Synthesis and anti-HIV-1 activity of novel 2,3-dihydro-7H-thiazolo[3,2- a]pyrimidin-7-ones

Article abstract of DOI:10.1021/jm970443m

Appropriately substituted 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7- ones 9-12 and 18 were considered as annulated analogues of HEPT (1-[(2- hydroxyethoxy)methyl]-6-(phenylthio)-thymine), and some of these compounds were also found active against HIV-1, t

Full text of DOI:10.1021/jm970443m

J . Med. Chem. 1998, 41, 191-198
191
Syn th esis a n d An ti-HIV-1 Activity of Novel
2,3-Dih yd r o-7H-th ia zolo[3,2-a ]p yr im id in -7-on es
Krzysztof Danel,† Erik B. Pedersen,*,† and Claus Nielsen‡
Department of Chemistry, Odense University, DK-5230 Odense M, Denmark, and Retrovirus Laboratory,
Department of Virology, Statens Seruminstitut, DK-2300 Copenhagen, Denmark
Received J uly 7, 1997X
Appropriately substituted 2,3-dihydro-7H-thiazolo[3,2-a]pyrimidin-7-ones 9-12 and 18 were
considered as annulated analogues of HEPT (1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)-
thymine), and some of these compounds were also found active against HIV-1, the most active
one being 2,3-dihydro-5-[(3,5-dimethylphenyl)methyl]-3-ethoxy-6-ethyl-7H-thiazolo[3,2-a]py-
rimidin-7-one (10b). S-Alkylation of 5-alkyl-6-(arylmethyl)-2-thiouracils 1-4 was performed
with 2-bromoacetaldehyde acetals to furnish the S-[bis(alkoxy)ethyl] derivatives 5-8 and with
allyl bromide to furnish S-allyl derivatives 17. The target compounds 9-12 were obtained by
an N1 regioselective intramolecular cyclization reaction of silylated 5-8 using trimethylsilyl
trifluoromethanesulfonate (TMS triflate) as the catalyst. Treatment of the S-allyl derivatives
17 with bromine in dry methylene chloride afforded the 3-(bromomethyl) derivatives 18.
Reverse transcriptase (RT), being the pivot in the
human immunodeficiency virus (HIV) replication,1 is
still one of the most attractive targets for the develop-
ment of new antiretroviral agents.2-4 Among the non-
nucleoside inhibitors of RT, 1-[(2-hydroxyethoxy)methyl]-
6-(phenylthio)thymine (HEPT) has been considered an
interesting lead compound for the synthesis of new
compounds with activity against HIV,5,6 e.g. MKC-442
F igu r e 1.
(Figure 1).7 Unlike AZT (Zidovudine) and its congeners,
Sch em e 1
their biological mechanism appears to be a noncompeti-
tive one due to the interaction at an allosteric site of
the reverse transcriptase.8 Unfortunately, these com-
pounds also lead to the emergence of virus-drug resis-
tance.9 That is why the irreversible inhibition of the
reverse transcriptase would be a very attractive per-
spective.
Previously, we reported6c the synthesis and activity
against HIV-1 for a series of S-DABOs derivatives which
are 2-alkylthio analogues of dihydroalkoxybenzyloxopy-
rimidines (DABO).10 In this paper we describe an easy
and fast method for the synthesis of new thiazolo[3,2-
a]pyrimidines, which could be considered as hybrids
between S-DABOs and HEPT analogues. Although
thiazolo[3,2-a]pyrimidines have been well studied as
immunomodulators,11 anticancer agents,12,13 analge-
sics,14,15 psychotropes,12,16 and, more recently, as anti-
inflammatory and positive inotropic agents,17 they have
not yet been explored as possible anti-HIV-1 agents.
Ch em istr y
Our general strategy for the synthesis of nonnucleo-
side analogues was based on intramolecular condensa-
tion of silylated S-DABOs (Scheme 1).
The required thiouracils 1-4 were easily synthesized
from the appropriate â-oxo esters by treatment with
thiourea.6 Thus the obtained thiopyrimidines 1-4 were
nearly quantatitavely S-alkylated with the appropriate
2-bromoacetaldehyde acetals in the presence of anhy-
drous potassium carbonate. The products 5-8 could be
† Odense University.
‡ Statens Seruminstitut.
X Abstract published in Advance ACS Abstracts, December 15, 1997.
S0022-2623(97)00443-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/15/1998

192 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2
Danel et al.
Sch em e 2
used as raw materials in subsequent reactions without
further purification. The report of Bormann and Trox-
ler18 showed that base-catalyzed reaction of thiouracil
with bromoacetaldehyde diethyl acetal gave nearly
equal amounts of the S-alkylated thiouracil and its N1
and N3 cyclized products. We were interested in obtain-
ing the N1 cyclized regioisomer as the main products.
Therefore, the 4-oxo group of the pyrimidines 5-8 was
protected by treatment with N,O-bis(trimethylsilyl)-
acetamide (BSA). The intramolecular cyclization was
carried out by a modification of the method of Niedballa
and Vorbru¨ggen using trimethylsilyl trifluoromethane-
sulfonate (TMS triflate) as the catalyst.19 As a result,
the N1 regioisomers were isolated as the main products
in 10-50% yield whereas the N3 regioisomers were
isolated in minor yields (4-9%) after chromatographic
purification. The observed regioselectivity is in agree-
ment with the Vorbru¨ggen-type glycosylation of 2-thio-
uracil showing N1 more nucleophilic than N3.20 The
reactivity of 5-8 decreased in the following order (R3):
methyl, ethyl, and ethylene. Very low yields were
sometimes obtained for R3 ) ethylene. The reaction was
easily followed on TLC, and the N1- and the N3-
Sch em e 3
alkylated products could always be identified by their
N-3
Rf values (Rf
> RfN-1). Thiazolo[3,2-a]pyrimidines
9-12 were obtained in a state of purity after recrystal-
lization or chromatographic purification. Compound
12b was easily distinguished from its corresponding
regioisomer 16b by 1H nuclear Overhauser effects
(NOE). Only for 12b an NOE in 3-H (3%) could be
observed on irradiation of the methylene group of the
arylmethyl substituent. Also, comparison of the spec-
troscopic data of the new compounds with those of
Bormann and Troxler18 together with those of the
HEPT6a,b and xanthine analogues21 confirmed the above
structures. The characteristic features one can use for
identification are the NMR shifts of H-3 protons at lower
fields in 13-16 than in 9-12 and the splitting of the
CH2 protons in the arylmethyl group into two doublets
in case of the N1 regioisomers due to creation of a chiral
center in the proximity of these protons.
It is well proved that the sterical factors5,22,23 might
influence the activity of HEPT analogues. It could be
explanable in terms of better hydrophobic interactions
of the aromatic system at the modulatory site of the
reverse transcriptase. The presence of a good leaving
group such as bromine in close proximity to the amino
acid residues (Tyr181-OH)23 would also be a very
attractive goal to achieve with possible alkylation at
that place. That could disturb the catalytic site of
reverse transcriptase more drastically, eventually lead-
ing to irreversible inhibition of the enzyme. The syn-
thesis of alkylating compounds in the thiazolo[3,2-
a]pyrimidines series was achieved in two-step reaction
as delineated in Scheme 2. The exocyclic bromomethyl
group in 18 is believed to have the same lability of
bromine in alkylation reactions as the one found for
2-(bromomethyl)-1,3-dioxalanes.24
(alkylated) products (19b,d and 20b,d ) was assigned on
the basis of data of similar compounds.25
When anhydrous methanol and sodium methoxide
were used, only the S-alkylated product was obtained.
We noticed that usage of excess allyl bromide led to
better yields. Thus, when allyl bromide was used in the
ratio 5:1 for 3, we obtained 17c nearly quantatitavely.
The ratio 1:1 led to 55% yield of the S-alkylated
derivative. The crude 2-allylthiouracils 17a -d were
treated with bromine in methylene chloride after silyla-
tion with BSA to avoid the N-3 regioisomer formation.
Thus electrophilic attack of secondary carbocation at the
N1 provided the corresponding thiazolo[3,2-a]pyrim-
idines in moderate yields after column purification. All
of the synthesized bromine analogues were properly
substituted at N1, which can be easily seen on the basis
1
of the splitting of the CH2Ar in the H NMR spectrum.
The N3 products were not observed.
Resu lts of th e An ti-HIV Assa y a n d Discu ssion
Table 1 shows those of the newly synthesized com-
pounds which showed antiviral activity against HIV-1
in MT-4 cells. All other compounds were either inactive
against HIV-1 at 100 µM (9c, 11a ,c, 12a ,c, 13b,c, 14c,
18a , and 19b) or toxic to the MT-4 cells at 100 µM (5a -
c, 7b,c, 8b,c, 12b, 14a ,b, 15a -c, 16a ,c, 18c,d , and
20a ,b) or at 10 µM (19a ), but without showing any
antiviral activity against HIV-1 at subtoxic concentra-
tions.
The target compounds 9-12 share some structural
features with compounds belonging to the HEPT class
and are considered as their annulated analogues. As
in the HEPT series, the two methyl groups at the 3-
and 5-positions of the benzyl substituent play an
important role in the biological activity.26,27 Thus the
3,5-dimethylbenzyl derivatives 10a -c showed higher
Alkylation of 2, 4 with allyl bromide (1:1) in the
presence of K2CO3 in DMF gave a mixture of N3,S- and
S,N1-bis(alkylated) products, 19b,d and 20b,d (Scheme
3). The mono-S-alkylated derivative 17b,d was ob-
served in a low yield (5%). The structure of bis-

Anti-HIV-1 Activity of Thiazolopyrimidin-7-ones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2 193
Ta ble 1. Antiviral Activity against HIV-1 in MT-4 Cells
removed in vacuo and the oily residue coevaporated with
toluene (2 × 10 mL). EtOAc/petroleum ether (bp 60-80 °C)
(1:1) was added. A precipitate could result (K2CO3) and was
filtered off. The filtrate was evaporated to dryness, and the
residue started to crystallize on standing. Thus obtained crude
products 5-8 were used without further purification for the
next step.
a
compd
6b
ED50
,
µM
CD50,b µM
SIc
21
3
>100
37
>5
6c
12
8
7a
4
32
8a
9a
9b
32
36
46
3
0.7
19
100
1.5
2
1.5
2.8
0.04
0.005
>100
>100
>100
>100
>100
>100
>100
>100
68
>3
>3
6-Ben zyl-2-[(2,2-d im et h oxyet h yl)t h io]-5-et h ylp yr im i-
>2
1
d in -4(1H)-on e (5a ): prepared from 1;6a mp 115-117 °C; H
10a
10b
10c
11b
17a
17b
17c
18b
AZT
MKC-442
>33
>140
>5
NMR (CDCl3) δ 0.92 (t, 3H, J ) 7.4 Hz, CH3), 2.43 (q, 2H, J )
7.4 Hz, CH2), 3.19 (d, 2H, J ) 5.3 Hz, SCH2), 3.23 (s, 6H, 2 ×
CH3), 3.83 (s, 2H, CH2Ph), 4.40 (t, 1H, J ) 5.3 Hz, CH), 7.14-
7.26 (m, 5H, Harom), 8.82 (s, 1H, NH); 13C NMR (CDCl3) δ 13.3
(CH3), 18.8 (CH2), 32.5 (CH2Ph), 40.2 (SCH2), 53.9 (OCH3),
103.4 (CH), 121.0 (C-5), 126.0, 128.1, 128.8, 139.0 (Ph), 159.8
(C-6), 161.2 (C-4), 168.9 (C-2). Anal. (C17H22N2O3S‚0.5H2O)
C, H, N.
