Alkoxycarbonyloxyethyl ester prodrugs of FR900098 with improved in vivo antimalarial activity

Article abstract of DOI:10.1002/ardp.200500976

FR900098 represents a derivative of the new antimalarial drug fosmidomycin with enhanced activity. The mechanism of action is the inhibition of the 1-desoxy-D-xylulose 5-phosphate (DOXP) reductoisomerase, an essential enzyme of the mevalonate independent

Full text of DOI:10.1002/ardp.200500976

Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
DOI 10.1002/ardp.200500976
305
Alkoxycarbonyloxyethyl Ester Prodrugs of FR900098
with Improved In Vivo Antimalarial Activity
Regina Ortmanna, Jochen Wiesnerb, Armin Reichenbergb, Dajana Henschkerb,
Ewald Beckb, Hassan Jomaab, Martin Schlitzera
a Department für Pharmazie, Ludwig-Maximilians-Universität, München, Germany
b Biochemisches Institut, Justus-Liebig-Universität, Gießen, Germany
FR900098 represents a derivative of the new antimalarial drug fosmidomycin with enhanced activity.
The mechanism of action is the inhibition of the 1-desoxy-d-xylulose 5-phosphate (DOXP) reductoiso-
merase, an essential enzyme of the mevalonate independent pathway of isoprenoid biosynthesis. Pro-
drugs with increased oral activity in mice infected with the rodent malaria parasite Plasmodium vinckei
were obtained by masking the phosphonate moiety of FR900098 as alkoxycarbonyloxyethyl esters.
Keywords: Malaria; Prodrug; Plasmodium falciparum; Isoprenoid biosynthesis
Received: January 31, 2005; Accepted: May 16, 2005 [FP976]
Introduction
1.5 to 3 million people die from malaria every year, most
of them children. Because of the increasing resistance of
Plasmodium falciparum, the causative agent of Malaria
tropica, to many of the presently available drugs there is an
urgent need for new efficient antimalarial agents [1].
In malaria parasites, isoprenoids are synthesized via a
mevalonate independent pathway, the so-called DOXP
pathway, which is absent in humans. Fosmidomycin (Figure
1) is a strong inhibitor of the DOXP reductoisomerase, the
Figure 1. Structures of fosmidomycin and FR900098.
second enzyme in this pathway, FR900098 (Figure 1) is ap-
prox. twice as active against P. falciparum in vitro and in
the P. vinckei mouse model [2]. However, the oral bioavail-
ability of both compounds is only moderate, with a resorp-
tion rate of approx. 30% [3].
prepared with the goal to obtain crystalline prodrugs since
all previous diaryl and bis[(acyloxy)alkyl] esters were of oily
consistency which is unfavorable for the formulation as tab-
lets or capsules; (ii) Bis[(alkoxycarbonyloxy)ethyl] esters
were prepared as possible alternatives to the previous
bis[(acyloxy)ethyl] esters.
In previous work, we transformed the charged phosphonate
moiety of FR900098 into diaryl esters to increase the re-
sorption rate [4]. These prodrugs resulted in improved oral
efficacy in P. vinckei infected mice, but concerns about the
toxicity of the phenol derivative released through cleavage
of the prodrugs prompted us to investigate (acyloxy)alkyl
esters as an alternative strategy.
Results and discussion
Syntheses
First, we synthesized a series of several bis[(acyloxy)alkyl]
esters. In this series, the bis[(acetyloxy)ethyl] ester, was at
least twice as active as FR900098 [5]. In a second series, we
tested the antimalarial activity of two additional types of
FR900098 prodrugs: (i) Mono[(acyloxy)alkyl] esters were
Synthesis of the prodrugs was achieved starting from the
aldehyde 2, which is readily accessible from the commer-
cially available corresponding acetale 1 (Scheme 1). Treat-
ment of the aldehyde 2 with O-benzylhydroxylamine gave
the oxime, which was then reduced without prior isolation
with sodium cyanoborohydride and hydrochloric acid to
yield the O-(benzylhydroxylamino)propylphosphonic acid
diethyl ester 3 [6]. Acetylation to 4 and subsequent reaction
of 4 with trimethylbromosilane [7] and hydrolysis of the re-
Correspondence: Martin Schlitzer, Department für Pharmazie,
Zentrum für Pharmaforschung, Ludwig-Maximilians-Universität,
Butenandtstraße 5-13, D-81377 München, Germany. Phone:
ϩ49 89 2180-77804, Fax: ϩ49 89 2180-77802, e-mail:
Martin.Schlitzer@cup.uni-muenchen.de
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Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
Scheme 1. Synthesis route of 7a-g. Conditions and yields: (i) 2N HCl, overnight, rt, 63%; (ii) O-benzylhydroxylamine in metha-
nol, 3 h, 40°C, and then NaCNBH3 in methanol, HCl, 1 h, rt, 99%; (iii) acetylchloride in CH2Cl2, (H3C)3N, overnight, rt, 97%;
(iv) trimethylbromosilane in CH2Cl2, 30 min, 0°C, and then H2O, overnight, rt, 82%; (v) (a and b) RCl in DMF, (H3C)3N, 6 h,
60°C, (cϪk) RCl, DMPU, NaI, (CH3)3N, 6 h, 60°C; (vi) H2, Pd/C, MeOH.
sulting silylester with water yielded the O-benzyl protected
FR900098 5.
acid 5 with chloroethyl ethylcarbonate (commercially avail-
able) or chloroethyl methylcarbonate [10] to obtain the
esters 6h and i as diastereomeric mixtures Removal of the
protecting group led to the prodrugs 7h and 7i.
Phosphonic acid 5 was then coupled with commercially
available chloroacetic acid methylester or chloromethyl piv-
alate, respectively, in DMF in the presence of triethylamine
leading to the phosphonic acid diesters 6a and 6b [8]. This
method was unsuccessful in the case of 1-chloroethyl pival-
ate and 1-chloroethyl benzoate. However, when the phos-
phonic acid 5 and the chloroalkyl esters [9] were reacted in
N,N Ј-dimethyl-N,N Ј-propyleneurea (DMPU) in the pres-
ence of triethylamine and sodium iodide, the bis(acyloxy)al-
kyl esters 6cϪg and 6k were obtained as diastereomeric mix-
tures [8]. Removal of the protecting groups with hydrogen
and 10% Pd/C in methanol gave the prodrugs 7aϪg and 7k.
Synthesis of the mono[(acyloxy)alkyl] esters also started
from phosphonic acid 5 by reaction with thionyl chloride in
DMF (Scheme 2). The resulting phosphonic acid mono-
chloride was directly coupled with benzyl alcohol to obtain
the monobenzyl ester 8 [11]. Reaction of 8 with the 1-chloro
ethyl esters in DMPU in the presence of triethylamine and
sodium iodide [8] led to the esters 9a and b as dia-
stereomeric mixtures. The protection groups were removed
hydrogenolytically to obtain the mono-pivaloyl prodrug 10a
as a powder and the mono-palmitoyl derivative 10b as a
waxy substance.
Synthesis of the bis[(alkoxycarbonyloxy)ethyl] of the second
series was done in a similar way by coupling phosphonic
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Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
Prodrugs of FR900098 with improved antimalarial activity
307
Scheme 2. Synthesis of compounds 9Ϫ10. Conditions: (a) 1. Thionyl chloride, DMF; 2. benzyl alcohol 0.5 h at Ϫ10°C, 1 h at
0°C (b) RCl, DMPU, NaI, (CH3)3N, 6 h, 60°C; (c) H2, Pd/C, MeOH.
The antimalarial activity of the prodrugs was tested in the
P. vinckei mouse model similar as described before [4]. On
day zero, Balb/c mice were inoculated by i.p. injection of
5 ϫ 107 infected erythrocytes from a donor mouse. On days
one and two, the mice were treated by oral administration
of 40 mg/kg of the prodrugs [12]. For comparison, another
group of mice was treated with an equivalent dosage of
FR900098. This dosage was estimated to result in a partial
reduction of parasitaemia. On the following days, parasita-
emia was monitored to assess the efficacy of the com-
pounds.
significantly more active than the parent compound. In or-
der to avoid the release of formaldehyde, the dioxymethylen
group of 7b was replaced by a 1,1-dioxyethylen group gener-
ating the less toxic acetaldehyde. The resulting pivaloyloxy-
ethyl ester 7c and the benzoyloxyethyl ester 7d displayed
activities comparable with but not superior to FR900098.
The two derivatives which carry less bulky acyl residues, the
acetyloxyethyl ester 7e and the propionyloxyethyl ester 7f,
proved to be more effective than FR900098, with 7e being
slightly more active than 7f. In contrast, the propionyloxyi-
sobutyl derivative 7g did not lead to an improved activity.
In the first experiment, the efficacy of 7a and 7b was tested
(Figure 2). The treatment with the acetyl ester derivative 7a
resulted in a marked reduction of parasitaemia compared
with untreated control mice, but was less effective than
FR900098. In contrast, the pivaloyloxymethyl ester 7b was
To obtain a quantitative assessment of the increase in effi-
cacy, the acetyloxyethyl ester 7e was characterized further
(Figure 3). Mice were treated with 10 mg/kg and 20 mg/kg
of 7e, respectively, and compared with another group of
mice receiving 40 mg/kg FR900098. The treatment with
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Schlitzer et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
10 mg/kg 7e resulted in a reduced efficacy compared with
40 mg/kg FR900098. The treatment with 20 mg/kg 7e, how-
ever, was slightly more effective than 40 mg/kg FR900098.
