Nonnucleoside HIV-1 reverse-transcriptase inhibitors, part 5.1) synthesis and anti-HIV-1 activity of novel 6-naphthylthio HEPT analogues

Article abstract of DOI:10.1248/cpb.53.886

As part of a series of studies to discover new HIV reverse-transcriptase inhibitors, various novel 6 α- and 6 β-naphthylthio 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio) thymine (HEPT) derivatives were synthesized, and in vitro anti-HIV-1 activity was evaluated. The results revealed that most of 6α-naphthylthio HEPT derivatives (7a - w) showed good activity [for 7e, IC₅₀ value of 0.048 μM and selectivity index (SI) value of 735; for 7h, IC₅₀ value of 0.057 μM and SI value of 579; for 7k, IC₅₀ value of 0.063 μM and SI value of 565], 6 β-naphthylthio HEPT derivatives (8a - f) showed low activity, but the introduction of α nitro group to the C-1 position of the 6 β-naphthyl ring in the 6 β-naphthylthio series (11a - c) resulted in a dramatic increase in anti-HIV-1 activity.

Full text of DOI:10.1248/cpb.53.886

886
Chem. Pharm. Bull. 53(8) 886—892 (2005)
Vol. 53, No. 8
Nonnucleoside HIV-1 Reverse-Transcriptase Inhibitors, Part 5.1)
Synthesis and Anti-HIV-1 Activity of Novel 6-Naphthylthio HEPT
Analogues
Guang-Fu SUN,a Xu-Xiang CHEN,b Fen-Er CHEN,*,a Yue-Ping WANG,a Erik De CLERCQ,c
c
Jan BALZARINI,c and Christophe PANNECOUQUE
b
a Department of Chemistry, Fudan University; Shanghai 200433, People’s Republic of China: School of Pharmaceutical
c
Engineering, Shenyang Pharmaceutical University; 110016, People’s Republic of China: and Rega Institute for Medical
Research, Katholieke Universiteit Leuven; 10 Minderbroedersstraat, B-3000 Leuven, Belgium.
Received November 8, 2004; accepted March 25, 2005
As part of a series of studies to discover new HIV reverse-transcriptase inhibitors, various novel 6a- and 6b-
naphthylthio 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio) thymine (HEPT) derivatives were synthesized, and in
vitro anti-HIV-1 activity was evaluated. The results revealed that most of 6a-naphthylthio HEPT derivatives
(7a—w) showed good activity [for 7e, IC50 value of 0.048 mM and selectivity index (SI) value of 735; for 7h, IC50
value of 0.057 mM and SI value of 579; for 7k, IC50 value of 0.063 mM and SI value of 565], 6b-naphthylthio HEPT
derivatives (8a—f) showed low activity, but the introduction of a nitro group to the C-1 position of the 6b-naph-
thyl ring in the 6b-naphthylthio series (11a—c) resulted in a dramatic increase in anti-HIV-1 activity.
Key words nonnucleoside reverse-transcriptase inhibitor; 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio) thymine (HEPT) ana-
logue; HIV-1; mutation
As a key component in combination therapy for acquired research and to investigate thoroughly the structure–activity
immunodeficiency syndrome (AIDS), nonnucleoside reverse- relationship at N-1 and C-6 of HEPT derivatives, we initiated
transcriptase inhibitors (NNRTIs) play an essential role in the present study of the synthesis and biological evaluation
suppressing HIV-1 replication.2) Unlike nucleoside reverse- of 6-naphthylthio-substituted HEPT analogues.
transcriptase inhibitors (NRTIs),3) NNRTIs generally show
low toxicity since they do not bind to cellular polymerases, Chemistry
but interact with a specific allosteric site adjacent to the poly-
The synthetic route to 6-naphthylthio HEPT analogues
merase site of HIV-1 RT and thus lead to a noncompetitive (7a—w, 8a—f) is depicted in Chart 1. The 6-chlorouracil de-
mechanism.4,5) Many efforts have been made to develop rivatives 5a—e were known to be readily available from bar-
NNRTIs for the treatment of AIDS in the past two decades, bituric acid derivatives 4a—e14); the intermediates 6a—w
and more than 30 structurally different classes of NNRTIs were prepared by silylation and N-1 alkylation of 5a—e
have been identified to have high anti-HIV activity,6,7) from under three different conditions15—17): 1) compounds 6a—p
among which the three drugs nevirapine, delavirdine, and were prepared in 74—97% yields by silylation of 5a—e with
efavirenz are currently approved by the US FDA for clinical N,O-bis-(trimethylsilyl)-acetamide (BSA) in CH2Cl2, fol-
use.8) However, their clinical use is limited by the rapid lowed by N-1 alkylation with various alkyloxy chloromethyl
development of drug-resistant viral strains.9) Therefore re- ethers using tetrabutylammonium iodide as a catalyst; 2)
search interest in the NNRTI field is now focused on looking 6q—v were prepared in 36—58% yields by silylation of
for novel NNRTIs with the ability to inhibit both wild type 5b, c with BSA in CH3CN and in situ N-1 alkylation with
HIV-1 and clinically resistant mutants.
different acetals using TMS triflate as a catalyst; 3) 6w was
1-[(2-Hydroxyethoxy)methyl]-6-(phenylthio) thymine prepared in 54% yield by N-1 alkylation of 5c with 2-ace-
(HEPT, 1) analogues are an attractive class of NNRTIs, some toxyethyl acetoxymethyl ether in the presence of SnCl4 as a
of which have been found to show high activity against mu- catalyst. Subsequently, the target 5-alkyl-1-alkyloxymethyl-
tant HIV-1 strains,10,11) such as GCA-186 (2a), TNK6123 6a-naphthanethiouracils (7a—v) and 6b-isomers (8a—f)
(2b), etc. Very recently, based on the crystal structure of were obtained by sulfenylation of 6a—v using two methods:
HEPT analogues complexed with RT4) and our 3D-QSAR 1) 7a—v were prepared by sulfenylation of 6a—v with
studies of HEPT analogues, we have designed and synthe- a-naphthanethiol in C2H5OH and 1 M ethanolic NaOH solu-
sized a series of 6-naphthylmethyl HEPT analogues (3) with tion in 59—96% yields. 2) Owing to the unpleasant smell
high anti-HIV-1 activity and moderate activity against the from a and b-naphthanethiol, the above sulfenylation
Y181CꢀK103N mutant.12,13) In continuation of the above method was modified with a one-pot reduction-sulfenyla-
tion.18) Thus 1-alkoxymethyl-5-alkyl-6-chlorouracils (6a—
f, w) were reacted with dinaphthyl disulfides and NaBH4
using CH3OH as a solvent to afford the target compounds 7w
and 8a—f in 69—90% yields.
The synthesis of 6-(1-substituted 2-naphthylthio) HEPT
derivatives (11a—c, 12a—c, 13) is shown in Chart 2. 5-
Ethyl-6-chlorouracil 5b was transferred to the thioether 9 fol-
Fig.
1
lowing the route to 8a—f shown in Chart 1. The nitration of
∗ To whom correspondence should be addressed. e-mail: rfchen@fudan.edu.cn
© 2005 Pharmaceutical Society of Japan

August 2005
887
Chart 1. Synthesis of 6-Naphthylthio HEPT Analogues (7a—w)
Chart 2. Synthesis of 6-(1-Substituted-2-naphthylthio) HEPT Analogues
9 with concentrated HNO3/H2SO4 provided the crude 6-(1-
nitro-2-naphthylthio) ethyluracil 10, without separation,
which was directly subjected to the next N-1 alkylation with
various alkyl chloromethyl ethers to afford 6-(1-nitro-2-naph-
thylthio) HEPT derivatives 11a—c in 22—37% yields. The
1
structures of 11a—c were elucidated based on H-NMR
spectra, in which four doublets and two quadruplets in the
naphthyl region were observed, and no singlet was present in
the naphthyl region. This clearly indicated that the nitro sub-
stituent should be located at the C-1 position of the 2-naph-
thyl ring. Further reduction of the nitro groups in 11a—c
with Na2S2O3 in CH3OH/CH2Cl2 formed 6-(1-amine-2-naph-
thylthio) HEPT derivatives 12a—c in 51—65% yields. Acy-
lation of 12c with acetyl chloride in the presence of Et3N in
CH2Cl2 provided 6-(1-acetylamine-2-naphthylthio) HEPT
derivative 13 in 32% yield.
The synthesis of 6-(1-chloro-2-naphthylthio) HEPT deriv-
ative 15 is shown in Chart 3. Compound 12a was reacted
with NaNO2/CuCl/concentrated HCl via Sandmeryer’s reac-
tion/dealkylation to provide 14 in 39% yield. Realkylation of
14 with methyloxy chloromethyl ether in CH2Cl2 produced
the target compound 15 in 64% yield.
