Synthesis and anti-HIV-1 activity of a series of 1-alkoxy-5-alkyl-6- (arylthio)uracils

Article abstract of DOI:10.1021/jm9607921

A series of 1-alkoxy-5-alkyl-6-(arylthio)uracils was synthesized and tested for their ability to inhibit HIV-1 replication. Treatment of 2-alkyl- 3,3-bis(methylthio)acryloyl chlorides (5a-e) with AgOCN in benzene followed by reaction of the resulting isocyanates 6a-e with an appropriate alkoxyamine gave N-alkoxy-N'-((2-alkyl-3,3-bis(methylthio)acryloyl)ureas (10a-z) in good to excellent yields. Cyclization of 10a-z in AcOH containing a catalytic amount of p-TsOH produced 1-alkoxy-5-alkyl-6-(methylthio)uracils (11a-z). Oxidation of 11a-z with 3-chloroperoxybenzoic acid in CH₂Cl₂ resulted in high yields of 1-alkoxy-5-alkyl-6-(methylsulfonyl)uracils (12a-x and 12z) and 1-(benzyloxy)-6-(methylsulfinyl)thymine (12y), which were subsequently reacted with an appropriate arenethiol in ethanolic NaOH solution to afford 1-alkoxy-5-alkyl-6-(arylthio)uracils (14-49). Substitution at the 3- and 5- positions of the C-6-(phenylthio) ring by two methyl groups significantly increased its original anti-HIV-1 activity (EC₅₀: 6-((3,5- dimethylphenyl)thio)-5-isopropyl-1-propoxyuracil (18), 0.064 μM; 6-((3,5- dimethylphenyl)thio)-1-(3-hydroxypropoxy)-5-isopropyluracil (23), 0.19 μM). Among the various alkoxy substituents at the N-1, the propoxy group was the most beneficial for improving the anti-HIV-1 activity. The 1-propoxy derivative 18 proved to be the most potent inhibitor of HIV-1 replication, followed by the 1-(3-hydroxypropoxy) derivative 23. Introduction of an isopropyl group at C-5 of the uracil base also remarkably enhanced the activity. When compound 18 was incubated with a rat liver homogenate preparation, no metabolite was observed, thus confirming the metabolic stability of the N-O bond in these 1-alkoxyuracils.

Full text of DOI:10.1021/jm9607921

J . Med. Chem. 1997, 40, 2363-2373
2363
Syn th esis a n d An ti-HIV-1 Activity of a Ser ies of
1-Alk oxy-5-a lk yl-6-(a r ylth io)u r a cils
Dae-Kee Kim,* J ongsik Gam, Young-Woo Kim, J insoo Lim, Hun-Taek Kim, and Key H. Kim
Life Science Research Center, Sunkyong Industries, 600 J ungja-Dong, Changan-Ku, Suwon-Si, Kyungki-Do 440-745, Korea
Received November 13, 1996X
A series of 1-alkoxy-5-alkyl-6-(arylthio)uracils was synthesized and tested for their ability to
inhibit HIV-1 replication. Treatment of 2-alkyl-3,3-bis(methylthio)acryloyl chlorides (5a -e)
with AgOCN in benzene followed by reaction of the resulting isocyanates 6a -e with an
appropriate alkoxyamine gave N-alkoxy-N′-((2-alkyl-3,3-bis(methylthio)acryloyl)ureas (10a -
z) in good to excellent yields. Cyclization of 10a -z in AcOH containing a catalytic amount of
p-TsOH produced 1-alkoxy-5-alkyl-6-(methylthio)uracils (11a -z). Oxidation of 11a -z with
3-chloroperoxybenzoic acid in CH2Cl2 resulted in high yields of 1-alkoxy-5-alkyl-6-(methylsul-
fonyl)uracils (12a -x and 12z) and 1-(benzyloxy)-6-(methylsulfinyl)thymine (12y), which were
subsequently reacted with an appropriate arenethiol in ethanolic NaOH solution to afford
1-alkoxy-5-alkyl-6-(arylthio)uracils (14-49). Substitution at the 3- and 5-positions of the C-6-
(phenylthio) ring by two methyl groups significantly increased its original anti-HIV-1 activity
(EC50: 6-((3,5-dimethylphenyl)thio)-5-isopropyl-1-propoxyuracil (18), 0.064 µM; 6-((3,5-dim-
ethylphenyl)thio)-1-(3-hydroxypropoxy)-5-isopropyluracil (23), 0.19 µM). Among the various
alkoxy substituents at the N-1, the propoxy group was the most beneficial for improving the
anti-HIV-1 activity. The 1-propoxy derivative 18 proved to be the most potent inhibitor of
HIV-1 replication, followed by the 1-(3-hydroxypropoxy) derivative 23. Introduction of an
isopropyl group at C-5 of the uracil base also remarkably enhanced the activity. When
compound 18 was incubated with a rat liver homogenate preparation, no metabolite was
observed, thus confirming the metabolic stability of the N-O bond in these 1-alkoxyuracils.
In tr od u ction
include nevirapine,9 R82913,10 atevirdine,11 L-697,661,12
1-((2-hydroxyethoxy)methyl)-6-(phenylthio)thymine
(HEPT),13 and TSAO-T.14 Although these inhibitors are
structurally distinct, they share some common behaviors
toward RT. All of these compounds are potent inhibitors
of HIV-1 RT but not HIV-2 or other retroviral RTs.15
Although HEPT and TSAO-T can be considered nucleo-
side analogs, they do not require phosphorylation in
order to inhibit HIV-1 RT.14,16
Since the discovery of HEPT as a novel lead for
specific anti-HIV-1 agents, a number of HEPT analogs
have been synthesized to increase its potency.17-25
Several of these compounds such as 6-((3,5-dimeth-
ylphenyl)thio)-1-(ethoxymethyl)-5-ethyluracil and 6-(3,5-
dimethylbenzyl)-1-(ethoxymethyl)-5-isopropyluracil
inhibit HIV-1 replication in the nanomolar concentra-
tion range. From synthetic studies of HEPT analogs,
it has been found that the presence of the 2′-oxygen
atom in the acyclic chain of HEPT is not essential for
anti-HIV-1 activity.23-25 This result prompted us to
synthesize the 1-alkoxy analogs of HEPT to examine the
effect of an oxygen atom adjacent to the uracil base on
anti-HIV-1 activity since a number of acyclic N-O
linked nucleosides show potent and selective anti-
herpesvirus activity.26-30 In addition, the N-O linkage
of these 1-alkoxy analogs is expected to be chemically
and metabolically stable on the basis of a recent report.27
In this report we describe the synthesis, anti-HIV-1
activity, and structure-activity relationships of a series
of 1-alkoxy-5-alkyl-6-(arylthio)uracils.
Human immunodeficiency virus type 1 (HIV-1) is the
causative agent of acquired immunodeficiency syndrome
(AIDS), which is one of the world’s most serious health
problems, with current protocols being inadequate for
either prevention or successful long-term treatment.1
Since reverse transcriptase (RT) is an essential enzyme
for the replication of HIV, it is regarded as one of the
most important targets for the antiviral chemotherapy
against HIV infections.2 3′-Azido-3′-deoxythymidine
(AZT), a potent RT inhibitor of HIV, is the first drug to
have been clinically used in the treatment of AIDS.3,4
In spite of its clinical efficacy, the long-term administra-
tion of AZT is often associated with serious side effects
such as bone marrow suppression.5 2′,3′-Dideoxyinosine
(DDI),6 2′,3′-dideoxycytidine (DDC),7 and 2′,3′-didehy-
dro-3′-deoxythymidine (D4T)8 have more recently been
approved for the patients who do not tolerate AZT, yet
they also have unfavorable side effects.2 These nucleo-
side analogs act as inhibitors of viral RT following
intracellular conversion to their corresponding 5′-triph-
osphates.2 While such 5′-triphosphates exhibit a much
higher affinity for the HIV-1 RT and other retroviral
RTs than for the host cellular DNA polymerases, their
nonspecific interaction with the host cellular DNA
polymerases may contribute to the side effects of this
class of compounds.3,6 It seems, therefore, still impera-
tive to find novel chemotherapeutic agents having
potent antiviral activity and low toxicity, preferably,
through a different mechanism of action.
Several nonnucleoside inhibitors of the HIV-1 RT
have recently been discovered. Examples of these
Ch em istr y
The LDA lithiation is highly efficient for synthesizing
various 6-substituted HEPT analogs.13,17-24 However,
when the 1-alkoxy-5-alkyluracils 1a -d were treated
* Author to whom correspondence should be addressed.
X Abstract published in Advance ACS Abstracts, J une 15, 1997.
S0022-2623(96)00792-3 CCC: $14.00 © 1997 American Chemical Society

2364 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Kim et al.
Sch em e 1a
a
(a) LDA or lithium 2,2,6,6-tetramethylpiperidide, THF, -78
°C, 1 h; (b) PhS-SPh or D2O.
(7a), (3-((tert-butyldimethylsilyl)oxy)propoxy)amine (7b),
butoxyamine (7c), (2-phenylethoxy)amine (7d ), (2-(3-
methylphenyl)ethoxy)amine (7e), (2-methoxyethoxy)-
amine (7f), (2-phenoxyethoxy)amine (7g), and (benzy-
loxy)amine (7h ) gave N-alkoxy-N′-((2-alkyl-3,3-
bis(methylthio)acryloyl)ureas (10a-z) in good to excellent
yields (Table 1). Synthesis of the requisite alkoxy-
amines 7a -g was accomplished in high overall yields
by reaction of the alcohols 8a -g with N-hydroxyphthal-
imide in the presence of betaine formed from triph-
enylphosphine and diethyl azodicarboxylate followed by
cleavage of the resulting N-alkoxyphthalimides 9a -g
with either hydrazine hydrate in MeOH at reflux
temperature or N-methylhydrazine in CH2Cl2 at room
temperature (Scheme 3). Cyclization of the ureas
10a -z in AcOH containing a catalytic amount of p-
TsOH produced 1-alkoxy-5-alkyl-6-(methylthio)uracils
(11a -z) (Table 2). Oxidation of the 6-(methylthio)-
uracils 11a -z with 3-chloroperoxybenzoic acid in CH2-
Cl2 at reflux temperature resulted in high yields of
1-alkoxy-5-alkyl-6-(methylsulfonyl)uracils (12a -x and
12z) and 1-(benzyloxy)-6-(methylsulfinyl)thymine (12y)
(Table 2). It has been known that 6-(phenylthio)uridine
derivatives or 6-(phenylsulfinyl)acyclouridine deriva-
tives were highly susceptible to nucleophillic addition-
elimination reactions with a variety of nucleophiles
under mild conditions.18,22,34 When the compounds
12a -z were allowed to react with the appropriate
arenethiols such as thiophenol (13a ), o-thiocresol (13b),
m-thiocresol (13c), p-thiocresol (13d ), 3,5-dimethylth-
iophenol (13e), 3-fluorothiophenol (13f), and 3,5-difluo-
rothiophenol (13g) in ethanolic NaOH solution, 1-alkoxy-
5-alkyl-6-(arylthio)uracils (14-49) were obtained mostly
in good to excellent yields. The physical and spectral
properties of the target compounds 14-49 are listed in
Table 3.
