Water-soluble prodrugs of the human immunodeficiency virus protease inhibitors lopinavir and ritonavir

Article abstract of DOI:10.1021/jm900080g

We studied the synthesis, cleavage rates, and oral administration of prodrugs of the HIV protease inhibitors (PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs did not demonstrate enzyme-mediated

Full text of DOI:10.1021/jm900080g

2964
J. Med. Chem. 2009, 52, 2964–2970
Water-Soluble Prodrugs of the Human Immunodeficiency Virus Protease Inhibitors Lopinavir
and Ritonavir
David A. DeGoey,* David J. Grampovnik, William J. Flosi, Kennan C. Marsh, Xiu C. Wang, Larry L. Klein,
Keith F. McDaniel, Yaya Liu, Michelle A. Long, Warren M. Kati, Akhteruzzaman Molla, and Dale J. Kempf
AntiViral Research, Global Pharmaceutical Research and DeVelopment, Abbott Laboratories, 100 Abbott Park Road,
Abbott Park, Illinois 60064
ReceiVed January 20, 2009
We studied the synthesis, cleavage rates, and oral administration of prodrugs of the HIV protease inhibitors
(PIs) lopinavir and ritonavir. Phosphate esters attached directly to the central hydroxyl groups of these PIs
did not demonstrate enzyme-mediated cleavage in vitro and did not provide measurable plasma levels of
the parent drugs in vivo. However, oxymethylphosphate (OMP) and oxyethylphosphate (OEP) prodrugs
provided improved rates of cleavage, high levels of aqueous solubility, and high plasma levels of the parent
drugs when dosed orally in rats and dogs. Dosing unformulated capsules containing the solid prodrugs led
to plasma levels equivalent to those observed for dosing formulated solutions of the parent drugs. A direct
synthetic process for the preparation of OMP and OEP prodrugs was developed, and the improved synthetic
method may be applicable to the preparation of analogous soluble prodrugs of other drug classes with limited
solubility.
Introduction
HIV protease inhibitors (PIsa) are relatively lipophilic mol-
ecules and are poorly soluble in water. When dosed orally,
insoluble drugs are not efficiently absorbed from the solid state
and require specialized formulations to enhance their solubility
in the gastrointestinal tract. Consequently, HIV PIs have been
associated with high pill counts and large capsule sizes. Prodrugs
that enhance aqueous solubility could reduce the pill burden
for these important therapies, impacting patient compliance and
quality of life. Prodrugs have been widely used by medicinal
chemists to mask the properties of drug molecules to allow for
absorption and distribution to the targeted sites of action.1
Several prodrug approaches for HIV PIs have been reported.
Phosphate esters, which undergo cleavage by phosphatase in
vivo to provide the parent drug, have been employed to provide
improved aqueous solubility, since they are highly ionized at
physiological pH.2 In fact, fosamprenavir (Figure 1), a phosphate
ester prodrug with a lower pill burden, is the currently marketed
form of amprenavir (APV).3 Other approaches for water-soluble
prodrugs of HIV PIs have employed self-cleavable spacers and
oxygen to nitrogen acyl migration.4,5 In this report, we present
the synthesis, cleavage rates, and oral pharmacokinetics (PK)
of prodrugs of the HIV PIs, lopinavir (LPV) and ritonavir
(RTV), shown in Figure 1.6 LPV is coformulated with RTV to
enhance its pharmacokinetic profile and is widely used in highly
active antiretroviral therapy (HAART) in combination with two
nucleoside reverse transcriptase inhibitors. LPV and RTV also
have poor aqueous solubilities, and the original formulation for
LPV/RTV required three soft-gelatin capsules (SGC) taken twice
daily. We explored water-soluble prodrugs of LPV and RTV
Figure 1. Structures of fosamprenavir, lopinavir, and ritonavir.
with the goal of achieving equivalent pharmacokinetics with a
lower pill burden.
Results and Discussion
Initially, we investigated phosphate esters attached to the
central hydroxyl groups of LPV and RTV. The prodrugs were
prepared under the standard conditions using the phosphora-
midite method (Scheme 1). Deprotection of the phosphate
triesters was accomplished by hydrogenolysis with Pd on carbon
for LPV and by treatment with trimethylsilyl bromide for RTV.
A pharmacokinetic study of phosphate 1 was conducted in rats
at 5 mg/kg. Dosed intravenously, 1 had a short half-life (0.23
h) and a high clearance rate (2.58 L/(h ·kg)). Dosed orally,
plasma concentrations of 1 or RTV were not detected in any of
the plasma samples (out to 3 h after dosing). The pharmaco-
kinetic results for 1 are in contrast to those observed with
* To whom correspondence should be addressed. Phone: (847) 937-7205.
Fax: (847) 938-2756. E-mail: David.DeGoey@abbott.com.
a Abbreviations: PI, protease inhibitor; OMP, oxymethylphosphate; OEP,
oxyethylphosphate; APV, amprenavir; PK, pharmacokinetic; LPV, lopinavir;
RTV, ritonavir; HAART, highly active antiretroviral therapy; CIAP, calf
intestinal alkaline phosphatase; MTM, methylthiomethyl; OBP, oxybu-
tylphosphate; OIBP, oxyisobutylphosphate; EC, enteric coating.
10.1021/jm900080g CCC: $40.75
2009 American Chemical Society
Published on Web 04/06/2009

Prodrugs of LopinaVir and RitonaVir
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2965
Scheme 1. Synthesis of LPV and RTV Phosphatesa
a Reagents and conditions: (a) (BzlO)2PN(Et)2, 1H-tetrazole; (b) mCPBA; (c) Pd(OH)2 on C, H2 for LPV or trimethylsilyl bromide for RTV; (d) Na2CO3.