Chart 3. Synthesis of 6-(1-Chloro-2-naphthylthio) HEPT Analogues (15)
Results and Discussion
The target compounds 7a—w, 8a—f, 11a—c, 12a—c, 13,
and 15 together with HEPT and 2,3-dideoxy inosine (DDI)
were examined for their activity against wild-type HIV-1 in
MT-4 cells, and some were also selected for testing against
the NNRTI-resistant strain S0561945 with Y181CꢀK103N
mutations. The results are listed in Table 1.
Most of the 6a-naphthylthio series 7a—w showed high
activity against wild-type HIV-1. In particular, 1-benzyl-
oxymethyl-5-ethyl-6-(1-naphthylthio)uracil 7e was the most
potent, with an IC50 value of 0.048 mM and selectivity index
(SI) of 735, followed by 1-ethoxymethyl-5-isopropyl-6-(1-
naphthylthio)uracil 7h with an IC50 value of 0.057 mM and SI
of 579. Compared with GCA-186 (2a) and TNK6123 (2b),
7e was still 48- and 16-fold less potent against wild-type

888
Vol. 53, No. 8
Table 1. Inhibition of HIV-1 Replication in MT-4 by 6-Naphthylthio Substituted HEPT Analogues
a)
b)
IC50
CC50
S0561845
(mM)
IC50
(mM)
CC50
(mM)
S0561845
(mM)
Compd.
SIc)
Compd.
SI
(mM)
(mM)
7a
7b
7c
7d
7e
7f
7g
7h
7i
0.46
0.18
0.50
0.15
0.048
0.21
0.51
0.057
0.65
0.38
0.063
0.25
1.86
0.83
7.37
2.96
0.21
0.092
12.53
0.11
39.6
52.5
38.78
38.4
87
286
78
250
735
137
75
579
54
85
565
118
20
39
5
37.4
33.4
NDd)
39.3
8.54
ND
ND
338
ND
ND
34.72
ND
ND
ND
ND
ND
ND
28.67
ND
30.67
7u
7v
7w
8a
8b
8c
8d
8e
8f
11a
11b
11c
12a
12b
12c
13c
15
0.067
2.77
0.23
22.02
3.37
0.65
4.69
2.65
0.83
0.47
0.099
0.065
25.99
7.06
3.65
8.78
22.66
5.06
5.37
30.23
31.40
77.07
210.09
42.19
154.50
59.58
36.30
187.34
50.13
43.89
34.19
180.48
195.23
ꢂ37.88
155.47
192.90
405.37
529
451
11
340
ND
ND
ND
212.6
42.19
ND
9.5
34.28
28.73
38.40
33.20
35.58
32.75
35.30
29.60
37.11
32.57
36.12
32.51
31.47
30.96
171.92
32.82
13
238
13
ND
14
34.73
289.4
49.87
46.63
34.34
198.04
42.32
ꢂ57.7
ꢂ26.74
205.32
500
228
107
446
466
7
28
ꢂ10
18
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
11
150
326
14
8.5
79
98
HEPT
DDI
7.15
327
a) Inhibitory concentration of compound achieving 50% inhibition of HIV-1 multiplication in MT-4 infected cells. b) Cytotoxic concentration of compound required to re-
duce the viability of normal uninfected MT-4 cells by 50%. c) Selectivity index: ratio CC50/IC50. d) NDꢃnot tested.
HIV-1.
tive 7d was found to be less potent, with an IC50 value of
The 6b-naphthylthio series 8a—f generally showed low 0.15 mM.
activity, and their results were in full agreement with those of
Some target compounds were also examined for ac-
our reported 6a- and 6b-naphthylmethyl HEPT analogues.12) tivity against the NNRTI-resistant strain S0561945 with
However, the corresponding 6b-1-nitro-naphthylthio series Y181CꢀK103N mutations. Only compound 7e was found to
11a—c showed remarkable activity against wild-type HIV-1 show good activity against the resistant strain, with an IC50
and were, respectively, 47-, 34-, and 10-fold more active than value of 8.54 mM. However, that was 178-fold less than its ac-
their corresponding unsubstituted 6b-naphthylthio com- tivity against the wild-type strain, and therefore compound
pounds 8a—c. However, no increase in activity was observed 7e was still sensitive to the Y181CꢀK103N mutation.
for compounds 12a—c with a-amino, 15 with a-chloro, and
13 with a-acetamino substituents. Based on a molecular Conclusion
modeling study, we deduced that this difference in antiviral
The present paper describe the synthesis and structure–
activity might be due to the following reasons: 1) the a-nitro activity relationships of a new series of 6a- and 6b-naph-
group in 11a—c could reduce the electron density of the 6b- thylthio analogues of HEPT. Of these, 7e in particular
naphthyl ring, thereby enhancing the p–p stacking interac- showed the greatest activity against both wild-type HIV-1
tion between the 6b-naphthyl ring and the phenyl group of MT-4 strain and the Y181CꢀK103N mutant strain; signifi-
Tyr181, 188 in RT; however, the a-amino substituent at an cant effects on structural modification were obtained by the
equivalent position could decrease this action, and thus the introduction of a nitro group to the C-1 position of the 6b-
6b-1-nitro-naphthylthio series 11a—c contributed more to naphthyl ring.
the potency against HIV-1 than the 6b-1-amino-naphthylthio
Experimental
series 12a—c. 2) Concerning the lower activity of 6b-1-
Melting points (mp) were measured on a WRS-1B digital melting point
chloro-naphthylthio analogue 15 than that of its 6b-1-nitro-
naphthylthio counterpart 11a, we suggest there might be an
H-bond interaction between the a-nitro group and phenolic
group of Tyr181, but this viewpoint needs to be further vali-
apparatus. IR spectra were recorded on an Avvatar 360 FT-IR instrument.
1H- and 13C-NMR spectra were recorded with a Bruker DMX500 (500 MHz)
or JEOL EX-400 (400 MHz) spectrometers. Chemical shifts (d) were ex-
pressed in ppm with the protonated solvent as a reference. Mass spectra
(MS) were recorded on MAT95 and for the electronic impacts (EI) at 70 eV.
Column chromatography was performed with silica gel G (300—400 mesh),
dated by theoretical calculations.
We also investigated the structure–activity relationships of
the N-1 side chain in the 6a-naphthylthio series. When the
C-5 substituent was an isopropyl group (for 7g—l, s—w), the
1-ethoxy derivative 7h proved to be the most active, followed
by 1-benzyloxy derivative 7k and 1-(4-fluorobenzyloxy) de-
rivative 7u; the others such as 1-(3-fluorobenzyloxy) deriva-
tive 7t, 1-hydroxyethoxy derivative 7w, etc., had much less
potency than the above three compounds. When the C-5 sub-
stituent was an ethyl group (for 7c—f, q—r), the 1-benzyl-
oxy derivative 7e was found to be the most potent, followed
and TLC was performed on plates coated with silica gel GF254. Solvents
were purified using standard procedures.19)
Anti-HIV-1 Activity Assays The activity of the compounds against
HIV-1 (HTLV-IIIB strain) and the Y181CꢀK103N mutant strain was based
on the inhibition of virus-induced cytopathologic effects in MT-4 cells using
the MTT method.20) Briefly, virus stocks were titrated in MT-4 cells and ex-
pressed as the 50% cell culture infective dose (CCID50). MT-4 cells were
suspended in culture medium at 1ꢁ105 cells/ml and infected with HIV at a
multiplicity of infection of 0.02. Immediately after viral infection, 100 ml of
the cell suspension was placed in each well of a flat-bottomed microtiter tray
containing various concentrations of the test compounds. The test com-
pounds were dissolved in DMSO at 50 mM or higher. After 4-d incubation at
by 1-(4-fluorobenzyloxy) derivative 7r. The 1-ethoxy deriva- 37 °C, the number of viable cells was determined using the 3-(4,5-di-

August 2005
889
(125 MHz, CDCl3) d: 13.8, 14.9, 64.8, 74.8, 119.9, 123.6, 125.9, 126.0,
126.8, 127.1, 128.1, 128.9, 130.1, 131.1, 134.1, 146.7, 151.3, 162.5. IR
(KBr) cmꢄ1: 3422, 3032, 1701, 1664, 1105. MS m/z (%): 342 (56), 283 (42),
128 (45), 57 (100).
methylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Com-
pounds were tested in parallel for cytotoxic effects in uninfected MT-4 cells.
General Procedure for the Synthesis of 5-Alkyl-1-alkoxymethyl-6-
chlorouracils 6a—p To a stirred suspension of 5-alkyl-6-chlorouracil
5a—e (2.0 mmol) in CH2Cl2 (8 ml) at room temperature under a nitrogen
atmosphere BSA (4.4 mmol) was added dropwise via a syringe, and after
stirring for an additional 30 min, the mixture became clear. n-Bu4NI (7 mg,
0.02 mmol) was added in one portion, the mixture was cooled to 0 °C, alkyl
chloromethyl ether (3.0 mmol) was added dropwise, and then stirring was
continued for an additional 2 h at 0 °C. The mixture was poured into cold
saturated NaHCO3 solution (20 ml) and stirred for 30 min. The organic layer
was separated, and the aqueous phase was extracted with CH2Cl2 (20 mlꢁ2).