Figure 3. Antimalarial efficacy of 10 mg/kg and 20 mg/kg 7e
in comparison to 40 mg/kg FR900098. Mice were infected on
day 0 and treated on day 1 and 2. Parasitaemia was moni-
tored on day 3 to 8.
Figure 4. Plasma concentration of FR900098 in mice after
oral administration of 40 mg/kg FR900098 and 7e.
To confirm whether the improved efficacy of 7e correlates
with an increased bioavailability, the plasma levels of
FR900098 were monitored at different times after oral ad-
ministration of identical doses of FR900098 and 7e (Figure
4). Since currently no chromatographic methods for the de-
termination of low amounts of FR900098 are available, the
inhibitory activity of the plasma samples against recombi-
nant DOXP reductoisomerase was measured to provide an
estimation of the FR900098 plasma concentration [12]. As
expected, the FR900098 plasma concentration was signifi-
cantly higher after administration of the prodrug. At
0.5 h after administration the plasma level was 3.0 μM after
administration of 7e in comparison to 1.2 μM after adminis-
tration of FR900098. After 2 h the plasma concentration
fell to the limit of quantification at approx. 0.4 μM in
both groups.
Figure 2. Antimalarial efficacy of the prodrugs 7aϪg in com-
parison to FR900098. Mice were infected on day 0 and tre-
ated with 40 mg/kg of the respective compound on day 1 and
2. Parasitaemia was monitored on day 3 to 8.
In the second series, first the efficacy of the crystalline pro-
drug 10a was tested. The mono[(pivaloyloxy)ethyl] ester de-
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Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
Prodrugs of FR900098 with improved antimalarial activity
309
infected erythrocytes from a donor mouse. On days 1 and
2, the mice were treated by oral administration of 40 mg/kg
of the prodrugs [13]. For comparison, another group of
mice was treated with an equivalent dosage of FR900098.
This dosage was estimated to result in a partial reduction
of parasitaemia. On the following days, parasitaemia was
monitored to assess the efficacy of the compounds.
Acknowledgments
This study was supported by grants of the Deutsche
Malaria Initiative and the European Commission (INCO-
Dev, 5th Framework Programme, Contract No. ICA4-CT-
2001-10078).
Figure 5. Antimalarial efficacy of prodrugs 7h؊k and 10b in
comparison to FR900098. Mice were infected on day 0 and
treated on day 1 and 2 by oral administration of 40 mg/kg of
the indicated compounds. Parasitaemia was monitored on
day 3 through 11.
Experimental
Preparation
1H and 13C NMR spectra were recorded on a Jeol Eclipse 400 and
a Jeol Eclipse 500 spectrometer (Jeol, Tokyo, Japan). Mass spectra
were obtained with a PE Biosystems API 2000 (Applied Biosystems,
Darmstadt, Germany) or with a Jeol MStation JMS 700 (in case of
FAB spectra). IR spectra were recorded on a JASCO FT/IR Ϫ 410
Fourier Transform Infrared Spectrometer (Jasco Labor- und Daten-
technik GmbH, Gross-Umstadt, Germany). Microanalyses were ob-
tained from an elementar vario el. Melting points were obtained
with a Reichert Austria microscope (C. Reichert, Vienna, Austria)
and are uncorrected. Liquid chromatography was carried out using
silica gel 60 from ICN Biomedicals (ICN Biomedicals, Eschwege,
Germany).
rivative 10a displayed activity comparable with but not su-
perior to FR900098 (data not shown). In order to increase
the lipophilicity of the prodrug the waxy mono[(palmitoyl-
oxy)ethyl] derivative 10b was prepared. However, 10b dis-
played significantly less activity than FR900098 (Figure 5).
The waxy bis[(palmitoyloxy)ethyl] derivative 7k which was
assayed for comparison showed similarly lower activity. In
contrast, the two bis[(alkoxycarbonyloxy]ethyl] esters 7h
and 7i were significantly more active than the parent com-
pound with 7h being slightly more active than 7i. In mice
treated with both compounds there was a delay in the devel-
opment of parasitaemia of about two days compared to
control animals treated with FR900098. The decrease of
parasitaemia in the FR900098 treated mice after day 9 is
caused by the development of immunity, which is frequently
observed in this animal model when sub-therapeutic doses
are administered.
[3-[Acetyl(phenylmethoxy)amino]propyl]phosphonic acid diethyl
ester 4
Acetylchloride (11 mmol) was added dropwise to a solution of 3
(10 mmol) and triethylamine (11 mmol) in dichloromethane. The
reaction mixture was stirred at room temperature overnight, washed
with water, aqueous NaHCO3 and water, and dried (Na2SO4). The
solvent was removed by rotary evaporation and the residue was
purified by column chromatography on silica gel, eluting with di-
chloromethane methanol mixtures. Colourless oil, yield 83%. IR
(film), cmϪ1: 1664 (CϭO). 1H-NMR (CDCl3, 500 MHz), δ (ppm):
1.29Ϫ1.32 (m, 6 H, 2 ϫ CH2-CH3); 1.70Ϫ1.77 (m, 2 H, CH2);
1.78Ϫ1.96 (m, 2 H, CH2); 2.10 (s, 3 H, CH3); 3.71 (m, 2 H, N-
CH2); 4.06Ϫ4.10 (m, 4 H, 2 ϫ CH2-CH3); 4.82 (s, 2 H, N-O-CH2);
7.37Ϫ7.41 (m, 5 H, 5 Ar-H). 13C-NMR (CDCl3, 125 MHz, COM,
In summary, prodrugs of FR900098 with increased oral
antimalarial efficacy were obtained by masking the polar
phosphonate moiety as acyloxyalkyl esters. The acetyloxy-
ethyl ester 7e, which is expected to release only acetic acid
and acetaldehyde upon hydrolysis in addition to the active
compound, was at least twice as active as FR900098 [13].
3
APT), δ (ppm): 16.39 (d, JC,P ϭ 5.8 Hz, 2 ϫ O-CH2-CH3); 20.20
1
(P-CH2-CH2); 20.43 (CϭO-CH3); 25.42 (d, JC,P ϭ 143.0 Hz, P-
2
CH2); 45.43 (N-CH2); 61.52 (d, JC,P ϭ 5.8 Hz, 2 ϫ O-CH2-CH3);
In addition, prodrugs significantly more active than
FR900098 were also obtained by masking the polar phos-
phonate moiety as bis[(alkoxycarbonyloxy)ethyl] esters 7h
and 7i.
76.34 (N-O-CH2); 128.67, 128.96, 129.13 (5 Ar-C); 134.24 (1 q Ar-
C); 172.41 (CϭO). 31P-NMR (CDCl3, 202 MHz), δ (ppm): 31.87.
MS (EI), m/z (%): 343 (22, Mϩ), 236 (7), 210 (8), 194 (28), 180 (5),
166 (4), 152 (4), 138 (3), 92 (9), 91 (100), 55 (3). Anal. calcd. for
C16H26NO5P: C 55.97, H 7.63, N 4.08. Found C 55.87, H 7.40,
N 4.35.
Biological testing
[3-[Acetyl(phenylmethoxy)amino]propyl]phosphonic acid 5
The antimalarial activity of the prodrugs was tested in the
P. vinckei mouse model as described previously [4]. On day
0, Balb/c mice were inoculated by i.p. injection of 5 ϫ 107
Bromotrimethylsilane (150 mmol) was added dropwise under argon
atmosphere to 30 mmol of 4 and stirred at room temperature over-
night. Ethyl bromide and excess silylating agent were removed by
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Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
rotary evaporation. Then 50 mL of water were added. After stirring
for several hours, the precipitated solid was filtered off, washed with
ether, and dried in vacuo. Colourless solid, mp 145Ϫ146°C, yield
83%. IR (cmϪ1): 1607 (CϭO). 1H-NMR (DMSO-d6, 500 MHz),
δ (ppm): 1.46Ϫ1.53 (m, 2 H, CH2), 1.71Ϫ1.80 (m, 2 H, CH2), 2.01
(s, 3 H, CH3), 3.65 (t, 2 H, 3J ϭ 7.2 Hz, N-CH2), 4.87 (s, 2 H, N-O-
CH2), 7.36Ϫ7.45 (m, 5 H, Ar-H). 13C-NMR (DMSO-d6, 125 MHz,
COM, APT), δ (ppm): 20.72 (CϭO-CH3), 21.11 (P-CH2-CH2),
25.42 (d, JC,P ϭ 138.2 Hz, P-CH2), 40.17 (d, JC,P ϭ 21.1 Hz, N-
CH2), 75.75 (N-O-CH2), 128.83, 129.03, 129.76 (5 Ar-C), 135.28 (1
q Ar-C). 31P-NMR (CDCl3, 202 MHz), δ (ppm): 26.70. ESI-MS,
m/z (%): 597 (6 [2 M ϩ Na]ϩ), 575 (100 [2 M ϩ H]ϩ), 310
(7 [M ϩ Na]ϩ), 288 (63 [M ϩ H]ϩ). Anal. calcd. for C12H18NO5P:
C 50.18, H 6.32, N 4.88. Found C 50.36, H 6.17, N 5.02.