>1
>67
34
>67
16
>100
46
52
1300
28000
141
6-Ben zyl-2-[(2,2-d ieth oxyeth yl)th io]-5-eth ylp yr im id in -
4(1H)-on e (5b): prepared from 1; mp 95-96 °C; 1H NMR
(CDCl3) δ 0.90 (t, 3H, J ) 7.2 Hz, CH3), 1.10 (t, 6H, J ) 7.0
Hz, CH3), 2.45 (q, 2H, J ) 7.2 Hz, CH2), 3.19 (d, 2H, J ) 5.2
Hz, SCH2), 3.38-3.57 (m, 4H, 2 × CH2), 3.83 (s, 2H, CH2Ph),
4.53 (t, 1H, J ) 5.2 Hz, CH), 7.14-7.25 (m, 5H, Harom), 9.62
(s, 1H, NH); 13C NMR (CDCl3) δ 13.4 (CH3), 15.1 (CH3), 18.9
(CH2), 33.6 (CH2Ph), 40.2 (SCH2), 62.5 (OCH2), 101.8 (CH),
120.7 (C-5), 125.9, 128.1, 128.9, 139.1 (Ph), 161.0 (C-6), 161.2
(C-4), 169.6 (C-2). Anal. (C19H26N2O3S) C, H, N.
a
Effective dose of compound, achieving 50% inhibition of HIV-1
antigen production in MT-4 cultures. b Cytotoxic dose of compound,
required to reduce the proliferation of normal uninfected MT-4
cells by 50%. c Selectivity index: ratio CD50/ED50. ED50 and CD50
are expressed as the mean values of three independent determina-
tions.
activity than their benzyl (9) or 1-naphthylmethyl (12)
counterparts, the latter being devoid of any activity at
100 µM. Compounds 10a -c are only moderately active
when compared with 6-benzyl-1-(ethoxymethyl)-5-iso-
propyluracil (MKC-442), which is the HEPT analogue
chosen as the candidate for clinical trials with AIDS
patients.28 It should be noticed that compounds 10a -c
are lacking the 3-NH of the pyrimidine which is a
prerequisite for the hydrogen bond to the carbonyl of
Lys101 of RT in RT-HEPT complexes.23 However,
hydrogen bonding of the nonnucleoside inhibitor in the
hydrophobic pocket of RT could still be possible if N-3
protonation of 10 is assumed. Compound 18b, showing
similar antiviral activity, is also a 2,3-dihydro-7H-
thiazolo[3,2-a]pyrimidin-7-one like compounds 9-12,
the only difference being replacement the 3-alkoxy with
bromomethyl.
6-Ben zyl-2-[(1,3-d ioxola n -2-yl)th io]-5-eth ylp yr im id in -
o
1
4(1H)-on e (5c): prepared from 1; mp 127-130 C; H NMR
(CDCl3) δ 0.82 (t, 3H, J ) 7.3 Hz, CH3), 2.35 (q, 2H, J ) 7.3
Hz, CH2), 3.15 (d, 2H, J ) 4.3 Hz, SCH2), 3.60-3.78 (m, 6H,
2 × CH2, CH2Ph), 4.90 (t, 1H, J ) 4.4 Hz, CH), 7.10-7.39 (m,
5H, Harom); 13C NMR (CDCl3) δ 13.3 (CH3), 18.9 (CH2), 33.3
(CH2Ph), 40.2 (SCH2), 65.0 (OCH2), 102.7 (CH), 120.0 (C-5),
125.8, 128.0, 129.0, 139.3 (Ph), 161.3 (C-6), 161.4 (C-4), 171.2
(C-2). Anal. (C17H20N2O3S‚0.5H2O) C, H, N.
2-[(2,2-Dim eth oxyeth yl)th io]-6-[(3,5-d im eth ylp h en yl)-
m eth yl]-5-eth ylp yr im id in -4(1H)-on e (6a ): prepared from
2; mp 132-133 °C; 1H NMR (CDCl3) δ 1.10 (t, 3H, J ) 7.4 Hz,
CH3), 2.27 (s, 6H, CH3), 2.45 (q, 2H, J ) 7.4 Hz, CH2), 3.31 (d,
2H, J ) 5.5 Hz, SCH2), 3.32 (s, 6H, 2 × CH3), 3.83 (s, 2H,
CH2Ph), 4.48 (t, 1H, J ) 5.5 Hz, CH), 6.83 (s, 3H, Harom), 12.78
(s, 1H, NH); 13C NMR (CDCl3) δ 13.2 (CH3), 18.7 (CH2), 21.2
(2 × CH3), 32.5 (CH2Ph), 40.2 (SCH2), 54.0 (OCH2), 103.1 (CH),
122.5 (C-5), 126.7, 128.0, 137.8, 138.0 (Ar), 156.1 (C-6), 161.6
(C-4), 165.1 (C-2). Anal. (C19H26N2O3S‚0.25H2O) C, H, N.
2-[(2,2-Diet h oxyet h yl)t h io]-6-[(3,5-d im et h ylp h en yl)-
m eth yl]-5-eth ylp yr im id in -4(1H)-on e (6b): prepared from
2; mp 119-121 °C; 1H NMR (CDCl3) δ 1.09 (t, 3H, J ) 7.4 Hz,
CH3), 1.19 (t, 6H, J ) 7.0 Hz, CH3), 2.27 (s, 6H, CH3), 2.58 (q,
2H, J ) 7.4 Hz, CH2), 3.29 (d, 2H, J ) 5.4 Hz, SCH2), 3.42-
3.67 (m, 4H, 2 × CH2), 3.82 (s, 2H, CH2Ph), 4.61 (t, 1H, J )
5.5 Hz, CH), 6.83 (s, 3H, Harom), 12.71 (s, 1H, NH); 13C NMR
(CDCl3) δ 13.1 (CH3), 15.1 (CH3), 18.7 (CH2), 21.2 (2 × CH3),
33.6 (CH2Ph), 40.1 (SCH2), 62.6 (OCH2), 101.3 (CH), 122.6 (C-
5), 126.5, 127.9, 137.8, 138.0 (Ar), 156.3 (C-6), 161.6 (C-4),
165.0 (C-2). Anal. (C21H30N2O3S) C, H, N.
The activity of compounds 6b,c, 7a , 8a , and 17a -c
against HIV-1 is to be expected since these compounds
are merely new S-DABO derivatives. Their activity
against HIV-1 is of comparable magnitude to those
previously reported for S-DABOs.10
Exp er im en ta l Section
NMR spectra were recorded on a Bruker AC-250 FT NMR
spectrometer at 250 MHz for 1H and 62.9 MHz for 13C with
TMS as an internal standard. Mass spectra were recorded
on a Varian MAT 311A spectrometer. The progress of the
reaction was monitored by TLC analytical silica gel plates 60
6-[(3,5-Dim eth ylp h en yl)m eth yl]-2-[(1,3-d ioxola n -2-yl)-
th io]-5-eth ylp yr im id in -4(1H)-on e (6c): prepared from 2;
mp 154-156 °C; purified by column chromatography (0-50%
EtOAc/petroleum ether (bp 60-80 °C)); 1H NMR (CDCl3) δ 1.08
(t, 3H, J ) 7.4 Hz, CH3), 2.27 (s, 6H, CH3), 2.57 (q, 2H, J )
7.4 Hz, CH2), 3.38 (d, 2H, J ) 4.3 Hz, SCH2), 3.81 (s, 2H, CH2-
Ph), 3.83-4.02 (m, 4H, 2 × CH2), 5.11 (t, 1H, J ) 4.4 Hz, CH),
6.83 (s, 1H, Harom), 6.86 (s, 2H, Harom), 12.39 (s, 1H, NH); 13C
NMR (CDCl3) δ 13.1 (CH3), 18.8 (CH2), 21.2 (2 × CH3), 33.6
(CH2Ph), 40.2 (SCH2), 65.3 (OCH2), 102.1 (CH), 122.5 (C-5),
126.8, 128.0, 137.8, 138.0 (Ar), 155.8 (C-6), 161.6 (C-4), 164.8
(C-2).
6-Ben zyl-2-[(2,2-d im et h oxyet h yl)t h io]-5-isop r op ylp y-
r im id in -4(1H)-on e (7a ): prepared from 3;6b mp 106-107 °C;
1H NMR (CDCl3) δ 1.13 (d, 6H, J ) 6.9 Hz, CH3), 3.05 (heptet,
1H, J ) 6.9 Hz, CH), 3.19 (d, 2H, J ) 5.1 Hz, SCH2), 3.22 (s,
6H, 2 × CH3), 3.89 (s, 2H, CH2Ph), 4.40 (t, 1H, J ) 4.4 Hz,
F
254. Merck silica gel (0.040-0.063 mm) was used for column
chromatography and Merck silica gel (0.063-0.200 mm) for
preparative thin-layer chromatography (PTLC). Extracts were
dried over Na2SO4, and the solvents were removed under
reduced pressure. Solvents were reagent grade and, when
necessary, purified and dried by standards methods. Elemen-
tal analyses were performed by the Microanalytical Laboratory
at the Research Institute for Pharmacy and Biochemistry in
Prague, Czech Republic.