The combined organic phases were washed with brine (30 mlꢁ2), dried over
Na2SO4, and evaporated in vacuo to dryness to afford a yellow solid, which
was purified by column chromatography on silica gel with the eluent of
EtOAc and petroleum ether (60—90 °C, 1 : 2) to afford pure 6a—p.
6a: White powder, 87% yield, mp 152—155 °C; 6b: yellow powder, 79%
yield, mp 145—147 °C; 6c: white powder, 93% yield, mp 135—157 °C; 6d:
white powder, 86% yield, mp 124—126 °C; 6e: yellow powder, 81% yield,
mp 117—118 °C; 6f: yellow powder, 83% yield, mp 104—106 °C; 6g: white
powder, 97% yield, mp 138—139 °C; 6h: white powder, 92% yield, mp 93—
94 °C; 6i: white powder, 93% yield, mp 91—93 °C; 6j: white powder, 85%
yield, mp 84—86 °C; 6k: yellow powder, 91% yield, mp 142—143 °C; 6l:
yellow powder, 75% yield, mp 111—114 °C; 6m: white powder, 87% yield,
mp 127—129 °C; 6n: yellow powder, 74% yield, mp 130—131 °C; 6o: white
powder, 91% yield, mp 101—103 °C; 6p: yellow powder, 92% yield, mp
95—97 °C.
General Procedure for the Synthesis of 5-Alkyl-1-alkoxymethyl-6-
chlorouracils (6q—v) To a stirred solution of 5-alkyl-6-chlorouracil 5b, c
(2 mmol) in anhydrous CH3CN (30 ml), BSA (6.0 mmol, 1.56 ml) was added
dropwise under a nitrogen atmosphere via a syringe. After stirring at room
temperature for 30 min, the mixture was cooled to ꢄ50 °C and trimethylsi-
lyltrifluoromethansulfonate (TMS triflate) (0.36 ml, 2 mmol) was added, fol-
lowed by dropwise addition of bis(2-alkenyloxy)methane (4 mmol). The
reaction mixture was then stirred at room temperature for 3—4 h. Cold satu-
rated NaHCO3 solution (10 ml) was added, and the solvent was evaporated
under reduced pressure at room temperature. The residue was extracted with
EtOAc (3ꢁ30 ml), dried over MgSO4 and evaporated under reduced pres-
sure. The product was chromatographed on silica gel using the eluent of
EtOAc and petroleum ether (60—90 °C, 1 : 3) to afford pure 6q—v.
6q: White solid, 44% yield, mp 108—110 °C; 6r: white solid, 36% yield,
mp 113—114 °C; 6s: yellow solid, 58% yield, mp 42—44 °C; 6t: white solid,
48% yield, mp 94—96 °C; 6u: white solid, 40% yield, mp 103—105 °C; 6v:
yellow solid, 58% yield, mp 67—69 °C.
1-[(Benzyloxy)methyl]-5-methyl-6-(1-naphthylthio)uracil (7b) Syn-
1
thesized from 6b as a white solid in 83% yield, mp 158—159 °C. H-NMR
(500 MHz, CDCl3) d: 1.93 (3H, s), 4.63 (2H, s), 5.63 (2H, s), 7.22—7.29
(5H, m), 7.35—8.20 (7H, m), 8.80 (1H, s). 13C-NMR (125 MHz, CDCl3)
d: 13.7, 71.5, 74.9, 120.0, 123.5, 125.9, 126.0, 126.8, 127.1, 127.6, 127.8,
128.0, 128.3, 128.9, 129.9, 131.0, 134.0, 137.2, 146.4, 151.3, 162.5. IR
(KBr) cmꢄ1: 3157, 3031, 1697, 1669, 1585, 1081. MS m/z (%): 404 (8), 283
(15), 217 (30), 91(100).
1-Methoxymethyl]-5-ethyl-6-(1-naphthylthio)uracil (7c) Synthesized
from 6c as a white solid in 72% yield, mp 131—133 °C. 1H-NMR
(400 MHz, CDCl3) d: 1.06 (3H, t, Jꢃ7.3 Hz), 2.41 (2H, q, Jꢃ7.3 Hz), 3.91
(3H, s), 4.51 (2H, s), 6.89—7.97 (7H, m), 9.29 (1H, s). 13C-NMR (100 MHz,
DMSO-d6) d: 13.6, 22.2, 56.4, 76.2, 123.5, 125.8, 125.8, 127.0, 127.4,
127.8, 127.9, 129.4, 130.4, 131.4, 134.1, 144.1, 151.8, 161.5. IR (KBr)
cmꢄ1: 3025, 1711, 1676, 1567, 1075. MS m/z (%): 342 (42), 297 (100), 254
(34), 159 (56), 115 (68).
1-Ethoxymethyl-5-ethyl-6-(1-naphthylthio)uracil
(7d) Synthesized
from 6d as a white powder in 96% yield, mp 166—168 °C. 1H-NMR
(500 MHz, DMSO-d6) d: 0.77 (3H, t, Jꢃ7.3 Hz), 0.88 (3H, t, Jꢃ7.0 Hz),
2.45 (2H, q, Jꢃ7.3 Hz), 3.39 (2H, q, Jꢃ7.0 Hz), 5.29 (2H, s), 7.38—8.18
(7H, m), 11.80 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 13.2, 14.8, 22.1,
64.8, 74.8, 123.4, 125.0, 125.9, 126.6, 126.7, 127.0, 127.7, 128.8, 130.7,
130.9, 134.0, 145.1, 151.6, 162.2; IR (KBr) cmꢄ1: 3026, 1712, 1649, 1579,
1069. MS m/z (%): 356 (56), 297 (100), 254 (31), 115 (74).
1-[(Benzyloxy)methyl]-5-ethyl-6-(1-naphthylthio)uracil (7e) Synthe-
sized from 6e as a white solid in 79% yield, mp 162—166 °C. 1H-NMR
(500 MHz, CDCl3) d: 0.95 (3H, t, Jꢃ7.4 Hz), 2.63 (2H, q, Jꢃ7.3 Hz), 4.58
(2H, s), 5.47 (2H, s), 7.15—7.21 (5H, m), 7.25—8.31 (7H, m), 8.48 (1H, s).
13C-NMR (125 MHz, CDCl3) d: 13.3, 22.1, 71.7, 75.0, 123.4, 125.1, 125.9,
126.7, 126.8, 127.1, 127.5, 127.7, 127.8, 128.3, 128.9, 130.7, 134.1, 137.3,
145.0, 151.4, 161.8. IR (KBr) cmꢄ1: 3034, 1718, 1656, 1581, 1061. MS m/z
(%): 418 (6), 297(15), 217 (30), 91(100).
1-[3-Methyl(benzyloxy)methyl]-5-ethyl-6-(1-naphthylthio)uracil (7f)
1
Synthesized from 6f as a white solid in 71% yield, mp 172—175 °C. H-
NMR (400 MHz, DMSO-d6) d: 0.76 (3H, t, Jꢃ7.3 Hz), 2.38 (3H, s), 2.63
(2H, q, Jꢃ7.3 Hz), 4.45 (2H, s), 5.39 (2H, s), 6.89—7.18 (5H, m), 7.35—
8.14 (7H, m), 11.78 (1H, s). 13C-NMR (100 MHz, DMSO-d6) d: 13.4, 22.2,
31.8, 71.4, 75.1, 123.3, 124.6, 124.9, 125.7, 126.7, 127.1, 127.6, 128.0,
128.1, 128.5, 128.9, 128.9, 130.6, 131.2, 134.1, 137.6, 144.8, 151.4, 161.5.
IR (KBr) cmꢄ1: 3054, 1713, 1669, 1575, 1073. MS m/z (%): 432 (13), 297
(55), 217 (30), 105 (100).
1-[(2-Acetoxyethoxy)methyl]-5-isopropyl-6-chlorouracils (6w) To
a
1-Methoxymethyl-5-isopropyl-6-(1-naphthylthio)uracil (7g) Synthe-
sized from 6g as a white solid in 86% yield, mp 171—173 °C. 1H-NMR
(500 MHz, DMSO-d6) d: 0.98 (6H, d, Jꢃ7.0 Hz), 3.30 (1H, q, Jꢃ7.0 Hz),
3.35 (3H, s), 5.31 (2H, s), 7.39—8.17 (7H, m), 11.67 (1H, s). 13C-NMR
(125 MHz, DMSO-d6) d: 20.2 (d), 31.4, 56.3, 76.2, 123.3, 125.9, 126.7,
127.2, 127.6, 127.7, 127.7, 129.3, 130.3, 131.5, 134.0, 144.1, 151.4, 161.6.