1.73Ϫ1.92 (m, 4 H, 2 ϫ CH2); 2.01 (s, 3 H, H3C-CϭO); 3.63 (t,
3J ϭ 6.4 Hz, 2 H, N-CH2); 4.74 (s, 2 H, N-O-CH2); 5.59 (d, 3JH,P ϭ
12.5 Hz, 4 H, 2 ϫ P-O-CH2); 7.31Ϫ7.36 (m, 5 H, Ar-H). 13C-NMR
2
(CDCl3, 100 MHz, COM), δ (ppm): 19.96 (d, JC,P ϭ 5.2 Hz, P-
1
CH2-CH2); 20.53 (CϭO-CH3); 24.05 (d, JC,P ϭ 142.0 Hz, P-CH2);
26.92 (6 ϫ CH3); 38.80 (2 ϫ C(CH3)3); 45.39 (N-CH2); 76.54 (N-
2
O-CH2); 81.43 (d, JC,P ϭ 5.6 Hz, 2 ϫ P-O-CH2); 128.84, 129.12,
129.34 (5 Ar-C); 134.32 (1 q Ar-C); 172.49 (CϭO); 176.95 (2 ϫ Cϭ
O). 31P-NMR (CDCl3, 161 MHz), δ (ppm): 32.97. CI-MS m/z 516
([M ϩ H]ϩ). Anal. calcd. for C24H38NO9P (%): C 55.91, H 7.43, N
2.72. Found (%): C 55.59, H 7.14, N 2.65.
1
3
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-bis[1-
(2,2-dimethylpropionyloxy)ethyl]ester 6c
Prepared according to general method B. Light yellow viscous oil,
yield 38%. IR (film), cmϪ1: 1742 (O-CϭO), 1666 (N-CϭO). 1H-
NMR (CDCl3, 400 MHz), δ (ppm): 1.18Ϫ1.20 (m, 18 H, 2 ϫ
C(CH3)3); 1.50Ϫ1.54 (m, 6 H, 2 ϫ CH-CH3); 1.83Ϫ1.89 (m, 4 H,
2 ϫ CH2); 2.09 (s, 3 H, H3C-CϭO); 3.68Ϫ3.70 (m, 2 H, N-CH2);
4.82 (s, 2 H, N-O-CH2); 6.48Ϫ6.59 (m, 2 H, 2 ϫ P-O-CH);
7.27Ϫ7.38 (m, 5 H, Ar-H). 13C-NMR (CDCl3, 100 MHz, COM,
DEPT), δ (ppm): 20.02, 20.16 (P-CH2-CH2); 20.49 (CϭO-CH3);
21.55, 21.57, 21.62, 21.66, 21.70, 21.75 (2 ϫ CH-CH3); 23.94 (d,
1JC,P ϭ 141.8 Hz, P-CH2); 26.84 (6 ϫ CH3); 38.56, 38.58, 38.62 (2
ϫ CϭO-C(CH3)3); 45.34 (N-CH2); 76.39, 76.42, 76.44 (N-O-CH2);
89.37, 89.44, 90.21, 90.26, 90.90, 90.96, 91.07, 91.11 (2 ϫ P-O-CH);
128.71, 128.75, 128.997, 129.00, 129.04, 129.23, 129.25 (5 Ar-C);
134.33 (1 q Ar-C); 172.39 (CϭO); 176.07, 176.29, 176.46, 176.53 (2
ϫ CϭO). 31P-NMR (CDCl3, 202 MHz), δ (ppm): 26.00, 29.12,
33.79. ESI-MS m/z 1109 [2 M ϩ Na]ϩ, 566 [M ϩ Na]ϩ. Anal. calcd.
for C26H42NO9P (%): C 57.45, H 7.79, N 2.58. Found (%): C 57.29,
H 7.85, N 2.58.
Preparation of benzyl-protected bis[(acyloxy)alkyl] esters and
bis[(alkoxycarbonyloxy)ethyl] esters
General Method A
A mixture of 5 (3 mmol) and triethylamine (6 mmol) in 30 mL of
DMF was stirred at room temperature for 5 min. Then, the appro-
priate alkylating agent (30 mmol) was added and the resulting solu-
tion was stirred at 60°C for 6 h. The solvent was removed and the
residue was dissolved in dichloromethane. The solution was washed
with aqueous NaHCO3 and water and dried (Na2SO4). The solvent
was removed and the residue was purified by column chromatogra-
phy on silica gel, eluting with dichloromethane methanol mixtures.
General Method B
A mixture of 5 (3 mmol) and triethylamine (7 mmol) in 20 mL
DMPU was stirred at room temperature for 10 min. Then, the ap-
propriate alkylating agent was added followed by sodium iodide (3.5
mmol). The resulting reaction mixture was stirred at 60°C for 3 h.
A further quantity of sodium iodide was added and the stirring was
continued for another 3 h. The mixture was precipitated into hexane
(600 mL) at 0°C and the hexane solution was removed by decan-
tation. The last step was repeated twice and the residue was dis-
solved in dichloromethane. The solution was washed with aqueous
NaHCO3, water, aqueous Na2S2O3 and water, and dried (Na2SO4).
The solvent was removed and the residue was purified by column
chromatography on silica gel, eluting with dichloromethane meth-
anol mixtures.
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-bis[1-
(benzoyloxy)ethyl]ester 6d
Prepared according to general method B. Light yellow viscous oil,
yield 49%. IR (film), cmϪ1: 1730 (O-CϭO), 1665 (N-CϭO). 1H-
NMR (CDCl3, 400 MHz), δ (ppm): 1.60Ϫ1.68 (m, 6 H, 2 ϫ CH-
CH3); 1.77Ϫ2.05 (m, 7 H, 2 ϫ CH2 ϩ H3C-CϭO); 3.66Ϫ3.69 (m,
2 H, N-CH2); 4.71Ϫ4.77 (m, 2 H, N-O-CH2); 6.77Ϫ6.92 (m, 2 H,
2 ϫ P-O-CH); 7.29Ϫ7.47 (m, 9 H, Ar-H); 7.53Ϫ7.61 (m, 2 H, Ar-
H); 7.97Ϫ8.00 (m, 2 H, Ar-H); 8.03Ϫ8.08 (m, 2 H, Ar-H). 13C-
NMR (CDCl3, 100 MHz, COM, DEPT), δ (ppm): 19.91, 19.94,
20.08, 20.13, 20.22, 20.26 (P-CH2-CH2); 20.43 (CϭO-CH3); 21.64,
21.68, 21.78, 21.82, 21.88, 21.94 (2 ϫ CH-CH3); 23.25, 23.60, 24.66,
25.04 (P-CH2); 45.40 (N-CH2); 76.27, 76.32, 76.37 (N-O-CH2);
89.97, 90.03, 90.89, 90.93, 91.28, 91.35, 91.55, 91.59 (2 ϫ P-O-CH);
128.37, 128.43, 128.46, 128.63, 128.66, 128.70, 128.87, 128.92,
128.99, 129.18, 129.21, 129.82, 129.86, 129.91, 133.40, 133.47,
133.53 (15 Ar-C); 129.10, 129.13, 129.15 (2 q Ar-C); 134.30 (1 q Ar-
C); 164.22, 164.26, 164.50, 164.54 (3 ϫ CϭO). ESI-MS m/z
583(Mϩ), 606 ([M ϩ Na]ϩ). Anal. calcd. for C30H34NO9P (%): C
61.74, H 5.87, N 2.40. Found (%): C 61.69, H 5.88, N 2.47.
3-Acetyl-7-(2-methoxy-2-oxoethoxy)-1-phenyl-7-oxide-2,8-dioxa-3-
aza-7-phophadecan-10-oic acid methyl ester 6a
Prepared according to general method A. Light yellow viscous oil,
yield 41%. IR (film), cmϪ1: 1763 (O-CϭO), 1671 (N-CϭO). 1H-
NMR (CDCl3, 400 MHz), δ (ppm): 1.93Ϫ2.11 (m, 4 H, 2 ϫ CH2);
2.10 (s, 3 H, H3C-CϭO); 3.69Ϫ3.80 (m, 2 H, N-CH2); 3.77 (s, 6 H,
2 ϫ O-CH3); 4.58Ϫ4.72 (m, 4 H, 2 ϫ O-CH2); 4.84 (s, 2 H, N-O-
CH2); 7.39 (s, 5 H, Ar-H). 13C-NMR (CDCl3, 125 MHz, COM,
DEPT), δ (ppm): 19.99 (d, 2JC,P ϭ 4.8 Hz, P-CH2-CH2); 20.47 (Cϭ
1
O-CH3); 23.58 (d, JC,P ϭ 145.0 Hz, P-CH2); 45.29 (N-CH2); 52.29
2
(O-CH3); 61.82 (d, JC,P ϭ 6.3 Hz, 2 P-O-CH2); 76.41 (N-O-CH2);
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-bis[1-
(acetyloxy)ethyl]ester 6e
129.21, 128.95, 128.69 (5 Ar-C); 134.35 (1 q Ar-C);168.79, 168.74
(CϭO). CI-MS m/z 432 ([M ϩ H]ϩ). Anal. calcd. for C18H36NO9P
(%): C 49.76, H 6.38, N 3.30. Found (%): C 50.12, H 6.07, N 3.25.