Gen er a l P r oced u r e for th e P r ep a r a tion 5-8. To a
mixture of thiouracil6 (1-4) (4 mmol) and anhydrous potas-
sium carbonate (4 mmol) in DMF (10 mL) was added the
appropriate 2-bromoacetaldehyde acetal (4.5 mmol). The
mixture was stirred at 65 °C for 3 h. The reaction was
monitored by TLC with MeOH/CHCl3. After cooling to room
temperature, the mixture was filtered and the solid residue
washed with a small amount of DMF. The solvent was

194 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2
Danel et al.
CH), 7.14-7.26 (m, 5H, Harom); 13C NMR (CDCl3) δ 20.1 (CH3),
27.2 (CH), 32.4 (CH2Ph), 40.8 (SCH2), 54.0 (OCH2), 103.5 (CH),
123.7 (C-5), 125.9, 128.1, 128.6, 139.3 (Ph), 160.2 (C-6), 161.0
(C-4), 169.3 (C-2). Anal. (C18H24N2O3S) C, H, N.
5-Ben zyl-2,3-d ih yd r o-6-et h yl-3-m et h oxy-7H -t h ia zolo-
[3,2-a ]p yr im id in -7-on e (9a ): oil which started to crystallize;
column chromatography (0-2% MeOH/CH2Cl2); Rf ) 0.16 (5%
MeOH/CH2Cl2); yield 551 mg (46%); mp 152-154 °C; 1H NMR
(CDCl3) δ 1.10 (t, 3H, J ) 7.4 Hz, CH2CH3), 2.52-2.68 (m,
2H, CH2CH3), 3.21 (d, 1H, J ) 12.8 Hz, 2-H), 3.33 (s, 3H,
OCH3), 3.38 (dd, 1H, J ) 12.8, 5.9 Hz, 2-H), 3.95 (d, 1H, J )
16.9 Hz, 5-CHH), 4.27 (d, 1H, J ) 16.9 Hz, 5-CHH), 5.45 (d,
1H, J ) 5.5 Hz, 3-H), 7.12-7.39 (m, 5H, Harom); 13C NMR
(CDCl3) δ 13.3 (CH3), 19.6 (CH2), 29.6 (5-CH2), 33.4 (C-2), 53.2
(OCH3), 90.1 (C-3), 123.1, 127.4, 129.3, 135.0 (C-6, Ph), 144.4
(C-5), 166.5 (C-7), 169.2 (C-8a). Anal. Calcd (C16H18N2O2S):
C, 63.55; H, 6.00; N, 9.26. Found: C, 63.04; H, 6.01; N, 8.90.
6-Ben zyl-2-[(2,2-d iet h oxyet h yl)t h io]-5-isop r op ylp yr i-
1
m id in -4(1H)-on e (7b): prepared from 3; as an oil; H NMR
(CDCl3) δ 1.19 (t, 6H, J ) 7.1 Hz, CH3), 1.27 (d, 6H, J ) 6.9
Hz, CH3), 3.10 (heptet, 1H, J ) 6.9 Hz, CH), 3.28 (d, 2H, J )
5.4 Hz, SCH2), 3.45-3.65 (m, 4H, 2 × CH2), 3.93 (s, 2H, CH2-
Ph), 4.58 (t, 1H, J ) 5.5 Hz, CH), 7.18-7.30 (m, 5H, Harom),
12.64 (s, 1H, NH); 13C NMR (CDCl3) δ 15.1 (CH3), 19.6 (CH3),
27.9 (CH), 33.5 (CH2Ph), 40.8 (SCH2), 62.7 (OCH2), 101.4 (CH),
125.3 (C-5), 126.2, 128.3, 128.5, 138.4 (Ph), 156.4 (C-6), 160.9
(C-4), 164.2 (C-2). Anal. (C20H28N2O3S) C, H, N.
5-Ben zyl-2,3-d ih yd r o-3-eth oxy-6-eth yl-7H-th ia zolo[3,2-
a ]p yr im id in -7-on e (9b): column chromatography (0-2%
MeOH/CH2Cl2); Rf ) 0.21 (5% MeOH/CH2Cl2); yield 447 mg
6-Ben zyl-2-[(1,3-d ioxola n -2-yl)th io]-5-isop r op ylp yr im i-
d in -4(1H)-on e (7c): prepared from 3; precipitated from the
crude mixture with CHCl3/petroleum ether (bp 60-80 °C); 1H
NMR (DMSO-d6) δ 1.11 (d, 6H, J ) 6.8 Hz, CH3), 2.93 (heptet,
1H, J ) 6.9 Hz, CH), 3.13 (d, 2H, J ) 4.8 Hz, SCH2), 3.69 (s,
2H, CH2Ph), 3.74-3.93 (m, 4H, 2 × CH2), 4.96 (t, 1H, J ) 4.7
Hz, CH), 7.14-7.26 (m, 5H, Harom); 13C NMR (DMSO-d6) δ 20.1
(CH3), 27.2 (CH), 32.5 (CH2Ph), 40.9 (SCH2), 64.3 (OCH2),
103.2 (CH), 120.5 (C-5), 125.4, 127.9, 128.3, 140.6 (Ph), 158.1
(C-6), 163.1 (C-4), 171.9 (C-2). Anal. (C18H22N2O3S‚0.25H2O)
C, H, N.
1
(35%); mp 167-170 °C; H NMR (CDCl3) δ 1.10 (t, 3H, J )
7.4 Hz, CH2CH3), 1.19 (t, 3H, J ) 7.0 Hz, CH2CH3), 2.49-
2.60 (m, 2H, CH2CH3), 3.19 (d, 1H, J ) 12.6 Hz, 2-H), 3.38
(dd, 1H, J ) 12.7, 5.9 Hz, 2-H), 3.51-3.57 (m, 2H, OCH2CH3),
4.00 (d, 1H, J ) 16.9 Hz, 5-CHH), 4.26 (d, 1H, J ) 16.9 Hz,
5-CHH), 5.60 (d, 1H, J ) 5.6 Hz, 3-H), 7.11-7.39 (m, 5H,
H
arom); 13C NMR (CDCl3) δ 13.2, 14.8 (2 × CH3), 19.6 (CH2),
30.3 (5-CH2), 33.4 (C-2), 61.9 (OCH2), 89.4 (C-3), 123.1, 127.3,
129.2, 135.0 (C-6, Ph), 144.4 (C-5), 166.5 (C-7), 169.3 (C-8a).
Anal. (C17H20N2O2S) C, H, N.
2-[(2,2-Dim e t h oxye t h yl)t h io]-5-e t h yl-6-(1-n a p h t h yl-
m eth yl)p yr im id in -4(1H)-on e (8a ): prepared from 4;6c 1H
NMR (CDCl3) δ 1.11 (t, 3H, J ) 7.4 Hz, CH3), 2.63 (q, 2H, J )
7.4 Hz, CH2), 3.06 (d, 2H, J ) 5.5 Hz, SCH2), 3.14 (s, 6H, 2 ×
CH3), 4.24 (t, 1H, J ) 5.4 Hz, CH), 4.35 (s, 2H, CH2C10H7),
7.11-8.08 (m, 7H, Harom), 12.81 (s, 1H, NH); 13C NMR (CDCl3)
δ 13.0 (CH3), 18.8 (CH2), 32.3 (CH2C10H7), 37.4 (SCH2), 53.9
(OCH3), 102.7 (CH), 123.0 (C-5), 123.8, 125.3, 125.5, 126.0,
126.5, 127.1, 128.6, 132.2, 133.7, 134.3 (Ar), 156.3 (C-6), 161.3
(C-4), 165.0 (C-2).
5-Ben zyl-2,3-d ih yd r o-6-eth yl-3-(2-h yd r oxyeth oxy)-7H-
th ia zolo[3,2-a ]p yr im id in -7-on e (9c): Rf ) 0.09 (8% MeOH/
CH2Cl2); yield 127 mg (10%); mp 140-141 °C (EtOH/EtOAc,);
1H NMR (DMSO-d6) δ 0.86 (t, 3H, J ) 7.3 Hz, CH2CH3), 2.34
(q, 2H, J ) 7.3 Hz, CH2CH3), 3.38-3.51 (m, 5H, 2-H and OCH2-
CH2), 3.58 (dd, 1H, J ) 12.9, 5.0 Hz, 2-H), 4.09 (d, 1H, J )
17.2 Hz, 5-CHH), 4.21 (d, 1H, J ) 17.1 Hz, 5-CHH), 4.81 (t,
1H, J ) 5.1 Hz, OH), 5.81 (d, 1H, J ) 4.6 Hz, 3-H), 7.19-7.39
(m, 5H, Harom); 13C NMR (DMSO-d6) δ 12.7 (CH3), 19.0 (CH2),
30.3 (5-CH2), 33.0 (C-2), 59.7, 68.6 (OCH2CH2), 90.2 (C-3),
121.4, 126.7, 127.5, 128.7, 136.0 (C-6, Ph), 145.3 (C-5), 166.3
(C-7), 168.2 (C-8a). Anal. (C17H20N2O3S) C, H, N.
2-[(2,2-Dieth oxyeth yl)th io]-5-eth yl-6-(1-n a p h th ylm eth -
yl)p yr im id in -4(1H)-on e (8b): prepared from 4; mp 128-130
1
°C; H NMR (DMSO-d6) δ 0.92-1.02 (m, 9H, 3 × CH3), 2.51
2,3-Dih yd r o-5-[(3,5-d im eth ylp h en yl)m eth yl]-6-eth yl-3-
m eth oxy-7H-th ia zolo[3,2-a ]p yr im id in -7-on e (10a ): pre-
cipitated with EtOAc/petroleum ether (bp 60-80 °C) from the
crude mixture; Rf ) 0.21 (8% MeOH/CH2Cl2); yield 662 mg
(q, 2H, J ) 7.4 Hz, CH2), 2.99 (d, 2H, J ) 5.4 Hz, SCH2), 3.15-
3.35 (m, 4H, 2 × CH2), 4.34 (s, 2H, CH2C10H7), 4.34 (t, 1H, J
) 4.4 Hz, CH), 7.21-8.16 (m, 7H, Harom), 12.57 (s, 1H, NH);
13C NMR (DMSO-d6) δ 12.9 (CH3), 14.9 (CH3), 18.2 (CH2), 32.4
(CH2C10H7), 36.6 (SCH2), 61.5 (OCH3), 100.3 (CH), 123.9 (C-
5), 125.3, 125.5, 125.8, 126.2, 126.7, 128.3, 131.8, 132.2, 134.6
(Ar), 158.7 (C-6), 161.0 (C-4), 168.3 (C-2). Anal. (C23H28N2O3S)
C, H, N.