IR (KBr) cmꢄ1: 3173, 3031, 1713, 1686, 1560, 1090. MS m/z (%): 356
(3.7), 311 (11.9), 159 (3.9), 115 (12.8), 45 (100).
1-Ethoxymethyl-5-isopropyl-6-(1-naphthylthio)uracil (7h) Synthe-
sized from 6h as a white solid in 85% yield, mp 182—183 °C. 1H-NMR
(500 MHz, CDCl3) d: 1.06 (3H, t, Jꢃ7.0 Hz), 1.13 (6H, d, Jꢃ7.0 Hz), 3.45
(1H, q, Jꢃ7.0 Hz), 3.52 (2H, q, Jꢃ7.0 Hz), 5.46 (2H, s), 7.19—8.30 (7H,
m), 8.57 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 14.9, 20.0 (d), 31.7, 64.8,
75.0, 123.4, 125.1, 125.8, 126.8, 127.0, 127.7, 128.9, 129.0, 130.7, 131.3,
134.1, 145.0, 151.4, 161.2. IR (KBr) cmꢄ1: 3037, 1700, 1672, 1561, 1084.
MS m/z (%): 370 (6), 254 (32), 159 (52), 115 (100).
1-[(2-Methoxyethyloxy)methyl]-5-isopropyl-6-(2-naphthylthio)uracil
(7i) Synthesized from 6i as a white solid in 90% yield, mp 122—123 °C.
1H-NMR (500 MHz, CDCl3) d: 1.14 (6H, d, Jꢃ7.0 Hz), 3.25 (3H, s), 3.38
(2H, t, Jꢃ4.6 Hz), 3.45 (1H, m), 3.69 (2H, t, Jꢃ4.6 Hz), 5.54 (2H, s), 7.18—
8.22 (7H, m), 9.50 (1H, br s). 13C-NMR (125 MHz, CDCl3) d: 20.0 (d), 31.7,
58.9, 68.9, 71.6, 75.2, 123.4, 125.0, 125.8, 126.8, 127.0, 127.6, 128.8, 129.1,
130.6, 131.3, 134.0, 144.9, 151.6, 161.3. IR (KBr) cmꢄ1: 3160, 3036, 1705,
1686, 1566, 1083. MS m/z (%): 400 (32.9), 311 (40.7), 297 (10.8), 89 (100),
59 (87.2).
stirred mixture of 5-iospropyl-6-chlorouracil 5c (0.376 g, 2.0 mmol) and 2-
acetoxyethyl acetoxymethyl ether (0.54 g, 3.0 mmol) in CH2Cl2 (5 ml), BSA
(1.2 ml, 4.8 mmol) was added dropwise. After stirring at room temperature
for 0.5 h, the resulting clear solution was cooled to 0 °C, SnCl4 (0.04 ml,
0.4 mmol) was added, and the mixture left to stir at room temperature
overnight, then poured into cold saturated NaHCO3 solution (50 ml) and ex-
tracted with CH2Cl2 (20 mlꢁ3), The combined organic phases were washed
with brine (50 ml), dried over Na2SO4, and evaporated in vacuo to dryness to
afford a yellow solid. The crude product was purified by column chromatog-
raphy on silica gel with a mixture of EtOAc and petroleum ether (60—
90 °C, 1 : 2) as eluent to afford 6w in 54% yield. mp 121—123 °C, 1H-NMR
(500 MHz, CDCl3) d: 1.27 (6H, d, Jꢃ7.0 Hz), 2.10 (s, 3H), 3.23 (1H, m),
3.83 (2H, t, Jꢃ6.6 Hz), 4.23 (2H, t, Jꢃ6.6 Hz), 5.54 (2H, s), 8.87 (1H, s).
General Procedure for the Preparation of HEPT Analogues 7a—v
To a stirred solution of 5-alkyl-1-alkoxymethyl-6-chlorouracils (6q—v)
(1.0 mmol) in anhydrous EtOH (4 ml) was added ethanloic NaOH solution
0.5 M (2.0 ml) and 1-naphthanethiol (0.16 g, 1.0 mmol), and stirring was con-
tinued at room temperature overnight. The solvent was evaporated under re-
duced pressure, the residue was suspended in water (5 ml), acidified to pH
5—6 with HCl 1 M, and extracted with CH2Cl2 (10 mlꢁ3). The combined or-
ganic phases were washed with brine (30 ml), dried over Na2SO4, and evapo-
rated in vacuo to dryness. The crude product was purified by column chro-
matography on silica gel with a mixture of EtOAc and petroleum ether
(60—90 °C, 1 : 2) as eluent to afford the product.
1-Ethoxymethyl-5-methyl-6-(1-naphthylthio)uracil (7a) Synthesized
from 6a as a white powder in 78% yield, mp 229—232 °C. 1H-NMR
(500 MHz, DMSO-d6) d: 0.95 (3H, t, Jꢃ6.9 Hz), 1.77 (3H, s), 3.44 (2H, q,
Jꢃ6.9 Hz), 5.40 (2H, s), 7.44—8.18 (7H, m), 11.50 (1H, s). 13C-NMR
1-[(Cyclopropylmethoxy)methyl]-5-isopropyl-6-(1-naphthylthio)uracil
(7j) Synthesized from 6j as a white solid in 82% yield, mp 150 °C (dec.).
1H-NMR (500 MHz, DMSO-d6) d: 0.05 (2H, t, Jꢃ4.4, 4.8 Hz), 0.34 (2H, d,

890
Vol. 53, No. 8
130.8, 133.1, 134.2, 145.0, 151.6, 161.2. IR (KBr) cmꢄ1: 3175, 1709, 1682,
1588, 1517, 1061. MS m/z (%): 436 (2.9), 297 (12.6), 235 (28.7), 109 (100).
1-[(Cyclohexylmethoxy)methyl]-5-isopropyl-6-(1-naphthylthio)uracil
(7s) Synthesized from 6s as a white solid in 76% yield, mp 149—153 °C.
1H-NMR (400 MHz, CDCl3) d: 0.93 (6H, d, Jꢃ6.9 Hz), 1.15 (6H, m), 1.76
(6H, m), 3.39 (1H, m), 3.45 (2H, d, Jꢃ7.4 Hz), 5.45 (2H, s), 7.20—8.23
(7H, m), 8.45 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 20.1 (d), 30.2, 25.8
(d), 26.7, 29.6 (d), 40.6, 68.9, 71.9, 123.6, 125.7, 125.9, 126.9, 127.6, 127.8,
Jꢃ1.5, 6.6 Hz), 0.80 (1H, m), 1.06 (6H, d, Jꢃ6.9 Hz), 3.25 (2H, d,
Jꢃ6.9 Hz), 3.36 (1H, m), 5.40 (2H, s), 7.42—8.17 (7H, m), 11.65 (1H, s).
13C-NMR (125 MHz, DMSO-d6) d: 3.2 (d), 10.7, 20.1 (d), 31.5, 73.1, 74.8,
123.3, 126.1, 126.7, 127.2, 127.4, 127.6, 127.7, 129.2, 130.3, 131.6, 133.9,
144.3, 151.3, 161.6. IR (KBr) cmꢄ1: 3018, 1710, 1642, 1589, 1086. MS m/z
(%): 396 (16), 297 (24), 159 (22), 55 (100).
1-[(Benzyloxy)methyl]-5-isopropyl-6-(1-naphthylthio)uracil (7k)
1
Synthesized from 6k as a white solid in 81% yield, mp 146—147 °C. H-
128.5, 129.3, 129.9, 131.6, 133.7, 144.6, 151.5, 161.2. IR (KBr) cmꢄ1
:
NMR (500 MHz, CDCl3) d: 1.12 (6H, d, Jꢃ7.0 Hz), 3.44 (1H, m), 4.60 (2H,
s), 5.53 (2H, s), 7.15—7.22 (5H, m), 7.27—8.20 (7H, m), 8.21 (1H, s). 13C-
NMR (125 MHz, CDCl3) d: 20.0 (d), 31.7, 71.7, 75.1, 123.4, 125.1, 125.9,
126.8, 127.0, 127.5, 127.7, 127.7, 127.8, 128.3, 128.4, 128.8, 129.2, 130.6,
131.1, 134.1, 137.4, 144.7, 151.4, 161.1. IR (KBr) cmꢄ1: 3037, 1718, 1662,
1561, 1074. MS m/z (%): 432 (18), 311 (53), 217 (22), 91 (100).
3363, 1725, 1663, 1562, 1089. MS m/z (%): 438 (3.0), 311 (7.4), 189 (23.4),
97 (37.1), 55 (100).
