.4, 73.3, 81.2, 103.3,
117.3, 123.6, 126.8, 128.7, 129.9, 147.4, 151.0, 152.3, 159.3.
Anal. Calcd for C29H23Cl2IN2O8 (725.31): C, 58.02; H, 3.20; N,
3.86. Found: C, 48.11; H, 3.11; N, 3.96.
MS (ESI–): m/z = 471.0 [M – 1].
Anal. Calcd for C15H15BrCl2N2O6 (470.10): C, 38.32; H, 3.22; N,
5.96. Found: C, 38.38; H, 3.18; N, 5.90.
5-Chloro-2-{[6-(2,4-dichlorophenoxymethyl)-2,4-dioxo-1-pyri-
midinyl]methoxy}-1,3-propanediyl Dibenzoate (16b)
Yield: 2.60 g (41%); mp 105–107 °C.
1H NMR (DMSO-d6/TMS): d = 4.26–4.51 (m, 5 H, 2 CH2 andCH),
5.10 (s, 2 H, CH2Oaryl), 5.55 (s, 2 H, OCH2N), 7.11–7.91 (m, 13
Haryl), 11.98 (br s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 64.1, 64.7, 65.2, 73.2, 74.8, 117.2,
123.6, 126.8, 128.6, 129.1, 129.4, 129.5, 129.9, 133.8, 145.0, 150.9,
152.1, 158.6, 165.7.
1-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-6-(2,4-dichlorophe-
noxymethyl)-5-iodouracil (18a)
Yield: 1.90 g (22%); mp 130–132 °C.
1H NMR (DMSO-d6/TMS): d = 4.42–4.59 (m, 2 H, H-5¢,5¢¢), 4.62–
4.79 (m, 1 H, H-4¢), 4.92 (s, 2 H, CH2Oaryl), 6.02–6.21 (m, 2 H, H-
2¢, H-3¢), 6.61 (d, J = 2.5 Hz, 1 H, H-1¢), 7.20–7.92 (m, 18 Haryl),
12.03 (br s, 1 H, NH).
MS (ESI–): m/z = 634.0 [M – 1].
13C NMR (DMSO-d6/TMS): d = 64.0, 66.2, 70.9, 71.4, 74.3, 79.6,
86.5, 116.3, 125.0, 128.8, 129.3, 129.4, 129.9, 130.0, 130.2, 130.3,
131.0, 133.4, 133.7, 133.8, 133.9, 148.9, 151.3, 159.3, 165.5, 165.9.
Anal. Calcd for C29H23Cl3N2O8 (633.86): C, 54.95; H, 3.66; N, 4.42.
Found: C, 54.82; H, 3.71; N, 4.49.
MS (ESI–): m/z = 857.0 [M – 1].
5-Bromo-2-{[6-(2,4-dichlorophenoxymethyl)-2,4-dioxo-1-pyri-
midinyl]methoxy}-1,3-propanediyl Dibenzoate (16c)
Yield: 2.20 g (32%); mp 146–148 °C.
Anal. Calcd for C37H27Cl2IN2O10 (857.43): C, 51.83; H, 3.17; N,
3.27. Found: C, 51.74; H, 3.20; N, 3.33.
1H NMR (DMSO-d6/TMS): d = 4.51–4.80 (m, 5 H, 2 CH2 andCH),
5.41 (s, 2 H, CH2Oaryl), 5.80 (s, 2 H, OCH2N), 7.30–8.03 (m, 13
1-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-5-chloro-6-(2,4-
dichlorophenoxymethyl)uracil (18b)
Haryl), 11.94 (br s, 1 H, NH).
Yield: 2.3 g (30%); mp 136–138 °C.
13C NMR (DMSO-d6/TMS): d = 64.1, 67.2, 73.3, 74.8, 104.1,
117.2, 123.6, 126.8, 128.6, 129.1, 129.4, 129.5, 129.9, 133.8, 146.6,
151.1, 152.2, 159.0, 165.7.