1
(50%); mp 151-153 °C; H NMR (CDCl3) δ 1.11 (t, 3H, J )
7.4 Hz, CH2CH3), 2.29 (s, 6H, 2 × CH3), 2.44-2.67 (m, 2H,
CH2CH3), 3.20 (d, 1H, J ) 12.9 Hz, 2-H), 3.35 (s, 3H, OCH3),
3.38 (dd, 1H, J ) 12.9, 6.0 Hz, 2-H), 3.85 (d, 1H, J ) 16.8 Hz,
5-CHH), 4.19 (d, 1H, J ) 16.7 Hz, 5-CHH), 5.56 (d, 1H, J )
5.8 Hz, 3-H), 6.71 (s, 2H, Harom), 6.91 (s, 1H, Harom); 13C NMR
(CDCl3) δ 13.3 (CH3), 19.6 (CH2), 21.2 (2 × CH3), 29.6 (5-CH2),
33.2 (C-2), 53.1 (OCH2), 90.0 (C-3), 123.0, 125.1, 129.1, 134.8,
139.0 (C-6, Ar), 144.7 (C-5), 166.5 (C-7), 169.3 (C-8a). Anal.
(C18H22N2O2S‚0.25H2O) C, H, N.
2-[(1,3-Dioxola n -2-yl)th io]-5-eth yl-6-(1-n a p h th ylm eth -
yl)p yr im id in -4(1H)-on e (8c): prepared from 4; mp 155-157
1
°C; H NMR (CDCl3) δ 1.10 (t, 3H, J ) 7.4 Hz, CH3), 2.62 (q,
2H, J ) 7.4 Hz, CH2), 3.12 (d, 2H, J ) 4.3.4 Hz, SCH2), 3.70-
3.89 (m, 4H, 2 × CH2), 4.35 (s, 2H, CH2C10H7), 4.79 (t, 1H, J
) 4.4 Hz, CH), 7.21-8.07 (m, 7H, Harom), 12.41 (s, 1H, NH);
13C NMR (CDCl3) δ 13.0 (CH3), 18.9 (CH2), 33.4 (CH2C10H7),
37.5 (SCH2), 65.2 (OCH3), 101.7 (CH), 123.1 (C-5), 124.0, 125.4,
125.5, 126.0, 126.8, 127.1, 128.6, 132.3, 133.8, 134.3 (Ar), 155.8
(C-6), 161.2 (C-4), 164.7 (C-2). Anal. (C21H22N2O3S‚0.5H2O)
C, H, N.
2,3-Dih yd r o-5-[(3,5-d im eth ylp h en yl)m eth yl]-3-eth oxy-
6-eth yl-7H-th ia zolo[3,2-a ]p yr im id in -7-on e (10b): precipi-
tated with EtOAc/petroleum ether (bp 60-80 °C); Rf ) 0.24
o
1
(8% MeOH/CH2Cl2); yield 403 mg (29%); mp 155-157 C; H
NMR (CDCl3) δ 1.10 (t, 3H, J ) 7.4 Hz, CH2CH3), 1.22 (t, 3H,
J ) 7.0 Hz, CH2CH3), 2.29 (s, 6H, 2 × CH3), 2.34-2.65 (m,
2H, CH2CH3), 3.18 (d, 1H, J ) 12.7 Hz, 2-H), 3.38 (dd, 1H, J
) 12.7, 5.9 Hz, 2-H), 3.45-3.62 (m, 2H, OCH2), 3.86 (d, 1H, J
) 16.8 Hz, 5-CHH), 4.18 (d, 1H, J ) 16.8 Hz, 5-CHH), 5.60 (d,
1H, J ) 5.6 Hz, 3-H), 6.71 (s, 2H, Harom), 6.91 (s, 1H, Harom);
13C NMR (CDCl3) δ 13.3, 14.9 (2 × CH3), 19.6 (CH2), 21.2 (2 ×
CH3), 30.3 (5-CH2), 33.2 (C-2), 61.8 (OCH2), 89.2 (C-3), 123.0,
125.1, 129.1, 134.8, 139.0 (C-6, Ar), 144.7 (C-5), 166.5 (C-7),
169.4 (C-8a). Anal. (C19H24N2O2S) C, H, N.
Gen er a l P r oced u r e for 9-12 a n d 13-16. The crude
5-8 (4 mmol) was dissolved in dry MeCN (10 mL) under Ar.
N,O-Bis(trimethylsilyl)acetamide (0.89 g, 4.4 mmol, 1.08 mL)
was added. The mixture was cooled to -40 °C, and TMS
triflate (0.89 g, 4 mmol, 0.77 mL) was added dropwise. The
mixture was allowed to warm to room temperature slowly
(typically overnight). Cold saturated aqueous NaHCO3 was
added, and the mixture was extracted with CH2Cl2 (3 × 20
mL). The organic phase was washed with saturated aqueous
NaCl, dried, and evaporated in vacuo. Compounds 9-12 were
in some cases isolated by crystallization, and isomeric com-
pounds 13-16 in the mother liquor were purified by PTLC.
In all other cases the typical procedure was to isolate 9-12
by column chromatography and to purify the fraction of 13-
16 from the column chromatography by subsequent PTLC. The
yields are overall yields based on compounds 1-4.
2,3-Dih yd r o-5-[(3,5-d im eth ylp h en yl)m eth yl]-6-eth yl-3-
(2-h yd r oxyet h oxy)-7H -t h ia zolo[3,2-a ]p yr im id in -7-on e
(10c): Rf ) 0.12 (8% MeOH/CH2Cl2); yield 350 mg (27%); mp
203-205 °C (EtOH/H2O); 1H NMR (DMSO-d6) δ 0.89 (t, 3H, J
) 7.3 Hz, CH2CH3), 2.24 (s, 6H, 2 × CH3), 2.28-2.49 (m, 2H,
CH2CH3), 3.44-3.49 (m, 5H, 2-H and OCH2CH2), 3.58 (dd, 1H,
J ) 12.9, 5.1 Hz, 2-H), 3.99 (d, 1H, J ) 17.1 Hz, 5-CHH), 4.12
(d, 1H, J ) 17.0 Hz, 5-CHH), 4.82 (t, 1H, J ) 5.1 Hz, OH),

Anti-HIV-1 Activity of Thiazolopyrimidin-7-ones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2 195
5.78 (d, 1H, J ) 4.7 Hz, 3-H), 6.79 (s, 2H, Harom), 6.88 (s, 1H,
) 7.1 Hz, CH2CH3), 3.27-3.43 (m, 5H, OCH2CH2, 2-H), 3.56
(dd, 1H, J ) 12.9, 5.2 Hz, 2-H), 4.56 (s, 2H, 5-CH2), 4.67 (br s,
1H, OH), 5.65 (d, 1H, J ) 5.1 Hz, 3-H), 7.05-8.25 (m, 7H,
H
arom); 13C NMR (DMSO-d6) δ 12.7 (CH3), 19.0 (CH2), 20.8 (2
× CH3), 30.3 (5-CH2), 32.8 (C-2), 59.7, 68.7 (OCH2CH2), 90.2
(C-3), 121.4, 125.1, 128.2, 135.8, 137.8 (C-6, Ar), 145.3 (C-5),
166.3 (C-7), 168.2 (C-8a). Anal. (C19H24N2O3S) C, H, N.
H
naphthyl); 13C NMR (DMSO-d6) δ 12.5 (CH3), 18.8 (CH2), 30.0
(5-CH2), 30.3 (C-2), 59.5, 68.6 (OCH2CH2OH), 90.3 (C-3),
122.0-133.1 (C-6, Ar), 144.8 (C-5), 166.1 (C-7), 167.9 (C-8a).
Anal. (C21H22N2O3S‚0.25H2O) C, H, N.
5-Ben zyl-2,3-d ih yd r o-6-isop r op yl-3-m eth oxy-7H-th ia -
zolo[3,2-a ]p yr im id in -7-on e (11a ): column chromatography
(0-2% MeOH/CH2Cl2); Rf ) 0.29 (5% MeOH/CH2Cl2); yield 382
7-Ben zyl-2,3-d ih yd r o-6-et h yl-3-m et h oxy-5H -t h ia zolo-
[3,2-a ]p yr im id in -5-on e (13a ): PTLC (2% MeOH/CH2Cl2); Rf
) 0.58 (5% MeOH/CH2Cl2); yield 47 mg (4%) as an oil; 1H NMR
(CDCl3) δ 1.05 (t, 3H, J ) 7.4 Hz, CH2CH3), 2.56 (q, 2H, J )
7.4 Hz, CH2CH3), 3.23 (d, 1H, J ) 12.2 Hz, 2-H), 3.57 (dd, 1H,
J ) 12.0, 5.5 Hz, 2-H), 3.57 (s, 3H, OCH3), 3.88 (s, 2H, 7-CH2),
6.13 (d, 1H, J ) 5.2 Hz, 3-H), 7.19-7.31 (m, 5H, Harom); 13C
NMR (CDCl3) δ 13.0 (CH3), 19.1 (CH2), 33.6 (7-CH2), 40.3 (C-
2), 58.4 (OCH3), 89.1 (C-3), 122.1, 126.4, 128.4, 128.7, 137.8
(C-6, Ar), 160.3, 161.2, 161.8 (C-5, C-7, C-8a); EI MS m/z 302
(M+).
7-Ben zyl-2,3-d ih yd r o-3-eth oxy-6-eth yl-5H-th ia zolo[3,2-
a ]p yr im id in -5-on e (13b): PTLC (2% MeOH/CH2Cl2); Rf )
0.57 (5% MeOH/CH2Cl2); yield 96 mg (8%) as an oil; 1H NMR
(CDCl3) δ 1.04 (t, 3H, J ) 7.4 Hz, CH2CH3), 1.21 (t, 3H, J )
7.0 Hz, CH2CH3), 2.56 (q, 2H, J ) 7.4 Hz, CH2CH3), 3.19 (d,
1H, J ) 12.1 Hz, 2-H), 3.55 (dd, 1H, J ) 12.0, 5.5 Hz, 2-H),
3.79-3.85 (m, 2H, OCH2CH3), 3.87 (s, 2H, 7-CH2), 6.18 (d, 1H,
J ) 5.4 Hz, 3-H), 7.16-7.27 (m, 5H, Harom); 13C NMR (CDCl3)
δ 12.8, 15.0 (2 × CH3), 19.0 (CH2), 34.0 (7-CH2), 40.2 (C-2),
66.6 (OCH2), 87.8 (C-3), 121.9, 126.3, 128.2, 128.5, 137.7 (C-6,
Ph), 160.2, 161.0, 161.5 (C-5, C-7, C-8a); EI MS m/z 316 (M+).