Scheme 2. Attempted Synthesis of Homologated Phosphatesa
Table 1. In Vitro Cleavage of Phosphates
compd
prodrug
CIAP t1/2 (min)a
1
2
3
4
5
6
7
8
RTV-phosphate
LPV-phosphate
RTV-OMP
RTV-OEP
RTV-OBP
RTV-OIBP
LPV-OMP
no dephosb
no dephosb
7.0
14.8
31.7
>30
13.9
20.4
LPV-OEP
a Reagents and conditions: (a) Me2S, (PhCO)2O2; (b) (RO)2P(O)OH,
N-iodosuccinimide.
a Calf intestinal alkaline phosphatase. b No dephosporylation was
observed.
fosamprenavir, which provided systemic levels of APV when
dosed orally in rats.3 In order to understand the in vivo results,
the rates of dephosphorylation of the prodrugs were evaluated
in vitro using calf intestinal alkaline phosphatase (CIAP). As
shown in Table 1, no dephosphorylation could be detected for
phosphate prodrug 1 or 2, while fosamprenavir demonstrated a
half-life of 13.2 min in this assay. As a possible explanation
for this observation, the peptidomimetic cores of APV and RTV
differ significantly in structure. The core of APV and thus
fosamprenavir (Figure 1) is an (R)-hydroxyethylsulfonamide
dipeptide isostere,3 whereas the core of LPV and RTV is a
pseudo-C2-symmetric dipeptide isostere with an S stereochem-
ical configuration at the central hydroxyl group.6 Thus, the
structural features in the vicinity of the phosphate ester differ
both in stereochemistry and in P2′ amide structure (carboxamide
for LPV and RTV vs sulfonamide for fosamprenavir), and the
accessibility of the phosphate ester by the phosphatase enzyme
might differ significantly.
One potential solution to this problem was to move the
phosphate ester cleavage site away from the peptidomimetic
core through a formaldehyde acetal linkage, which would release
parent drug and formaldehyde upon phosphate ester cleavage.7
Attempts to synthesize such oxymethylphosphate (OMP) pro-
drugs from the methylthiomethyl (MTM) ethers of pseudo-C2-
symmetric HIV PI cores (Scheme 2) using the chemistry
employed for the synthesis of paclitaxel prodrugs (reaction with
protected phosphate diesters in the presence of N-iodosuccin-
imide)8 failed to give the desired phosphate triester products.
This was most likely due to high instability of the oxymethyl-
linked phosphate triesters attached to these cores, although the
triesters could not be isolated to test this hypothesis. We
discovered, in an attempt to avoid the phosphate triesters, that
treatment of the MTM ethers with crystalline phosphoric acid
(orthophosphoric acid)9 in the presence of N-iodosuccinimide,
followed by treatment with sodium carbonate, gave the OMP
prodrugs 3 (RTV-OMP) and 7 (LPV-OMP) directly (Scheme
3). The reaction was conducted in the presence of 4 Å molecular
sieves to scavenge water, and workup involved filtration to
remove the sieves, treatment with sodium thiosulfate to remove
any iodine or N-iodosuccinimide, and finally treatment with
Na2CO3 to give the sodium salts. Final products were purified
by elution on reversed-phase HPLC. We discovered that this
methodology was also applicable to the synthesis of homolo-
gated prodrugs with alkyl branching on the methylene group.
For example, oxyethylphosphate (OEP) prodrugs 4 (RTV-OEP)
and 8 (LPV-OEP) were synthesized starting from ethyl sulfide
in place of methyl sulfide.10 The thioether intermediates also
underwent clean conversion to the OEP prodrugs using crystal-
line phosphoric acid in the presence of N-iodosuccinimide. The
prodrugs were obtained as a mixture of diastereomers at the
branching carbon. By use of the same methods, oxybutylphos-
phate 5 (RTV-OBP) and oxyisobutylphosphate 6 (RTV-OIBP)
prodrugs were prepared. Upon cleavage by phosphatase, the
OEP, OBP, and OIBP phosphates release acetaldehyde, bu-
tyraldehyde, and isobutyraldehyde, respectively, instead of
formaldehyde that is released by the OMP prodrugs. Although
the amount of formaldehyde generated from OMP prodrugs
would be small, formaldehyde is a probable human carcinogen.11
In contrast to prodrugs 1 and 2, which showed no dephos-
phorylation in the CIAP assay, the half-lives of OMP prodrugs
3 and 7 were 7 and 14 min, respectively, values similar to those
observed for fosamprenavir in this assay (Table 1). The OEP
prodrugs 4 and 8 had 2-fold longer half-lives compared to the
OMP prodrugs. Slower rates of cleavage were also observed
for 5 and 6.
The OMP and OEP prodrugs were completely soluble in
water at 5 mg/mL, whereas the parent drugs had low aqueous
solubilities (Table 2). We examined the pH-dependent chemical

2966 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
DeGoey et al.
Scheme 3. Synthesis of Homologated Phosphates Using Phosphoric Acida
a Reagents and conditions: (a) RCH2SCH2R, (PhCO)2O2; (b) H3PO4, N-iodosuccinimide; (c) Na2CO3.
Table 2. Aqueous Solubility Dataa
Table 4. Oral PK in Rats at 5 mg/kg
compd
solubility (µg/mL)
parent plasma level
a
entry
compd
Cmax
AUC b
LPV
7
RTV
3
1
2
3
4
5
6
7
RTV
1.36
1.55
0.13
0.26
0.13
2.27
2.19
3.53
9.28
0.46
0.63
0.45
19.65
9.53
3, RTV-OMP
4, RTV-OEP
7, LPV-OMP
8, LPV-OEP
>5000
>5000
>5000
>5000
LPVc
3, RTV-OMP
4, RTV-OEP
5, RTV-OBP
7, LPV-OMPc
8, LPV-OEPc
a Unbuffered at 25 °C by the shake flask method.
Table 3. pH-Dependent Chemical Stability of Prodrugs at 25 °C
a µg/mL. b µg·h/mL. c Codosed with 5 mg/kg RTV.
t1/2
the parent (entries 3, 4, and 5 vs entry 1). In contrast, dosing
LPV-OMP 7 with RTV in rats led to plasma levels of LPV
that were 2-fold higher than dosing of the parent LPV/RTV
(cf. entries 2 and 6). Similarly, LPV-OEP 8 gave comparable
LPV levels to those observed for dosing the parent (cf. entries
2 and 7). Observed plasma concentrations of the prodrugs were
low (Cmax ) 0.02 µg/mL for 3, Cmax ) 0.14 µg/mL for 7),
suggesting efficient release of parent in the intestine prior to
absorption.
The pharmacokinetic properties of the prodrugs were studied
more extensively in dogs (Table 5), the preferred species for
evaluation of RTV formulations for human study.13 Unlike the
lower bioavailability of RTV-OMP 3 in rats, oral dosing of 3
provided nearly identical RTV plasma levels to dosing parent
in dogs (cf. entries 1 and 2). Codosing LPV-OMP 7 with parent
RTV provided LPV plasma exposure levels nearly identical to
those obtained after dosing parent LPV (cf. entries 3 and 4).