1-[(3-Fluorobenzyloxy)methyl]-5-isopropyl-6-(1-naphthylthio)uracil
(7t) Synthesized from 6t as a white solid in 67% yield, mp 145—147 °C.
1H-NMR (400 MHz, CDCl3) d: 1.16 (6H, d, Jꢃ7.3 Hz), 3.49 (1H, m), 4.56
(2H, s), 5.54 (2H, s), 6.87—7.20 (4H, m), 7.28—8.22 (7H, m), 9.70 (1H, s).
13C-NMR (100 MHz, CDCl3) d: 20.2 (d), 31.9, 71.0, 75.1, 114.5, 122.1,
122.3, 123.1, 123.5, 125.1, 126.0, 127.0, 127.2, 127.9, 129.0, 129.3, 130.1,
131.1, 133.2, 134.2, 144.7, 151.7, 161.3. IR (KBr) cmꢄ1: 3044, 1706, 1664,
1560, 1085. MS m/z (%): 450 (4.0), 311 (21.7), 297 (9.7), 235 (12.3), 109
(100).
1-[(4-Fluorobenzyloxy)methyl]-5-isopropyl-6-(1-naphthylthio)uracil
(7u) Synthesized from 6u as a white solid in 73% yield, mp 177—181 °C.
1H-NMR (400 MHz, CDCl3) d: 1.12 (6H, d, Jꢃ7.3 Hz), 3.45 (1H, m), 4.51
(2H, s), 5.50 (2H, s), 6.90—7.21 (4H, m), 7.30—8.19 (7H, m), 9.68 (1H, s).
13C-NMR (100 MHz, CDCl3) d: 20.1 (d), 31.9, 70.9, 75.0, 115.5, 123.5,
125.2, 126.2, 127.0, 127.2, 127.9, 128.5, 128.8, 128.8, 128.9, 129.0, 129.4,
129.5, 131.2, 136.7, 144.7, 151.6, 161.3. IR (KBr) cmꢄ1: 3044, 1715, 1659,
1563, 1084. MS m/z (%): 450 (1.9), 311 (12.2), 235 (11.4), 115 (8.1), 109
(100).
1-[(3-Methyl-phenylmethyloxy)methyl]-5-isopropyl-1-naphthyl-
thio)uracil (7l) Synthesized from 6l as a white solid in 88% yield, mp
1
137—141 °C. H-NMR (500 MHz, CDCl3) d: 1.11 (6H, d, Jꢃ7.0 Hz), 2.29
(3H, s), 2.46 (1H, m), 4.56 (2H, s), 5.53 (2H, s), 7.02—7.17 (5H, m), 7.35—
8.21 (7H, m), 8.48 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 20.00 (d), 21.3,
31.7, 71.7, 75.1, 123.4, 124.7, 125.0, 125.9, 126.8, 127.0, 127.7, 128.3,
128.3, 128.5, 128.8, 129.1, 130.6, 131.1, 134.0, 137.9, 144.7, 151.4, 161.1.
IR (KBr) cmꢄ1: 3053, 1711, 1663, 1588, 1068. MS m/z (%): 446 (14.4), 311
(54.2), 231 (50.2), 115 (10.3), 105 (100).
1-Ethoxymethyl-5-propyl-6-(1-naphthylthio)uracil (7m) Synthesized
from 6m as a white solid in 83% yield, mp 155—156 °C. 1H-NMR
(500 MHz, CDCl3) d: 0.77 (3H, t, Jꢃ7.2 Hz), 1.04 (3H, t, Jꢃ7.0 Hz), 1.37
(2H, m), 2.59 (2H, t, Jꢃ7.7 Hz), 3.50 (2H, q, Jꢃ7.0 Hz), 5.40 (2H, s),
7.19—8.26 (7H, m), 9.25 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 14.0,
14.9, 22.3, 30.4, 64.8, 74.9, 123.5, 125.3, 125.4, 125.9, 126.8, 127.1, 127.8,
128.9, 130.8, 130.9, 134.1, 145.6, 151.7, 162.4. IR (KBr) cmꢄ1: 3047, 1700,
1671, 1580, 1097. MS m/z (%): 370 (48), 311 (100), 283 (44), 115 (38).
1-[(Benzyloxy)methyl]-5-propyl-6-(1-naphthylthio)uracil (7n) Syn-
1-[(2-Phenylethoxy)methyl]-5-isopropyl-6-(1-naphthylthio)uracil (7v)
1
Synthesized from 6v as a white solid in 59% yield, mp 157—161 °C. H-
NMR (400 MHz, CDCl3) d: 1.14 (6H, d, Jꢃ7.0 Hz), 2.66 (2H, t, Jꢃ7.6 Hz),
3.42 (1H, m), 3.67 (2H, t, Jꢃ7.6 Hz), 5.44 (2H, s), 7.08—7.25 (5H, m),
7.31—8.22 (7H, m), 8.42 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 20.1 (d),
31.8, 47.2, 56.9, 75.1, 123.2, 124.9, 125.3, 125.8, 126.0, 126.5, 127.3, 127.5,
127.8, 128.5, 128.6, 128.9, 129.3, 130.1, 131.1, 137.1, 144.7, 151.5, 161.2.
IR (KBr) cmꢄ1: 3369, 1701, 1676, 1497, 1077. MS m/z (%): 446 (3.2), 312
(18.0), 297 (14.8), 115 (14.9), 105 (100).
General Procedure for the Preparation of HEPT Analogues (7w, 8a—
f, 9) To a stirring solution of 6-chlorouracil 6 (2.0 mmol), diaryl disulfide
(1.1 mmol) in CH3OH (5 ml) and NaBH4 (79 mg, 2.0 mmol) were added at
0 °C in portions under a nitrogen atmosphere. The resulting mixture was
warmed to room temperature and stirring continued for about 12 h. Evapora-
tion of the solvent in vacuo gave a pale solid, which was dissolved in H2O
(5 ml), and the mixture was adjusted to pH 6 with aqueous HCl 1 M, and ex-
tracted with CH2Cl2 (10 mlꢁ2). The combined organic phases were washed
with brine, dried over Na2SO4, and evaporated in vacuo to dryness. The
residue was washed with petroleum ether (60—90 °C), and the crude prod-
ucts were chromatographed with a solution of EtOAc and petroleum ether
(60—90 °C, 1 : 3) as eluent or recrystallized from EtOAc to give the pure
product (7w, or 8a—f, 9).
1
thesized from 6n as a white solid in 75% yield, mp 104—107 °C. H-NMR
(500 MHz, CDCl3) d: 0.80 (3H, t, Jꢃ7.3 Hz), 1.36 (2H, m), 2.56 (2H, t,
Jꢃ7.8 Hz), 4.58 (2H, s), 5.47 (2H, s), 7.16—7.20 (5H, m), 7.32—8.23 (7H,
m), 9.27 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 14.1, 21.9, 30.4, 70.7,
75.0, 123.4, 124.1, 126.0, 126.7, 127.2, 127.6, 127.7 (d), 127.8 (d), 128.4
(d), 129.2, 130.4, 131.1, 138.0, 144.5, 151.5, 162.4. IR (KBr) cmꢄ1: 3009,
1711, 1640, 1561, 1065. MS m/z (%): 432 (13.9), 311 (33.1), 217 (47.7),
115 (11.5), 91 (100).
1-Ethoxymethyl-5-isobutyl-6-(1-naphthylthio)uracil (7o) Synthesized
from 6o as a white solid in 89% yield, mp 148—150 °C. 1H-NMR
(500 MHz, CDCl3) d: 0.90 (6H, d, Jꢃ6.6 Hz), 1.00 (3H, t, Jꢃ7.0 Hz), 1.98
(1H, m), 2.56 (2H, d, Jꢃ7.3 Hz), 3.47 (2H, q, Jꢃ7.0 Hz), 5.35 (2H, s),
7.13—8.24 (7H, m), 9.03 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 14.9,
22.3 (d), 28.7, 36.5, 64.8, 75.0, 123.4, 124.8, 124.9, 126.9, 125.9, 126.8,
127.0, 127.7, 128.8, 130.6, 134.1, 145.9, 151.7, 162.5. IR (KBr) cmꢄ1
:
3031, 1714, 1663, 1577, 1100. MS m/z (%): 384 (75.4), 311 (73.3), 283
(92.1), 115 (52.8), 59 (100).
1-[(Benzyloxy)methyl]-5-isobutyl-6-(1-naphthylthio)uracil (7p) Syn-
1
thesized from 6p as a white solid in 91% yield, mp 129—130 °C. H-NMR
1-(Hydroxyethoxymethyl)-6-(a-naphthalenethio)-5-isopropyluracil
(7w) Synthesized from 6w as a white solid in 69% yield, mp 184—187 °C.