1
mg (45%) as a white foam; H NMR (CDCl3) δ 1.31 (d, 3H, J
) 7.0 Hz, CHMe2), 1.33 (d, 3H, J ) 7.0 Hz, CHMe2), 3.01
(heptet, 1H, J ) 7.0 Hz, CHMe2), 3.21 (d, 1H, J ) 12.8 Hz,
2-H), 3.33 (s, 3H, OCH3), 3.38 (dd, 1H, J ) 12.8, 5.9 Hz, 2-H),
3.93 (d, 1H, J ) 17.2 Hz, 5-CHH), 4.32 (d, 1H, J ) 17.2 Hz,
5-CHH), 5.56 (d, 1H, J ) 5.6 Hz, 3-H), 7.11-7.40 (m, 5H,
H
arom); 13C NMR (CDCl3) δ 19.7, 20.0 (2 × CH3), 27.9 (CH),
29.7 (5-CH2), 33.3 (C-2), 53.3 (OCH3), 90.2 (3-C), 125.7, 127.3,
129.3, 135.1 (C-6, Ph), 143.9 (C-5), 166.0 (C-7), 168.4 (C-8a).
Anal. Calcd (C17H20N2O2S‚0.75H2O): C, 61.89; H, 6.57; N,
8.49. Found: C, 61.90; H, 6.16; N, 8.12.
5-Ben zyl-2,3-dih ydr o-3-eth oxy-6-isopr opyl-7H-th iazolo-
[3,2-a ]p yr im id in -7-on e (11b): an oil which started to crys-
tallize; column chromatography (0-2% MeOH/CH2Cl2); Rf )
o
0.23 (5% MeOH/CH2Cl2); yield 357 mg (40%); mp 140-142 C;
1H NMR (CDCl3) δ 1.19 (t, 3H, J ) 7.0 Hz, CH2CH3), 1.31 (d,
3H, J ) 7.0 Hz, CHMe2), 1.33 (d, 3H, J ) 7.0 Hz, CHMe2),
3.00 (heptet, 1H, J ) 7.0 Hz, CHMe2), 3.18 (d, 1H, J ) 12.6
Hz, 2-H), 3.38 (dd, 1H, J ) 12.6, 5.7 Hz, 2-H), 3.46-3.57 (m,
2H, OCH2), 3.94 (d, 1H, J ) 17.2 Hz, 5-CHH), 4.32 (d, 1H, J
) 17.2 Hz, 5-CHH), 5.60 (d, 1H, J ) 5.6 Hz, 3-H), 7.11-7.40
(m, 5H, Harom); 13C NMR (CDCl3) δ 14.9 (CH3), 19.7, 20.2 (2 ×
CH3), 27.9 (CH), 30.4 (5-CH2), 33.3 (C-2), 62.0 (OCH2), 89.5
(3-C), 125.6, 127.3, 129.3, 135.2 (C-6, Ph), 143.8 (C-5), 165.9
(C-7), 168.5 (C-8a). Anal. (C18H22N2O2S‚0.75H2O) C, H, N.
7-Ben zyl-2,3-d ih yd r o-6-eth yl-3-(2-h yd r oxyeth oxy)-5H-
th ia zolo[3,2-a ]p yr im id in -5-on e (13c): PTLC (3% MeOH/
1
CH2Cl2); Rf ) 0.26 (8% MeOH/CH2Cl2); yield 38 mg (4%); H
NMR (CDCl3) δ 1.03 (t, 3H, J ) 7.4 Hz, CH2CH3), 2.55 (q, 2H,
J ) 5.6 Hz, CH2CH3), 3.25 (d, 1H, J ) 12.3 Hz, 2-H), 3.54 (dd,
1H, J ) 12.3, 5.5 Hz, 2-H), 3.71-3.86 (m, 5H, OCH2CH2OH),
3.87 (s, 2H, 7-CH2), 6.26 (d, 1H, J ) 5.4 Hz, 3-H), 7.18-7.30
(m, 5H, Harom); 13C NMR (CDCl3) δ 12.9 (CH3), 18.9 (CH2), 33.3
(7-CH2), 40.2 (C-2), 61.7, 71.7 (OCH2CH2OH), 88.7 (C-3), 121.9,
126.3, 128.3, 128.5, 137.6 (C-6, Ph), 160.2, 161.5, 161.7 (C-5,
C-7, C-8a); EI MS m/z 332 (M+).
5-Ben zyl-2,3-d ih yd r o-3-(2-h yd r oxyeth oxy)-6-isop r op yl-
7H-th ia zolo[3,2-a ]p yr im id in -7-on e (11c): Rf ) 0.07 (8%
MeOH/CH2Cl2); yield 126 mg (14%); mp 158-160 °C; (EtOH/
EtOAc); 1H NMR (DMSO-d6) δ 1.09 (d, 3H, J ) 6.8 Hz,
CHMe2), 1.33 (d, 3H, J ) 6.8 Hz, CHMe2), 2.84 (heptet, 1H, J
) 6.9 Hz, CHMe2), 3.41-3.54 (m, 5H, 2-H and OCH2CH2), 3.58
(dd, 1H, J ) 12.7, 5.0 Hz, 2-H), 4.08 (d, 1H, J ) 17.4 Hz,
5-CHH), 4.32 (d, 1H, J ) 17.3 Hz, 5-CHH), 5.86 (d, 1H, J )
4.7 Hz, 3-H), 7.18-7.39 (m, 5H, Harom); 13C NMR (DMSO-d6) δ
19.1, 19.4 (2 × CH3), 27.3 (CH), 30.3 (5-CH2), 33.0 (C-2), 59.7,
68.7 (OCH2CH2), 90.4 (C-3), 123.7, 126.5, 127.5, 128.7, 136.2
(C-6, Ph), 145.0 (C-5), 165.7 (C-7), 167.5 (C-8a). Anal.
(C18H22N2O3S) C, H, N.
2,3-Dih yd r o-6-eth yl-3-m eth oxy-5-(1-n a p h th ylm eth yl)-
7H-th iazolo[3,2-a ]pyr im idin -7-on e (12a): PTLC (2% MeOH/
CHCl3); yield 256 mg (38%); mp 174-178 °C (CHCl3/toluene);
1H NMR (CDCl3) δ 1.10 (t, 3H, J ) 7.5 Hz, CH2CH3), 2.47-
2.59 (m, 2H, CH2CH3), 3.13 (d, 1H, J ) 12.9 Hz, 2-H), 3.26 (s,
3H, OCH3), 3.34 (dd, 1H, J ) 12.9, 5.9 Hz, 2-H), 4.45 (d, 1H,
J ) 17.4 Hz, 5-CHH), 4.55 (d, 1H, J ) 17.4 Hz, 5-CHH), 5.32
(d, 1H, J ) 5.7 Hz, 3-H), 7.02-8.10 (m, 7H, Hnaphthyl); 13C NMR
(CDCl3) δ 13.4 (CH3), 19.6 (CH2), 29.7 (5-CH2), 30.0 (C-2), 53.5
(OCH3), 90.4 (C-3), 122.1-133.9 (C-6, Ar), 144.4 (C-5), 166.5
(C-7), 169.2 (C-8a). Anal. (C20H20N2O2S) C, H, N.
2,3-Dih ydr o-3-eth oxy-6-eth yl-5-(1-n aph th ylm eth yl)-7H-
th ia zolo[3,2-a ]p yr im id in -7-on e (12b): PTLC (3% MeOH/
CH2Cl2); Rf ) 0.24 (5% MeOH/CH2Cl2); yield 151 mg (21%) as
a yellow foam; 1H NMR (CDCl3) δ 1.06 (t, 3H, J ) 7.4 Hz,
CH2CH3), 1.14 (t, 3H, J ) 7.0 Hz, CH2CH3), 2.41-2.56 (m, 2H,
CH2CH3), 3.14 (d, 1H, J ) 12.8 Hz, 2-H), 3.26-3.49 (m, 3H,
2-H, OCH2), 4.46 (d, 1H, J ) 17.5 Hz, 5-CHH), 4.54 (d, 1H, J
) 17.5 Hz, 5-CHH), 5.45 (d, 1H, J ) 5.5 Hz, 3-H), 7.02-8.10
(m, 7H, Hnaphthyl); 13C NMR (CDCl3) δ 13.1, 14.7 (2 × CH3),
19.4 (CH2), 30.0 (5-CH2), 30.3 (SCH2), 62.3 (OCH2), 89.7 (NCH),
121.9-133.5 (C-6, Ar), 144.5 (C-5), 166.5 (C-7), 169.2 (C-8a).
Anal. (C21H22N2O2S‚0.25H2O) C, H, N.
2,3-Dih yd r o-7-[(3,5-d im eth ylp h en yl)m eth yl]-6-eth yl-3-
m eth oxy-5H-th ia zolo[3,2-a ]p yr im id in -5-on e (14a ): col-
umn chromatography (0-2% MeOH/CH2Cl2); Rf ) 0.68 (8%
1
MeOH/CH2Cl2); yield 94 mg (7%); H NMR (CDCl3) δ 1.06 (t,
3H, J ) 7.4 Hz, CH2CH3), 2.26 (s, 6H, 2 × CH3), 2.58 (q, 2H,
J ) 7.5 Hz, CH2CH3), 3.22 (d, 1H, J ) 12.2 Hz, 2-H), 3.52-
3.60 (m, 4H, 2-H, OCH3), 3.80 (s, 2H, 7-CH2), 6.12 (d, 1H, J )
5.3 Hz, 3-H), 6.84 (s, 1H, Harom), 6.85 (s, 2H, Harom); 13C NMR
(CDCl3) δ 13.0 (CH3), 19.1 (CH2), 21.2 (2 × CH3), 33.6 (7-CH2),
40.2 (C-2), 58.3 (OCH3), 89.2 (C-3), 122.0, 126.4, 128.1, 137.5,
137.8 (C-6, Ph), 160.1, 161.3, 161.7 (C-5, C-7, C-8a); EI MS m/z
330 (M+).