Importantly, administration of a mixture of the solid RTV-OMP
3 and LPV-OMP 7 in unformulated capsules resulted in plasma
levels of both LPV and RTV comparable to codosing of the
parents (cf. entries 3 and 5). This finding indicates that, as
expected, dissolution of the soluble prodrugs in vivo is efficient.
This result also demonstrates that prodrugs of each parent
compound can be used together in combination and undergo
efficient dephosphorylation.
compd
pH 2
8.6 h
7.8 h
<15 min
<15 min
pH 5
pH 7.4
pH 9
3, RTV-OMP
7, LPV-OMP
4, RTV-OEP
8, LPV-OEP
NAa
NAa
NAa
NAa
NAa
NAa
76 min
133 min
12 days
19 days
>100 days
>100 days
a NA ) not available.
stability of the prodrugs, as shown in Table 3. The OMP
prodrugs 3 and 7 demonstrated half-lives of 8 h at pH 2, a value
similar to the gastric pH in humans. The OEP prodrugs 4 and
8, however, showed pH-dependent stability and rapidly degraded
with conversion to parent at low pH and were markedly more
stable at higher pH values. The short half-lives at pH 2 for the
OEP prodrugs could result in acid mediated removal of the
prodrug moiety in the stomach, resulting in precipitation of
parent drug. As a result, protection from stomach acid through
enteric coating (EC) might be necessary for the OEP prodrugs
in order to realize the benefit of their high aqueous solubilities.
The pharmacokinetic properties of the prodrugs were initially
characterized in rats (Table 4). Since LPV has low bioavail-
ability in rats when dosed alone due to rapid metabolism by
cytochrome P450 3A isoenzymes (CYP3A), LPV prodrugs were
codosed with RTV, which potently inhibits CYP3A and
enhances LPV plasma concentrations.12 While dosing of the
parent compounds required the use of formulations containing
ethanol and propylene glycol, the high solubility of the prodrugs
allowed for dosing as solutions in 5% dextrose in water. RTV
prodrugs 3, 4, and 5 produced RTV plasma exposures that were
82-87% lower than the AUC obtained after administration of
The gastric pH of fasted dogs is variable and can reach high
values.3,13 Therefore, in order to simulate the lower gastric pH
environment found in humans, dogs were pretreated with
histamine to stimulate the release of gastric acid.13 Histamine

Prodrugs of LopinaVir and RitonaVir
Table 5. Oral PK in Dogs at 5 mg/kga
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2967
LPV level
RTV level
b
b
entry
LPV form
RTV form
parent
3, RTV-OMP
parent
dosage form
Cmax
AUCc
Cmax
AUCc
1
2
3
4
solutiond
solutiond
solutiond
solutiond
capsulee
3.58
3.73
1.32
2.13
2.74
1.34
0.64
0.76
0.35
0.30
0.61
1.64
8.06
8.14
2.19
4.43
5.74
2.71
1.26
2.14
0.77
0.58
1.27
3.84
parent
2.50
2.36
2.62
3.90
1.76
2.98
2.35
1.47
1.60
3.14
11.26
12.71
16.35
14.42
6.09
13.08
9.31
5.63
7, LPV-OMP
7, LPV-OMP
7, LPV-OMP
7, LPV-OMP
7, LPV-OMP
7, LPV-OMP
7, LPV-OMP
8, LPV-OEP
8, LPV-OEP
parent
5
3, RTV-OMP
3, RTV-OMP
4, RTV-OEP
4, RTV-OEP
5, RTV-OBP
6, RTV-OIBP
4, RTV-OEP
4, RTV-OEP
6f
7f
8f
9f
10f
11f
12f
capsulee
capsulee
EC capsuleg
capsulee
capsulee
capsulee
5.82
13.61
EC capsuleg
a Prodrugs were dosed at the molar equivalent of 5 mg/kg of the parent. b µg/mL. c µg·h/mL. d RTV and LPV were dissolved in 5% dextrose containing
20% ethanol, 30% propylene glycol, with 2 equiv of methanesulfonic acid; 3 and 7 were dissolved in 5% dextrose. e Unformulated. f Dogs were pretreated
with histamine prior to dosing. g EC ) enteric coating that dissolves at pH 5.5.
pretreatment had no effect on the LPV plasma levels observed
for codosed OMP prodrugs 3 and 7 (cf. entries 5 and 6),
consistent with their stability at low pH. However, codosing of
LPV-OMP 7 with RTV-OEP 4 after histamine pretreatment
resulted in low plasma exposure levels of both LPV and RTV
(entry 7). As described earlier, the OEP prodrugs decompose
to parent under low pH conditions and this degradation could
result in precipitation of the drugs, resulting in lower absorption.
In order to test this hypothesis, LPV-OMP 7 and RTV-OEP 4
were codosed in enteric coated capsules (coating dissolves at
pH 5.5), and improved parent exposure levels resulted (cf.
entries 7 and 8). Coadministration of LPV-OMP 7 with RTV-
OBP 5 or RTV-OIBP 6 in histamine pretreated dogs provided
similarly low plasma levels to those observed for coadminis-
tration with RTV-OEP 4 (entries 9 and 10). It is likely that 5
and 6 share similar pH dependent stability profiles with 4,
leading to precipitation of parent in the gut. Codosing of two
OEP produgs 8 and 4 together also resulted in low plasma levels
of both parent drugs (entry 11). Once again, enteric coating
improved the observed levels of the parent drugs and the levels
were comparable to those observed for dosing the parents (cf.
entries 3 and 12).
preparation of analogous soluble prodrugs of other drug classes
with limited solubility.
Experimental Section
Methods. Calf Intestinal Alkaline Phosphatase Assay. The
prodrugs (30 mM) in sodium phosphate (50 mM, pH 7.4) were
incubated with CIAP (0.000 125 units/µL) in Tris buffer at pH 8.0
(400 µL, 10 mM) at 37 °C for 30 min. The samples were quenched
with 20 µL of 5 M NaCl and 160 µL of 50% MeOH and 50%
acetonitrile, allowed to stand on ice for 30 min, and then centrifuged
at 10000 rpm for 10 min @ 4 °C. The supernatant was analyzed
by HPLC or LC/MS/MS.