with LDA (2.2 equiv) in THF -78 °C for 1 h, the
corresponding C-6-lithiated species were not generated,
which was confirmed by reaction with phenyl sulfide
or D2O as an electrophile. The use of a more basic
lithiating agent, lithium 2,2,6,6-tetramethylpiperidide,
under the same reaction conditions also failed to gener-
ate the C-6-lithiated species (Scheme 1). We have
recently developed a general and convenient synthetic
route to the 6-substituted 1,5-dialkyluracils from readily
accessible ethyl 2-alkyl-3,3-bis(methylthio)acrylates.25,31
Alternatively, this synthetic approach was successfully
applied to the preparation of the target compounds 14-
49 as shown in Scheme 2. The carboxylic esters 2a -e
were treated with LDA to generate their lithium eno-
lates according to a published procedure,32,33 which were
reacted with CS2 at -78 °C followed by MeI to afford
ethyl 2-alkyl-3,3-bis(methylthio)acrylates (3a -e). Hy-
drolysis of the esters 3a -e with 2 N KOH in EtOH and
subsequent reaction of the corresponding carboxylic
acids 4a -e with oxalyl chloride in benzene in the
presence of a catalytic amount of DMF afforded 2-alkyl-
3,3-bis(methylthio)acryloyl chlorides (5a -e) in good
yields. Treatment of the 5a -e with AgOCN in benzene
followed by reaction of the resulting isocyanates 6a -e
with the appropriate alkoxyamines such as propoxyamine
A presumed metabolite of 6-((3,5-dimethylphenyl)-
thio)-5-isopropyl-1-propoxyuracil (18), 6-((3,5-dimeth-
ylphenyl)thio)-5-isopropyluracil (51), was synthesized by
reaction of 6-chloro-5-isopropyluracil (50) with 13e in
ethanolic NaOH solution in 91% yield (Scheme 4).
Resu lts a n d Discu ssion
The anti-HIV-1 (HTLV-IIIB) activity and cytotoxicity
of the compounds 14-49 were tested by the Develop-
mental Therapeutics Program of the National Cancer
Institute as previously described,35 and the results are
summarized in Table 4 along with those of AZT, DDC,
DDI, and HEPT. An active compound was defined as
one which protected CEM-SS lymphocytes from the
cytopathic effect of the virus by 50% or more in at least

1-Alkoxy-5-alkyl-6-(arylthio)uracils
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2365
Sch em e 2a
a
(a) (i) LDA, THF, -78 °C, 30 min; (ii) MeI, -78 °C, then room temperature, 16 h; (b) 2 N KOH, EtOH, reflux, 3 h (for 4b, 4d , and 4e)
or 72 h (for 4a and 4c); (c) (COCl)2, DMF, benzene, room temperature, 3 h; (d) AgOCN, benzene, reflux, 30 min; (e) alkoxyamine (7a -h ),
room temperature, 1 h; (f) p-TsOH, AcOH, 80 °C, 1 h; (g) 3-chloroperoxybenzoic acid, CH2Cl2, reflux, 16 h; (h) ArSH (13a -g), 1 N ethanolic
NaOH, EtOH, room temperature, 20 min.
Ta ble 1. Physical and Spectral Properties of N-Alkoxy-N′-(2-alkyl-3,3-bis(methylthio)acryloyl)ureas
compd
R1
R2
% yield
crystn solvent
mp, °C
EI-MS, m/z
formula
anal.a
10a
10b
10c
10d
10e
10f
10g
10h
10i
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
Et
Et
Et
Et
n-Pr
(CH2)3OTBDMS
n-Bu
57
77
63
70
80
80
78
84
69
47
67
55
89
59
83
88
94
83
85
88
83
86
68
77
73
61
EtOAc
EtOAc-hexane
EtOAc
EtOH
EtOH
EtOH
EtOH
136.0-137.0
68.0-69.0
115.0-116.0
149.5-150.3
146.1-146.3
150.0-151.0
96.3-97.8
306 (M+)
C12H22N2O3S2
C18H36N2O4S2Si
C13H24N2O3S2
C16H22N2O3S2
C17H24N2O3S2
C18H26N2O3S2
C12H22N2O4S2
C17H24N2O4S2
C11H20N2O3S2
C17H34N2O4S2Si
C12H22N2O3S2
C15H20N2O3S2
C16H22N2O3S2
C11H20N2O4S2
C12H20N2O3S2
C18H34N2O4S2Si
C16H20N2O3S2
C17H22N2O3S2
C12H22N2O3S2
C18H36N2O4S2Si
C16H22N2O3S2
C17H24N2O3S2
C10H18N2O3S2
C16H32N2O4S2Si
C14H18N2O3S2
C15H20N2O3S2
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
436 (M+)
320 (M+)
CH2Ph
355 (M + H)+
368 (M+)
(CH2)2Ph
(CH2)2Ph(3-Me)
(CH2)2OMe
(CH2)2OPh
n-Pr
(CH2)3OTBDMS
n-Bu
CH2Ph
(CH2)2Ph
(CH2)2OMe
n-Pr
(CH2)3OTBDMS
CH2Ph
(CH2)2Ph
n-Pr
(CH2)3OTBDMS
CH2Ph
382 (M+)
322 (M+)
EtOH
123.4-124.1
117.1-117.3
87.0-87.8
385 (M + H)+
292 (M+)
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOAc
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOH
10j
10k
10l
422 (M+)
91.4-91.7
306 (M+)
146.0-146.5
132.8-133.7
82.5-82.9
340 (M+)
10m
10n
10o
10p
10q
10r
10s
10t
10u
10v
10w
10x
10y
10z
354 (M+)
Et
308 (M+)
c-Pr
c-Pr
c-Pr
c-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Me
123.3-123.8
82.2-84.4
153.0-154.0
147.7-148.0
115.4-115.6
68.7-70.3
135.5-136.6
113.4-113.6
120.3-122.3
79.7-81.7
149.7-151.2
129.7-131.6
305 (M + H)+
435 (M + H)+
353 (M + H)+
367 (M + H)+
306 (M+)
436 (M+)
354 (M+)
(CH2)2Ph
n-Pr
(CH2)3OTBDMS
CH2Ph
EtOH
368 (M+)
EtOAc-hexane
EtOAc-hexane
EtOH
278 (M+)
Me
Me
Me
408 (M+)
326 (M+)
(CH2)2Ph
EtOH
340 (M+)
a
Analytical results for the indicated elements are within (0.4% of theoretical values.
two independent experiments. If the EC50 (50% effec-
tive concentration) was <10 µM and if >90% protection
was observed, the compound was judged to be active;
otherwise, it was called moderately active. Compounds
that exhibited <50% protection were considered inac-
tive.
The previous studies of the structure-activity rela-
tionships of HEPT analogs indicate that the anti-HIV-1
activity of HEPT could be potentiated by modification
at the 3-position of the C-6-(phenylthio) ring with simple
alkyl and halogen substituents.22-25 Therefore, we first
examined the effect of a methyl or fluoro substituent of
the C-6-(phenylthio) ring on HIV-1 replication with the
compounds 14-20, having an isopropyl group at C-5
and a propoxy group at N-1. Introduction of a methyl
or fluoro substituent at the 3-position or 3- and 5-posi-
tions of this moiety significantly increased its original
anti-HIV-1 activity. The 6-((3,5-dimethylphenyl)thio)
derivative 18 was the most inhibitory to HIV-1 replica-
tion with an EC50 value of 0.064 µM and a selectivity
index (SI, ratio of 50% cytotoxic concentration (CC50)
to EC50) of 516. However, modification at the 2- or
4-position of the C-6-(phenylthio) ring with a methyl
group diminished, or destroyed, the anti-HIV-1 activity;
the 6-((2-methylphenyl)thio) derivative 15 was found to
be moderately active, and the 6-((4-methylphenyl)thio)

2366 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Kim et al.
Sch em e 3a
tion of the 5-cyclopropyl group showed significantly
weakened anti-HIV-1 activity compared with their
5-isopropyl and 5-ethyl counterparts; thus, all the
5-cyclopropyl derivatives 38-41 were moderately active
regardless of the alkoxy substituent at N-1. The 5-pro-
pyl derivatives 42-45 and the 5-methyl derivatives 46-
49 were more inhibitory to HIV-1 replication than their
5-cyclopropyl counterparts in terms of EC50 value, but
EC50 values of these derivatives were higher than those
of their 5-isopropyl and 5-ethyl counterparts. This
result is consistent with the previous findings of Mi-
yasaka et al.,20,22-24 in which introduction of an isopro-
pyl or an ethyl group at C-5 of HEPT and its analogs
significantly contributed to the anti-HIV-1 activity.
a
(a) Ph3P, diethyl azodicarboxylate, N-hydroxyphthalimide,
THF, room temperature, 16 h; (b) (i) H2NNH2‚H2O, MeOH, reflux,
4 h (for 7d -g), or (ii) MeNHNH2, CH2Cl2, room temperature, 1 h
(for 7b).
Overall, structure-activity relationships in these
1-alkoxy-5-alkyl-6-(arylthio)uracils are in good agree-
ment with those established in HEPT analogs.20,22-25
When the anti-HIV-1 activity of the most potent com-
pound 18 was compared with that of AZT, DDC, DDI,
and HEPT, 18 was 14-fold less potent than AZT, but
3-, 44-, and 130-fold more potent than DDC, DDI, and
HEPT, respectively. The inhibitory effect of compound
18 on the replication of HIV-1 (HTLV-IIIB) in human
peripheral blood mononuclear cells (PBMCs) was evalu-
ated as previously described,10,17 and the results are
shown in Table 5 along with that of AZT. Compound
18 inhibited HIV-1 replication with an EC50 value of
0.15 µM and a selectivity index of 467, but was found
to be 17-fold less potent than AZT. In addition, com-
pound 18 was examined for its inhibition of HIV-1,
avian myeloblastosis virus (AMV), and Molony murine
leukemia virus (Mo-MuLV) recombinant reverse tran-
scriptases (rRTs) (Table 6). It inhibited HIV-1 rRT at
an IC50 value of 12.30 µM but did not inhibit AMV and
Mo-MuLV rRTs at concentrations up to 100 µM, thus
showing high selectivity, whereas foscarnet inhibited all
three rRTs in the micromolar concentration range.