1H-NMR (500 MHz, DMSO-d6) d: 0.97 (6H, d, Jꢃ6.9 Hz), 3.31 (1H, m),
3.47 (2H, t, Jꢃ6.6 Hz), 4.01 (2H, t, Jꢃ6.6 Hz), 4.4 (1H, br s) 5.41 (2H, s),
7.40—8.17 (7H, m), 11.64 (1H, s). 13C-NMR (125 MHz, DMSO-d6) d: 20.1,
31.4, 60.4, 70.8, 75.3, 123.3, 125.9, 126.7, 127.2, 127.5, 127.6, 127.6, 129.2,
130.3, 131.6, 133.9, 144.2, 151.4, 161.6. IR (KBr) cmꢄ1: 3485, 3065, 2960,
1693, 1425, 1406, 1113. MS m/z (%): 386 (Mꢀ, 5), 318 (43), 115 (100).
1-Methoxymethyl-5-ethyl-6-(2-naphthylthio)uracil (8a) Synthesized
from 6c as a white solid in 78% yield, mp 139—145 °C. 1H-NMR
(400 MHz, CDCl3) d: 1.00 (3H, t, Jꢃ7.3 Hz), 2.73 (2H, q, Jꢃ7.3 Hz), 3.36
(3H, s), 5.45 (2H, s), 7.26—7.81 (7H, m), 9.12 (1H, br s). 13C-NMR
(100 MHz, CDCl3) d: 13.2, 22.2, 56.3, 74.7, 124.4, 125.9, 126.4, 126.6,
126.7, 127.2, 127.9, 129.7, 130.8, 132.0, 133.6, 144.9, 151.4, 162.3. IR
(KBr) cmꢄ1: 3023, 1701, 1686, 1582, 1074. MS m/z (%): 342 (6), 254 (14),
159 (34), 115 (100).
(500 MHz, CDCl3) d: 0.91 (6H, d, Jꢃ6.6 Hz), 1.96 (1H, m), 2.54 (2H, d,
Jꢃ7.3 Hz), 4.55 (2H, s), 5.59 (2H, s), 7.10—7.22 (5H, m), 7.33—8.20 (7H,
m), 8.81 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 22.4 (d), 28.8, 36.6, 71.7,
75.1, 123.5, 124.9, 125.0, 127.0, 126.9, 127.1, 127.5, 127.7, 127.7, 128.0,
128.3, 128.5, 128.9, 130.5, 130.6, 134.1, 137.4, 145.6, 151.7, 162.5. IR
(KBr) cmꢄ1: 3031, 1712, 1649, 1560, 1074. MS m/z (%): 446 (11.7), 325
(24.0), 217 (15.4), 115 (9.0), 91 (100).
1-[(3-Fluorobenzyloxy)methyl]-5-ethyl-6-(1-naphthylthio)uracil (7q)
1
Synthesized from 6q as a white solid in 82% yield, mp 134—136 °C. H-
NMR (400 MHz, CDCl3) d: 0.98 (3H, t, Jꢃ7.3 Hz), 2.68 (2H, q, Jꢃ7.8 Hz),
4.55 (2H, s), 5.48 (2H, s), 6.85—7.23 (4H, m), 7.34—8.22 (7H, m,), 9.14
(1H, s). 13C-NMR (100 MHz, CDCl3) d: 13.5, 22.3, 71.0, 75.2, 114.4, 122.9,
123.5, 125.1, 126.0, 126.7, 126.9, 127.0, 127.3, 128.0, 129.0, 129.9, 130.8,
134.2, 138.5, 140.1, 144.9, 151.5, 161.8. IR (KBr) cmꢄ1: 3036, 1719, 1663,
1546, 1065. MS m/z (%): 436 (7.8), 297 (20.6), 235 (16.8), 115 (26.2), 109
(100).
1-Ethoxymethyl-5-ethyl-6-(2-naphthylthio)uracil (8b) Synthesized
from 6d as a white crystals in 86% yield, mp 141—142 °C. 1H-NMR
(500 MHz, CDCl3) d: 1.00 (3H, t, Jꢃ7.4 Hz), 1.06 (3H, t, Jꢃ7.0 Hz), 2.70
(2H, q, Jꢃ7.4 Hz), 3.56 (2H, q, Jꢃ7.0 Hz), 5.48 (2H, s), 7.27—7.81 (7H,
m), 8.57 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 13.3, 14.9, 22.1, 64.9,
74.8, 124.9, 125.8, 126.5, 126.5 (d), 127.2, 127.8, 129.6, 130.8, 132.1,
1-[(4-Fluorobenzyloxy)methyl]-5-ethyl-6-(1-naphthylthio)uracil (7r)
Synthesized from 6r as a white solid in 73% yield, mp 184—185 °C. H-
NMR (400 MHz, CDCl3) d: 0.97 (3H, t, Jꢃ7.7 Hz), 2.66 (2H, q, Jꢃ7.6 Hz),
4.50 (2H, s), 5.46 (2H, s), 6.88—7.17 (4H, m), 7.28—8.21 (7H, m), 9.70
(1H, s). 13C-NMR (100 MHz, CDCl3) d: 13.5, 22.3, 70.9, 74.9, 115.2, 123.5,
125.0, 126.1, 126.1, 127.1, 127.2, 127.5, 127.9, 128.8, 129.0, 129.4, 129.5,
1

August 2005
891
133.8, 144.9, 151.4, 162.1. IR (KBr) cmꢄ1: 3024, 2976, 1718, 1697, 1449, cmꢄ1: 3178, 1701, 1685, 1649, 1588, 1069. MS m/z (%): 401 (8.0), 342
1419, 1101. MS m/z (%): 356 (Mꢀ, 12), 318 (36), 297 (22), 159 (51), 115 (10.9), 171 (10.8), 149 (24.5), 115 (9.4), 59 (100).
(100).
1-[(Benzyloxy)methyl]-5-ethyl-6-(1-nitro-2-naphthylthio)uracil (11c)
1-[(Benzyloxy)methyl]-5-ethyl-6-(2-naphthylthio)uracil (8c) Synthe- Synthesized from crude 10 (0.68 g, 2.0 mmol) and benzyl chloromethyl
sized from 6e as a white solid in 85% yield, mp 120—123 °C. 1H-NMR ether (0.47 g, 3.0 mmol) in a similar manner to the preparation of 11a as a
(400 MHz, CDCl3) d: 0.97 (3H, t, Jꢃ7.3 Hz), 2.68 (2H, q, Jꢃ7.3 Hz), 4.62 yellow powder (0.21 g, 22%). mp 156—157 °C. 1H-NMR (400 MHz, CDCl3)
(2H, s), 5.51 (2H, s), 7.18—7.26 (5H, m), 7.33—8.07 (7H, m), 9.06 (1H, d: 1.02 (3H, t, Jꢃ7.3 Hz), 2.68 (2H, q, Jꢃ7.3 Hz), 4.56 (2H, s), 5.57 (2H, s),
br s). 13C-NMR (100 MHz, CDCl3) d: 13.2, 22.5, 71.8, 75.7, 124.8, 125.8, 7.07—7.18 (5H, m), 7.46 (1H, dd, Jꢃ6.9, 9.2 Hz), 7.55 (1H, dd, Jꢃ7.8,
126.0, 126.2, 126.7, 126.7, 127.3, 127.7 (d), 127.9, 128.4, 128.6, 130.0, 8.2 Hz), 7.64 (1H, d, Jꢃ6.9 Hz), 7.93 (1H, d, Jꢃ8.2 Hz), 8.20 (1H, d,
132.4, 133.4, 137.2, 142.9, 151.7, 161.9. IR (KBr) cmꢄ1: 3030, 1702, 1671, Jꢃ7.8 Hz), 8.48 (1H, d, Jꢃ9.2 Hz), 9.41 (1H, s). 13C-NMR (100 MHz,
1583, 1066. MS m/z (%): 418 (12), 297(35), 217 (41), 91 (100).
CDCl3) d: 13.6, 22.3, 71.7, 75.1, 123.7, 124.4, 125.0, 125.5, 125.6, 127.5,
1-Methoxymethyl-5-isopropyl-6-(2-naphthylthio)uracil (8d) Synthe- 127.6, 127.6, 127.9, 128.0, 128.3, 128.3, 133.7, 133.9, 134.9, 137.1, 143.5,
sized from 6g as a white solid in 73% yield, mp 166—170 °C. 1H-NMR 146.5, 151.4, 161.9. IR (KBr) cmꢄ1: 3029, 1701, 1677, 1655, 1589, 1522,
(400 MHz, CDCl3) d: 1.18 (6H, d, Jꢃ6.9 Hz), 3.38 (3H, s), 3.56 (1H, m), 1068. MS m/z (%): 463 (1.3), 357 (3.2), 262 (19.5), 91 (100), 92 (9.0).