Prepared according to general method B. Light yellow viscous oil,
yield 35%. IR (film), cmϪ1: 1755 (O-CϭO), 1664 (N-CϭO). 1H-
NMR (CDCl3, 500 MHz), δ (ppm): 1.52Ϫ1.54 (m, 6 H, 2 ϫ CH2-
CH3); 1.79Ϫ1.97 (m, 4 H, 2 ϫ CH2); 2.05 (s, 3 H, H3C-CϭO-N);
2.08Ϫ2.10 (m, 6 H, 2 ϫ H3C-CϭO-O); 3.69Ϫ3.71, (m, 2 H, N-
CH2); 4.82 (s, 2 H, N-O-CH2); 6.48Ϫ6.59 (m, 2 H, 2 ϫ P-O-CH);
7.37Ϫ7.42 (m, 5 H, Ar-H). 13C-NMR (CDCl3, 125 MHz, COM,
DEPT), δ (ppm): 19.82, 19. 93 (P-CH2-CH2); 20.44 (N-CϭO-CH3);
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-bis[1-
(2,2-dimethylpropionyloxy)methyl]ester 6b
Prepared according to general method A. Light yellow viscous oil,
yield 49%. IR (film), cmϪ1: 1753 (O-CϭO), 1665 (N-CϭO). 1H-
NMR (CDCl3, 400 MHz), δ (ppm): 1.14 (s, 18 H, 2 ϫ C(CH3)3);
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
Prodrugs of FR900098 with improved antimalarial activity
311
20.82, 20.85, 20.88, 20.90 (2 ϫ CH-CH3); 21.52, 21.56, 21.60, 21.64,
21.68, 21.72 (2 ϫ O-CϭO-CH3); 23.29, 23.20 (P-CH2); 45.33 (N-
CH2); 76.39, 76.42 (N-O-CH2); 89.57, 89.62, 90.02, 90.06, 90.45,
90.51, 90.71, 90.73 (2 ϫ O-CH-O) 128.69, 128.71, 128.72, 128.96,
128.99, 129.03, 129.18 (5 Ar-C); 134.28 (1 q Ar-C), 168.62, 168.85,
169.00, 169.04 (CϭO). CI-MS m/z 460 ([M ϩ H]ϩ). Anal. calcd.
for C20H30NO9P (%): C 52.29, H 6.58, N 3.05. Found (%): C 51.82,
H 6.66, N 3.12.
(%): 874 ([MϪ2 H ϩ Na]ϩ), 869, 852 (Mϩ), 808, 764. Anal. calcd.
for C48H86NO9P: C 67.65, H 10.17, N 1.64. Found: C 67.52, H
10.24, N 1.70.
[3-[Acetyl(phenylmethoxy)amino]propyl]-3,7-dimethyl-5-oxide-
2,4,6,8-tetraoxa-5-phosphanonanedioic acid-dimethyl ester 6h
Prepared according to general method B. Light yellow viscous oil,
yield 5%. IR (film), cmϪ1: 1761 (O-CϭO), 1644 (N-CϭO). 1H-
NMR (CDCl3, 500 MHz), δ (ppm): 1.54Ϫ1.58 (m, 6 H, 2 ϫ P-O-
CH-CH3); 1.76Ϫ2.01 (m, 4 H, 2 ϫ CH2); 2.08 (s, 3 H, CϭO-CH3);
3.69Ϫ3.70 (m, 2 H, N-CH2); 3.75Ϫ3.79 (m, 6 H, 2 ϫ CϭO-O-CH3);
4.79Ϫ4.83 (m, 2 H, N-O-CH2); 6.37Ϫ6.49 (m, 2 H, 2 ϫ P-O-CH);
7.34Ϫ7.40 (m, 5 H, Ar-H). 13C-NMR (CDCl3, 125 MHz, COM,
DEPT), δ (ppm): 19.95, 20.08 (P-CH2-CH2); 20.43 (N-CϭO-CH3);
21.43, 21.74, 21.56, 21.64, 21.69 (2 ϫ O-CH-CH3); 23.26, 23.37,
24.51 (P-CH2); 45.39 (N-CH2); 54.99, 55.01, 55.03, 55.07, 55.10
(CϭO-O-CH3); 76. 43, 76.44, 76.46 (N-O-CH2); 92.99, 93.04, 93.45,
93.49, 93.77, 93.99, 94.03 (2 ϫ O-CH); 128.69, 128.71, 128.74,
129.97, 129.02, 129.18 (5 Ar-C); 134.36 (1 q Ar-C); 153.51, 153.56,
153.70 (CϭO); 163.57 (CϭO). ESI-MS m/z 492 ([M ϩ 1]ϩ). Anal.
calcd. for C20H30NO11P: C 48.88, H 6.15, N 2.85. Found: C 48.89,
H 6.40, N 2.86.
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-bis[1-
(propionyloxy)ethyl]ester 6f
Prepared according to general method B. Light yellow viscous oil,
yield 25%. IR (film), cmϪ1: 1754 (O-CϭO), 1665 (N-CϭO). 1H-
NMR (CDCl3, 500 MHz), δ (ppm): 1.09Ϫ1.16 (m, 6 H, 2 ϫ CH2-
CH3); 1.51Ϫ1.54 (m, 6 H, 2 ϫ CH-CH3); 1.75Ϫ1.99 (m, 4 H, 2 ϫ
CH2); 2.09 (s, 3 H, H3C-CϭO); 2.29Ϫ2.41 (m, 4 H, 2 ϫ H2C-Cϭ
O-O); 3.69Ϫ3.71 (t, J ϭ 6.3 Hz, 2 H, N-CH2); 4.82 (s, 2 H, N-O-
CH2); 6.50Ϫ6.61 (m, 2 H, 2 ϫ P-O-CH); 7.37Ϫ7.41 (m, 5 H, Ar-
H). 13C-NMR (CDCl3, 125 MHz, COM, DEPT), δ (ppm): 8.65,
8.68, 8.70 (CH2-CH3); 19.87, 19.93, 20.01, 20.05, 20.14, 20.29 (P-
CH2-CH2); 20.50 (CϭO-CH3); 21.59, 21.63, 21.66, 21.70, 21.73,
21.77, 21.82 (P-CH2 ϩ 2 ϫ CH2-CH3); 22.21, 23.29, 23.37, 23.71,
24.41, 24.51, 24.86, 27.42, 27.43 (2 ϫ O-CH-CH3); 45.34, 45.41 (N-
CH2); 76.42, 76.44, 76.47 (O-CH2); 89.53 89.59, 90.07, 90.11, 90.53,
90.59, 90.79, 90.83 (2 ϫ P-O-CH); 128.74, 128.76, 128.77, 129.00,
129.04, 129.07, 129.23, 129.25 (5 Ar-C); 134.35, 134.42 (1 q Ar-C);
172.14, 172.35, 172.50, 172.54 CϭO). CI-MS m/z 488 ([M ϩ H]ϩ).
Anal. calcd. for C22H34NO9P (%): C 54.20, H 7.03, N 2.87. Found
(%): C 53.60, H 7.17, N 3.25.
[3-[Acetyl(phenylmethoxy)amino]propyl]-3,7-dimethyl-5-oxide-
2,4,6,8-tetraoxa-5-phosphanonanedioic acid-diethyl ester 6i
Prepared according to general method B. Light yellow viscous oil,
yield 20%. IR (film), cmϪ1: 1754 (O-CϭO), 1666 (N-CϭO). 1H-
NMR (DMSO-d6, 500 MHz), δ (ppm): 1.16Ϫ1.24 (m, 6 H, 2 ϫ O-
CH2-CH3); 1.46Ϫ1.49 (m, 6 H, 2 ϫ P-O-CH-CH3); 1.67Ϫ1.89 (m,
4 H, 2 ϫ CH2); 2.02 (s, 3 H, CϭO-CH3); 3.62Ϫ3.69 (m, 2 H, N-
CH2); 4.07Ϫ4.19 (m, 4 H, 2 ϫ O-CH2-CH3); 4.87 (s, 2 H, N-O-
CH2); 6.26Ϫ6.36 (m, 2 H, 2 ϫ P-O-CH-CH3); 7.39Ϫ7.46 (m, 5 H,
Ar-H). 13C-NMR (DMSO-d6, 125 MHz, COM, DEPT), δ (ppm):
13.96, 13.83, 13.80 (2 ϫ CϭO-O-CH2-CH3); 19.47 (P-CH2-CH2);
20.20 (CϭO-CH3); 21.67, 21.42, 21.30, 21.25, 21.23, 21.19, 21.12,
21.08 (2 ϫ P-O-CH-CH3); 23.68, 23.66, 23.60, 22.56 (P-CH2); 38.97
(N-CH2); 64.13, 64.09, 64.07 (2 ϫ CϭO-O-CH2); 75.29 (N-O-CH2);
93.15, 93.10, 93.05, 92.94, 92.89, 92.61, 92.57 (2 ϫ P-O-CH-CH3);
129.30, 128.59, 128.37 (5 Ar-C); 134.69, 134.67 (q Ar-C); 152.45,
152.42, 152.27 (2 ϫ O-CϭO-O). CI-MS m/z 520 (Mϩ), 430, 386,
270. Anal. calcd. for C22H34NO11P: C 50.87, H 6.60, N 2.70. Found:
C 50.86, H 6.58, N 2.91.