2,3-Dih yd r o-7-[(3,5-d im eth ylp h en yl)m eth yl]-3-eth oxy-
6-eth yl-5H-th ia zolo[3,2-a ]p yr im id in -5-on e (14b): column
chromatography (0-2% MeOH/CH2Cl2); Rf ) 0.73 (8% MeOH/
CH2Cl2); yield 90 mg (7%); 1H NMR (CDCl3) δ 1.06 (t, 3H, J )
7.4 Hz, CH2CH3), 1.21 (t, 3H, J ) 7.0 Hz, CH2CH3), 2.27 (s,
6H, 2 × CH3), 2.58 (q, 2H, J ) 7.4 Hz, CH2CH3), 3.20 (d, 1H,
J ) 12.1 Hz, 2-H), 3.56 (dd, 1H, J ) 12.1, 5.4 Hz, 2-H), 3.79
(s, 2H, 7-CH2), 3.82-3.86 (m, 2H, OCH2), 6.19 (d, 1H, J ) 5.3
Hz, 3-H), 6.83 (s, 1H, Harom), 6.86 (s, 2H, Harom); 13C NMR
(CDCl3) δ 12.8, 15.0 (2 × CH3), 19.0 (CH2), 21.0 (2 × CH3),
34.0 (7-CH2), 40.1 (C-2), 66.6 (OCH2), 87.8 (C-3), 121.8, 126.3,
128.0, 137.5, 137.7 (C-6, Ph), 160.1, 161.2, 161.6 (C-5, C-7,
C-8a); EI MS m/z 344 (M+).
2,3-Dih yd r o-7-[(3,5-d im eth ylp h en yl)m eth yl]-6-eth yl-3-
(2-h yd r oxyet h oxy)-5H -t h ia zolo[3,2-a ]p yr im id in -5-on e
(14c): column chromatography (0-2% MeOH/CH2Cl2); Rf )
1
0.33 (8% MeOH/CH2Cl2); yield 74 mg (6%); H NMR (CDCl3)
2,3-Dih yd r o-6-eth yl-3-(2-h yd r oxyeth oxy)-5-(1-n a p h th -
ylm eth yl)-7H-th ia zolo[3,2-a ]p yr im id in -7-on e (12c): pre-
cipitated by adding EtOAc to the crude mixture; Rf ) 0.14 (8%
MeOH/CH2Cl2); yield 230 mg (30%); mp 226-228 °C; 1H NMR
(DMSO-d6) δ 0.90 (t, 3H, J ) 7.3 Hz, CH2CH3), 2.30 (q, 2H, J
δ 1.05 (t, 3H, J ) 7.4 Hz, CH2CH3), 2.27 (s, 6H, 2 × CH3),
2.52-2.62 (m, 2H, CH2CH3), 3.26 (d, 1H, J ) 12.3 Hz, 2-H),
3.56 (dd, 1H, J ) 12.3, 5.5 Hz, 2-H), 3.73-3.87 (m, 5H, OCH2-
CH2OH), 3.80 (s, 2H, 7-CH2), 6.29 (d, 1H, J ) 5.3 Hz, 3-H),
6.85 (s, 3H, Harom); 13C NMR (CDCl3) δ 12.8 (CH3), 19.0 (CH2),

196 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2
Danel et al.
21.0 (2 × CH3), 33.3 (7-CH2), 40.1 (C-2), 61.8, 71.5 (OCH2CH2),
88.6 (C-3), 121.9, 126.3, 128.0, 137.3, 137.8 (C-6, Ph), 160.1,
161.8, 161.9 (C-5, C-7, C-8a); EI MS m/z 360 (M+).
analysis, water was added (10 mL). The precipitate was
filtered off, dried, and recrystallized from EtOAc/petroleum
ether (bp 60-80 °C) (17a ,c). In the case of 17b and 17d the
mixture was extracted with Et2O.
7-Ben zyl-2,3-d ih yd r o-6-isop r op yl-3-m eth oxy-5H-th ia -
zolo[3,2-a ]p yr im id in -5-on e (15a ): PTLC (2% MeOH/CH2-
Cl2); Rf ) 0.59 (5% MeOH/CH2Cl2); yield 50 mg (6%); 1H NMR
(CDCl3) δ 1.23 (d, 3H, J ) 7.0 Hz, CHMe2), 1.26 (d, 3H, J )
7.0 Hz, CHMe2), 3.08 (heptet, 1H, J ) 7.0 Hz, CHMe2), 3.22
(d, 1H, J ) 12.2 Hz, 2-H), 3.56 (dd, 1H, J ) 12.0, 5.5 Hz, 2-H),
3.56 (s, 3H, OCH3), 3.91 (s, 2H, 7-CH2), 6.12 (d, 1H, J ) 5.2
Hz, 3-H), 7.16-7.31 (m, 5H, Harom); 13C NMR (CDCl3) 19.5, 19.6
(2 × CH3), 28.1 (CH), 33.6 (7-CH2), 41.0 (C-2), 58.3 (OCH3),
89.0 (C-3), 124.8, 126.3, 128.4, 128.5, 138.1 (C-6, Ph), 160.3,
160.8, 160.8 (C-5, C-7, C-8a); EI MS m/z 316 (M+).
7-Ben zyl-2,3-dih ydr o-3-eth oxy-6-isopr opyl-5H-th iazolo-
[3,2-a ]p yr im id in -5-on e (15b): PTLC (2% MeOH/CH2Cl2); Rf
) 0.72 (5% MeOH/CH2Cl2); yield 48 mg (5%); 1H NMR (CDCl3)
δ 1.19-1.27 (m, 9H, CHMe2 and CH2CH3), 3.08 (heptet, 1H, J
) 7.0 Hz, CHMe2), 3.21 (d, 1H, J ) 12.1 Hz, 2-H), 3.58 (dd,
1H, J ) 12.0, 5.5 Hz, 2-H), 3.78-3.90 (m, 2H, OCH2CH3), 3.91
(s, 2H, 7-CH2), 6.19 (d, 1H, J ) 5.1 Hz, 3-H), 7.16-7.31 (m,
5H, Harom); 13C NMR (CDCl3) δ 15.2 (CH3), 19.5, 19.6 (2 × CH3),
28.1 (CH), 34.8 (7-CH2), 41.0 (C-2), 66.8 (OCH2), 87.8 (C-3),
124.7, 126.3, 128.4, 128.5, 138.1 (C-6, Ph), 160.3, 160.7, 160.8
(C-5, C-7, C-8a); EI MS m/z 330 (M+).
2-(Allylt h io)-6-b e n zyl-5-e t h ylp yr im id in -4(3H )-on e
(17a ): Rf ) 0.40 (30% EtOAc/petroleum ether (bp 60-80 °C);
yield 314 mg (55%); mp 136-138 °C (EtOAc/petroleum ether
(bp 60-80 °C); 1H NMR (CDCl3) δ 1.08 (t, 3H, J ) 7.4 Hz,
CH2CH3), 2.59 (q, 2H, J ) 7.4 Hz, CH2CH3), 3.74 (d, 2H, J )
7.0 Hz, SCH2), 3.91 (s, 2H, 6-CH2), 5.03 (dd, 1H, J ) 10.1, 1.3
Hz, CHdCH2), 5.18 (dd, 1H, J ) 17.0, 1.3 Hz, CHdCH2), 5.81
(ddt, 1H, J ) 17.0, 10.1, 7.0 Hz, CHdCH2), 7.19-7.28 (m, 5H,
H
arom), 12.65 (br s, 1H, NH); 13C NMR (CDCl3) δ 13.1 (CH3),
18.7 (CH2), 33.2 (6-CH2), 40.4 (SCH2), 118.3 (CHdCH2), 122.4
(C-5), 126. 4, 128.3, 129.0, 132.9 (Ph), 138.3 (CHdCH2), 156.0
(C-6), 161.7 (C-4), 165.2 (C-2). Anal. (C16H18N2OS) C, H, N.
2-(Allylth io)-6-[(3,5-dim eth ylph en yl)m eth yl]-5-eth ylpy-
r im id in -4(3H)-on e (17b): column chromatography (0-10%
EtOAc/petroleum ether (bp 60-80 °C); Rf ) 0.15 (20% EtOAc/
petroleum ether (bp 60-80 °C); yield 319 mg (51%); mp 146-
1
149 °C; H NMR (CDCl3) δ 1.09 (t, 3H, J ) 7.4 Hz, CH2CH3),
2.27 (s, 6H, 2 × CH3), 2.59 (q, 2H, J ) 7.4 Hz, CH2CH3), 3.76
(d, 2H, J ) 6.9 Hz, SCH2), 3.83 (s, 2H, 6-CH2), 5.05 (dd, 1H, J
) 10.0, 1.0 Hz, CHdCH2), 5.17 (dd, 1H, J ) 17.0, 1.3 Hz,
CHdCH2), 5.83 (ddt, 1H, J ) 16.9, 10.0, 6.9 Hz, CHdCH2),
6.84 (s, 1H, Harom), 6.86 (s, 2H, Harom), 12.60 (br s, 1H, NH);
13C NMR (CDCl3) δ 13.2 (CH3), 18.8 (CH2), 21.2 (2 × CH3),
33.2 (6-CH2), 40.3 (SCH2), 118.2 (CHdCH2), 122.3 (C-5), 126.8,
128.0, 133.0, 137.8 (Ph), 138.1 (CHdCH2), 156.0 (C-6), 161.8
(C-4), 165.2 (C-2).
7-Ben zyl-2,3-d ih yd r o-3-(2-h yd r oxyeth oxy)-6-isop r op yl-
5H-th iazolo[3,2-a ]pyr im idin -5-on e (15c): PTLC (4% MeOH/
1
CH2Cl2); Rf ) 0.30 (8% MeOH/CH2Cl2); yield 38 mg (4%); H
NMR (CDCl3) δ 1.22 (d, 3H, J ) 6.9 Hz, CHMe2), 1.25 (d, 3H,
J ) 6.9 Hz, CHMe2), 3.09 (heptet, 1H, J ) 6.9 Hz, CHMe2),
3.27 (d, 1H, J ) 12.3 Hz, 2-H), 3.57 (dd, 1H, J ) 12.2, 5.5 Hz,
2-H), 3.74-3.89 (m, 5H, OCH2CH2OH), 3.92 (s, 2H, 7-CH2),
6.28 (d, 1H, J ) 5.4 Hz, 3-H), 7.16-7.31 (m, 5H, Harom); 13C
NMR (CDCl3) δ 19.4, 19.5 (2 × CH3), 28.0 (CH), 33.2 (7-CH2),
40.1 (C-2), 61.8, 71.6 (OCH2CH2OH), 88.5 (C-3), 124.7, 126.3,
128.3, 128.4, 137.8 (C-6, Ph), 160.1, 161.0, 161.3 (C-5, C-7,
C-8a); EI MS m/z 346 (M+).