Considering that some HEPT analogs inhibit HIV-1
replication in the nanomolar concentration range,20,22-25
these isosteric analogs of HEPT seem to be approxi-
mately 1 order of magnitude less potent compared with
the corresponding HEPT analogs. The relatively lower
selectivity indices of these 1-alkoxy analogs compared
with those HEPT analogs also seem to be attributed to
their lower potency because the level of cytotoxicity of
these analogs was similar to that reported for HEPT
analogs.
derivative 17 was devoid of activity. Again, among the
compounds 21-25 with an isopropyl group at C-5 and
a 3-hydroxypropoxy group at N-1, the 6-((3,5-dimeth-
ylphenyl)thio) derivative 23 (EC50 ) 0.19 µM) was found
to be 100-fold more potent than the corresponding
6-(phenylthio) derivative 21 (EC50 ) 19.0 µM). Since it
has been confirmed that the two methyl groups at the
3- and 5-positions of the C-6-(phenylthio) ring contrib-
uted to the maximum activity in these 1-alkoxy-5-
isopropyl-6-(arylthio)uracils 14-25 as shown previously
in the HEPT analogs,22-25 we selected a ((3,5-dimeth-
ylphenyl)thio) group as the C-6 substituent for the
following target compounds 26-49.
Sch em e 4a
a
(a) 3,5-Dimethylthiophenol, 1 N ethanolic NaOH, EtOH,
reflux, 6 h.
Next, we evaluated the effect of an alkoxy substituent
at the N-1 on HIV-1 replication with the compounds 18,
23, and 26-31 having an isopropyl group at C-5 and a
((3,5-dimethylphenyl)thio) substituent at C-6. The 1-pro-
poxy derivative 18 proved to be the most potent inhibitor
of HIV-1 replication, followed by the 1-(3-hydroxypro-
poxy) derivative 23. Although the 1-butoxy derivative
26, the 1-(2-phenylethoxy) derivative 28, the 1-(2-(3-
methylphenyl)ethoxy) derivative 29, the 1-(2-methoxy-
ethoxy) derivative 30, and the 1-(2-phenoxyethoxy)
derivative 31 were all active with EC50 values of 0.42,
0.49, 0.84, 0.43, and 0.46 µM, respectively, they were
6.6-13.1-fold less inhibitory to HIV-1 compared with
18. Introduction of a benzyloxy group at N-1 signifi-
cantly reduced the anti-HIV-1 activity; thus, compound
27 was only moderately active (EC50 ) 8.45 µM). Again,
this trend was observed in compounds 32-37, having
an ethyl group at C-5, in which the 1-propoxy derivative
32 (EC50 ) 0.35 µM) was the most potent and the
1-benzyloxy derivative 35 (EC50 ) 5.77 µM) was the
least potent. Finally, the effect of an alkyl substituent
at the C-5 on the anti-HIV-1 activity was investigated.
The 5-isopropyl derivatives 18 and 23 were 5.5- and 2.8-
fold more potent than their 5-ethyl counterparts 32 and
33 (EC50 ) 0.54 µM), respectively. However, introduc-
The chemical and metabolic stability of the N-O bond
in these 1-alkoxy compounds was examined with com-
pound 18. Although HEPT was reported to be hydro-
lyzed in concentrated aqueous HCl-MeOH at 80 °C to
afford 6-(phenylthio)thymine,23 we found that 18 was
completely inert in the same reaction condition. When
18 was incubated with a rat liver homogenate prepara-
tion for 1 h, at 37 °C, a presuemd metabolite, 6-((3,5-
dimethylphenyl)thio)-5-isopropyluracil (51) was not de-
tected in this experiment. These results indicate that
the N-O bond in these 1-alkoxyuracils are chemically
and metabolically quite stable, as we expected.
In conclusion, 6-((3,5-dimethylphenyl)thio)-5-isopro-
pyl-1-propoxyuracil (18) showed the most potent and
selective anti-HIV-1 activity in a series of 1-alkoxy-5-
alkyl-6-(arylthio)uracils and was found to be chemically
and metabolically quite stable. But, the anti-HIV-1
activity of these isosteric analogs of HEPT was ap-

1-Alkoxy-5-alkyl-6-(arylthio)uracils
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2367
Ta ble 2. Physical and Spectral Properties of 1-Alkoxy-5-alkyl-6-(methylthio)-, -6-(methylsulfonyl)-, or -6-(methylsulfinyl)uracils
compd
X
R1
R2
% yield crystn solvent
mp, °C
EI-MS, m/z
formula
anal.a
11a
11b
11c
11d
11e
11f
11g
11h
11i
11j
11k
11l
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
i-Pr n-Pr
i-Pr (CH2)3OAc
i-Pr n-Bu
92
83
94
91
95
96
95
84
97
62
90
99
93
92
68
84
60
81
99
64
97
80
90
66
99
91
91
90
96
92
84
86
91
84
77
62
73
89
93
82
72
72
85
59
83
99
99
99
95
91
99
98
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOAc-hexane
EtOAc-hexane
EtOH-EtOAc
EtOAc-hexane
EtOH
EtOH
EtOH
EtOH
84.6-86.5
67.3-68.7
258 (M+)
C11H18N2O3S C, H, N
C13H20N2O5S C, H, N
C12H20N2O3S C, H, N
C15H18N2O3S C, H, N
C16H20N2O3S C, H, N
C17H22N2O3S C, H, N
C11H18N2O4S C, H, N
C16H20N2O4S C, H, N
C10H16N2O3S C, H, N
C12H18N2O5S C, H, N
C11H18N2O3S C, H, N
C14H16N2O3S C, H, N
C15H18N2O3S C, H, N
C10H16N2O4S C, H, N
C11H16N2O3S C, H, N
C13H18N2O5S C, H, N
C15H16N2O3S C, H, N
C16H18N2O3S C, H, N
C11H18N2O3S C, H, N
C13H20N2O5S C, H, N
C15H18N2O3S C, H, N
C16H20N2O3S C, H, N
C9H14N2O3S C, H, N
C11H16N2O5S C, H, N
C13H14N2O3S C, H, N
C14H16N2O3S C, H, N
C11H18N2O5S C, H, N
C13H20N2O7S C, H, N
C12H20N2O5S C, H, N
C15H18N2O5S C, H, N
C16H20N2O5S C, H, N
C17H22N2O5S C, H, N
C11H18N2O6S C, H, N
C16H20N2O6S C, H, N
C10H16N2O5S C, H, N
C12H18N2O7S C, H, N
C11H18N2O5S C, H, N
C14H16N2O5S C, H, N
C15H18N2O5S C, H, N
C10H16N2O6S C, H, N
C11H16N2O5S C, H, N
C13H18N2O7S C, H, N
C15H16N2O5S C, H, N
317 (M + H)+
272 (M+)
96.1-96.8
i-Pr CH2Ph
157.3-157.5
104.9-106.3
100.3-101.2
79.7-81.4
148.2-148.8
132.4-133.9
98.7-99.2
306 (M+)
i-Pr (CH2)2Ph
i-Pr (CH2)2Ph(3-Me)
i-Pr (CH2)2OMe
i-Pr (CH2)2OPh
320 (M+)
335 (M + H)+
274 (M+)
336 (M+)
Et
Et
Et
Et
Et
Et
n-Pr
(CH2)3OAc
n-Bu
CH2Ph
(CH2)2Ph
(CH2)2OMe
244 (M+)
303 (M + H)+
258 (M+)
114.7-116.4
156.8-157.8
90.3-91.2
292 (M+)
11m SMe
306 (M+)
11n
11o
11p
11q
11r
11s
11t
11u
11v
11w SMe
11x
11y
11z
12a
12b
12c
12d
12e
12f
12g
12h
12i
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
SMe
102.5-103.5
94.8-96.0
206 (M+)
c-Pr n-Pr
257 (M + H)+
315 (M + H)+
305 (M + H)+
319 (M + H)+
258 (M+)
c-Pr (CH2)3OAc
c-Pr CH2Ph
c-Pr (CH2)2Ph
n-Pr n-Pr
n-Pr (CH2)3OAc
n-Pr CH2Ph
n-Pr (CH2)2Ph
70.0-70.4
137.8-139.8
87.5-89.8
101.5-103.2
72.4-74.8
316 (M+)
135.6-137.6
71.9-74.1
307 (M + H)+
320 (M+)
Me
Me
Me
Me
n-Pr
(CH2)3OAc
CH2Ph
EtOAc-hexane 125.5-126.0
230 (M+)
SMe
SMe
SMe
EtOH
EtOH
EtOH
108.3-110.4
280.0 dec
113.0-114.1
289 (M + H)+
278 (M+)
(CH2)2Ph
293 (M + H)+
291 (M + H)+
349 (M + H)+
305 (M + H)+
339 (M + H)+
353 (M + H)+
367 (M + H)+
307 (M + H)+
368 (M+)
SO2Me i-Pr n-Pr
SO2Me i-Pr (CH2)3OAc
SO2Me i-Pr n-Bu
EtOAc-hexane 144.5-145.0
EtOAc-hexane 134.4-135.5
EtOAc-hexane 143.2-145.5
CH2Cl2
CH2Cl2
EtOAc-hexane 140.3-140.7
EtOAc-hexane 137.3-138.2
CH2Cl2
CH2Cl2
SO2Me i-Pr CH2Ph
180 dec
145.0-146.0
SO2Me i-Pr (CH2)2Ph
SO2Me i-Pr (CH2)2Ph(3-Me)
SO2Me i-Pr (CH2)2OMe
SO2Me i-Pr (CH2)2OPh
SO2Me Et
SO2Me Et
SO2Me Et
SO2Me Et
151.4-151.8
160.5-161.5
n-Pr
(CH2)3OAc
n-Bu
CH2Ph
(CH2)2Ph
(CH2)2OMe
276 (M+)
12j
12k
12l
EtOAc-hexane 140.6-141.0
335 (M + H)+
291 (M + H)+
325 (M + H)+
339 (M + H)+
293 (M + H)+
288 (M+)
CH2Cl2
CH2Cl2
CH2Cl2
155.0-156.0
184.0 dec
141.2-141.6
12m SO2Me Et
12n
12o
12p
12q
12r
12s
12t
SO2Me Et
SO2Me c-Pr n-Pr
EtOAc-hexane 135.6-136.7
MeOH-CH2Cl2 140.0 dec
EtOH
SO2Me c-Pr (CH2)3OAc
SO2Me c-Pr CH2Ph
SO2Me c-Pr (CH2)2Ph
SO2Me n-Pr n-Pr
SO2Me n-Pr (CH2)3OAc
SO2Me n-Pr CH2Ph
SO2Me n-Pr (CH2)2Ph
119.6-120.2 (dec) 347 (M + H)+
EtOH-CH2Cl2 145.8 dec
336 (M+)
EtOAc
CH2Cl2
CH2Cl2
EtOH
183.0 dec
230 (M + H-C8H9O)+ C16H18N2O5S C, H, N
167.2-168.9
99.6-102.5
180.4-180.8
290 (M+)
C11H18N2O5S C, H, N
C13H20N2O7S C, H, N
C15H18N2O5S C, H, N
C16H20N2O5S C, H, N
C9H14N2O5S C, H, N
C11H16N2O7S C, H, N
C13H14N2O4S C, H, N
C14H16N2O5S C, H, N
349 (M + H)+
339 (M + H)+
353 (M + H)+
262 (M+)
12u
12v
EtOAc-hexane 140.0-141.0
EtOH
EtOH
CH2Cl2
CH2Cl2
12w SO2Me Me
n-Pr
(CH2)3OAc
CH2Ph
149.6-151.6
152.3-153.5
300.0 dec
12x
12y
12z
SO2Me Me
SOMe Me
SO2Me Me
321 (M + H)+
294 (M+)
(CH2)2Ph
155.2-157.2
325 (M + H)+
a
See footnote of Table 1.