1H NMR (DMSO-d6/TMS): d = 4.50–4.58 (m, 2 H, H-5¢,5¢¢), 4.71–
4.82 (m, 1 H, H-4¢), 5.21 (s, 2 H, CH2Oaryl), 6.11–6.23 (m, 2 H, H-
2¢, H-3¢), 6.62 (d, J = 2.5 Hz, 1 H, H-1¢), 7.31–7.98 (m, 18 Haryl),
12.19 (br s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 63.4, 65.5, 70.3, 73.8, 78.3, 86.7,
116.2, 123.3, 126.2, 128.6, 128.8, 128.9, 129.1, 129.5, 129.7, 129.9,
133.7, 134.0, 134.2, 149.5, 152.6, 159.1, 164.9, 165.1, 165.8.
MS (ESI–): m/z = 678.0 [M – 1].
Anal. Calcd for C29H23BrCl2N2O8 (678.31): C, 51.35; H, 3.42; N,
4.13. Found: C, 51.44; H, 3.35; N, 4.20.
6-(2,4-Dichlorophenoxymethyl)-1-[2-hydroxy-1-(hydroxy-
methyl)ethoxymethyl]-5-iodouracil (17a)
Yield: 2.20 g (42%); mp 155–157 °C.
1H NMR (DMSO-d6/TMS): d = 3.31–3.50 (m, 5 H, 2 CH2 and CH),
4.49 (m, 2 H, OH), 5.35 (s, 2 H, CH2Oaryl), 5.40 (s, 2 H, OCH2N),
7.20–7.61 (m, 3 Haryl), 11.88 (br s, 1 H, NH).
MS (ESI–): m/z = 764.0 [M – 1].
Anal. Calcd for C37H27Cl3N2O10 (765.98): C, 58.02; H, 3.55; N,
3.66. Found: C, 58.10; H, 3.62; N, 3.72.
1-(2,3,5-Tri-O-benzoyl-b-D-ribofuranosyl)-5-bromo-6-(2,4-
dichlorophenoxymethyl)uracil (18c)
Yield: 1.70 g (20%); mp 123–125 °C.
13C NMR (DMSO-d6/TMS): d = 61.1, 71.6, 73.3, 81.1, 82.6, 117.3,
123.6, 126.7, 128.7, 129.9, 150.0, 151.4, 152.4, 160.9.
1H NMR (DMSO-d6/TMS): d = 4.41–4.59 (m, 2 H, H-5¢,5¢¢), 4.60–
4.71 (m, 1 H, H-4¢), 5.01 (s, 2 H, CH2Oaryl), 6.01–6.19 (m, 2 H, H-
2¢, H-3¢), 6.60 (d, J = 2.6 Hz, 1 H, H-1¢), 7.20–7.99 (m, 18 Haryl),
12.10 (br s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 60.1, 63.3, 67.7, 70.2, 73.9, 78.3,
86.9, 116.2, 123.3, 126.2, 128.6, 128.7, 128.9, 129.1, 129.5, 129.7,
129.8, 129.9, 133.7, 134.0, 134.2, 152.6, 159.2, 164.8, 165.2, 165.9.
MS (ESI–): m/z = 517.1 [M – 1].
Anal. Calcd for C15H15Cl2IN2O6 (517.10): C, 34.84; H, 2.92; N,
5.42. Found: C, 34.89; H, 2.88; N, 5.49.
5-Chloro-6-(2,4-dichlorophenoxymethyl)-1-[2-hydroxy-1-(hy-
droxymethyl)ethoxymethyl]uracil (17b)
Yield: 2.30 g (54%); mp 138–140 °C.
MS (ESI–): m/z = 810.0 [M – 1].
1H NMR (DMSO-d6/TMS): d = 3.41–3.70 (m, 5 H, 2 CH2 and CH),
4.82 (m, 2 H, OH), 5.51 (s, 2 H, CH2Oaryl), 5.69 (s, 2 H, OCH2N),
7.45–7.89 (m, 3 Haryl), 12.10 (br s, 1 H, NH).