2-(Allylt h io)-6-b e n zyl-5-isop r op ylp yr im id in -4(3H )-
on e (17c): Rf ) 0.49 (30% EtOAc/petroleum ether (bp 60-80
°C); yield 593 mg (99%); mp 123-125 °C (EtOAc/petroleum
1
ether (bp 60-80 °C); H NMR (CDCl3) δ 1.27 (d, 6H, J ) 6.9
Hz, CHMe), 3.09 (heptet, 1H, J ) 6.9 Hz, CHMe2), 3.75 (d,
2H, J ) 6.9 Hz, SCH2), 3.94 (s, 2H, 6-CH2), 5.05 (dd, 1H, J )
10.0, 0.9 Hz, CHdCH2), 5.18 (dd, 1H, J ) 16.9, 1.3 Hz,
CHdCH2), 5.83 (ddt, 1H, J ) 16.9, 10.0, 6.9 Hz, CHdCH2),
7.16-7.30 (m, 5H, Harom), 12.81 (br s, 1H, NH); 13C NMR
(CDCl3) δ 19.6 (2 × CH3), 27.9 (CH), 33.0 (6-CH2), 40.9 (SCH2),
118.1 (CHdCH2), 125.0 (C-5), 126.2, 128.3, 128.7, 132.9 (Ph),
138.5 (CHdCH2), 156.0 (C-6), 161.2 (C-4), 164.6 (C-2). Anal.
Calcd (C17H20N2OS‚0.25H2O): C, 66.96; H, 6.61; N, 9.18.
Found: C, 66.82; H, 6.79; N, 8.72.
2,3-Dih yd r o-6-eth yl-3-m eth oxy-7-(1-n a p h th ylm eth yl)-
5H-th iazolo[3,2-a ]pyr im idin -5-on e (16a): PTLC (2% MeOH/
CHCl3); Rf ) 0.40 (2% MeOH/CHCl3); yield 60 mg (9%); 1H
NMR (CDCl3) δ 1.03 (t, 3H, J ) 7.5 Hz, CH2CH3), 2.55 (q, 2H,
J ) 7.5 Hz, CH2CH3), 3.18 (d, 1H, J ) 12.3 Hz, 2-H), 3.49-
3.58 (m, 4H, OCH3, 2-H), 4.33 (s, 2H, 7-CH2), 6.13 (d, 1H, J )
5.4 Hz, 3-H), 7.14-8.10 (m, 7H, Hnaphthyl); 13C NMR (CDCl3) δ
13.0 (CH3), 19.2 (CH2), 33.6 (7-CH2), 37.5 (C-2), 58.4 (OCH3),
89.3 (C-3), 123.1-133.7 (C-6, Ar), 160.4, 161.0, 161.7 (C-5, C-7,
C-8a); EI MS m/z 352 (M+).
2-(Allylt h io)-5-et h yl-6-(1-n a p h t h ylm et h yl)p yr im id in -
4(3H)-on e (17d ): column chromatography (0-10% EtOAc/
petroleum ether (bp 60-80 °C)); yield 337 mg (50%); mp 162-
1
165 °C; H NMR (CDCl3) δ 1.11 (t, 3H, J ) 7.4 Hz, CH2CH3),
2,3-Dih ydr o-3-eth oxy-6-eth yl-7-(1-n aph th ylm eth yl)-5H-
th ia zolo[3,2-a ]p yr im id in -5-on e (16b): PTLC (3% MeOH/
2.64 (q, 2H, J ) 7.4 Hz, CH2CH3), 3.43 (d, 2H, J ) 6.9 Hz,
SCH2), 4.37 (s, 2H, 6-CH2), 4.84 (dd, 1H, J ) 10.0, 1.0 Hz,
CHdCH2), 4.91 (dd, 1H, J ) 17.0, 1.3 Hz, CHdCH2), 5.51 (ddt,
1H, J ) 17.0, 10.0, 6.9 Hz, CHdCH2), 7.23-8.08 (m, 7H,
1
CH2Cl2); Rf ) 0.72 (5% MeOH/CH2Cl2); yield 56 mg (8%); H
NMR (CDCl3) δ 1.02 (t, 3H, J ) 7.4 Hz, CH2CH3), 1.23 (t, 3H,
J ) 7.0 Hz, CH2CH3), 2.53 (q, 2H, J ) 7.4 Hz, CH2CH3), 3.21
(d, 1H, J ) 12.0 Hz, 2-H), 3.56 (dd, 1H, J ) 12.1, 5.4 Hz, 2-H),
3.80-3.93 (m, 2H, OCH2CH3), 4.33 (s, 2H, 7-CH2), 6.22 (d, 1H,
J ) 5.4 Hz, 3-H), 7.14-8.11 (m, 7H, Hnaphthyl); 13C NMR (CDCl3)
δ 12.9, 15.2 (2 × CH3), 19.2 (CH2), 34.2 (7-CH2), 37.5 (C-2),
62.3 (OCH2), 88.0 (C-3), 123.1-133.7 (C-6, Ar), 160.5, 161.0,
161.7 (C-5, C-7, C-8a); EI MS m/z 366 (M+).
H
naphthyl), 12.65 (br s, 1H, NH); 13C NMR (CDCl3) δ 13.0 (CH3),
18.8 (CH2), 33.0 (6-CH2), 37.5 (SCH2), 117.9 (CHdCH2), 122.7-
133.8 (C-5, Ar), 134.4 (CHdCH2), 156.0 (C-6), 161.5 (C-4), 165.1
(C-2).
P r oced u r e for P r ep a r a tion of 18a -d . Compound 17
(0.78 mmol) was dissolved in anhydrous CH2Cl2 (5 mL). To
the clear solution was added equimolar amount of N,O-bis-
(trimethylsilyl)acetamide (160 mg, 0.20 mL) followed by drop-
wise addition of dry bromine (250 mg, 2 mmol) dissolved in
CH2Cl2 (5 mL). After completion of the reaction according to
TLC analysis and evaporation of the solvent, the oily residue
was chromatographed on a silica gel column with 0.5-1%
MeOH/CH3Cl to afford product 18.
2,3-Dih yd r o-6-eth yl-3-(2-h yd r oxyeth oxy)-7-(1-n a p h th -
ylm eth yl)-5H-th ia zolo[3,2-a ]p yr im id in -5-on e (16c): PTLC
(50% EtOAc/petroleum ether (60-80 °C)); Rf ) 0.42 (8%
1
MeOH/CH2Cl2); yield 50 mg (7%); H NMR (CDCl3) δ 1.02 (t,
3H, J ) 7.4 Hz, CH2CH3), 2.46-2.62 (m, 2H, CH2CH3), 3.25
(d, 1H, J ) 12.4 Hz, 2-H), 3.54 (dd, 1H, J ) 12.3, 5.5 Hz, 2-H),
3.62-3.92 (m, 5H, OCH2CH2OH), 4.33 (s, 2H, 7-CH2), 6.30 (d,
1H, J ) 5.3 Hz, 3-H), 7.13-8.09 (m, 7H, Hnaphthyl); 13C NMR
(CDCl3) δ 12.9 (CH3), 19.1 (CH2), 33.3 (7-CH2), 37.5 (C-2), 61.9,
71.7 (OCH2CH2OH), 88.8 (C-3), 123.0-133.7 (C-6, Ar), 160.4,
161.6, 161.8 (C-5, C-7, C-8a); EI MS m/z 382 (M+).
5-Ben zyl-3-(br om om eth yl)-2,3-d ih yd r o-6-eth yl-7H-th i-
a zolo[3,2-a ]p yr im id in -7-on e (18a ): Rf ) 0.25 (5% MeOH/
1
CH2Cl2); yield 210 mg (73%); mp 78-80 °C; H NMR (CDCl3)
δ 1.10 (t, 3H, J ) 7.4 Hz, CH2CH3), 2.52-2.63 (m, 2H, CH2-
CH3), 3.11 (m, 1H, CHHBr), 3.34 (d, 1H, J ) 11.9 Hz, 2-H),
3.46 (m, 1H, 2-H), 3.64 (t, 1H, J ) 10.7 Hz, CHHBr), 3.85 (d,
1H, J ) 16.8 Hz, 5-CHH), 4.23 (d, 1H, J ) 16.8 Hz, 5-CHH),
4.64-4.72 (m, 1H, 3-H), 7.14-7.43 (m, 5H, Harom); 13C NMR
(CDCl3) δ 13.3 (CH3), 19.8 (CH2), 28.2 (CH2Br), 30.4, 34.7 (5-
Gen er a l P r oced u r e for P r ep a r a tion 17a-d . Compound
1-4 (2 mmol) was dissolved in anhydrous methanol (6 mL),
and MeONa (118 mg, 2.2 mmol) was added followed by
addition of allyl bromide (4.4 mmol). A white precipitate could
occur. After completion of the reaction according to TLC

Anti-HIV-1 Activity of Thiazolopyrimidin-7-ones
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 2 197
CH2, C-2), 63.9 (C-3), 123.6 (C-6), 127.4, 127.8, 129.5, 134.3
(Ph), 143.9 (C-5), 165.1, 169.0 (C-7, C-8a).