300 spectrometer at 75.4 MHz. When CDCl3 or DMSO-d6 was
used as solvent, it served as the internal standard at δ 77.0
or 39.5, respectively. Electron impact mass spectra (EI-MS)
were obtained on a VG Quattro mass spectrometer. Analytical
thin-layer chromatography (TLC) was performed on Merck
silica gel 60F-254 glass plates. Flash column chromatography
was performed using Merck silica gel 60 (230-400 mesh).
Elemental analyses were performed on a Carlo Erba 1106
elemental analyzer. Where indicated by the symbols of the
elements, analyses were within (0.4% of theoretical values.
proximately 1 order of magnitude less potent compared
with that reported for HEPT analogs.
Exp er im en ta l Section
Melting points were determined on either an Electrothermal
F500MA digital or a Mettler FP62 melting point apparatus
and are uncorrected. Infrared spectra were recorded on a
Perkin-Elmer 1600 FTIR spectrophotometer. 1H NMR spectra
were recorded on a Varian Unity 300 spectrometer. The
chemical shifts are reported in parts per million (ppm) relative
to internal tetramethylsilane in CDCl3 or DMSO-d6. 1H noise-
decoupled 13C NMR spectra were recorded on a Varian Unity
Eth yl Cyclop r op yla ceta te (2c). A solution of cyclopro-
paneacetonitrile (37 g, 456 mmol) in 3 N HCl in EtOH (500

2368 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Kim et al.
Ta ble 3. Physical and Spectral Properties of 1-Alkoxy-5-alkyl-6-(arylthio)uracils
compd
R1
R2
R3
% yield
crystn solvent
mp, °C
EI-MS, m/z
formula
anal.a
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
Et
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
n-Pr
(CH2)3OH
(CH2)3OH
(CH2)3OH
(CH2)3OH
(CH2)3OH
n-Bu
CH2Ph
(CH2)2Ph
(CH2)2Ph(3-Me) 3,5-Me2
(CH2)2OMe
(CH2)2OPh
n-Pr
(CH2)3OH
n-Bu
H
2-Me
3-Me
4-Me
3,5-Me2
3-F
3,5-F2
H
3-Me
3,5-Me
3-F
92
99
88
79
99
99
99
81
91
99
82
79
99
72
97
99
99
94
79
76
96
65
86
67
80
93
78
99
95
97
94
99
83
93
93
99
EtOH
EtOAc-hexane
EtOH
EtOAc-hexane
EtOH
EtOH
106.1-106.7 320 (M+)
118.5-119.2 334 (M+)
C16H20N2O3S
C17H22N2O3S
C17H22N2O3S
C17H22N2O3S
C18H24N2O3S
C16H19FN2O3S
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
89.4-90.0
334 (M+)
116.8-117.3 334 (M+)
130.9-131.9 348 (M+)
136.4-136.9 338 (M+)
172.7-173.3 356 (M+)
EtOH
C16H18F2N2O3S C, H, N
EtOAc-hexane
EtOAc-hexane
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOAc-hexane
EtOH
EtOAc-hexane
EtOH
EtOH
90.6-91.7
79.1-81.8
336 (M+)
350 (M+)
C16H20N2O4S
C17H22N2O4S
C18H24N2O4S
C16H19FN2O4S
C16H18F2N2O4S C, H, N
C19H26N2O3S
C22H24N2O3S
C, H, N
C, H, N
C, H, N
C, H, N
128.0-129.0 364 (M+)
94.7-95.5
354 (M+)
3,5-F2
3,5-Me2
3,5-Me2
3,5-Me2
136.7-137.0 372 (M+)
126.0-127.0 362 (M+)
155.6-156.4 396 (M+)
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
113.3-113.9 410 (M - H)+ C23H26N2O3S
122.0-124.0 425 (M + H)+ C24H28N2O3S
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
3,5-Me2
104.0-105.0 364 (M+)
138.0-139.0 426 (M+)
115.3-116.0 334 (M+)
124.9-125.8 350 (M+)
128.2-128.8 348 (M+)
153.7-154.4 382 (M+)
134.6-134.9 396 (M+)
128.2-128.7 350 (M+)
152.5-152.9 346 (M+)
147.7-148.9 362 (M+)
149.2-150.0 394 (M+)
C18H24N2O4S
C23H26N2O4S
C17H22N2O3S
C17H22N2O4S
C18H24N2O3S
C21H22N2O3S
C22H24N2O3S
C17H22N2O4S
C18H22N2O3S
C18H22N2O4S
C22H22N2O3S
Et
Et
Et
Et
CH2Ph
(CH2)2Ph
(CH2)2OMe
n-Pr
(CH2)3OH
CH2Ph
(CH2)2Ph
n-Pr
(CH2)3OH
CH2Ph
(CH2)2Ph
n-Pr
(CH2)3OH
CH2Ph
Et
EtOH
EtOAc-hexane
EtOH
c-Pr
c-Pr
c-Pr
c-Pr
n-Pr
n-Pr
n-Pr
n-Pr
Me
EtOH
EtOAc-hexane
EtOAc-hexane
EtOAc-hexane
EtOH
137.0-137.4 409 (M + H)+ C23H24N2O3S
101.5-103.6 348 (M+)
108.6-109.0 364 (M+)
136.0-137.0 396 (M+)
114.2-114.4 410 (M+)
118.3-119.7 320 (M+)
C18H24N2O3S
C18H24N2O4S
C22H24N2O3S
C23H26N2O3S
C16H20N2O3S
C16H20N2O4S
C20H20N2O3S
C21H22N2O3S
EtOH
EtOAc-hexane
Me
Me
Me
EtOAc-hexazne 153.2-154.3 336 (M+)
EtOH
EtOH
178.1-179.4 368 (M+)
143.9-144.5 382 (M+)
(CH2)2Ph
a
See footnote of Table 1.
mL) was gently heated under reflux for 3 h, and the excess
solvent was removed by distillation. To the residue was added
H2O (150 mL), and the aqueous solution was extracted with
Et2O (50 mL × 6). The combined ethereal solution was washed
with saturated NaHCO3 solution until the washings were
neutral and brine. The organic phase was dried over anhy-
drous MgSO4, and the solvent was removed by distillation to
give 36.41 g of crude 2c which contained ∼9% (w/w) of Et2O
confirmed by 1H NMR spectrum (33.2 g, 57% for pure 2c) and
was used in the next step without further purification: IR
mixture was stirred for an additional 16 h at room temperature
and then poured into H2O (400 mL). The aqueous phase was
extracted with Et2O (100 mL × 3). The combined ethereal
solution was washed with H2O (50 mL) and brine (50 mL),
dried over anhydrous MgSO4, filtered, and evaporated to
dryness. The brick red oily residue was distilled in vacuo or
purified by flash column chromatography to give 3a -e as a
yellow oil.
Eth yl 3,3-Bis(m eth ylth io)-2-isop r op yla cr yla te (3a ).33
This compound was synthesized from 2a in 85% yield.
Eth yl 3,3-Bis(m eth ylth io)-2-eth yla cr yla te (3b).32,33 This
compound was synthesized from 2b in 90% yield.
1
(neat) 1740 (CdO) cm-1; H NMR (CDCl3) δ 0.12-0.19 (m, 2
H, CH2CH2), 0.50-0.59 (m, 2 H, CH2CH2), 1.05 (m, 1 H, CH),
1.26 (t, J ) 7.2 Hz, 3 H, OCH2CH3), 2.20 (d, J ) 7.2 Hz, 2 H,
CH2), 4.15 (q, J ) 7.2 Hz, 2 H, OCH2); 13C NMR (CDCl3) δ
4.29, 6.88, 14.22, 39.41, 60.22, 173.23.
Eth yl 2-Cyclop r op yl-3,3-bis(m eth ylth io)a cr yla te (3c).
This compound was synthesized from 2c and purified by flash
column chromatography on silica gel with Et2O-hexane (1:9)
Gen er a l P r oced u r e for t h e P r ep a r a t ion of E t h yl
2-Alk yl-3,3-bis(m eth ylth io)a cr yla tes 3a -e. To a stirred
solution of diisopropylamine (84.1 mL, 600 mmol) in anhydrous
THF (600 mL) was added butyllithium (1.6 M solution in
hexanes, 312.5 mL, 500 mmol) at -78 °C over 15 min. After
the mixture was stirred at -30 °C for 30 min, ethyl ester 2a -e
(500 mmol) in anhydrous THF (80 mL) was added over 30 min,
and the stirred solution was maintained at 0 °C for 30 min.
The contents were then cooled to -78 °C, and carbon disulfide
(45.1 mL, 750 mmol) was added over 30 min. The temperature
of the mixture was not allowed to rise above -70 °C during
the addition. The mixture was further stirred for 30 min, and
then MeI (93.4 mL, 1.5 mol) was added over 5 min. The
as eluent: yield 81%; IR (neat) 1723 (CdO) cm-1 1H NMR
;
(CDCl3) δ 0.60-0.68 (m, 2 H, CH2CH2), 0.82-0.90 (m, 2 H,
CH2CH2), 1.31 (t, J ) 7.2 Hz, 3 H, CH2CH3), 2.17 (tt, J ) 8.6
Hz, J ) 5.3 Hz, 1 H, CH), 2.26 (s, 3 H, SCH3), 2.35 (s, 3 H,
SCH3), 4.21 (q, J ) 7.2 Hz, 2 H, OCH2CH3); 13C NMR (CDCl3)
δ 7.07, 13.76, 14.10, 16.08, 17.58, 60.91, 132.60, 144.24, 166.85;
MS (EI) m/z 232 (M+). Anal. (C10H16O2S2) C, H.
Eth yl 3,3-Bis(m eth ylth io)-2-p r op yla cr yla te (3d ). This
compound was synthesized from 2d : yield 72%; bp 98-100
°C/0.8 mmHg; IR (neat) 1722 (CdO) cm-1; 1H NMR (CDCl3) δ
0.93 (t, J ) 7.4 Hz, 3 H, CH2CH2CH3), 1.32 (t, J ) 7.2 Hz, 3
H, OCH2CH3), 1.47 (tq, J ) 7.7 Hz, J ) 7.4 Hz, 2 H, CH2CH2-
CH3), 2.29 (s, 3 H, SCH3), 2.32 (s, 3 H, SCH3), 2.57 (t, J ) 7.7

1-Alkoxy-5-alkyl-6-(arylthio)uracils
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2369
Ta ble 4. Inhibition of HIV-1 Replication in CEM-SS Cells by
Ta ble 5. Inhibition of HIV-1 Replication in Human Peripheral
Blood Mononuclear Cells (PBMCs) by 18 and AZTa
1-Alkoxy-5-alkyl-6-(arylthio)uracilsa
SId
467
16556
b
compd
EC50 (µM)
CC50c (µM)
18
AZT
0.15
0.009
70
149
a
The antiviral activity and cytotoxicity of the compound were
tested at the National Institute of Health (Seoul, Korea). Each
value represents the mean value of two independent experiments
b
run in duplicate. Effective concentration of compound required
to reduce the production of p24 antigen of untreated control by
b
c
EC50
CC50
50%. c Cytotoxic concentration of compound required to reduce the
d
[3H]thymidine incorporation into DNA by control by 50%. Se-
compd R1
R2
R3
(µM)
(µM)
SId
11
2.9
41
lectivity index: ratio of CC50/EC50
.