5.50 (2H, s), 7.28—7.82 (7H, m), 9.01 (1H, s). 13C-NMR (100 MHz, CDCl3)
1-Methoxymethyl-5-ethyl-6-(1-amino-2-naphthylthio)uracil (12a) To
d: 20.1 (d), 31.8, 57.1, 76.9, 125.1, 126.1, 126.7, 127.3, 127.3, 128.0, 129.0, a stirred mixture of Na2S2O3 (4.6 g, 29 mmol), CH3OH (25 ml) and H2O
129.8, 131.1, 132.2, 133.9, 144.8, 151.3, 161.3. IR (KBr) cmꢄ1: 3015, 1709, (10 ml), a solution of 1-methoxymethyl-5-ethyl-6-(1-nitro-2-naphthylthio)-
1647, 1560, 1095. MS m/z (%): 356 (6), 311 (22), 159 (32), 115 (57), 45 uracil 11a (1.2 g, 3.1 mmol) in CH2Cl2 (15 ml) was added at 0 °C. Stirring
(100).
was continued for an additional 1 h. The solid was separated by filtration and
1-Ethoxymethyl-5-isopropyl-6-(2-naphthylthio)uracil (8e) Synthe- washed with CH2Cl2 (20 mlꢁ3), the filtrate was diluted with H2O (30 ml),
1
sized from 6h as a yellow solid in 83% yield, mp 181 °C (dec.). H-NMR the organic phase was separated, and the aqueous phase was extracted with
(500 MHz, DMSO-d6) d: 0.93 (3H, t, Jꢃ7.0 Hz), 1.01 (6H, d, Jꢃ7.0 Hz), CH2Cl2 (30 mlꢁ2). The combined organic phases were washed with brine
3.36 (1H, q, Jꢃ7.0 Hz), 3.50 (2H, q, Jꢃ7.0 Hz), 5.42 (2H, s), 7.43—7.97 (50 mlꢁ2), dried over Na2SO4, evaporated, and chromatographed on silica
(7H, m), 11.66 (1H, s). 13C-NMR (125 MHz, CDCl3) d: 14.9, 20.0 (d), 31.7, gel with a mixture of EtOAc and petroleum ether (60—90 °C, 1 : 1) as eluent
1
64.8, 74.9, 125.0, 126.0, 126.5, 127.2 (d), 127.8, 128.8, 129.5, 131.2, 132.1, to afford 12a as a yellow solid (0.59 g, 53 %). mp 161—164 °C. H-NMR
133.8, 144.8, 151.4, 161.4. IR ( KBr) cmꢄ1: 3162, 2970, 1717, 1647, 1584, (400 MHz, CDCl3) d: 0.94 (3H, t, Jꢃ7.3 Hz), 2.64 (2H, q, Jꢃ7.3 Hz), 3.29
1413, 1087. MS m/z (%): 370 (6), 283 (38), 254 (32), 159 (55), 115 (100).
(3H, s), 4.05 (2H, br s), 5.37 (2H, s), 6.74 (1H, dd, Jꢃ0.9, 6.9 Hz), 7.13—
1-[(Benzyloxy)methyl]-5-isopropyl-6-(2-naphthylthio)uracil (8f) Syn- 7.22 (3H, m), 7.67—7.68 (2H, m), 9.10 (1H, s). 13C-NMR (100 MHz,
1
thesized from 6k as a white solid in 77% yield, mp 166—167 °C. H-NMR CDCl3) d: 13.4, 22.3, 56.4, 74.4, 111.2, 118.9, 120.4, 124.3, 125.2, 126.3,
(500 MHz, DMSO-d6) d: 0.96 (6H, d, Jꢃ6.9 Hz), 3.37 (1H, m), 4.56 (2H, s), 127.3, 129.4, 130.4, 133.4, 141.5, 145.3, 151.4, 162.2. IR (KBr) cmꢄ1
:
5.53 (2H, s), 7.16—7.22 (5H, m), 7.41—7.90 (7H, m), 11.62 (1H, s). 13C- 3465, 3230, 1719, 1682, 1568, 1078. MS m/z (%): 357 (35.5), 312 (14.0),
NMR (125 MHz, CDCl3) d: 20.0 (d), 31.7, 71.7, 75.0, 125.0, 126.1, 126.5, 269 (16.2), 57 (43.6), 45 (100).
127.2 (d), 127.6 (d), 127.8 (d), 128.3 (d), 128.9, 129.6, 131.0, 132.1, 133.8,
137.3, 144.5, 151.3, 161.1. IR (KBr) cmꢄ1: 3035, 1719, 1654, 1563, 1077. thesized from 11b (0.27 g, 0.67 mmol) and Na2S2O3 (1.0 g, 6.7 mmol) in a
MS m/z (%): 432 (8), 311 (28), 217 (32), 91 (100). similar manner to the preparation of 12a as a yellow powder (0.16 g, 65%).
1-Ethoxymethyl-5-ethyl-6-(1-amino-2-naphthylthio)uracil (12b) Syn-
1
5-Ethyl-6-(2-naphthanethio)uracil (9) Synthesized from 5b as a white mp: 169—173 °C. H-NMR (400 MHz, CDCl3) d: 0.99 (3H, t, Jꢃ7.4 Hz),
solid in 90% yield, mp 256—258 °C. 1H-NMR (500 MHz, DMSO-d6) d: 1.10 (3H, t, Jꢃ6.9 Hz), 2.71 (2H, q, Jꢃ7.3 Hz), 3.57 (2H, q, Jꢃ6.9 Hz),
0.96 (3H, t, Jꢃ7.3 Hz), 2.30 (2H, q, Jꢃ7.4 Hz), 7.41—8.14 (7H, m), 11.32 4.25 (2H, br), 5.49 (2H, s), 6.82 (1H, dd, Jꢃ1.4, 6.4 Hz), 7.19—7.32 (3H,
(1H, s), 11.82 (1H, s). 13C-NMR (125 MHz, DMSO-d6) d: 14.2, 20.3, 118.8, m), 7.73—7.76 (2H, m), 9.30 (1H, s). 13C-NMR (100 MHz, CDCl3) d: 13.5,
127.1, 127.3, 127.8, 128.0, 128.1, 128.7, 129.5, 130.5, 132.6, 133.8, 143.7, 15.0, 22.3, 65.1, 75.1, 111.2, 118.9, 120.3, 124.2, 125.1, 126.3, 127.3, 129.3,
151.2, 163.6. IR (KBr) cmꢄ1: 3155, 3018, 2962, 1710, 1655, 1589, 1469, 130.4, 133.3, 141.7, 145.5, 151.4, 162.2. IR (KBr) cmꢄ1: 3397, 1701, 1671,
1421, 1196. MS m/z (%): 318 (Mꢀ, 36), 115 (100).
1567, 1096. MS m/z (%): 371 (64.6), 312 (34.9), 269 (25.9), 130 (46.1), 59
5-Ethyl-6-(1-nitro-2-naphthylthio)uracil (10) To a stirred mixture of (100).
5-ethyl-6-(2-naphthanethio)uracil 9 (2.98 g, 10 mmol) and concentrated
1-[(Benzyloxy)methyl]-5-ethyl-6-(1-amino-2-naphthylthio)uracil (12c)
H2SO4 (20 ml), a mixture of concentrated H2SO4 (4.3 ml) and fumed HNO3 Synthesized from 11c (0.40 g, 0.87 mmol) and Na2S2O3 (1.4 g, 8.7 mmol) in
(0.48 ml, 11 mmol) was added dropwise at about ꢄ5 °C, stirring was contin- a similar manner to the preparation of 12a as a yellow powder (0.19 g, 51%).
1
ued at 0 to ꢄ5 °C for an additional 1 h. The mixture was poured onto mp 147—151 °C. H-NMR (400 MHz, CDCl3) d: 0.95 (3H, t, Jꢃ7.3 Hz),
crushed ice (120 g), filtered, and washed successively with H2O (30 mlꢁ3) 2.64 (2H, q, Jꢃ7.3 Hz), 4.13 (2H, br s), 4.58 (2H, s), 5.53 (2H, s), 6.74—
and EtOH (25 mlꢁ2). The resulting yellow solid was dried in vacuo and 7.17 (4H, m), 7.22—7.71 (6H, m), 9.81 (1H, br). 13C-NMR (100 MHz,
subjected to the next step without further purification (3.2 g, 93%).