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-bis[2-
methyl-1-(1-oxopropoxy)propyl]ester 6g
Prepared according to general method B. Light yellow viscous oil,
yield 10%. IR (film), cmϪ1: 1754 (O-CϭO), 1658 (N-CϭO). 1H-
NMR (CDCl3, 500 MHz), δ (ppm): 0.93Ϫ0.99 (m, 12 H, 4 ϫ CH3);
1.11Ϫ1.17 (m, 6 H, 2 ϫ CH2-CH3); 1.81Ϫ2.08 (m, 4 H, P-CH2-
CH2), 2.10 (s, 3 H, H3C-CϭO); 2.31Ϫ2.44 (m, 6 H, 2 ϫ CH2-CH3
ϩ 2 ϫ CH); 3.69Ϫ3.72 (m, 2 H, N-CH2); 4.82 (s, 2 H, N-O-CH2);
6.28Ϫ6.37 (m, 2 H, 2 ϫ P-O-CH); 7.36Ϫ7.41 (m, 5 H, Ar-H). 13C-
NMR (CDCl3, 125 MHz, COM, DEPT), δ (ppm): 8.77, 8.82 (2 ϫ
CH2-CH3); 15.63, 15.80, 15.89, 16.04, 16.24, 16.31, 16.44 (4 ϫ CH-
CH3); 20.19, 20.21, 20.23 (P-CH2-CH2); 20.47 (CϭO-CH3); 27.46,
27.49 (P-CH2); 32.95, 32.96, 32.99, 33.01, 33.03, 33.06 (2 ϫ CH);
45.46 (N-CH2); 76.44, 76.46 (N-O-CH2); 94.56, 94.62, 94.67, 94.73,
94.75, 94.77, 95.02, 95.06, 95.11 (2 ϫ O-CH-O); 128.74, 129.02,
129.22 (5 Ar-C); 136.54 (1 q Ar-C); 172.29, 172.45, 172.67 (CϭO);
FAB-MS m/z 544 ([M ϩ H]ϩ). Anal. calcd. for C26H42NO9P (%):
C 57.45, H 7.79, N 2.58. Found (%): C 57.47, H 7.88, N 2.84.
[3-[Acetyl(phenylmethoxy)amino]propyl]phosphonic acid monoben-
zyl ester 8
A stirred solution of 5 (10 mmol) in dry DMF (200 mL) was cooled
in an ice/NaCl bath. Thionyl chloride (15 mmol) was added through
a syringe and the reaction mixture was stirred for 30 min. With
further cooling 50 mL benzyl alcohol was added slowly. The re-
sulting solution was stirred at 0°C for 1 h and then at room tem-
perature overnight. DMF was removed on a rotary evaporator and
excess benzyl alcohol was removed by vacuum distillation. The resi-
due was dissolved in 5% aqueous NaHCO3 which was extracted
with ethyl acetate. The aqueous solution was acidified to pH 2Ϫ3
with concentrated hydrochloric acid at 0°C and extracted with ethyl
acetate. The organic extracts were dried over sodium sulfate and
the solvent was evaporated. The residue was used without further
purification. Yellow viscous oil, yield 67%. IR (film, cmϪ1): 1659
(CϭO). 1H-NMR (CDCl3, 500 MHz), δ (ppm): 1.64Ϫ1.67 (m, 2 H,
CH2); 1.75Ϫ1.77 (m, 2 H, CH2); 2.01 (s, 3 H, CH3); 3.66 (t, 2 H,
3J ϭ 6.9 Hz, N-CH2); 4.85 (s, 2 H, N-O-CH2); 4.93 (d, 2 H, 3JH,P ϭ
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-bis[1-
(hexadecanoyloxy)ethyl]ester 6k
Prepared according to general method B. White waxy solid, yield
35%, mp 32Ϫ34°C. IR (film), cmϪ1: 1754 (O-CϭO), 1671 (N-Cϭ
O). 1H-NMR (CDCl3, 500 MHz), δ (ppm): 0.89 (t, 6 H 3J ϭ 6.9
Hz, 2 ϫ CH2-CH3); 1.25 (bs, 48 H, 24 ϫ CH2); 1.51Ϫ1.99 (m, 14
H, 4 ϫ CH2 ϩ 2 ϫ P-O-CH-CH3); 2.10 (s, 3 H, CϭO-CH3);
2.27Ϫ2.38 (m, 4 H, 2 ϫ CϭO-CH2); 3.70Ϫ3.71 (m, 2 H, N-CH2);
4.82 (s, 2 H, N-O-CH2); 6.50Ϫ6.61 (m, 2 H, 2 ϫ P-O-CH);
7.37Ϫ7.44 (m, 5 H, Ar-H). 13C-NMR (CDCl3, 125 MHz, COM,
DEPT), δ (ppm): 14.19 (2 ϫ CH2-CH3). 20.15 (P-CH2-CH2); 21.86,
21.75, 20.56 (3 ϫ CH3); 34.19, 32.01, 29.77, 29.55, 29.43, 29.35,
29.13, 24.63, 22.76 (29 ϫ CH2); 45.54 (N-CH2); 76.52 (N-O-CH2);
90.85, 90.62, 89.58 (2 ϫ P-O-CH); 129.30, 129.09, 128.82 (5 Ar-C);
134.43 (q Ar-C); 171.94, 171.72, 171.52 (3 ϫ CϭO). ESI-MS, m/z
7.65 Hz, P-O-CH2); 7.27Ϫ7.40 (m, 10 H, Ar-H). 13C-NMR
2
(DMSO-d6, 100 MHz, COM, DEPT), δ (ppm): 20.29 (d, JC,P
ϭ
1
4.6 Hz, P-CH2-CH2); 21.00 (CϭO-CH3); 23.35 (d, JC,P ϭ 137.7
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

312
Schlitzer et al.
Hz, P-CH2); 39.84 (d, JC,P ϭ 21.1 Hz, N-CH2); 65.33 (d, JC,P
5.8 Hz, 2 P-O-CH2); 75.27 (N-O-CH2); 127.41, 127.79, 128.30,
128.35, 128.43, 128.59, 128.63, 129.36 (10 Ar-C); 134.75 (1 q
Ar-C ); 137.31 (d, 3JC,P ϭ 6.7 Hz, P-O-CH2-C); 171.93 (CϭO). 31P-
NMR (CDCl3, 202 MHz), δ (ppm): 29.25. HRFAB-MS: m/z
378.1467 for [M ϩ H]ϩ (calcd. 378.1470 for C19H24NO5PH).
Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
3
2
ϭ
sure with 10% Pd/C (20 mg) as a catalyst. The mixture was filtered,
and the solvent was removed by rotary evaporation.
6-[3-(Acetylhydroxyamino)propyl]-3-oxo-2,5,7-trioxa-6-phophan-
onan-9-oic acid methyl ester 7a
Light red viscous oil, yield 88%. IR (film), cmϪ1: 3185 (OH), 1763
(O-CϭO), 1643 (N-CϭO). 1H-NMR (CDCl3, 400 MHz),
δ
Synthesis of benzyl protected mono[(acyloxy)alkyl] esters
(ppm):2.01Ϫ2.09 (m, 4 H, 2 ϫ CH2); 2.16 (s, 3 H, H3C-CϭO);
3.72Ϫ3.83 (m, 2 H, N-CH2); 3.80 (s, 6 H, 2 ϫ O-CH3); 4.65 (d, 4
H, JH,P ϭ 11.6 Hz, 2 ϫ O-CH2); 8.88 (bs, 1 H, OH). 13C-NMR
A mixture of 8 (3 mmol) and triethylamine (3 mmol) in 10 mL
DMPU was stirred at room temperature for 10 min. Then, the ap-
propriate alkylating agent (6 mmol) was added followed by sodium
iodide (3 mmol). The resulting reaction mixture was stirred at 60°C
for 3 h. A further quantity of sodium iodide (3 mmol) was added,
and the stirring was continued for another 3 h. The mixture was
precipitated into hexane (600 mL) at 0°C, and the hexane solution
was removed by decantation. The last step was repeated twice, and
the residue was dissolved in dichloromethane. The solution was
washed with aqueous NaHCO3, water, aqueous Na2S2O3 and water,
and dried (Na2SO4). The solvent was removed and the residue was
purified by column chromatography on silica gel, eluting with di-
chloromethane methanol mixtures.