14
i-Pr n-Pr
H
6.75 (A)
13.9 (M)
0.98 (A)
NA (I)
75
41
40
69
33
72
15
16
17
18
19
20
i-Pr n-Pr
i-Pr n-Pr
i-Pr n-Pr
i-Pr n-Pr
i-Pr n-Pr
i-Pr n-Pr
2-Me
3-Me
4-Me
Ta ble 6. Inhibitory Effect of 18 and Foscarnet of HIV-1, Avian
Myeloblastosis Virus (AMV), and Molony Murine Leukemia
Virus (Mo-MuLV) Recombinant Reverse Transcriptases (rRTs)
3,5-Me2 0.064 (A)
516
38
>84
8.9
28
3-F
3,5-F2
H
1.90 (A)
2.39 (A) >200
19.0 (M)
4.70 (A)
3,5-Me2 0.19 (A)
a
IC50 (µM)
21
22
23
24
25
26
i-Pr (CH2)3OH
i-Pr (CH2)3OH
i-Pr (CH2)3OH
i-Pr (CH2)3OH
i-Pr (CH2)3OH
i-Pr n-Bu
170
118
75
compd
18
foscarnet
HIV-1
AMV
>100
9.31
Mo-MuLV
3-Me
12.30
2.03
>100
395
17.6
3-F
NA (I)
3.4
a
3,5-F2
7.52 (A)
150
30
24
15
13
20
71
2.8
31
15
The concentration required to reduce optical density (OD) of
3,5-Me2 0.42 (A)
3,5-Me2 8.45 (M)
3,5-Me2 0.49 (A)
control by 50%. Each value represents the mean value of at least
three independent experiments run in duplicate.
27
28
i-Pr CH2Ph
i-Pr (CH2)2Ph
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
i-Pr (CH2)2Ph(3-Me) 3,5-Me2 0.84 (A)
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Alk yl-3,3-
bis(m eth ylth io)a cr ylic Acid s 4a -e. A mixture of ethyl
2-alkyl-3,3-bis(methylthio)acrylate 3a -e (300 mmol) and 2 N
KOH (300 mL for 3b and 3d -e or 600 mL for 3a and 3c) in
EtOH (300 mL for 3b and 3d -e or 1.2 L for 3a and 3c) was
heated under reflux for 3 h (for 3b and 3d -e) or 72 h (for 3a
and 3c). The reaction mixture was concentrated to remove
EtOH and poured into H2O (300 mL). The aqueous phase was
washed with Et2O (200 mL × 2), acidified with concentrated
HCl to pH 3, and extracted with Et2O (200 mL × 3). The
combined ethereal solution was washed with brine, dried over
anhydrous MgSO4, filtered, and evaporated to dryness. The
residue was crystallized from hexane to give 4a -e as white
crystals.
i-Pr (CH2)2OMe
i-Pr (CH2)2OPh
3,5-Me2 0.43 (A)
3,5-Me2 0.46 (A)
3,5-Me2 0.35 (A)
3,5-Me2 0.54 (A)
3,5-Me2 0.97 (A)
96
16
54
123
40
223
35
154
228
41
>35
78
69
4.9
8.5
>13
7.1
18
13
11
41
69
25
>20
>39
Et
Et
Et
Et
Et
Et
n-Pr
(CH2)3OH
n-Bu
CH2Ph
(CH2)2Ph
(CH2)2OMe
3,5-Me2 5.77 (A) >200
3,5-Me2 0.46 (A)
3,5-Me2 1.97 (A)
3,5-Me2 6.12 (M)
3,5-Me2 15.1 (M)
3,5-Me2 15.9 (M)
3,5-Me2 6.03 (M)
3,5-Me2 2.57 (A)
3,5-Me2 8.22 (A)
3,5-Me2 10.3 (M)
3,5-Me2 0.70 (A)
3,5-Me2 0.93 (A)
3,5-Me2 5.55 (A)
3,5-Me2 10.1 (M)
36
136
30
128
>200
43
c-Pr n-Pr
c-Pr (CH2)3OH
c-Pr CH2Ph
c-Pr (CH2)2Ph
n-Pr n-Pr
n-Pr (CH2)3OH
n-Pr CH2Ph
n-Pr (CH2)2Ph
Me n-Pr
45
107
114
29
64
140
>200
3,3-Bis(m eth ylth io)-2-isopr opylacr ylic Acid (4a).25 This
compound was synthesized from 3a in 82% yield.
45
46
47
48
Me (CH2)3OH
Me CH2Ph
Me (CH2)2Ph
3,3-Bis(m eth ylth io)-2-eth yla cr ylic Acid (4b).25 This
compound was synthesized from 3b in 86% yield.
49
3,5-Me2 3.08 (A) >121
2-Cyclopr opyl-3,3-bis(m eth ylth io)acr ylic Acid (4c). This
compound was synthesized from 3c: yield 77%; mp 63.5-64.6
AZT
DDC
DDIe
HEPTf
0.0045
0.19
2.8
>1.0 >220
>10
>53
>3.6
48
1
°C (hexane); IR (KBr) 1691 (CdO) cm-1; H NMR (CDCl3) δ
>10
0.69-0.75 (m, 2 H, CH2CH2), 0.86-0.94 (m, 2 H, CH2CH2),
2.10 (tt, J ) 8.6 Hz, J ) 5.3 Hz, 1 H, CH), 2.30 (s, 3 H, SCH3),
2.38 (s, 3 H, SCH3), 10.43 (br s, 1 H, COOH); 13C NMR (CDCl3)
δ 7.47, 13.21, 13.79, 16.92, 124.80, 129.31, 172.02; MS (EI)
m/z 205 (M + H)+. Anal. (C8H12O2S2) C, H.
8.3
400
a
The antiviral activity and cytotoxicity of the compound were
tested by the Developmental Therapeutics Program of the National
Cancer Institute. All data is the mean value of at least two
b
independent experiments run in duplicate. Effective concentra-
3,3-Bis(m eth ylth io)-2-p r op yla cr ylic Acid (4d ). This
compound was synthesized from 3d : yield 76%; mp 44.2-45.2
tion of compound required to achieve 50% protection of CEM-SS
cells against the cytopathic effect of HIV-1. If the EC50 was <10
µM and if >90% protection was observed, the compound was
judged to be active (A); otherwise, it was called moderately active
(M). Compounds that exhibited <50% protection were considered
inactive (I). NA, not applicable. c Cytotoxic concentration of
1
°C (hexane); IR (KBr) 1662 (CdO) cm-1; H NMR (CDCl3) δ
0.95 (t, J ) 7.4 Hz, 3 H, CH2CH2CH3), 1.52 (tq, J ) 7.8 Hz, J
) 7.4 Hz, 2 H, CH2CH2CH3), 2.36 (s, 6 H, 2 SCH3), 2.64 (t, J
) 7.8 Hz, 2 H, CH2CH2CH3), 10.55 (br s, 1 H, COOH); 13C NMR
(CDCl3) δ 13.79, 17.20, 18.24, 22.16, 35.36, 137.88, 143.57,
173.09; MS (EI) m/z 206. Anal. (C8H14O2S2) C, H.
compound required to reduce the viability of mock-infected CEM-
d
SS cells by 50%. Selectivity index: ratio of CC50/EC50
.
e Inhibition
of HIV-1 replication in CEM-V cells. f Data from ref 17. Inhibition
of HTLB-IIIB replication in CEM cells.
3,3-Bis(m eth ylth io)-2-m eth yla cr ylic Acid (4e). This
compound was synthesized from 3e: yield 89%; mp 82.4-82.8
1
°C (hexane); IR (KBr) 1677 (CdO) cm-1; H NMR (CDCl3) δ
Hz, 2 H, CH2CH2CH3), 4.25 (q, J ) 7.2 Hz, 2 H, OCH2CH3);
13C NMR (CDCl3) δ 13.75, 14.18, 16.65, 17.70, 21.83, 35.24,
60.88, 137.50, 141.32, 168.63; MS (EI) m/z 234 (M+). Anal.
(C10H18O2S2) C, H.
2.22 (s, 3 H, CH3), 2.38 (s, 6 H, 2 SCH3), 12.13 (br s, 1 H,
COOH): 13C NMR (CDCl3) δ 17.30, 18.50, 19.27, 131.10,
145.98, 172.80; MS (EI) m/ z 178 (M+). Anal. (C6H10O2S2) C,
H.
Eth yl 3,3-Bis(m eth ylth io)-2-m eth yla cr yla te (3e). This
compound was synthesized from 2e: yield 71%; bp 82-106
°C/0.5 mmHg; IR (neat) 1721 (CdO) cm-1; 1H NMR (CDCl3) δ
1.33 (t, J ) 7.1 Hz, 3 H, OCH2CH3), 2.15 (s, 3 H, CH3), 2.31 (s,
3 H, SCH3), 2.34 (s, 3 H, SCH3), 4.25 (q, J ) 7.1 Hz, 2 H, OCH2-
CH3); 13C NMR (CDCl3) δ 14.14, 16.72, 17.83, 19.11, 60.91,
134.92, 139.24, 168.46; MS (EI) m/z 206 (M+). Anal.
(C8H14O2S2) C, H.
Gen er a l P r oced u r e for th e P r ep a r a tion of 2-Alk yl-3,3-
bis(m eth ylth io)a cr yloyl Ch lor id es 5a -e. To a stirred
solution of 2-alkyl-3,3-bis(methylthio)acrylic acid 4a -e (100
mmol) in anhydrous benzene (100 mL) were added oxalyl
chloride (10.5 mL, 120 mmol) dropwise and 3 drops of DMF
at 0 °C under a nitrogen atmosphere. The mixture was stirred
at room temperature for 3 h and evaporated to dryness. The
residue was distilled in vacuo to give 5a -e as a brick red oil.

2370 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Kim et al.
1
3,3-Bis(m eth ylth io)-2-isopr opylacr yloyl Ch lor ide (5a).25
This compound was synthesized from 4a in 91% yield.
3,3-Bis(m eth ylth io)-2-eth ylacr yloyl Ch lor ide (5b).25 This
compound was synthesized from 4b in 91% yield.
2-Cyclopr opyl-3,3-bis(m eth ylth io)acr yloyl Ch lor ide (5c).