Anal. Calcd for C37H27BrCl2N2O10 (810.43): C, 54.83; H, 3.36; N,
3.46. Found: C, 54.75; H, 3.28; N, 3.53.
6-(2,4-Dichlorophenoxymethyl)-1-(b-D-ribofuranosyl)-5-iodo-
uracil (19a)
Yield: 1.50 g (28%); mp 108–110 °C.
1H NMR (DMSO-d6/TMS): d = 3.57–3.73 (m, 2 H, H-5¢,5¢¢), 4.08–
4.15 (m, 1 H, H-4¢), 4.45–4.48 (m, 1 H, H-3¢), 4.49–4.53 (m, 1 H,
H-2¢), 4.59 (t, J = 5.6 Hz, 1 H, OH), 4.90 (s, 2 H, CH2Oaryl), 5.10
and 5.0 (2 d, J = 5.8 Hz, 2 H, 2 × OH), 5.12 (s, 1 H, CH uracil), 6.10
(d, J = 2.7 Hz, 1 H, H-1¢), 7.20–7.68 (m, 3 Haryl), 11.87 (br s, 1 H,
NH).
13C NMR (DMSO-d6/TMS): d = 61.1, 64.8, 73.2, 81.2, 111.7,
117.4, 123.6, 126.8, 128.7, 129.9, 145.7, 150.7, 152.2, 159.0.
MS (ESI–): m/z = 427.1 [M – 1].
Anal. Calcd for C15H15Cl3N2O6 (425.65): C, 42.33; H, 3.55; N, 6.58.
Found: C, 42.39; H, 3.49; N, 6.64.
5-Bromo-6-(2,4-dichlorophenoxymethyl)-1-[2-hydroxy-1-(hy-
droxymethyl)ethoxymethyl]uracil (17c)
Yield: 2.50 g (53%); mp 158–160 °C.
Synthesis 2009, No. 5, 841–847 © Thieme Stuttgart · New York

846
M. F. Elshehry et al.
PAPER
13C NMR (DMSO-d6/TMS): d = 62.6, 70.5, 71.7, 84.9, 89.9, 105.9,
116.0, 123.2, 126.0, 128.5, 129.1, 131.5, 133.6, 150.4, 152.6.
Anal. Calcd for C19H15Cl3N2O4 (441.69): C, 51.67; H, 3.42; N, 6.34.
Found: C, 51.70; H, 3.48; N, 6.41.
MS (ESI–): m/z = 544.9 [M – 1].
1-(Benzyloxymethyl)-5-bromo-6-(2,4-dichlorophenoxymeth-
yl)uracil (20c)
Yield: 2.90 g (60%); mp 165–168 °C.
Anal. Calcd for C16H15Cl2IN2O7 (545.11): C, 35.25; H, 2.77; N,
5.14. Found: C, 35.31; H, 2.69; N, 5.22.
1H NMR (DMSO-d6/TMS): d = 4.41 (s, 2 H, CH2Ph), 5.20 (s, 2 H,
CH2Oaryl), 5.38 (s, 2 H, OCH2N), 7.21–7.65 (m, 8 Haryl), 11.95 (br
s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 67.3, 70.9, 73.6, 116.4, 117.2,
123.6, 126.7, 127.8, 128.0, 128.5, 128.7, 129.9, 137.7, 146.9, 150.6,
152.3, 159.8.
5-Chloro-6-(2,4-dichlorophenoxymethyl)-1-(b-D-ribofurano-
syl)uracil (19b)
Yield: 2.50 g (55%); mp 183–185 °C.
1H NMR (DMSO-d6/TMS): d = 3.46–3.66 (m, 2 H, H-5¢,5¢¢), 3.69–
3.72 (m, 1 H, H-4¢), 4.07–4.15 (m, 1 H, H-3¢), 4.49–4.53 (m, 1 H,
H-2¢), 4.62 (t, J = 5.6 Hz, 1 H, OH), 4.92 (s, 2 H, CH2Oaryl), 5.13
and 5.00 (2 d, J = 5.8 Hz, 2 H, 2 × OH), 6.11 (d, J = 2.7 Hz, 1 H, H-
1¢), 7.21–7.62 (m, 3 Haryl), 11.95 (br s, 1 H, NH).