1-Allyl-2-(a llylth io)-6-[(3,5-d im eth ylp h en yl)m eth yl]-5-
eth ylp yr im id in -4(1H)-on e (20a ): Rf ) 0.64 (15% EtOAc/
petroleum ether (bp 60-80 °C)); yield 263 mg (37%) as a yellow
3-(Br om om et h yl)-2,3-d ih yd r o-5-[(3,5-d im et h ylp h en -
yl)m e t h yl]-6-e t h yl-7H -t h ia zolo[3,2-a ]p yr im id in -7-on e
(18b): Rf ) 0.30 (5% MeOH/CH2Cl2); yield 180 mg (59%) as a
1
oil; H NMR (CDCl3) δ 1.00 (t, 3H, J ) 7.4 Hz, CH3), 2.25 (s,
6H, 2 × CH3), 2.58 (q, 2H, J ) 7.4 Hz, CH2), 3.77 (dd, 2H, J )
7.9, 1.1 Hz, SCH2), 3.94 (s, 2H, CH2Ph), 4.87 (dt, 2H, J ) 6.9,
1.5 Hz, NCH2), 5.06 (ddd, 1H, J ) 10.3, 1.4, 0.7 Hz, CHdCH2),
5.20 (m, 1H, CHdCH2), 5.24 (m, 1H, CHdCH2), 5.35 (m, 1H,
CHdCH2), 5.90-6.11 (m, 2H, CHdCH2), 6.81 (s, 1H, Hphenyl),
6.84 (s, 2H, Hphenyl); 13C NMR (CDCl3) δ 13.2 (CH3), 18.2 (CH2),
21.2 (2 × CH3), 33.7 (CH2), 40.3 (SCH2), 66.9 (NCH2), 116.7
(C-5), 117.0 (CHdCH2), 117.4 (CHdCH2), 126.6, 127.9 (Ar),
132.8 (CHdCH2), 134.4 (CHdCH2), 137.7, 138.2 (Ar), 166.1
(C-6), 166.3 (C-4), 167.0 (C-2); EI MS m/z 354 (M+). Anal.
Calcd (C21H26N2OS): C, 71.15; H, 7.39; N, 7.90. Found: C,
71.19; H, 7.60; N, 7.43.
1
foam; H NMR (CDCl3) δ 1.11 (t, 3H, J ) 7.4 Hz, CH2CH3),
2.31 (s, 6H, 2 × CH3), 2.52-2.65 (m, 2H, CH2CH3), 3.11 (m,
1H, CHHBr), 3.35 (d, 1H, J ) 11.9 Hz, 2-H), 3.47 (m, 1H, 2-H),
3.59 (t, 1H, J ) 10.6 Hz, CHHBr), 3.83 (d, 1H, J ) 16.6 Hz,
5-CHH), 4.06 (d, 1H, J ) 16.7 Hz, 5-CHH), 4.68-4.75 (m, 1H,
3-H), 6.74 (m, 2H, Harom), 6.95 (s, 1H, Harom); 13C NMR (CDCl3)
δ 13.3 (CH3), 19.9 (CH2), 21.2 (2 × CH3), 28.2 (CH2Br), 30.4,
34.6 (5-CH2, C-2), 63.8 (C-3), 123.4 (C-6), 125.2, 129.5, 134.1
139.3 (Ph), 144.3 (C-5), 165.1, 169.2 (C-7, C-8a); EI MS m/z
392 (M+).
5-Ben zyl-3-(br om om eth yl)-2,3-d ih yd r o-6-isop r op yl-7H-
th ia zolo[3,2-a ]p yr im id in -7-on e (18c): Rf ) 0.24 (5% MeOH/
CH2Cl2); yield 222 mg (38%) as a white foam; 1H NMR (CDCl3)
δ 1.31 (d, 3H, J ) 6.9 Hz, CHMe), 1.36 (d, 3H, J ) 6.9 Hz,
CHMe), 3.00 (heptet, 1H, J ) 6.9 Hz, CHMe2), 3.18 (m, 1H,
CHHBr), 3.34 (d, 1H, J ) 11.9 Hz, 2-H), 3.47 (m, 1H, 2-H),
3.65 (t, 1H, J ) 10.6 Hz, CHHBr), 3.83 (d, 1H, J ) 17.1 Hz,
5-CHH), 4.32 (d, 1H, J ) 17.1 Hz, 5-CHH), 4.70-4.77 (m, 1H,
3-H), 7.14-7.44 (m, 5H, Harom); 13C NMR (CDCl3) δ 19.4, 20.2
(2 × CH3), 28.1 (CH), 28.4 (CH2Br), 30.4, 34.5 (5-CH2, C-2),
63.9 (C-3), 126.1 (C-6), 127.3, 127.7, 129.4, 134.4 (Ph), 143.4
(C-5), 164.6, 168.2 (C-7, C-8a).
1-Allyl-2-(a llylth io)-5-eth yl-6-(1-n a p h th ylm eth yl)p yr i-
m id in -4(1H)-on e (20b): Rf ) 0.60 (20% EtOAc/petroleum
1
ether (bp 60-80 °C)); yield 272 mg (36%) as a yellow oil; H
NMR (CDCl3) δ 1.00 (t, 3H, J ) 7.4 Hz, CH3), 2.56 (q, 2H, J )
7.4 Hz, CH2), 3.58 (d, 2H, J ) 6.8 Hz, SCH2), 4.47 (s, 2H,
CH2C10H7), 4.87 (dd, 2H, J ) 6.3, 1.4 Hz, NCH2), 4.95 (m, 1H,
CHdCH2), 5.12 (m, 1H, CHdCH2), 5.25 (m, 1H, CHdCH2),
5.36 (m, 1H, CHdCH2), 5.71-5.87 (m, 1H, CHdCH2), 5.99-
6.12 (m, 1H, CHdCH2), 7.01-8.13 (m, 7H, Hnaphthyl); 13C NMR
(CDCl3) δ 13.1 (CH3), 18.3 (CH2), 33.6 (CH2), 37.6 (SCH2), 67.0
(NCH2), 116.9 (C-5), 117.3 (CHdCH2), 117.5 (CHdCH2), 123.9,
125.3, 125.5, 125.9, 126.4, 127.1, 128.6 (Ar), 132.2 (CHdCH2),
132.8 (CHdCH2), 133.7, 134.2, 134.5 (Ar), 165.6 (C-6), 166.5
(C-4), 167.0 (C-2); EI MS m/z 376 (M+). Anal. (C23H24N2OS)
C, H, N.
3-(Br om om et h yl)-2,3-d ih yd r o-6-et h yl-5-(1-n a p h t h yl-
m eth yl)-7H-th ia zolo[3,2-a ]p yr im id in -7-on e (18d ): yield 56
1
mg (20%); mp >275 °C dec (EtOH/EtOAc); H NMR (DMSO-
d6) δ 0.91 (t, 3H, J ) 7.3 Hz, CH2CH3), 2.31-2.49 (m, 2H, CH2-
CH3), 3.50 (d, 1H, J ) 12.1 Hz, 2-H), 3.73-3.85 (m, 3H, 2-H
and CH2Br), 4.56 (d, 1H, J ) 18.0 Hz, 5-CHH), 4.74 (d, 1H, J
) 18.1 Hz, 5-CHH), 5.03 (m, 1H, 3-H), 7.14-8.00 (m, 7H,
Vir u s a n d Cells. The HIV-1 strain HTLV-IIIB29 was
propagated in H9 cells30 at 37 °C, 5% CO2 using RPMI 1640
with 10% heat-inactivated fetal calf serum (FCS) and antibio-
tics (growth medium). Culture supernatant was filtered (0.45
nm), aliquotted, and stored at -80 °C until use.
H
naphthyl); 13C NMR (DMSO-d6) δ 12.5 (CH3), 19.2 (CH2), 31.3,
31.5, 31.7 (CH2Br, 5-CH2, C-2), 64.1 (C-3), 123.3-133.4 (C-6,
Ar), 147.4 (C-5), 165.6, 167.0 (C-7, C-8a).
In h ibition of HIV-1 Rep lica tion . Compounds were ex-
amined for possible antiviral activity against HIV-1 using
MT-4 cells as target cells. For screening studies, MT-4 cells
were incubated with virus (0.005 MOI) for 2 h, washed, and
thereafter added in a proportion of 1:10 to uninfected cells,
which had been preincubated in growth medium containing
the test compound for 2 h. Cultures were maintained with
the test compound for 6 days in parallel with virus-infected
control cultures without compound added. Expression of HIV
in the culture medium was quantitated by HIV-1 antigen
detection ELISA.31 Compounds mediating less than 30%
reduction of antigen expression were considered without
biological activity. Compounds mediating a reduction of 30%
or more were examined for cytotoxic effect using concentration-
dependent inhibition of MT-4 cell proliferation as measure of
P r ep a r a tion of Bis(a lk yla ted ) Der iva tives 19a ,b a n d
20a ,b. Two millimoles of 2 or 4 was dissolved in DMF (2 mL).
To the solution anhydrous was added K2CO3 (276 mg, 2 mmol)
followed by allyl bromide (242 mg, 0.17 mL, 2 mmol). The
mixture was stirred overnight. The mixture was filtered, the
residue was washed with a small amount of DMF, and the
combined organic fractions were evaporated to dryness. Col-
umn chromatography with 4% EtOAc/petroleum ether (bp 60-
80 °C) afforded two fractions.
3-Allyl-2-(a llylth io)-6-[(3,5-d im eth ylp h en yl)m eth yl]-5-
eth ylp yr im id in -4(3H)-on e (19a ): Rf ) 0.30 (15% EtOAc/
petroleum ether (bp 60-80 °C); yield 358 mg (51%) as a yellow
1
oil; H NMR (CDCl3) δ 1.10 (t, 3H, J ) 7.4 Hz, CH3), 2.27 (s,
6H, CH3), 2.60 (q, 2H, J ) 7.4 Hz, CH2), 3.74 (d, 2H, J ) 7.0
Hz, SCH2), 3.79 (s, 2H, CH2Ph), 4.61 (d, 2H, J ) 5.7 Hz, NCH2),
5.04-5.28 (m, 4H, CHdCH2), 5.75-5.94 (m, 2H, CHdCH2),
6.84 (s, 1H, Hphenyl), 6.88 (s, 2H, Hphenyl); 13C NMR (CDCl3) δ
13.1 (CH3), 19.4 (CH2), 21.2 (2 × CH3), 34.8 (CH2), 40.0 (SCH2),
46.5 (NCH2), 118.2 (CHdCH2), 118.7 (CHdCH2), 121.3 (C-5),
126.9, 127.9 (Ar), 130.6 (CHdCH2), 132.8 (CHdCH2), 137.7,
138.1 (Ar), 156.6 (C-6), 158.6 (C-4), 162.4 (C-2); EI MS m/z
353 (M+). Anal. Calcd (C21H26N2OS): C, 71.15; H, 7.39; N,
7.90. Found: C, 71.55; H, 7.77; N, 7.38.
cytotoxicity using the MTT assay as previously described.32
A
30% inhibition of cell growth relative to control cultures was
considered significant.
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