This compound was synthesized from 4c: yield 88%; bp 115-
119 °C/2 mmHg; IR (neat) 1782 (CdO) cm-1; 1H NMR (CDCl3)
δ 0.68-0.76 (m, 2 H, CH2CH2), 0.93-1.08 (m, 2 H, CH2,CH2),
1.95 (tt, J ) 8.4 Hz, J ) 5.4 Hz, 1 H, CH), 2.34 (s, 3 H, SCH3),
2.42 (s, 3 H, SCH3); 13C NMR (CDCl3) δ 8.16, 13.54, 16.54,
18.18, 140.98, 143.61, 165.88.
hexane); IR (KBr) 1735 (CdO) cm-1; H NMR (CDCl3) δ 3.39
(s, 3 H, OCH3), 3.76 (t, J ) 4.5 Hz, 2 H, CH2OCH3), 4.37 (t, J
) 4.5 Hz, 2 H, OCH2), 7.70-7.90 (m, 4 H, Ar H); 13C NMR
(CDCl3) δ 59.07, 70.41, 77.04, 123.46, 126.90, 128.96, 134.38,
163.37; MS (EI) m/z 222 (M + H)+. Anal. (C11H11NO4) C, H,
N.
N-(2-P h en oxyeth oxy)p h th a lim id e (9g). This compound
was synthesized from 2-phenoxyethanol (8g) and crystallized
from EtOAc: yield 72%; mp 136.2-136.7 °C (EtOAc); IR (KBr)
1726 (CdO) cm-1; 1H NMR (CDCl3) δ 4.34 (t, J ) 4.5 Hz, 2 H,
CH2OPh), 4.57 (t, J ) 4.5 Hz, 2 H, OCH2), 6.75-6.88 (m, 2 H,
Ar H), 6.90-6.98 (m, 1 H, Ar H), 7.18-7.30 (m, 2 H, Ar H),
7.70-7.88 (m, 4H, Ar H); 13C NMR (CDCl3) δ 66.07, 75.99,
114.56, 121.14, 123.44, 128.80, 129.33, 134.39, 158.15, 163.25;
MS (EI) m/z 283 (M+). Anal. (C16H13NO4) C, H, N.
Gen er a l P r oced u r e for t h e P r ep a r a t ion of Alk oxy-
a m in es 7a a n d 7c-g. A mixture of N-alkoxyphthalimide 9a
and 9c-g (10.0 mmol) and hydrazine monohydrate (0.49 mL,
10.0 mmol) in MeOH (60 mL) was heated under reflux for 4
h. After cooling, the resulting suspension was filtered, and
the filtrate was evaporated. The residue was triturated with
Et2O (60 mL) and filtered, and the filtrate was evaporated to
dryness. The residue was distilled or purified by flash column
chromatography to give 7a and 7c-g.
P r op oxya m in e (7a ). This compound was synthesized from
9a and purified by distillation: yield 72%; a colorless liquid;
bp 89-91 °C (lit.37 bp 90-91 °C); 1H NMR (CDCl3) δ 0.92 (t, J
) 7.5 Hz, 3 H, CH3), 1.60 (qt, J ) 7.5 Hz, J ) 6.6 Hz, 2 H,
OCH2CH2), 3.62 (t, J ) 6.6 Hz, 2 H, OCH2), 4.65 (br s, 2 H,
NH2).
Bu toxya m in e (7c). This compound was synthesized from
9c and purified by distillation: yield 77%; a colorless liquid;
bp 114-116 °C (lit.37 bp 115 °C); 1H NMR (CDCl3) δ 0.93 (t, J
) 7.2 Hz, 3 H, CH3), 1.36 (qt, J ) 7.2 Hz, J ) 6.9 Hz, 2 H,
OCH2CH2CH2), 1.56 (tt, J ) 6.9 Hz, J ) 6.6 Hz, 2 H,
OCH2CH2), 3.66 (t, J ) 6.6 Hz, 2 H, OCH2), 4.97 (br s, 2 H,
NH2).
3,3-Bis(m eth ylth io)-2-pr opylacr yloyl Ch lor ide (5d). This
compound was synthesized from 4d : yield 74%; bp 116-128
1
°C/4 mmHg; IR (neat) 1773 (CdO) cm-1; H NMR (CDCl3) δ
0.96 (t, J ) 7.4 Hz, 3 H, CH2CH2CH3), 1.55 (tq, J ) 7.8 Hz, J
) 7.4 Hz, 2 H, CH2CH2CH3), 2.36 (s, 3 H, SCH3), 2.39 (s, 3 H,
SCH3), 2.67 (t, J ) 7.8 Hz, 2 H, CH2CH2CH3); 13C NMR (CDCl3)
δ 13.50, 16.80, 17.92, 21.64, 35.11, 142.12, 143.48, 166.61.
3,3-Bis(m eth ylth io)-2-m eth yla cr yloyl Ch lor id e (5e).
This compound was synthesized from 4e: yield 90%; bp 100-
108 °C/2 mmHg; IR (neat) 1763 (CdO) cm-1; 1H NMR (CDCl3)
δ 2.28 (s, 3 H, CH3), 2.39 (s, 3 H, SCH3), 2.42 (s, 3 H, SCH3);
13C NMR (CDCl3) δ 17.35, 18.49, 19.81, 134.64 147.94, 166.10.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Alk ox-
yp h th a lim id es 9a -g. Diethyl azodicarboxylate (1.90 mL,
12.0 mmol) was added dropwise at 0 °C to a stirred suspension
of alcohol (8a -g) (10.0 mmol), triphenylphosphine (3.15 g, 12.0
mmol), and N-hydroxyphthalimide (1.96 g, 12.0 mmol) in THF
(50 mL). The mixture was stirred at room temperature for
16 h and evaporated to dryness. The residue was triturated
with Et2O (20 mL) and filtered, and the filtrate was evapo-
rated. The process was repeated, and then the residue was
purified by flash column chromatography or crystallized from
a suitable solvent to afford 9a -g as white crystals.
N-P r op oxyp h th a lim id e (9a ). This compound was syn-
thesized from 1-propanol (8a ) and purified by flash column
chromatography on silica gel with Et2O-hexane (1:3) as
eluent: yield 98%; mp 57.1-58.3 °C (Et2O-hexane); IR (KBr)
1732 (CdO) cm-1; 1H NMR (CDCl3) δ 1.07 (t, J ) 7.2 Hz, 3 H,
CH3), 1.82 (qt, J ) 7.2 Hz, J ) 6.9 Hz, 2 H, OCH2CH2), 4.17
(t, J ) 6.9 Hz, 2 H, OCH2), 7.75-7.85 (m, 4 H, Ar H); MS (EI)
m/z 206 (M + H)+. Anal. (C11H11NO3) C, H, N.
N -( 3 -( ( t e r t -B u t y l d i m e t h y l s i l y l ) o x y ) p r o p o x y ) -
p h th a lim id e (9b).27 This compound was synthesized from
3-((tert-butyldimethylsilyl)oxy)-1-propanol (8b) in 92% yield.
N-Bu toxyp h th a lim id e (9c). This compound wsa synthe-
sized from 1-butanol (8c) and purified by flash column chro-
matography on silica gel with Et2O-hexane (1:3) as eluent:
yield 98%; mp 29.2-30.2 °C (petroleum ether); IR (KBr) 1733
(CdO) cm-1; 1H NMR (CDCl3) δ 0.98 (t, J ) 7.5 Hz, 3 H, CH3),
1.53 (qt, J ) 7.5 Hz, J ) 7.2 Hz, 2 H, OCH2CH2CH2), 1.78 (tt,
J ) 7.2 Hz, J ) 6.6 Hz, 2 H, OCH2CH2), 4.21 (t, J ) 6.6 Hz,
2 H, OCH2), 7.75-7.85 (m, 4 H, Ar H); MS (EI) m/z 220 (M +
H)+. Anal. (C12H13NO3) C, H, N.
N-(2-P h en yleth oxy)p h th a lim id e (9d ). This compound
was synthesized from phenethyl alcohol (8d ) and purified by
flash column chromatography on silica gel with Et2O-hexane
(1:3) as eluent: yield 88%; mp 92.9-94.4 °C (EtOH) (lit.36 mp
91-92 °C); IR (KBr) 1730 (CdO) cm-1; 1H NMR (CDCl3) δ 3.14
(t, J ) 7.4 Hz, 2 H, CH2Ar), 4.43 (t, J ) 7.4 Hz, 2 H, OCH2),
7.16-7.35 (m, 5 H, Ar H), 7.68-7.90 (m, 4 H, Ar H).
N-(2-(3-Meth ylp h en yl)eth oxy)p h th a lim id e (9e). This
compund was synthesized from 3-methylphenethyl alcohol (8e)
and purified by flash column chromatography on silica gel with
Et2O-hexane (1:3) as eluent: yield 96%; mp 59.1-59.7 °C
(Et2O-hexane); IR (KBr) 1726 (CdO) cm-1; 1H NMR (CDCl3)
δ 2.32 (s, 3 H, CH3), 3.12 (t, J ) 7.5 Hz, 2 H, CH2Ar), 4.43 (t,
J ) 7.5 Hz, 2 H, OCH2), 6.98-7.22 (m, 4 H, Ar H), 7.70-7.86
(m, 4 H, Ar H); 13C NMR (CDCl3) δ 21.33, 34.55, 78.53, 123.46,
125.79, 127.31, 128.42, 128.91, 129.61, 134.41, 136.57, 138.11,
163.54; MS (EI) m/z 282 (M + H)+. Anal. (C17H15NO3) C, H,
N.
(2-P h en yleth oxy)a m in e (7d ).36 This compound was syn-
thesized from 9d and purified by flash column chromatography
on silica gel with Et2O-hexane (1:1) as eluent: yield 85%; a
pale yellow oil; IR (neat) 3314 (ONH2) cm-1; 1H NMR (CDCl3)
δ 2.90 (t, J ) 6.9 Hz, 2 H, CH2Ar), 3.88 (t, J ) 6.9 Hz, 2 H,
CH2ONH2), 5.34 (br s, 2 H, NH2), 7.10-7.40 (m, 5 H, Ar H).
(2-(3-Meth ylp h en yl)eth oxy)a m in e (7e). This compound
was synthesized from 9e and purified by flash column chro-
matography on silica gel with EtOAc-hexane (1:2) as eluent:
yield 89%; a yellow oil; IR (neat) 3314 (ONH2) cm-1; 1H NMR
(CDCl3) δ 2.33 (s, 3 H, CH3), 2.87 (t, J ) 7.1 Hz, 2 H, CH2Ar),
3.89 (t, J ) 7.1 Hz, 2 H, CH2ONH2), 6.98-7.06 (m, 3 H, Ar
H), 7.15-7.22 (m, 1 H, Ar H). Anal. (C9H13NO) C, H. N.
(2-Meth oxyeth oxy)a m in e (7f). This compound was syn-
thesized from 9f and purified by distillation: yield 50%; a
colorless liquid; bp 132-136 °C; IR (neat) 3315 (ONH2) cm-1
;
1H NMR (CDCl3) δ 3.39 (s, 3 H, OCH3), 3.57 (t, J ) 4.5 Hz, 2
H, CH2ONH2), 3.83 (t, J ) 4.5 Hz, 2 H, CH2OMe), 5.46 (br s,
2 H, NH2); 13C NMR (CDCl3) δ 58.77, 70.70, 74.44. Anal.
(C3H9NO2) C, H, N.