MS (ESI–): m/z = 486.9 [M – 1].
Anal. Calcd for C19H15BrCl2N2O4 (486.14): C, 46.94; H, 3.11; N,
5.76. Found: C, 46.99; H, 3.06; N, 5.83.
13C NMR (DMSO-d6/TMS): d = 62.5, 65.5, 70.4, 71.0, 84.9, 89.1,
106.9, 116.1, 123.2, 126.2, 128.6, 129.9, 145.4, 149.7, 152.5.
MS(ESI–): m/z = 453.2 [M – 1].
Acknowledgment
Anal. Calcd for C16H15Cl3N2O7 (453.66): C, 42.36; H, 3.33; N, 6.18.
Found: C, 42.44; H, 3.40; N, 6.27.
We are grateful for financial support from the University of Ham-
burg. M.E. is grateful for a fellowship of the Egyptian government.
5-Bromo-6-(2,4-dichlorophenoxymethyl)-1-(b-D-ribofurano-
syl)uracil (19c)
Yield: 1.30 g (26%); mp 96–98 °C.
References
1H NMR (DMSO-d6/TMS): d = 3.40–3.63 (m, 2 H, H-5¢,5¢¢), 3.69–
3.73 (m, 1 H, H-4¢), 4.07–4.14 (m, 1 H, H-3¢), 4.48–4.53 (m, 1 H,
H-2¢), 4.61 (t, J = 5.6 Hz, 1 H, OH), 4.91 (s, 2 H, CH2Oaryl), 5.11
and 5.00 (2 d, J = 5.8 Hz, 2 H, 2 × OH), 6.07 (d, J = 2.5 Hz, 1 H, H-
1¢), 7.00–7.62 (m, 3 Haryl), 11.88 (br s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 62.5, 65.2, 70.4, 71.1, 84.9, 89.3,
97.3, 116.1, 123.3, 126.2, 128.6, 129.1, 129.9, 147.1, 152.6.
(1) Richman, D. D.; Fischl, M. A.; Grieco, M. H.; Gottieb, M.
S.; Volberding, P. A.; Lasin, O. L.; Leedon, J. M.;
Groopman, J. E.; Mildran, D.; Hirsch, M. S.; Jackson, G. G.;
Durack, D. T.; Lehrman, N. S.and the AZT Collaborative
Working GroupN. Engl. J. Med. 1987, 317, 192.
(2) Yarchoan, R.; Mitsuya, H.; Thamas, R. V.; Pluda, J.;
Hartman, N. R.; Perno, C. F.; Marczyck, K. S.; Allain, J. P.;
Johns, D. G.; Broder, S. Science 1989, 245, 412.
(3) Larder, B. A.; Darby, G.; Richman, D. V. Science 1989, 243,
1731.
(4) (a) Roy-Burman, P. Analogues of Nucleic Acid Components;
Springer-Verlag: New York, 1970. (b) Goodman, L. In
Basic Principles in Nucleic Acid Chemistry, Vol. 1; Ts’V, P.
O. P., Ed.; Academic Press: New York, 1974, 146.
(c) Uesugi, S.; Ikehara, M. Chem. Pharm. Bull. 1978, 26,
3040.
(5) (a) Baba, M.; De Clercq, E.; Tanaka, H.; Ubasawa, M.;
Takashima, H.; Sekiya, K.; Nitta, I.; Umezu, K.; Walker, R.
T.; Mori, S.; Ito, M.; Shigeta, S.; Miyasaka, T. Mol.
Pharmacol. 1993, 39, 805. (b) Pontkis, R.; Benhida, R.;
Aubertin, A. M.; Grierson, D. S.; Monneret, C. J. Med.
Chem. 1997, 40, 1845. (c) Kim, D. K.; Gam, J.; Kim, Y. W.;
Lim, J.; Kim, H. T.; Kim, K. H. J. Med. Chem. 1997, 40,
2363.
MS (ESI–): m/z = 499.1 [M – 1].