Pharmacokinetic Analysis. All prodrugs were formulated as 5
mg/mL solutions in 5% dextrose in water, and ritonavir for codosing
was formulated as a 5 mg/mL solution in 5% dextrose containing
20% ethanol, 30% propylene glycol, and 2 equiv of methanesulfonic
acid. Sprague-Dawley-derived rats (male, 0.25-0.35 kg, n ) 3)
and beagle dogs (male and female, 8-12 kg, n ) 3) received
prodrug doses equivalent to 5 mg/kg of body weight doses of the
parent (5 mg equiv/kg) by oral gavage, with or without a prior 5
mg/kg dose of ritonavir by oral gavage. Alternatively, solid prodrugs
or mixtures of solid prodrugs were added to capsules and dosed
orally. Approximately 30 min prior to drug administration, some
dogs received a 100 µg/kg subcutaneous dose of histamine. Plasma
samples were analyzed by reversed-phase HPLC with an internal
standard.
Solubility. Approximately 5 mg of each compound was weighed
into 2 mL glass vials (in triplicate). One milliliter of distilled,
deionized water purified by a Milli Q filtration system was added,
and the samples were vortex mixed and sonicated. Vials were
wrapped in aluminum foil to protect them from light and equili-
brated by tumbling in a water bath maintained at 25 °C for 1 day.
Samples were centrifuged, filtered, and prepared for HPLC assay
by dilution to ensure concentrations within the standard curve.
Samples were assayed by HPLC, and the compounds were detected
using a UV detector set at 215 nm.
Prodrug Stability. Rapidly degrading samples were equilibrated
at 25 °C and directly assayed by HPLC. The peak area vs time
data were fit to a first order kinetic expression. More stable samples
were subjected to equilibration at elevated temperatures (40-90
°C) for up to 7 days, and a first order kinetic model was used to
predict stability at 25 °C.
Conclusions
Phosphate esters attached directly to the central hydroxyl
groups of LPV and RTV were not cleaved by phosphatase in
vitro and were ineffective for delivery of parent drugs in vivo,
in contrast to the HIV PI phosphate prodrug amprenavir.
However, the OMP and OEP prodrugs of LPV and RTV
provided dramatically improved aqueous solubilities compared
to the parent molecules, demonstrated rapid enzyme-mediated
cleavage in vitro, and produced high plasma levels of the parent
drugs in vivo (rats and dogs). We demonstrated that dosing
unformulated capsules in dogs containing the solid OMP and
OEP prodrugs led to plasma levels equivalent to those observed
for dosing formulated solutions of the parent drugs. Because
of their high aqueous solubilities, it is hoped that using OMP
and OEP prodrugs of LPV and RTV will lead to a lower pill
burden by reducing the need for solubility enhancing excipients.
We developed a direct method for the synthesis of these
prodrugs, avoiding unstable phosphate triester intermediates by
using phosphoric acid in place of the protected phosphate
diesters. This improved synthetic method was useful for the
preparation of methylene-linked as well as branched alkyl-linked
phosphate ester prodrugs and may be applicable for the
Chemistry. Unless otherwise noted, all materials were obtained
from commercial suppliers and used without further purification.
Anhydrous solvents were obtained from Aldrich (Milwaukee, WI)
and used directly. All reactions involving air- or moisture-sensitive
reagents were performed under a nitrogen or argon atmosphere.
All final compounds were purified to >95% purity as determined
by high-performance liquid chromatography (HPLC). Analytical
HPLC analysis was performed on a Waters Alliance HPLC system
and Waters Empower 2 software using a linear gradient (16 min)

2968 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
DeGoey et al.
starting with 5% acetonitrile in 1 mM NH4OAc (pH 8) and ending
with acetonitrile on a Waters XTerra RP18 column (5 µm, 4.6 mm
× 150 mm, flow rate ) 1 mL/min) with UV detection at 220 and
254 nm (RTV tR ) 10.90 min and LPV tR ) 11.0 min). Silica gel
chromatography was performed using either glass columns packed
with silica gel 60 (230-400 mesh) or prepacked silica gel cartridges
(Biotage, 36-63 µm). Preparative reversed-phase HPLC was
conducted on a Waters 600 system using Waters Nova-Pak C18 (6
µm, 60 Å) or Biotage KP-C18-HS cartridges. NMR spectra were
determined with Bruker ARX 300 MHz or Varian Unity INOVA
500 MHz spectrometers. Chemical shifts are reported in parts per
million (ppm) relative to tetramethylsilane internal standard.
Integrations of diastereomeric mixtures are approximate. Low-
resolution mass spectral (MS) ESI data were determined on a
Thermo-Finnigan SSQ7000 instrument. Combustion analysis was
performed by Quantitative Technologies Inc. (Whitehouse, NJ), and
data were within 0.4% of calculated values.
and then with 5% methanol in ethyl acetate to give the phosphate
triester (0.324 g, 90% yield). H NMR (300 MHz, DMSO-d6) δ
1
ppm 0.73 (d, J ) 6.62 Hz, 3H), 0.77 (d, J ) 6.25 Hz, 3H),
1.21-1.40 (m, 1H), 1.48-1.62 (m, 1H), 1.68-1.81 (m, 1H),
1.81-1.93 (m, 1H), 1.95-2.08 (m, 1H), 2.13 (s, 6H), 2.53-2.77
(m, 4H), 2.81-2.93 (m, 2H), 2.94-3.06 (m, 2H), 4.04-4.18 (m,
2H), 4.35 (d, J ) 11.03 Hz, 2H), 4.46-4.59 (m, 1H), 4.78 (t, J )
9.93 Hz, 1H), 5.11 (dd, J ) 7.91, 5.70 Hz, 4H), 6.30 (s, 1H),
6.86-6.96 (m, 1H), 6.97-7.05 (m, 2H), 7.08-7.26 (m, 12H),
7.30-7.45 (m, 10H), 7.60 (d, J ) 5.52 Hz, 1H), 7.63 (d, J ) 5.15
Hz, 1H). MS (ESI) m/z 889.0 (M + H)+. To a solution of the
product from the first step (0.320 g, 0.36 mmol) in a mixture of
ethyl acetate (1.8 mL) and methanol (1.8 mL) was added Pd(OH)2
on carbon (0.100 g, 20% by wt Pd), and the mixture was stirred
under an atmosphere of hydrogen (balloon pressure) for 16 h. The
mixture was filtered through Celite, and the solvent was evaporated.