(2-P h en oxyeth oxy)a m in e (7g). This compound was syn-
thesized from 9g and purified by flash column chromatography
on silica gel with EtOAc-hexane (1:1) as eluent: yield 63%;
mp 43.6-44.2 °C (EtOAc-hexane); IR (KBr) 1600 (OPh), 3324
(ONH2) cm-1; 1H NMR (CDCl3) δ 4.02 (t, J ) 4.5 Hz, 2 H, CH2-
OPh), 4.16 (t, J ) 4.5 Hz, 2 H, CH2ONH2), 5.23 (br s, 2 H,
NH2), 6.86-7.00 (m, 3 H, Ar H), 7.22-7.35 (m, 2 H, Ar H); 13
C
NMR (CDCl3) δ 65.91, 73.82, 114.52, 120.86, 129.38, 158.65;
MS (EI) m/z 153 (M+). Anal. (C8H11NO2) C, H, N.
(3-((ter t-Bu tyld im eth ylsilyl)oxy)p r op oxy)a m in e (7b).
This compound was synthesized from 9b in 84% yield accord-
ing to the published procedure.27
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Alk oxy-
N′-(2-a lk yl-3,3-bis(m eth ylth io)a cr yloyl)u r ea s 10a -z.
mixture of 2-alkyl-3,3-bis(methylthio)acryloyl chloride 5a -e
(10.0 mmol) and AgOCN (1.80 g, 12.0 mmol) in anhydrous
benzene (20 mL) was heated under reflux for 30 min under a
nitrogen atmosphere in the dark to generate isocyanate 6a -e
in situ and cooled to 0 °C. To this mixture was added
A
N-(2-Meth oxyeth oxy)p h th a lim id e (9f). This compound
was synthesized from 2-methoxyethanol (8f) and purified by
flash column chromatography on silica gel with EtOAc-
hexane (1:2) as eluent: yield 83%; mp 93.7-94.3 °C (EtOAc-

1-Alkoxy-5-alkyl-6-(arylthio)uracils
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15 2371
alkoxyamine 7a -h (11.0 mmol) in anhydrous benzene (10 mL).
After being stirred at room temperature for 1 h, the mixture
was filtered through a pad of Celite, and the filtrate was again
filtered using a millipore filter (0.22 µm). The filtrate was
evaporated to dryness, and the residue was purified by flash
column chromatography on silica gel or crystallized from a
suitable solvent to give 10a -z as white crystals.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-Alk oxy-
5-a lk yl-6-(m eth ylth io)u r a cils 11a -z. A stirred solution of
N-alkoxy-N′-(2-alkyl-3,3-bis(methylthio)acryloyl)urea 10a -z
(10.0 mmol) and p-TsOH (0.19 g, 1.0 mmol) in AcOH (50 mL)
was heated at 80 °C for 1 h. The reaction mixture was
evaporated to dryness, and the residue was dissolved in CH2-
Cl2 (100 mL). The CH2Cl2 solution was washed with saturated
NaHCO3 solution (50 mL) and brine (50 mL), dried over
anhydrous MgSO4, filtered, and evaporated to dryness. The
residue was purified by flash column chromatography on silica
gel or crystallized from a suitable solvent to give 11a -z as
white crystals.
reaction mixture was evaporated to dryness. The residue was
purified by flash column chromatography on silica gel with
EtOAc-hexane or MeOH-CH2Cl2 as eluent or crystallized
from a suitable solvent to give 14-49 as white crystals.
Starting materials and spectral data for selected compounds
are given below.
5-Isop r op yl-6-(p h en ylt h io)-1-p r op oxyu r a cil (14): 12a
1
and 13a ; IR (KBr) 1661, 1723 (CdO) cm-1; H NMR (CDCl3)
δ 0.90 (t, J ) 7.4 Hz, 3 H, OCH2CH2CH3), 1.26 (d, J ) 6.9 Hz,
6 H, CH(CH3)2), 1.64 (qt, J ) 7.4 Hz, J ) 6.8 Hz, 2 H,
OCH2CH2), 3.53 (septet, J ) 6.9 Hz, 1 H, CH(CH3)2), 4.07 (t,
J ) 6.8 Hz, 2 H, OCH2), 7.22-7.37 (m, 5 H, Ar H), 8.59 (br s,
1 H, NH); 13C NMR (CDCl3) δ 10.06, 20.24, 21.04, 30.95, 78.89,
125.07, 127.61, 128.80, 129.56, 132.92, 146.03, 147.54, 160.37.
6-((3,5-Dim et h ylp h en yl)t h io)-5-isop r op yl-1-p r op oxy-
u r a cil (18): 12a and 13e; IR (KBr) 1654, 1737 (CdO) cm-1
;
1H NMR (CDCl3) δ 0.92 (t, J ) 7.4 Hz, 3 H, OCH2CH2CH3),
1.26 (d, J ) 7.1 Hz, 6 H, CH(CH3)2), 1.67 (qt, J ) 7.4 Hz, J )
6.8 Hz, 2 H, OCH2CH2), 2.28 (s, 6 H, 2 Ar CH3), 3.52 (septet,
J ) 7.1 Hz, 1 H, CH(CH3)2), 4.05 (t, J ) 6.8 Hz, 2 H, OCH2),
6.90 (m, 3 H, Ar H), 8.90 (br s, 1 H, NH); 13C NMR (CDCl3) δ
10.06, 20.22, 21.05, 21.23, 30.92, 78.80, 124.79, 126.63, 129.54,
132.22, 139.28, 146.46, 147.71, 160.56.
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-Alk oxy-
5-a lk yl-6-(m eth ylsu lfon yl)u r a cils 12a -x a n d 12z a n d
1-(Ben zyloxy)-6-(m et h ylsu lfin yl)t h ym in e (12y). To a
stirred solution of 1-alkoxy-5-alkyl-6-(methylthio)uracil 11a -z
(5.0 mmol) in CH2Cl2 (20 mL) was added 3-chloroperoxybenzoic
acid (85%, 3.05 g, 15.0 mmol) in CH2Cl2 (20 mL) at room
temperature. The mixture was heated under reflux for 16 h
and then cooled to room temperature. After saturated NaH-
CO3 solution (20 mL) and saturated sodium thiosulfate solu-
tion (20 mL) were added to it, the mixture was stirred for an
additional 10 min. The organic phase was separated, and the
aqueous phase was extracted with CH2Cl2 (20 mL × 3). The
combined CH2Cl2 solution was washed with H2O (20 mL) and
brine (20 mL), dried over anhydrous MgSO4, filtered, and
evaporated to dryness. The residue was purified by flash
column chromatography on silica gel and then crystallized
from a suitable solvent to give 12a -z as white crystals.
3,5-Diflu or oth iop h en ol (13g). The stirred warm mixture
of 3,5-difluoroaniline (5.00 g, 38.7 mmol), concentrated HCl
(8 mL), and H2O (8 mL) was cooled to 0 °C and diazotized with
a solution of NaNO2 (2.75 g, 39.9 mmol) in H2O (6 mL), added
in such a rate that the temperature could be maintained by
cooling at 0-5 °C. The mixture was stirred at 0 °C for an
additional 30 min and filtered. To a stirred solution of
potassium ethyl xanthogenate (8.70 g, 54.3 mmol) in H2O (10
mL) was added the clear filtrate at 70 °C over 1 h. After the
addition was complete, the mixture was cooled to room
temperature and stirred for 1 h. The separated oily compound
was extracted with Et2O (30 mL × 3), and the ethereal solution
was evaporated. The residue was dissolved in EtOH (25 mL),
and the solution was heated under reflux under a nitrogen
atmosphere and cooled to room temperature. To this ethanolic
solution was added KOH (85%, 9.3 g, 141 mmol) in H2O (6
mL) over 30 min, and the mixture was heated under reflux
for 2 h and evaporated. The residue was dissolved in H2O (30
mL) and washed with Et2O (20 mL). Zinc (0.8 g) was added
to the aqueous phase, and the mixture was acidified at 10 °C
over 30 min with concentrated HCl. The oily product was
extracted with Et2O (30 mL × 3), dried over anhydrous MgSO4,
filtered, and evaporated to dryness to give 2.33 g (42%) of 13g
as a colorless liquid: bp 64 °C/20 mmHg; IR (neat) 2577 (SH)
6-((3,5-Diflu or op h en yl)t h io)-5-isop r op yl-1-p r op oxy-
u r a cil (20): 12a and 13g; IR (KBr) 1673, 1715 (CdO) cm-1
;
1H NMR (CDCl3) δ 0.91 (t, J ) 7.5 Hz, 3 H, OCH2CH2CH3),
1.30 (d, J ) 6.9 Hz, 6 H, CH(CH3)2), 1.65 (qt, J ) 7.5 Hz, J )
6.9 Hz, 2 H, OCH2CH2), 3.46 (septet, J ) 6.9 Hz, 1 H,
CH(CH3)2), 4.10 (t, J ) 6.9 Hz, 2 H, OCH2), 6.68-6.83 (m, 3
H, Ar H), 9.39 (br s, 1 H, NH); 13C NMR (CDCl3) δ 10.06, 20.36,
2
21.02, 31.04, 79.17, 103.19 (t, J C,F ) 25.3 Hz, C-4′), 110.91
2
4
(dd, J C,F ) 18.6 Hz, J C,F ) 9.5 Hz, C-2′ and C-6′), 136.57 (t,
3J C,F ) 10.1 Hz, C-1′), 163.08 (dd, J C,F ) 252.0 Hz, J C,F
13.1 Hz, C-3′ and C-5′).
)
1
3
6-((3,5-Dim eth ylp h en yl)th io)-1-(3-h yd r oxyp r op oxy)-5-
isop r op ylu r a cil (23): 12b and 13e; IR (KBr) 1646, 1714
1
(CdO), 3424 (OH) cm-1; H NMR (CDCl3) δ 1.26 (d, J ) 6.9
Hz, 6 H, CH(CH3)2), 1.80 (quintet, J ) 7.5 Hz, 2 H, OCH2CH2-
CH2OH), 2.29 (s, 6 H, 2 Ar CH3), 2.75 (br s, 1 H, OH), 3.51
(septet, J ) 6.9 Hz, 1 H, CH(CH3)2), 3.74 (t, J ) 5.7 Hz, 2 H,
CH2OH), 4.24 (t, J ) 5.7 Hz, 2 H, OCH2), 6.91 (m, 3 H, Ar H),
9.48 (br s, 1 H, NH); 13C NMR (CDCl3) δ 20.14, 21.22, 30.33,
30.89, 58.70, 74.45, 125.12, 126.80, 129.80, 131.94, 139.42,
146.23, 148.35, 160.42.