2
(CDCl3, 125 MHz, COM), δ (ppm): 18.87 (d, JC,P ϭ 5.7 Hz, P-
1
CH2-CH2); 20.52 (CϭO-CH3); 22.88 (d, JC,P ϭ 143.2 Hz, P-CH2);
45.33 (d, 3JC,P ϭ 7.7 Hz, N-CH2); 52.48 (O-CH3); 61.13 (d, 2JC,P
ϭ
6.9 Hz, 2 P-O-CH2); 172.88, 168.73, 168.69 (CϭO). CI-MS m/z 342
([M ϩ H]ϩ). Anal. calcd. for C11H20NO9P (%): C 38.41, H 6.28, N
4.06. Found (%): C 38.72, H 5.91, N 4.10.
[3-(Acetylhydroxyamino)propyl]-phosphonic
acid-bis[1-(2,2-di-
methylpropionyloxy)methyl]ester 7b
Light red viscous oil, yield 95%. IR (film), cmϪ1: 3190 (OH), 1754
(O-CϭO), 1627 (N-CϭO). 1H-NMR (CDCl3, 400 MHz), δ (ppm):
1.24 (s, 18 H, 2 ϫ C(CH3)3); 1.89Ϫ2.01 (m, 4 H, 2 ϫ CH2); 2.18 (s,
3 H, H3C-CϭO); 3.73Ϫ3.76 (m, 2 H, N-CH2); 5.65 (d, 3JH,P ϭ 12.8
Hz, 4 H, 2 ϫ P-O-CH2); 9.11 (bs, 1 H, OH). 13C-NMR (CDCl3,
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-benzyl-
[1-(2,2-dimethylpropionyloxy)ethyl]ester 9a
2
100 MHz, COM, DEPT), δ (ppm): 18.71 (d, JC,P ϭ 6.4 Hz, P-
Light yellow viscous oil, yield 12%. IR (film, cmϪ1): 1741 (O-Cϭ
O), 1665 (N-CϭO). 1H-NMR (DMSO-d6, 500 MHz), δ (ppm):
1.10Ϫ1.14 (m, 9H, CϭO-C-(CH3)3); 1.40Ϫ1.45 (m, 3 H, P-O-CH-
CH3); 1.68Ϫ1.86 (m, 4 H, 2 ϫ CH2); 2.00Ϫ2.01 (2 s, 3 H, CϭO-
CH3), 3.64Ϫ3.69 (m, 2 H, N-CH2); 4.83Ϫ4.87 (m, 2 H, N-O-CH2);
4.95Ϫ5.06 (m, 2 H, P-O-CH2); 6.36Ϫ6.49 (m, 1 H, P-O-CH-CH3);
7.33Ϫ7.44 (m, 10 H, Ar-H). 13C-NMR (CDCl3, 100 MHz, COM,
DEPT), δ (ppm): 20.02, 20.07, 20.25, 20.30 (P-CH2-CH2); 20.49
(CϭO-CH3); 21.55, 21.59, 21.64 (2 ϫ CH-CH3); 23.18, 24.29, 24.61
(P-CH2); 26.83 (6 ϫ CH3); 38.59 (CϭO-C(CH3)3); 45.29 (N-CH2);
66.57, 66.64, 67.40, 67.46 (P-O-CH2); 76.36, 76.39 (N-O-CH2);
90.15, 90.21, 90.54, 90.58 (P-O-CH); 127.93, 127.98, 128.39, 128.44,
128.58, 128.60, 128.71, 128.74, 128.97, 129.02, 129.21129.23, 129.25
(10 Ar-C); 136.20 (q Ar-C); 176.37, 176.67 (2 ϫ CϭO). 31P-NMR
(CDCl3, 202 MHz), δ (ppm): 30.22, 31.44. CI-MS m/z 506 ([M ϩ
H]ϩ).
1
CH2-CH2); 20.63 (CϭO-CH3); 23.05 (d, JC,P ϭ 140.1 Hz, P-CH2);
26.91 (6 ϫ CH3); 38.84 (2 ϫ C(CH3)3); 50.90 (N-CH2); 81.61 (d,
2JC,P ϭ 6.5 Hz, 2 ϫ P-O-CH2); 173.08 (CϭO); 177.06 (2 ϫ CϭO).
31P-NMR (CDCl3, 161 MHz), δ (ppm): 35.60. FAB-MS m/z 426
([M ϩ H]ϩ). Anal. calcd. for C17H32NO9P (%): C 47.50, H 7.58, N
3.29. Found (%): C 47.76, H 7.84, N 3.21.
[3-(Acetylhydroxyamino)propyl]-phosphonic
acid-bis[1-(2,2-di-
methylpropionyloxy)ethyl]ester 7c
Light red viscous oil, yield 83%. IR (film), cmϪ1: 3193 (OH), 1743
(O-CϭO), 1657 (N-CϭO). 1H-NMR (CDCl3, 400 MHz), δ (ppm):
1.15 (s, 18 H, 2 ϫ C(CH3)3); 1.45Ϫ1.49 (m, 6 H, 2 ϫ CH3);
1.82Ϫ1.86 (m, 4 H, 2 ϫ CH2); 2.10 (s, 3 H, H3C-CϭO); 3.49Ϫ3.84
(m, 2 H, N-CH2); 6.39Ϫ6.48 (m, 2 H, 2 ϫ P-O-CH). 13C-NMR
(CDCl3, 100 MHz, COM, DEPT), δ (ppm): 17.81, 17.86, 18.15 (P-
CH2-CH2); 19.56 (CϭO-CH3); 20.52, 20.57 (2 ϫ CH-CH3); 21.60,
21.72, 22.01, 22.71, 22.85, 23.12 (P-CH2); 25.80 (6 ϫ CH3); 37.58,
37.65 (2 ϫ C(CH3)3); 46.30 (N-CH2); 88.78, 88.83, 89.36, 89.41,
90.03, 90.06, 90.09, 90.15 (2 ϫ P-O-CH); 171.80, 171.90 (CϭO);
175.23, 175.44, 175.78, 175.97 (2 ϫ CϭO). 31P-NMR (DMSO-d6
202 MHz), δ (ppm): 28.40, 29.69, 29.97. HRFAB-MS m/z 454.2228
for [M ϩ H]ϩ (calcd. 454.2206 for C19H36NO9PH).
[3-[Acetyl(phenylmethoxy)amino]propyl]-phosphonic acid-benzyl-
[1-(hexadecanoyloxy)ethyl]ester 9b
White waxy solid, yield 5%, mp 32Ϫ34°C. IR (film), cmϪ1: 1751
(O-CϭO), 1666 (N-CϭO). 1H-NMR (DMSO-d6, 500 MHz), δ
(ppm): 0.85 (t, 3 H J ϭ 7.0 Hz, CH2-CH3); 1.23 (m, 24 H, 12 ϫ
CH2); 1.40 (d, 3 H J ϭ 5.3 Hz, P-O-CH-CH3); 1.46 (t, 2 H, J ϭ 6.9
Hz, CH2); 1.76 (m, 4 H, 2 ϫ CH2); 2.00 (s, 3 H, CϭO-CH3); 2.25
(t, 2 H, J ϭ 7.3 Hz, CϭO-CH2); 3.64 (t, 2 H, J ϭ 6.7 Hz, N-CH2);
4.84 (s, 2 H, N-O-CH2); 4.95Ϫ5.05 (m, 2 H, P-O-CH2); 6.40 (dq, 1
[3-(Acetylhydroxyamino)propyl]-phosphonic acid-bis[1-(benzoyl-
oxy)ethyl]ester 7d
3
3
H, JH,H ϭ 5.3 Hz, JH,P ϭ 7.3 Hz, P-O-CH-CH3); 7.33Ϫ7.42 (m,
10 H, Ar-H). 13C-NMR (DMSO-d6, 125 MHz, COM, DEPT), δ
(ppm): 14.37 (CH2-CH3); 21.82 (CϭO-CH3); 21.85 (CH-CH3);
22.51, 24.49, 28.68, 29.03, 29.12, 29.26, 29.36, 29.42, 29.45, 29.47,
29.49, 31.72, 33.71 (16 ϫ CH2); 66.43 (P-O-CH2); 79.14 (N-O-CH2);
90.39, 90.43 (P-O-CH-CH3); 128.11, 128.61, 128.87, 129.09, 129.79
(10 Ar-C); 136.86 (q Ar-C); 171.83 (CϭO). ESI-MS m/z 682 ([MϪH
ϩ Na]ϩ), 677, 660 ([M ϩ H]ϩ).