Methanol and water were added, and the pH was adjusted to 9 by
addition of 10% Na2CO3 solution. The sample was purified by
chromatography (C18), eluting with a gradient of 0-100% methanol
Disodium N1-((1S,3S,4S)-1-Benzyl-5-phenyl-3-(phosphonatooxy)-
4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-N2-{[[(2-iso-
propyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-L-valina-
mide (1). A solution of RTV (6.0 g, 8.32 mmol), dibenzyl N,N-
diethylphosphoramidite (3.96 g, 12.5 mmol), and 1H-tetrazole (2.63
g, 37.5 mmol) in THF (100 mL) was stirred at room temperature
for 4 h. The mixture was cooled to -45 °C, followed by dropwise
addition of a solution of m-chloroperoxybenzoic acid (7.2 g, 41.7
mmol) in dichloromethane (100 mL). The mixture was warmed to
room temperature and stirred for 1 h. A 10% solution of Na2S2O3
(100 mL) was added, and the mixture was stirred for 30 min. The
reaction mixture was extracted with ethyl acetate and washed with
10% Na2S2O3 and then saturated NaHCO3. The organic phase was
dried over MgSO4, filtered, and evaporated. The residue was purified
by chromatography on silica gel, eluting with 2% methanol in
dichloromethane containing 0.05% NH4OH, to give the phosphate
1
in water to give 2 (0.215 g, 79% yield). H NMR (300 MHz,
CD3OD), δ ppm 0.86 (d, J ) 6.6 Hz, 3H), 0.99 (d, J ) 6.6 Hz,
3H), 1.55-1.77 (m, 3H), 2.03-2.23 (m, 2H), 2.10 (s, 6H), 2.71
(d, J ) 7.4 Hz, 2H), 2.90-3.00 (m, 2H), 3.06-3.19 (m, 4H), 3.94
(q, J ) 14.3 Hz, 2H), 4.36-4.45 (m, 1H), 4.46 (d, J ) 11.0 Hz,
1H), 4.48-4.57 (m, 1H), 4.67-4.70 (m, 1H), 6.87-6.97 (m, 3H),
7.08-7.24 (m, 8H), 7.30-7.32 (m, 2H). MS (ESI) m/z 709.0 (M
+ H)+, 731.0 (M + Na)+. Anal. (C37H47N4Na2O8P·1.8H2O) C, H,
N. Analytical HPLC tR ) 8.28 min.
General Procedure for Preparation of Compounds 3-8.
Preparation of Disodium N1-((1S,3S,4S)-1-Benzyl-5-phenyl-3-
[(phosphonatooxy)methoxy]-4-{[(1,3-thiazol-5-ylmethoxy)car-
bonyl]amino}pentyl)N2-{[[(2-isopropyl-1,3-thiazol-4-yl)methyl]-
(methyl)amino]carbonyl}-L-valinamide (3). To a solution of RTV
(5.0 g, 6.9 mmol) and methyl sulfide (4.1 mL, 55.8 mmol) in
acetonitrile (35 mL) at 0 °C was added benzoyl peroxide (6.7 g,
27.7 mmol) in four equal portions over 20 min, and the mixture
was stirred at 0 °C for 1 h and then at room temperature for 1 h.
The mixture was diluted with ethyl acetate and washed with 10%
Na2CO3 and then brine. The organic phase was dried over MgSO4,
filtered, and evaporated. The residue was purified by chromatog-
raphy on silica gel, eluting with a gradient of 33-100% ethyl acetate
in chloroform to give the MTM ether (4.56 g, 84% yield). 1H NMR
(300 MHz, DMSO-d6) δ ppm 0.78 (d, J ) 6.62 Hz, 3H), 0.79 (d,
J ) 6.62 Hz, 3H), 1.30 (d, J ) 6.62 Hz, 6H), 1.46-1.66 (m, 2H),
1.82-2.02 (m, 1H), 2.14 (s, 3H), 2.57-2.77 (m, 4H), 2.88 (s, 3H),
3.11-3.29 (m, 1H), 3.62 (t, J ) 5.88 Hz, 1H), 3.93 (t, J ) 7.91
Hz, 1H), 4.00-4.11 (m, 1H), 4.20 (s, 1H), 4.37-4.55 (m, 2H),
4.58-4.76 (m, 2H), 5.04-5.21 (m, 2H), 6.07 (d, J ) 8.46 Hz,
1H), 7.03-7.28 (m, 10H), 7.74 (d, J ) 8.82 Hz, 1H), 7.84 (s, 1H),
9.05 (s, 1H). MS (ESI) m/z 781.3 (M + H)+. To a solution
containing the thioether from the first step (4.56 g, 5.8 mmol),
phosphoric acid (4.0 g, 40.8 mmol), and molecular sieves (4 Å,
18 g) in THF (60 mL) at 0 °C was added N-iodosuccinimide (2.0
g, 8.9 mmol), and the mixture was stirred at room temperature for
1 h. The reaction mixture was filtered through Celite, and the solids
were washed with methanol. The filtrate was treated with 1 M
Na2S2O3 until it was colorless and adjusted to pH 10 by addition
of solid Na2CO3, and the precipitate was removed by filtration. The
filtrate was concentrated under reduced pressure, and the residue
was purified by chromatography (C18), eluting with a gradient of
0-100% methanol in water to give 3 (2.64 g, 52% yield). 1H NMR
(300 MHz, CD3OD), δ ppm 0.81 (d, J ) 7.0 Hz, 3H), 0.86 (d, J
) 7.0 Hz, 3H), 1.35 (d, J ) 7.0 Hz, 6H), 1.64-1.73 (m, 1H),
1.89-2.03 (m, 2H), 2.60-2.90 (m, 4H), 2.98 (s, 3H), 3.24-3.28
(m, 1H), 3.63-3.67 (m, 1H), 4.02-4.09 (m, 2H), 4.20-4.30 (m,
1H), 4.46-4.64 (m, 2H), 4.95 (dd, J ) 5.3, 10.5 Hz, 1H), 5.10 (q,
J ) 12.5 Hz, 2H), 5.10-5.15 (m, 1H), 7.07-7.21 (m, 11H), 7.77
(s, 1H), 8.93 (s, 1H). MS (ESI) m/z 831.3 (M + H)+, 853.2 (M +
Na)+. Anal. (C38H49N6Na2O9PS2 ·3.1H2O) C, H, N. Analytical
HPLC tR ) 8.56 min.
1
triester (6.2 g, 76% yield). H NMR (300 MHz, CD3OD) δ ppm
0.81 (t, J ) 7.12 Hz, 6H), 1.36 (d, J ) 7.12 Hz, 6H), 1.74-2.01
(m, 3H), 2.53-2.82 (m, 4H), 2.95 (s, 3H), 3.90-4.10 (m, 1H),
4.31-4.58 (m, 5H), 5.04-5.12 (m, 4H), 5.16 (s, 2H), 6.07 (d, J )
8.48 Hz, 1H), 7.05-7.20 (m, 12H), 7.31-7.44 (m, 8H), 7.79 (s,
1H), 8.93 (s, 1H). MS (ESI) m/z 981.6 (M + H)+. To a solution of
the product from the first step (6.2 g, 6.32 mmol) in dichloromethane
(200 mL) at 0 °C was added trimethylsilyl bromide (3.87 g, 25.3
mmol) via syringe, and the mixture was stirred at 0 °C for 1 h.
The solvent was evaporated, and the residue was triturated with
water (50 mL), followed by evaporation under reduced pressure.
The residue was purified by chromatography (C18), eluting with
20% acetonitrile in water (0.1% trifluoroacetic acid) and then with
40% acetonitrile in water (0.1% trifluoroacetic acid) to give the
pure acid (1.21 g, 24%). The disodium salt was formed by treating
1.21 g of the purified acid in acetonitrile (75 mL) with a solution
of NaHCO3 (0.254 g) in water (50 mL). After the mixture was
1
stirred for 15 min the solvent was evaporated to give 1. H NMR
(300 MHz, DMSO-d6), δ ppm 0.66 (d, J ) 6.1 Hz, 3H), 0.75 (d,
J ) 6.1 Hz, 3H), 1.26 (d, J ) 6.8 Hz, 6H), 1.45-1.61 (m, 2H),
1.80-1.93 (m, 1H), 2.59-2.65 (m, 1H), 2.86 (s, 3H), 3.14-3.23
(m, 2H), 3.82 (t, J ) 9.0 Hz, 1H), 3.94-4.07 (m, 2H), 4.35-4.52
(m, 2H), 5.07 (d, J ) 12.9 Hz, 2H), 5.23 (d, J ) 12.9 Hz, 1H),
6.99-7.19 (m, 10H), 7.25 (s, 1H), 7.83 (s, 1H), 9.03 (s, 1H). MS
(ESI) m/z 801.4 (M + H)+. Analytical HPLC tR ) 7.89 min.
Disodium (1S,3S)-1-((1S)-1-{[(2,6-Dimethylphenoxy)acetyl]amino}-
2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyrimidin-
1(2H)-yl)butanoyl]amino}-4-phenylbutylphosphate (2). A solution
of LPV (0.250 g, 0.40 mmol), dibenzyl diethylphosphoramidite
(0.28 mL, 0.94 mmol), and 1H-tetrazole (0.14 g, 1.99 mmol) in
THF (4.0 mL) was stirred at room temperature for 68 h. Dichlo-
romethane (4.0 mL) was added, and the mixture was cooled to -45
°C, followed by addition of m-chloroperoxybenzoic acid (0.089 g,
0.52 mmol). After being stirred for 30 min at -45 °C, the mixture
was diluted with ethyl acetate and washed twice with 10% Na2CO3
and then with brine. The organic phase was dried over MgSO4,
filtered, and evaporated. The residue was purified by chromatog-
raphy on silica gel, eluting with 33% ethyl acetate in chloroform

Prodrugs of LopinaVir and RitonaVir
Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9 2969
1
Disodium N1-((1S,3S,4S)-1-Benzyl-5-phenyl-3-[1-(phosphonato-
oxy)ethoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-
N2-{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-
L-valinamide (4). The thioether was prepared by the general
procedure from RTV (0.50 g, 0.69 mmol), ethyl sulfide (1.9 mL,
17.6 mmol), and benzoyl peroxide (0.84 g, 3.47 mmol) as a mixture
general procedure to give 6 (0.49 g, 52% yield). H NMR (300
MHz, CD3OD), δ ppm 0.86-1.03 (m, 12H), 1.33-1.36 (m, 6H),
1.44-1.75 (m, 1H), 1.85-2.27 (m, 3H), 2.54-2.9 (m, 5H), 3.01
(s, 3H), 3.78-4.38 (m, 4H), 4.46-4.68 (m, 2H), 4.91-5.15 (m,
3H), 6.97-7.26 (m, 11H), 7.64-7.73 (m, 1H), 8.91-8.92 (m, 1H).
MS (ESI) m/z 895.0 (M
+
Na)+. Anal. (C41H55N6Na2-
1
of diastereomers (about 1:1) (0.42 g, 75% yield). H NMR (300
O9PS2 ·2.6H2O) C, H, N. Analytical HPLC tR ) 8.91 min.
MHz, DMSO-d6) δ ppm 0.69-0.85 (m, 6H), 1.09-1.23 (m, 3H),
1.30 (d, J ) 6.99 Hz, 6H), 1.46, 1.48 (2s, 3H), 1.50-1.62 (m,
2H), 1.86-2.09 (m, 1H), 2.54-2.84 (m, 6H), 2.87 (s, 3H).
3.12-3.29 (m, 1H), 3.57-3.73 (m, 1H), 3.87-4.12 (m, 2H),
4.13-4.29 (m, 1H), 4.35-4.60 (m, 2H), 4.67-4.85 (m, 1H),
5.03-5.31 (m, 2H), 6.07 (d, J ) 8.46 Hz, 2H), 7.08-7.31 (m,
10H), 7.65 (d, J ) 8.82 Hz, 1H), 7.79 (d, J ) 8.82 Hz, 1H), 7.84,
7.86 (2s, 1H) 9.03, 9.05 (2s, 1 H). MS (ESI) m/z 809.1 (M + H)+.
The thioether (0.15 g, 0.19 mmol) was treated with phosphoric acid
(0.090 g, 0.92 mmol) and N-iodosuccinimide (0.084 g, 0.37 mmol)
in DMF (4.5 mL) using the general procedure to give 4 as a mixture
of diastereomers (0.080 g, 48% yield). 1H NMR (300 MHz,
CD3OD) δ ppm 0.84-0.99 (m, 6 H), 1.33-1.39 (m, 9H), 1.44-1.71
(m, 1H), 1.95-2.11 (m, 1.5H), 2.20-2.35 (m, 0.5H), 2.55-2.97
(m, 4H), 3.01 (s, 3H), 3.22-3.27 (m, 1H), 3.74-3.84 (m, 0.5H),
3.90-4.02 (m, 1.5H), 4.07-4.16 (m, 1.5H), 4.21-4.31 (m, 0.5H),
4.42-4.63 (m, 2H), 4.91-4.96 (m, 1H), 5.07-5.12 (m, 1H),
5.31-5.38 (m, 0.5H), 5.42-5.48 (m, 0.5H), 6.94-7.25 (m, 11H),
7.65-7.73 (m, 1H), 8.90-8.92 (m, 1H). MS (ESI) m/z 867.1 (M
+ Na)+. Anal. (C39H51N6Na2O9PS2 ·4.8H2O) C, H, N. Analytical
HPLC tR ) 8.53 min.
Disodium [((1S,3S)-1-((1S)-1-{[(2,6-Dimethylphenoxy)acetyl]-
amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyri-
midin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]methylphos-
phate (7). To a solution LPV (3.0 g, 4.8 mmol), DMSO (18 mL),
and acetic acid (3.6 mL) at room temperature was added acetic
anhydride (23 mL), and the mixture was stirred for 48 h at room
temperature. The reaction was quenched with ice, and 10% Na2CO3
was added to adjust the pH to 7. The mixture was extracted with
ethyl acetate and washed with 10% Na2CO3 and then brine. The
organic was dried over Na2SO4, filtered, and evaporated to give
the crude product, which was purified by chromatography on silica
gel, eluting with a gradient of 25-100% ethyl acetate in dichlo-
romethane to give the thioether (2.1 g, 64% yield). 1H NMR (300
MHz, CDCl3) δ ppm 0.83 (d, J ) 6.62 Hz, 3H), 0.88 (d, J ) 6.62
Hz, 3H), 1.46-1.59 (m, 1H), 1.68-1.82 (m, 3H), 2.14 (s, 6H),
2.22 (s, 3H), 2.59 (dd, J ) 13.79, 9.38 Hz, 1H), 2.73-2.93 (m,
3H), 2.94-3.23 (m, 4H), 3.78 (t, J ) 6.25 Hz, 1H), 4.00-4.15
(m, 2H), 4.13-4.24 (m, 1H), 4.46-4.58 (m, 2H), 4.60-4.77 (m,
2H), 4.83-5.00 (m, 1H), 6.40 (s, 1H), 6.85-7.04 (m, 3H),
7.10-7.39 (m, 10H). MS (ESI) m/z 689.4 (M + H)+. The thioether
(1.73 g, 2.5 mmol) was treated with phosphoric acid (1.23 g, 12.6
mmol) and N-iodosuccinimide (1.13 g, 5.0 mmol) using the general
Disodium N1-((1S,3S,4S)-1-Benzyl-5-phenyl-3-[1-(phosphonato-
oxy)butoxy]-4-{[(1,3-thiazol-5-ylmethoxy)carbonyl]amino}pentyl)-
N2-{[[(2-isopropyl-1,3-thiazol-4-yl)methyl](methyl)amino]carbonyl}-
L-valinamide (5). The thioether was prepared by the general
procedure from RTV (3.0 g, 4.2 mmol), butyl sulfide (18.0 mL,
103.1 mmol), and benzoyl peroxide (2.0 g, 8.3 mmol) as a mixture
1
procedure to give 7 (1.19 g, 60% yield). H NMR (300 MHz,
CD3OD), δ ppm 0.84 (d, J ) 6.6 Hz, 3H), 0.90 (d, J ) 6.6 Hz,
3H), 1.54-1.77 (m, 3H), 1.98-2.19 (m, 2H), 2.12 (s, 6H),
2.64-2.78 (m, 2H), 2.87-2.95 (m, 2H), 3.04-3.23 (m, 4H), 3.80
(dd, J ) 3.4, 10.3 Hz, 1H), 3.96-4.07 (m, 2H), 4.33 (d, J ) 11.0
Hz, 1H), 4.41-4.50 (m, 1H), 4.71 (dd, J ) 4.0, 10.6 Hz, 1H),
5.09 (dd, J ) 5.5, 8.1 Hz, 1H), 5.15 (dd, J ) 5.5, 8.8 Hz, 1H),
6.87-6.98 (m, 3H), 7.08-7.25 (m, 8H), 7.31-7.33 (m, 2H). MS
1
of diastereomers (about 1:1) (2.43 g, 68% yield). H NMR (300
MHz, DMSO-d6) δ ppm 0.65-0.96 (m, 12H), 1.30, 1.31 (2d, J )
6.99 Hz, 6H), 1.33-2.05 (m, 6H), 2.53-2.83 (m, 6H), 2.87 (s,
3H), 3.15-3.29 (m, 1H), 3.64-3.78 (m, 1H), 3.86-4.28 (m, 3H),
4.37-4.48 (m, 2H), 4.61 (t, J ) 6.43 Hz, 1H), 5.04-5.37 (m, 2H),
6.07 (d, J ) 8.46 Hz, 1H), 6.99 (d, J ) 9.19 Hz, 1H), 7.09-7.29
(m, 10H), 7.35 (d, J ) 8.82 Hz, 1H), 7.63 (d, J ) 8.46 Hz, 1H),
7.80 (d, J ) 8.82 Hz, 1H), 7.84, 7.87 (2s, 1H), 7.94 (d, J ) 6.99
Hz, 1H), 9.03, 9.05 (2s, 1 H). MS (ESI) m/z 865.3 (M + H)+. The
thioether (1.2 g, 1.4 mmol) was treated with phosphoric acid (0.85
g, 8.7 mmol) and N-iodosuccinimide (0.406 g, 1.8 mmol) in DMF
(28 mL) using the general procedure to give 5 (0.605 g, 47% yield).
1H NMR (300 MHz, CD3OD) δ ppm 0.88-0.98 (m, 9H),
1.33-1.36 (m, 6H), 1.44-2.24 (m, 7H), 2.56-2.85 (m, 4H),
2.88-2.98 (m, 1H), 3.01 (s, 3H), 3.90-4.03 (m, 1H), 4.03-4.16
(m, 2H), 4.18-4.26 (m, 0.5H), 4.29-4.39 (m, 0.5H), 4.46-4.65
(m, 2H), 4.93-5.02 (m, 1H), 5.08-5.14 (m, 1H), 5.22-5.30 (m,
1H), 6.97-7.25 (m, 11H), 7.65-7.74 (m, 1H), 8.91-8.92 (m, 1H).
(ESI) m/z 739.5 (M
(C38H49N4Na2O9P·3.9H2O) C, H, N. Analytical HPLC tR ) 8.19
min.
+ +
H)+, 761.4 (M Na)+. Anal.
Disodium 1-[((1S,3S)-1-((1S)-1-{[(2,6-Dimethylphenoxy)acetyl]-
amino}-2-phenylethyl)-3-{[(2S)-3-methyl-2-(2-oxotetrahydropyri-
midin-1(2H)-yl)butanoyl]amino}-4-phenylbutyl)oxy]ethylphos-
phate (8). The thioether was prepared using the general procedure
from LPV (0.50 g, 0.80 mmol), ethyl sulfide (2.1 mL, 19.5 mmol),
and benzoyl peroxide (1.16 g, 4.8 mmol) as a mixture of
1
diastereomers (about 1.6:1) (0.36 g, 61% yield). H NMR (300
MHz, DMSO-d6) δ ppm 0.76 (d, J ) 6.62 Hz, 3H), 0.82, 0.90 (2d,
J ) 6.25 Hz, 3H), 1.18, 1.19 (2t, J ) 7.35 Hz, 3H), 1.36-1.78 (m,
3H), 1.46, 1.52 (2d, J ) 6.25 Hz, 3H), 1.97-2.11 (m, 1H), 2.14,
2.15 (2s, 6H), 2.53-2.96 (m, 7H), 2.98-3.07 (m, 2H), 3.61 (t, J
) 5.70 Hz, 1H), 3.78 (d, J ) 9.19 Hz, 1H), 4.06-4.13 (m, 2H),
4.17-4.32 (m, 1H), 4.32-4.40 (m, 1H) 4.44-4.68 (m, 1H),
4.79-4.96 (m, 1H), 6.27-6.36 (m, 1H), 6.88-6.97 (m, 1H),
6.99-7.04 (m, 2H), 7.08-7.30 (m, 8H), 7.45-7.57 (m, 1H),
7.59-7.68 (m, 1H), 7.89-7.98 (m, 1H). MS (ESI) m/z 717.3 (M
+ H)+. The thioether (0.15 g, 0.21 mmol) was treated with
phosphoric acid (0.082 g, 0.84 mmol) and N-iodosuccinimide (0.094
g, 0.42 mmol) in DMF (4.5 mL) using the general procedure to
give 8 as a mixture of diastereomers (0.066 g, 39% yield). 1H NMR
(300 MHz, CD3OD) δ ppm 0.85 (d, J ) 6.6 Hz, 1.5H), 0.86 (d, J
) 6.6 Hz, 1.5H), 0.94 (d, J ) 6.6 Hz, 1.5H), 0.96 (d, J ) 6.6 Hz,
1.5H), 1.45 (d, J ) 5.1 Hz, 1.5H), 1.46 (d, J ) 5.1 Hz, 1.5H),
1.50-1.74 (m, 3H), 1.88-1.98 (m, 0.5H), 2.09-2.25 (m, 1.5H),
2.09 (s, 3H), 2.13 (s, 3H), 2.74-2.77 (m, 2H), 2.85-3.19 (m, 6H),
3.92-4.03 (m, 2.5H), 4.16-4.21 (m, 0.5H), 4.23 (d, J ) 11.0 Hz,
0.5H), 4.35 (d, J ) 11.0 Hz, 0.5H), 4.40-4.54 (m, 1H), 4.63-4.70
(m, 1H), 5.39-5.50 (m, 1H), 6.88-6.99 (m, 3H), 7.07-7.30 (m,
10H). MS (ESI) m/z 775.3 (M + Na)+. Anal. (C39H51N4Na2-
O9P·0.8H2O) C, H, N. Analytical HPLC tR ) 8.73 min.
MS
(ESI)
m/z
895.4
(M
+
Na)+.
Anal.
(C41H55N6Na2O9PS2 ·1.7H2O) C, H, N. Analytical HPLC tR ) 8.92
min.
Disodium N1-((1S,3S,4S)-1-Benzyl-3-[2-methyl-1-(phospho-
natooxy)propoxy]-5-phenyl-4-{[(1,3-thiazol-5-ylmethoxy)car-
bonyl]amino}pentyl)-N2-{[[(2-isopropyl-1,3-thiazol-4-yl)methyl]-
(methyl)amino]carbonyl}-L-valinamide (6). The thioether was
prepared using the general procedure from RTV (1.0 g, 1.38 mmol),
diisobutyl sulfide (6.2 mL, 35.5 mmol), and benzoyl peroxide (2.0
g, 8.3 mmol) as a mixture of diastereomers (about 1:1) (0.890 g,
1
75% yield). H NMR (300 MHz, CD3OD) δ ppm 0.83-1.07 (m,
12H), 1.10, 1.11 (2d, J ) 6.80 Hz, 12H), 1.36, 1.37 (2d, J ) 6.99
Hz, 6H), 1.57-1.85 (m, 3H), 1.91-2.24 (m, 3H), 2.42-2.89 (m,
9H), 2.90-3.04 (m, 1H), 2.96 (s, 3H), 2.97 (s, 3H), 3.24-3.35
(m, 1H), 3.82-4.23 (m, 3H), 4.27-4.61 (m, 4H), 5.10-5.33 (m,
2H), 6.95-7.32 (m, 10H), 7.78, 7.81 (2s, 1H), 8.91, 8.92 (2s, 1H).
MS (ESI) m/z 865.2 (M + H)+. The thioether (0.888 g, 1.03 mmol)
was treated with phosphoric acid (0.50 g, 5.1 mmol) and N-
iodosuccinimide (0.46 g, 2.0 mmol) in DMF (20 mL) using the

2970 Journal of Medicinal Chemistry, 2009, Vol. 52, No. 9
DeGoey et al.
(7) For recent applications to other drugs classes, see the following: (a)
Dhareshwar, S. S.; Stella, V. J. A Functional Group Approach to
Prodrugs: Prodrugs of Alcohols and Phenols. In Prodrugs: Challenges
and Rewards; Stella, V. J., Borchardt, R. T., Hageman, M. J., Oliyai,
R., Maag, H., Tilley, J. W., Eds.; Springer Press/AAPS Press: New
York, 2007; Part 2, pp 31-99. (b) Fechner, J.; Schwilden, H.;
Schu¨ttler, J. Pharmacokinetics and Pharmacodynamics of GPI 15715
or Fospropofol (Aquavan Injection), a Water-Soluble Propofol Prodrug.
In Modern Anesthetics; Schu¨ttler, J., Schwilden, H., Eds.; Handbook
of Experimental Pharmacology, Vol. 182; Springer-Verlag: Berlin,
2008; pp 253-266. (c) Garnier, T.; Ma¨ntyla¨, A.; Ja¨rvinen, T.;
Lawrence, J.; Brown, M.; Croft, S. In vitro studies on the antileish-
manial activity of buparvaquone and its prodrugs. J. Antimicrob.
Chemother. 2007, 60, 802–810.
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