6-((3,5-Dim e t h ylp h e n yl)t h io)-5-isop r op yl-1-(2-p h e -
n ylet h oxy)u r a cil (28): 12e and 13e; IR (KBr) 1684, 1702
(CdO) cm-1; 1H NMR (CDCl3) δ 1.25 (d, J ) 6.9 Hz, 6 H, CH-
(CH3)2), 2.28 (s, 6 H, 2 Ar CH3), 2.96 (t, J ) 7.4 Hz, 2 H, CH2-
Ar), 3.51 (septet, J ) 6.9 Hz, 1 H, CH(CH3)2), 4.31 (t, J ) 7.4
Hz, 2 H, OCH2), 6.81-6.92 (m, 3 H, Ar H), 7.12-7.32 (m, 5 H,
Ar H), 8.39 (br s, 1 H, NH); 13C NMR (CDCl3) δ 20.23, 21.27,
30.97, 34.01, 77.51, 125.00, 126.49, 126.56, 128.43, 128.82,
129.58, 132.10, 136.71, 139.32, 146.16, 147.57, 160.27.
6-((3,5-D i m e t h y lp h e n y l)t h i o )-5-e t h y l-1-p r o p o x y -
u r a cil (32): 12i and 13e; IR (KBr) 1662, 1732 (CdO) cm-1
;
1H NMR (CDCl3) δ 0.90 (t, J ) 7.5 Hz, 3 H, OCH2CH2CH3),
1.07 (t, J ) 7.4 Hz, 3 H, CH2CH3), 1.65 (qt, J ) 7.5 Hz, J )
6.9 Hz, 2 H, OCH2CH2), 2.28 (s, 6 H, 2 Ar CH3), 2.69 (q, J )
7.4 Hz, 2 H, CH2CH3), 4.03 (t, J ) 6.9 Hz, 2 H, OCH2), 6.90
(m, 3 H, Ar H), 8.94 (br s, 1 H, NH); 13C NMR (CDCl3) δ 10.02,
13.72, 21.04, 21.22, 21.74, 78.79, 121.90, 126.76, 129.70,
131.73, 139.30, 146.77, 147.76, 161.28.
1
cm-1; H NMR (CDCl3) δ 3.59 (s, 1 H, SH), 6.59 (tt, J ) 9.0
Hz, J ) 2.1 Hz, 1 H, H-4), 6.78 (m, 2 H, H-2 and H-6); 13C
2
NMR (CDCl3) δ 101.28 (t, J C,F ) 25.3 Hz, C-4), 111.88 (dd,
6-((3,5-Dim et h ylp h en yl)t h io)-5-et h yl-1-(3-h yd r oxp r o-
p oxy)u r a cil (33): 12j and 13e; IR (KBr) 1676, 1718 (CdO),
2J C,F ) 18.0 Hz, 4J C,F ) 8.9 Hz, C-2 and C-6), 134.74 (t, 3J C,F
10.7 Hz, C-1), 162.93 (dd, J C,F ) 250.1 Hz, J C,F ) 13.4 Hz,
C-3 and C-5); MS (EI) m/z 145 (M - H)+. Anal. (C6H4F2S) C,
H.
)
1
3
1
3449 (OH) cm-1; H NMR (CDCl3) δ 1.07 (t, J ) 7.4 Hz, 3 H,
CH2CH3), 1.77 (quintet, J ) 5.7 Hz, 2 H, OCH2CH2CH2OH),
2.29 (s, 6 H, 2 Ar CH3), 2.69 (q, J ) 7.4 Hz, 2 H, CH2CH3),
3.72 (t, J ) 5.7 Hz, 2 H, CH2OH), 4.22 (t, J ) 5.7 Hz, 2 H,
OCH2), 6.93 (m, 3 H, Ar H), 9.07 (br s, 1 H, NH); 13C NMR
(CDCl3) δ 13.62, 21.20, 21.66, 30.31, 58.62, 74.36, 122.25,
126.91, 129.90, 131.48, 139.40, 146.41, 148.53, 161.37.
6-((3,5-Dim eth ylp h en yl)th io)-5-eth yl-1-(2-p h en yleth ox-
Gen er a l P r oced u r e for th e P r ep a r a tion of 1-Alk oxy-
5-a lk yl-6-(a r ylth io)u r a cils 14-49. To a stirred suspension
of 1-alkoxy-5-alkyl-6-(methylsulfonyl)uracil 12a -x and 12z or
1-(benzyloxy)-6-(methylsulfinyl)thymine (12y) (1.0 mmol) and
arenethiol 13a -g (1.0 mmol) in EtOH (2 mL) was added 1 N
ethanolic NaOH (1.10 or 3.30 mL for 12b, 12j, 12p , 12t, and
12x) at room temperature under a nitrogen atmosphere. After
the mixture was stirred for 20 min, 3 N HCl in EtOH (0.37 or
1.10 mL for 12b, 12j, 12p , 12t, and 12x) was added, and the
y)u r a cil (36): 12m and 13e; IR (KBr) 1663, 1734 (CdO) cm-1
;
1H NMR (CDCl3) δ 1.06 (t, J ) 7.4 Hz, 3 H, CH2CH3), 2.28 (s,
6 H, 2 Ar CH3), 2.68 (q, J ) 7.4 Hz, 2 H, CH2CH3), 2.93 (t, J
) 7.4 Hz, 2 H, CH2Ar), 4.30 (t, J ) 7.4 Hz, 2 H, OCH2), 6.83-

2372 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 15
Kim et al.
6.92 (m, 3 H, Ar H), 7.10-7.29 (m, 5 H, Ar H), 9.02 (br s, 1 H,
NH); 13C NMR (CDCl3) δ 13.74, 21.26, 21.77, 34.00, 77.46,
122.21, 126.54, 126.56, 128.42, 128.79, 129.70, 131.73, 136.69,
139.32, 146.36, 147.81, 161.21.
6-((3,5-Dim eth ylp h en yl)th io)-1-p r op oxyth ym in e (46):
12w and 13e; IR (KBr) 1700 (CdO) cm-1; 1H NMR (CDCl3) δ
0.95 (t J ) 7.5 Hz, 3 H, OCH2CH2CH3), 1.70 (qt, J ) 7.5 Hz,
J ) 6.8 Hz, 2 H, OCH2CH2), 2.06 (s, 3 H, CH3), 2.29 (s, 6 H, 2
Ar CH3), 4.09 (t, J ) 6.8 Hz, 2 H, OCH2), 6.91 (m, 3 H, Ar H),
8.44 (br s, 1 H, NH); 13C NMR (CDCl3) δ 10.09, 13.64, 21.06,
21.22, 78.91, 115.55, 127.13, 129.81, 131.29, 139.38, 147.61,
147.71, 161.77.
Dawley male rats after cervical dislocation, kept in ice-cold
0.25 M sucrose, and homogenized in 5 volumes of ice-cold 0.25
M sucrose. Liver homogenates were centrifuged at 3000g for
30 min, and the supernatant was diluted with of 0.1 M
potassium phosphate buffer (pH 7.5) to obtain a final protein
concentration of 300 µg/mL. Compound 18 (final concentration
of 30 µM) was incubated with diluted liver homogenates for 1
h at 37 °C. The incubation was terminated with the addition
of 2 volumes of methanol. Thereafter, the sample was
centrifuged at 3000g for 30 min, and the supernatant was
analyzed by HPLC. HPLC analysis was conducted using two
pumps, a Waters solvent delivery module (Model 600), a
multiwavelength UV detector (Model 600), and a Waters 717
autosampler (Waters, Milford, MA). The sample was chro-
matographed on a Sepadex column (25 cm × 4.6 mm) protected
with a C18 Gaurd-Pak column. For compounds 18 and 51, the
mobile phase contained methanol and water (1:1), and the flow
rate was 1.0 mL/min. The detection wavelength for these
compounds was 274 nm. Compounds 18 and 51 were identi-
fied by their approximate retention times 29.7 and 11.6 min,
respectively.
6-((3,5-Dim eth ylp h en yl)th io)-1-(2-p h en yleth oxy)th ym -
1
in e (49): 12z and 13e; IR (KBr) 1661, 1716 (CdO) cm-1; H
NMR (CDCl3) δ 2.06 (s, 3 H, CH3), 2.28 (s, 6 H, 2 Ar CH3),
2.99 (t, J ) 7.4 Hz, 2 H, CH2Ar), 4.35 (t, J ) 7.4 Hz, 2 H,
OCH2), 6.85 (s, 2 H, Ar H), 6.91 (s, 1 H, Ar H), 7.14-7.33 (m,
5 H, Ar H), 8.66 (br s, 1 H, NH); 13C NMR (CDCl3) δ 13.66,
21.24, 34.00, 77.56, 115.89, 126.55, 126.97, 128.43, 128.82,
129.80, 131.25, 136.67, 139.37, 147.25, 147.81, 161.88.
6-((3,5-Dim eth ylph en yl)th io)-5-isopr opylu r acil (51). To
a stirred solution of 6-chloro-5-isopropyluracil38 (50) (0.21 g,
1.1 mmol) in EtOH (4 mL) was added 1 N ethanolic NaOH
solution (1.1 mL). To this resulting suspension was added 3,5-
dimethylthiophenol (13e) (1.1 mmol, 151 µL) dropwise, and
then the mixture was heated under reflux for 6 h. The reaction
mixture was concentrated under reduced pressure, and the
residue was suspended in water (5 mL), acidified to pH 3-4
with 1 N HCl, and extracted with EtOAc (20 mL × 4). The
EtOAc solution was dried over anhydrous MgSO4, filtered, and
evaporated to dryness. The residue was crystallized from
EtOAc-hexane to give 0.29 g (91%) of 51: mp 209.3-210.1
A presumed metabolite of compound 18, 51, was not
detected in this study.
Ack n ow led gm en t. We would like to thank Dr. V.
L. Narayanan, Drug Synthesis and Chemistry Branch,
and Dr. J . P. Bader, Antiviral Evaluation Branch of the
National Cancer Institute, Rockville, MD, for evaluation
of the anti-HIV activity of our compounds.
Su p p or tin g In for m a tion Ava ila ble: Solvent system for
flash column chromatography and spectral (IR, 1H NMR, and
13C NMR) data for compounds 10a -z, 11a -z, and 12a -z (17
pages). Ordering information is given on any current mast-
head page.
°C; IR (KBr) 1645, 1650, 1682, 1710 (CdO) cm-1 1H NMR
;
(CDCl3) δ 1.33 (d, J ) 7.1 Hz, 6 H, CH(CH3)2), 2.34 (s, 6 H, 2
Ar CH3), 3.12 (septet, J ) 7.1 Hz, 1 H, CH(CH3)2), 7.10-7.20
(m, 3 H, Ar H), 7.19 (br s, 1 H, NH), 9.40 (br s, 1 H, NH); 13C
NMR (CDCl3) δ 19.91, 21.11, 28.37, 115.36, 124.87, 132.90,
133.00, 140.60, 145.39, 149.94, 161.67; MS (EI) m/z 290 (M+).
Anal. (C15H18N2O2S) C, H, N.
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