Anal. Calcd for C16H15BrCl2N2O7 (498.11): C, 38.58; H, 3.04; N,
5.62. Found: C, 38.65; H, 3.12; N, 5.71.
1-(Benzyloxymethyl)-6-(2,4-dichlorophenoxymethyl)-5-iodo-
uracil (20a)
Yield: 2.80 g (52%) mp 145–147 °C.
1H NMR (DMSO-d6/TMS): d = 4.40 (s, 2 H, CH2Ph), 5.20 (s, 2 H,
CH2Oaryl), 5.22 (s, 2 H, OCH2N), 7.10–7.42 (m, 8 Haryl), 12.10 (br
s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 70.8, 71.4, 73.6, 83.1, 116.2,
123.5, 126.6, 127.7, 128.5, 128.6, 128.7, 129.9, 137.6, 149.6, 151.4,
152.3, 160.8.
MS (ESI–): m/z = 533.0 [M – 1].
(6) (a) Niedballa, U.; Vorbrüggen, H. J. Org. Chem. 1974, 39,
3654. (b) Niedballa, U.; Vorbrüggen, H. J. Org. Chem.
1976, 41, 2084. (c) Vorbrüggen, H.; Krolikiewiecz, K.;
Bennua, B. Chem. Ber. 1981, 114, 1234.
(7) (a) Andersen, G. W.; Halverstadt, I. F.; Miller, W. H.;
Roblin, R. O. Jr. J. Am. Chem. Soc. 1945, 67, 2197. (b) El-
telbani, E. M.; Elshehry, M. F.; Nawwar, G. A. M. Monatsh.
Chem. 2008, 139, 685.
Anal. Calcd for C19H15Cl2IN2O4 (533.14): C, 42.80; H, 2.84; N,
5.25. Found: C, 42.89; H, 2.77; N, 5.31.
1-(Benzyloxymethyl)-5-chloro-6-(2,4-dichlorophenoxymeth-
yl)uracil (20b)
Yield: 2.60 g (59%); mp 198–200 °C.
1H NMR (DMSO-d6/TMS): d = 4.52 (s, 2 H, CH2Ph), 5.21 (s, 2 H,
CH2Oaryl), 5.44 (s, 2 H, OCH2N), 7.12–7.71 (m, 8 Haryl), 12.08 (br
s, 1 H, NH).
13C NMR (DMSO-d6/TMS): d = 64.8, 70.9, 73.5, 112.2, 117.2,
123.6, 126.7, 127.7, 128.0, 128.5, 128.7, 129.9, 137.6, 145.3, 150.6,
152.2, 158.8.
(8) Johnson, T. B.; Ambelang, J. C. J. Am. Chem. Soc. 1938, 60,
2941.
(9) Donleavy, J. J.; Kise, M. A. Org. Synth. Coll. Vol. II; Wiley:
New York, 1943, 422; Org. Synth. 1937, 17, 63.
(10) Asakura, J.-I.; Robins, M. J. J. Org. Chem. 1990, 55, 4928.
(11) Jourdan, F.; Laduree, D.; Robba, M. J. Heterocycl. Chem.
1994, 31, 305.
MS (ESI–): m/z = 442.0 [M – 1].
Synthesis 2009, No. 5, 841–847 © Thieme Stuttgart · New York

PAPER
New 5-Halouridine Derivatives as Potential Antiviral Agents
microtiter plate wells and mixed with 100 mL of the
847
(12) All new compounds were evaluated concerning their ability
to inhibit the replication of HIV in T-lymphocytes cells.
Briefly, a CEM cell suspension was infected with HIV-1 or
HIV-2. The mutant thymidine kinase-deficient CEM cell
cultures were only infected with HIV-2. Then, 100 mL of the
infected cell suspensions was transferred into 96-well
appropriate dilutions of the test compounds. After 4–5 days,
giant cell formation was recorded microscopically in the
HIV-infected cell cultures.
(13) Balzarini, J.; Karlsson, A.; De Clercq, E. Mol. Pharmacol.
1993, 44, 694.
Synthesis 2009, No. 5, 841–847 © Thieme Stuttgart · New York