CDCl3) d: 13.5, 22.2, 71.8, 74.9, 110.5, 118.3, 122.3, 123.0, 123.7, 126.6,
1-Methoxymethyl-5-ethyl-6-(1-nitro-2-naphthylthio)uracil (11a) Syn- 127.7 (d), 127.9, 128.0, 128.1, 128.4 (d), 130.7, 134.9, 137.4, 142.4, 151.5,
thesized from crude 10 (3.43 g, 10.0 mmol) and methyl chloromethyl ether 161.1. IR (KBr) cmꢄ1: 3230, 1719, 1650, 1578, 1561, 1090. MS m/z (%):
(1.61 g, 20 mmol) in a similar manner to the preparation of 6a—p as a yel- 433 (14.2), 297 (7.9), 235 (17.6), 109 (68.3), 91 (100).
low powder (1.43 g, 37%), but the chromatography was performed with a
1-[(Benzyloxy)methyl]-5-ethyl-6-(1-acetamino-2-naphthylthio)uracil
mixture of EtOAc and petroleum ether (60—90 °C, 1 : 1) as eluent. mp (13) A mixture of 12c (0.13 g, 0.3 mmol), CH2Cl2 (2 ml), and Et3N (1 ml)
1
179—186 °C. H-NMR (400 MHz, CDCl3) d: 1.02 (3H, t, Jꢃ7.3 Hz), 2.70 was stirred at ꢄ5 °C. Then a solution of AcCl (0.05 ml, 0.5 mmol) and
(2H, q, Jꢃ7.3 Hz), 3.34 (3H, s), 5.47 (2H, s), 7.39 (1H, dd, Jꢃ6.8, 9.2 Hz), CH2Cl2 (1 ml) was added dropwise and stirred at room temperature for 2 h.
7.56 (1H, dd, Jꢃ7.8, 8.3 Hz), 7.70 (1H, d, Jꢃ6.8 Hz), 7.91 (1H, d, H2O (5 ml) was added, the organic phase was separated, and the aqueous
Jꢃ8.2 Hz), 8.23 (1H, d, Jꢃ7.8 Hz), 8.38 (1H, d, Jꢃ9.2 Hz), 9.29 (1H, s). phase was extracted with CH2Cl2 (10 mlꢁ2). The combined organic phases
13C-NMR (100 MHz, CDCl3) d: 13.4, 22.3, 56.4, 74.9, 123.7, 124.9, 125.9, were washed with brine (20 ml), dried over Na2SO4, evaporated, and chro-
126.4, 126.7, 127.2, 128.1, 128.4, 133.9, 134.9, 143.3, 145.7, 151.4, 162.2. matographed on silica gel with a mixture of EtOAc and petroleum ether
IR (KBr) cmꢄ1: 3031, 1704, 1687, 1653, 1587, 1072. MS m/z (%): 387 (60—90 °C, 1 : 1) as eluent to afford 13 as yellow foam (45 mg, 0.1 mmol),
1
(11.6), 325 (13.6), 216 (8.8), 114 (8.1), 45 (100).
in 32% yield. H-NMR (400 MHz, CDCl3) d: 1.09 (3H, t, Jꢃ7.3 Hz), 2.58
1-Ethoxymethyl-5-ethyl-6-(1-nitro-2-naphthylthio)uracil (11b) Syn- (3H, s), 2.67 (2H, q, Jꢃ7.3 Hz), 4.61 (2H, s), 5.54 (2H, s), 7.09—7.23 (5H,
thesized from crude 10 (0.68 g, 2.0 mmol) and ethyl chloromethyl ether m), 7.34—7.83 (6H, m), 8.50 (1H, br). 13C-NMR (100 MHz, CDCl3) d:
(0.39 g, 4.0 mmol, 0.38 ml) in a similar manner to the preparation of 11a as a 13.8, 19.9, 30.7, 71.5, 75.1, 115.4, 119.7, 122.1, 122.9, 123.9, 127.0, 127.9,
1
yellow powder (0.19 g, 24), mp 65—69 °C. H-NMR (400 MHz, CDCl3) d: 128.1, 128.9, 129.0, 129.1 (d), 130.0, 131.0, 134.7, 138.8, 141.9, 146.8,
1.00 (3H, t, Jꢃ7.3 Hz), 1.02 (3H, t, Jꢃ7.0 Hz), 2.68 (2H, q, Jꢃ7.3 Hz), 3.55 151.5, 161.0. IR (KBr) cmꢄ1: 3203, 1721, 1701, 1656, 1546, 1490, 1080.
(2H, q, Jꢃ7.0 Hz), 5.49 (2H, s), 7.40 (1H, dd, Jꢃ6.8, 9.1 Hz), 7.61 (1H, dd, MS m/z (%): 475 (6.1), 311 (29.9), 159 (6.9), 217 (30), 115 (16.7), 109
Jꢃ7.7, 8.3 Hz), 7.72 (1H, d, Jꢃ6.8 Hz), 7.94 (1H, d, Jꢃ8.3 Hz), 8.25 (1H, d, (100).
Jꢃ7.7 Hz), 8.37 (1H, d, Jꢃ9.1 Hz), 9.25 (1H, s). 13C-NMR (100 MHz,
5-Ethyl-6-(1-chloro-2-naphthylthio)uracil (14) A mixture of 1-
CDCl3) d: 13.4, 15.1, 22.3, 65.1, 75.1, 123.7, 124.9, 125.9, 126.4, 126.7, methoxymethyl-5-ethyl-6-(1-amino-2-naphthylthio)uracil 12a (0.50 g, 1.4
127.2, 128.1, 128.4, 133.8, 134.8, 143.3, 145.7, 151.6, 162.2. IR (KBr) mmol), concentrated HCl (3.5 ml), and H2O (3.5 ml) was stirred at ꢄ5 °C, a

892
Vol. 53, No. 8
solution of NaNO2 (0.5 g, 7.2 mmol) and H2O (5 ml) was added dropwise
until KI-starch paper became blue. Then the resulting mixture was added to
the stirred solution of CuCl (0.8 g, 8.1 mmol) in concentrated HCl (36%,
2.5 ml) at 0 °C, and the reaction mixture was stirred for 1 h. The mixture was
poured onto crushed ice (10 g), the precipitate was collected by filtration,
washed with H2O (4 mlꢁ3) and EtOH (3 mlꢁ2), dried in vacuo to afford 14
as green solid, recrystallization from EtOH/DMF (1 : 1) afforded pure 14 as
a pale powder (0.18 g, 39%), mp 223—227 °C. 1H-NMR (400 MHz, DMSO-
d6) d: 0.97 (3H, t, Jꢃ7.3 Hz), 2.39 (2H, q, Jꢃ7.3 Hz), 7.53—8.17 (6H, m),
11.26 (1H, br s); 11.87 (1H, br s).
2, 293—302 (1995).
5) Hopkins A. L., Ren J., Esnouf R. M., Willcox B. E., Jones E. Y., Ross
C., Miyasaka T., Walker R. T., Tanaka H., Stammers K. D., Stuart D.
I., J. Med. Chem., 39, 1589—1600 (1996).
6) Pedersen O. S., Pedersen E. B., Antivir. Chem. Chemothe., 10, 285—
312 (1999).
7) Hajos G., Riedl Z., Molnar J., Szabo D., Drug Future, 25, 47—62
(2000).
8) Pomerantz R. J., Horn D. L., Nat. Med., 9, 867—873 (2003).
9) De Clercq E., J. Med. Chem., 38, 2491—2517 (1995).
10) Hopkins A. L., Ren J., Tanaka H., Stammers D. K., J. Med. Chem., 42,
4500—4505 (1999).
1-Methoxymethyl-5-ethyl-6-(1-chloro-2-naphthylthio)uracil (15) Fol-
lowing the route to 11a—c, this compound was synthesized from 5-
ethyl-6-(1-chloro-2-naphthylthio)uracil 14 (0.17 g, 0.52 mmol) and methyl 11) Tanaka H., Takashima H., Ubasawa M., Baba M., Walker R. T., De
1
chloromethyl ether as a pale powder (0.12 g, 64%). mp 187—190 °C. H-
NMR (400 MHz, CDCl3) d: 1.01 (3H, t, Jꢃ7.3 Hz), 2.67 (2H, q, Jꢃ7.3 Hz), 12) Meng G., Chen F. E., De Clercq E., Balzarini J., Pannecouque C.,
3.39 (3H, s), 5.47 (2H, s), 7.31—8.15 (6H, m), 9.09 (1H, br). 13C-NMR
Chem. Pharm. Bull., 51, 779—789 (2003).
Clercq E., Miyasaka T., J. Med. Chem., 35, 4713—4719 (1992).
(100 MHz, CDCl3) d: 13.2, 22.4, 56.8, 75.2, 123.5, 124.4, 125.1, 125.8, 13) Meng G., Doctoral dissertation, Fudan University, China, 2003.
126.8, 127.6, 128.0, 129.4, 131.3, 132.8, 134.1, 145.1, 151.6, 162.6. IR 14) Koroniak H., Jankowski A., Krasnowski M., Org. Prep. Proced. Int.,
(KBr) cmꢄ1: 3019, 1703, 1670, 1581, 1071. MS m/z (%): 376 (9), 331 (13),
25, 563—568 (1993).
288 (17), 193 (23), 45 (100).
15) Lee N., Kim Y.-W., Kim K. H., Kim D.-K., J. Heterocyclic. Chem., 34,
659—663 (1996).
References
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