Light red viscous oil, yield 90%. IR (film), cmϪ1: 3187 (OH), 1725
(O-CϭO), 1650 (N-CϭO). 1H-NMR (CDCl3, 500 MHz), δ (ppm):
1.61Ϫ1.68 (m, 6 H, 2 ϫ CH-CH3); 1.92Ϫ2.18 (m, 7 H, 2 ϫ CH2 ϩ
H3C-CϭO); 3.61Ϫ3.74 (m, 2 H, N-CH2); 6.74Ϫ6.91 (m, 2 H, 2 ϫ
P-O-CH); 7.40Ϫ7.48 (m, 2 H, Ar-H); 7.56Ϫ7.62 (m, 1 H, Ar-H);
7.99 Ϫ8.07 (m, 2 H, Ar-H). 13C-NMR (CDCl3, 125 MHz, COM,
DEPT), δ (ppm): 18.78, 19.01, 19.04 (P-CH2-CH2); 20.61, 20.56
(CϭO-CH3); 21.56, 21.62, 21.70, 21.75, 21.80 (2 ϫ CH-CH3); 22.83,
23.08, 23.96 (P-CH2); 47.33, 47.40 (N-CH2); 90.34, 90.38, 90.96,
91.00, 91.04, 91.47, 91.51, 91.61, 91.64 (2 ϫ P-O-CH); 128.42,
128.51, 128.57, 128.59, 128.87, 128.91, 128.95, 129.23, 129.87,
129.93, 129.96, 129.97 (10 Ar-C); 133.66, 133.74, 133.78, 133.83 (2
q Ar-C); 164.36 (CϭO); 172.87 (2 ϫ CϭO). FAB-MS m/z 494
Hydrogenation
1 mmol of the appropriate benzyl protected compound was dis-
solved in methanol (10 mL) and hydrogenated at atmospheric pres-
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
Prodrugs of FR900098 with improved antimalarial activity
313
([M ϩ H]ϩ), 516 ([M ϩ Na]ϩ). Anal. calcd. for C23H28NO9P (%):
C 55.98, H 5.72, N 2.84. Found (%): C 55.91, H 5.23, N 2.81.
O-CH2); 3.74 (t, 2 H, 3J ϭ 5.0 Hz, N-CH2); 6.48Ϫ6.56 (m, 2 H, 2
ϫ P-O-CH-CH3). 13C-NMR (CDCl3, 125 MHz, COM, DEPT), δ
(ppm): 14.22 (2 ϫ CH2-CH3); 21.71, 20.67 (2 ϫ CH3); 34.14, 32.01,
29.78, 29.55, 29.46, 29.33, 29.12, 24.61, 22.78 (30 ϫ CH2); 47.30,
47.17 (N-CH2); 90.98, 90.78, 90.73, 90.27, 90.20, 89.84, 89.79 (2 ϫ
P-O-CH-CH3); 172.35, 171.87, 171.69 (3 ϫ CϭO). HRFAB-MS m/z
784.5447 [M ϩ Na]ϩ (calcd. 784.5468 for C41H80NO9PNa).
[3-(Acetylhydroxyamino)propyl]-phosphonic acid-bis[1-(acetyloxy)-
ethyl]ester 7e
Light red viscous oil, yield 80%. IR (film), cmϪ1: 3183 (OH), 1754
(O-CϭO), 1650 (N-CϭO). 1H-NMR (CDCl3, 500 MHz), δ (ppm):
1.53Ϫ1.56 (m, 6 H, 2 ϫ CH-CH3); 1.60Ϫ1.99 (m, 4 H, 2 ϫ CH2);
2.10 (m, 6 H, 2 ϫ H3C-CϭO-O); 2.16 (s, 3 H, H3C-CϭO-N);
3.68Ϫ3.81 (m, 2 H, N-CH2); 6.47Ϫ6.55 (m, 2 H, 2 ϫ P-O-CH);
9.28 (bs, 1 H, OH). 13C-NMR (CDCl3, 125 MHz, COM, DEPT), δ
(ppm): 18.79, 18.83, 18.88 (P-CH2-CH2); 20.55, 20.90, 20.93, 21.44,
21.49, 21.52, 21.57, 21.58, 21.61, 21.62 (5 ϫ CH3); 22.71, 22.74,
22.78, 22.99, 23.86, 23.89, 24.13 (P-CH2); 47.22, 47.28 (N-CH2);
89.87, 89.93, 90.28, 90.33, 90.64, 90.68, 90.94, 90.99 (2 ϫ P-O-CH);
168.79,168.97, 169.25, 169.33 (CϭO); 172.89, 172.96 (CϭO). ESI-
MS m/z 370 ([M ϩ H]ϩ), 393 ([M ϩ Na]ϩ). Anal. calcd. for
C13H24NO9P (%): C 42.28, H 6.55, N 3.79. Found (%): C 42.08, H
6.77, N 3.86.
[3-(Acetylhydroxyamino)propyl]-3,7-dimethyl-5-oxide-2,4,6,8-
tetraoxa-5-phosphanonanedioic acid-dimethyl ester 7h
Light red viscous oil, yield 93%. IR (film), cmϪ1: 3150 (OH), 1759
(O-CϭO), 1633 (N-CϭO). 1H-NMR (CD3OD, 500 MHz), δ (ppm):
1.54Ϫ1.57 (m, 6 H, 2 ϫ P-O-CH-CH3); 1.80Ϫ1.96 (m, 4 H, 2 ϫ
CH2); 2.10 (s, 3 H, CϭO-CH3); 3.63Ϫ3.68 (m, 2 H, N-CH2);
3.80Ϫ3.81 (m, 6 H, 2 ϫ O-CH3); 6.38Ϫ6.47 (m, 2 H, 2 ϫ P-O-CH-
CH3). 13C-NMR (CD3OD, 125 MHz, COM, DEPT), δ (ppm):
18.88 (P-CH2-CH2); 19.45 (N-CϭO-CH3); 20.37, 20.41, 20.47,
20.51, 20.54 (2 ϫ O-CH-CH3); 22.82, 23.42, 23.82 (P-CH2); 54.39,
54.41, 54.45 (CϭO-O-CH3); 93.97, 94.37 (2 ϫ O-CH); 153.81,
154.03 (CϭO). HRFAB-MS 402.1201 [M ϩ H]ϩ (calcd. 402.1165
for C13H24NO11PH).
[3-(Acetylhydroxyamino)propyl]-phosphonic acid-bis[1-(propionyl-
oxy)ethyl]ester 7f
[3-Acetylhydroxyamino)propyl]-3,7-dimethyl-5-oxide-2,4,6,8-
Light red viscous oil, yield 80%. IR (film), cmϪ1: 3185 (OH), 1754
(O-CϭO), 1650 (N-CϭO). 1H-NMR (CDCl3, 400 MHz), δ (ppm):
1.15 ϩ 1.16 (2 ϫ t, 3J ϭ 7.5 Hz, 6 H, 2 ϫ CH2-CH3); 1.53Ϫ1.56
(m, 6 H, 2 ϫ CH-CH3); 1.89Ϫ2.00 (m, 4 H, 2 ϫ CH2); 2.17 (s, 3
H, H3C-CϭO); 2.36Ϫ2.41 (m, 4 H, 2 ϫ C H2- CH3); 3.63Ϫ3.85 (m,
2 H, N-CH2); 6.47Ϫ6.58 (m, 2 H, 2 ϫ P-O-CH); 9.32 (bs, 1 H,
OH). 13C-NMR (CDCl3, 100 MHz, COM, DEPT), δ (ppm): 8.75,
8.79 (2 ϫ CH2-CH3); 15.57, 15.72, 15.84, 15.97, 16.26, 16.41, 16.34
(4 ϫ CH-CH3); 18.81, 18.85 (P-CH2-CH2); 20.51, 20.55, 20.57 (Cϭ
O-CH3); 22.21, 22.62, 22.74, 23.74, 23.82, 23.86 (P-CH2); 27.45,
27.47, 27.50 (2 ϫ CH2-CH3); 32.89, 32.93, 32.99, 33.03, 33.05 (2 ϫ
CH); 47.19, 47.23, 47.29, 47.34, 47.92 (N-CH2); 94.93, 94.98, 95.18,
95.24, 95.30 (2 ϫ O-CH-O); 172.50, 172.74, 172.83, 172.91 (CϭO).
FAB-MS m/z 398 ([M ϩ H]ϩ). Anal. calcd. for C15H28NO9P (%):
C 45.34, H 7.12, N 3.52. Found (%): C 45.38, H 7.52, N 3.69).
tetraoxa-5-phosphanonanedioic acid-diethyl ester 7i
Light red viscous oil, yield 93%. IR (film), cmϪ1: 3187 (OH), 1758
(O-CϭO), 1649 (N-CϭO). 1H-NMR (DMSO-d6, 500 MHz), δ
(ppm): 1.22Ϫ1.25 (m, 6 H, 2 ϫ CH2-CH3); 1.47Ϫ1.51 (m, 6 H, 2
ϫ CH-CH3); 1.68Ϫ1.84 (m, 4 H, 2 ϫ CH2); 1.98 (s, 3 H, CϭO-
CH3); 3.48Ϫ3.55 (m, 2 H, N-CH2); 4.14Ϫ4.20 (m, 4 H, O-CH2-
CH3); 6.29Ϫ6.36 (m, 2 H, 2 ϫ P-O-CH). 13C-NMR (DMSO-d6,
125 MHz, COM, DEPT), δ (ppm): 13.83 (2 ϫ CϭO-O-CH2-CH3);
19.40 (CH2-CH2); 20.19 (CϭO-CH3); 21.33, 21.29, 21.25, 21.21,
21.14, 21.11 (2 ϫ P-O-CH-CH3); 23.68, 22.56 (P-CH2); 47.29, 47.12
(N-CH2); 64.16, 64.13, 64.07 (2 ϫ CϭO-O-CH2); 93.11, 93.08,
93.03, 92.91, 92.87, 92.60, 92.54 (2 ϫ P-O-CH-CH3); 152.45, 152.29
(2 ϫ O-CϭO-O); 170.39 (CϭO-CH3). 31P-NMR (CDCl3, 202
MHz), δ (ppm): 29.95, 27.95, 26.18. ESI-MS m/z (%): 881 ([2 MϪH
ϩ Na]ϩ), 468 ([MϪH ϩ K]ϩ), 452 ([MϪH ϩ Na]ϩ), 430 ([M ϩ
H]ϩ). Anal. calcd. for C15H28NO11P (%): C 41.93, H 6.57, N 3.26.
Found (%): C 41.21, H 6.37, N 3.54.
[3-Acetylhydroxyamino)propyl]-phosphonic acid-bis[2-methyl-1-(1-
oxopropoxy)propyl]ester 7g
Light red viscous oil, yield 94%. IR (film), cmϪ1: 3188 (OH), 1754
(O-CϭO), 1656 (N-CϭO). 1H-NMR (CDCl3, 500 MHz), δ (ppm):
0.95Ϫ1.00 (m, 12 H, 4 ϫ CH3); 1.15Ϫ1.18 (m, 6 H, 2 ϫ CH3);
1.90Ϫ2.08 (m, 6 H, 2 ϫ CH2 ϩ 2 ϫ CH); 2.16 (s, 3 H, H3C-CϭO);
2.34Ϫ2.46 (m, 4 H, 2 ϫ CH2); 3.62Ϫ3.84 (m, 2 H, N-CH2);
6.26Ϫ6.34 (m, 2 H, 2 ϫ P-O-CH); 9.22Ϫ9.36 (m, 1 H, OH). 13C-
NMR (CDCl3, 125 MHz, COM, DEPT), δ (ppm): 8.75, 8.79 (2 ϫ
CH2-CH3); 15.57, 15.72, 15.84, 15.97, 16.26, 16.41, 16.34 (4 ϫ CH-
CH3); 18.81, 18.85 (P-CH2-CH2); 20.51, 20.55, 20.57 (CϭO-CH3);
22.21, 22.62, 22.74, 23.74, 23.82, 23.86 (P-CH2); 27.45, 27.47, 27.50
(2 ϫ CH2-CH3); 32.89, 32.93, 32.99, 33.03, 33.05 (2 ϫ CH); 47.19,
47.23, 47.29, 47.34, 47.92 (N-CH2); 94.93, 94.98, 95.18, 95.24, 95.30
(2 ϫ O-CH-O); 172.50, 172.74, 172.83, 172.91 (CϭO). HRFAB-MS
m/z 454.2208 [M ϩ H]ϩ (calcd. 454.2206 for C19H36NO9PH).
[3-(Acetylhydroxyamino)propyl]-phosphonic acid-mono-[1-(2,2-di-
methylpropionyloxy)ethyl]ester 10a
Light red solid, yield 86%, mp 92Ϫ94°C. IR (KBr), cmϪ1: 3177
(OH), 1738 (O-CϭO), 1623 (N-CϭO). 1H-NMR (CDCl3, 500
1
MHz), δ (ppm): H-NMR (CDCl3, 500 MHz), δ (ppm): 1.11Ϫ1.16
(m, 9 H, C(CH3)3); 1.31Ϫ1.47 (m, 5 H, CH2 ϩ CH3); 1.67Ϫ1.80
(m, 2 H, CH2); 1.94Ϫ1.97 (m, 3 H, CH3); 3.44Ϫ3.54 (m, 2 H, N-
CH2); 6.27Ϫ6.43 (m, 1 H, P-O-CH). 13C-NMR (DMSO-d6, 100
MHz, COM, DEPT) δ (ppm): 20.96 (CϭO-CH3); 21.92, 21.41 (P-
CH2-CH2); 22.64 (P-O-CH-CH3); 25.10 (P-CH2); 27.59, 27.263
27.02 (C(CH3)3); 38.68, 38.28 (C(CH3)3); 47.92 (N-CH2); 91.57,
91.02, 90.96, 89.96 (P-O-CH-CH3); 170.43 (CϭO); 176.61 (CϭO).
31P-NMR (CDCl3, 202 MHz), δ (ppm): 23.79, 21.47. FAB-MS
m/z326 ([M ϩ H]ϩ). Anal. calcd. for C12H24NO7P (%): C 44.31, H
7.44, N 4.31. Found (%): C 44.39, H 6.65, N 4.19.
[3-(Acetylhydroxyamino)propyl]-phosphonic
acid-bis[1-(hexa-
decanoyloxy)ethyl]ester 7k
[3-(Acetylhydroxyamino)propyl]-phosphonic acid-mono-[1-(hexa-
decanoyloxy)ethyl]ester 10b
Light red waxy solid, yield 85%, mp 34°C. IR (film), cmϪ1: 3192
(OH), 1754 (O-CϭO), 1627 (N-CϭO). 1H-NMR (CDCl3, 500
MHz), δ (ppm): 0.88 (t, 6 H, 3J ϭ 6.9 Hz, 2 ϫ CH2-CH3); 1.25Ϫ1.31
(m, 48 H, 24 ϫ CH2); 1.52Ϫ1.55 (m, 6 H, 2 ϫ P-O-CH-CH3);
1.59Ϫ1.65 (m, 4 H, 2 ϫ CH2); 1.87Ϫ1.99 (m, 4 H, 2 ϫ CH2);
Light red waxy solid, yield 89%, mp 34Ϫ36°C. IR (film), cmϪ1
:
3400Ϫ2200 (b, OH), 1703 (O-CϭO), 1613 (N-CϭO). 1H-NMR
(CD3OD, 500 MHz), δ (ppm): 1.22Ϫ1.37 (m, 26 H, 13 ϫ CH2);
1.48Ϫ1.75 (m, 5 H, CH2 ϩ P-O-CH-CH3); 1.84Ϫ1.94 (m, 2 H,
3
2.16Ϫ2.17 (m, 3 H, CϭO-CH3); 2.34 (t, 4 H, J ϭ 7.1 Hz, 2 ϫ Cϭ
© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

314
Schlitzer et al.
Arch. Pharm. Chem. Life Sci. 2005, 338, 305−314
CH2); 2.00 (s, 3 H, CϭO-CH3); 2.36Ϫ2.25 (m, 2 H, CϭO-CH2);
3.67 (t, 2 H, 3J ϭ 6.5 Hz, N-CH2); 6.49 (bs, 1 H, P-O-CH-CH3);
0.89 (t, 3 H, 3J ϭ 6.9 Hz, CH2-CH3). 13C-NMR (CD3OD, 125
MHz, COM, DEPT), δ (ppm): 14.47 (CϭO-CH3);19.21, 20.23 (2 ϫ
CH3); 21.57, 23.76, 26.14, 30.28, 30.50, 30.64, 30.80, 33.11, 35.00
(16 ϫ CH2); 102.74 (P-O-CH); 173.99 (N-CϭO); 177.74 (O-CϭO).
ESI-MS m/z 478 (Mϩ). Anal. calcd. for C23H46NO7P (%): C 64.62,
H 10.58, N 1.84. Found (%): C 63.77, H 10.53, N 1.84.
[8] H. T. Serafinowska, R. J. Ashton, S. Bailey, M. R. Harnden,
S. M. Jackson, D. Sutton, J. Med. Chem. 1995, 38, 1372-1379.
[9] The chloroalkyl esters were prepared by reaction of acetalde-
hyde (or isobutyraldehyde in case of 6g) with the appropriate
acid chloride. K. Fleischmann, F. Adam, W. Dürckheimer, W.
Hertzsch, R. Hörlein, H. Jendralla, C. Lefebvre, P. Mackiewicz,
J.-M. Roul, T. Wollmann, Liebigs Ann. 1996, 1735Ϫ1741; W. S.
Saari, M. B. Freedman, R. D. Hartman, S. W. King, A. W.
Raab, W. C. Randall, E. L. Engelhardt, R. Hirschmann, J.
Med. Chem. 1978, 21, 746Ϫ753.
References
[10] Prepared from 1-chloroethyl carbonochloridate and methanol
according to G. Barcelo, J.-P. Sent, G. Sennyey, Synthesis 1986,
8, 627Ϫ632.
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[12] 7a was dissolved in H2O. The other prodrugs were dissolved in
DMSO at 150 mg/mL and further diluted in SSV (standard
suspension vehicle; 0.5% Na-carboxymethylcellulose, 0.5%
benzyl alcohol, 0.4%Tween 80). FR900098 was dissolved in
H2O (for comparison with 7a) or SSV (for comparison with
the other prodrugs). Parasitaemia was monitored by Giemsa-
stained blood smears. Mice were sacrificed when parasitaemia
was exceeding approx. 40%. Five mice were used for each treat-
ment group, and four mice for the untreated control group.
Results were expressed as geometric mean values for each
group.
[3] T. Tsuchiya, K. Ishibashi, M. Terakawa, M. Nishiyama, N.
Itoh, H. Noguchi, Eur. J. Drug. Metab. Pharmacokinet. 1982,
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[13] When calculating the dosages in molar units instead of mass
units (40 mg/kg FR900098 ϭ 0.18 mmol/kg; 20 mg/kg 7e ϭ
0.054 mmol/kg), 7e has three-fold increased activity compared
with FR900098.
[6] T. Kurz, D. Geffken, C. Wackendorff, Z. Naturforsch., B:
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© 2005 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim