1452 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 10
Mai et al.
Ta ble 4. Activity of Derivatives 6, 10, and 11 against wt and
(0.20 g, 0.58 mmol) in tetrahydrofuran (5 mL), and the mixture
was refluxed for 5 h. After cooling, the resulting mixture was
filtered, diluted with water (100 mL), and extracted with ethyl
acetate (3 × 50 mL). The organic layers were collected, washed
with brine (3 × 50 mL), dried, and evaporated to give a residue,
which was purified by column chromatography on silica gel
(eluent: chloroform): 1H-NMR (CDCl3) δ 1.26-1.48 (m, 6H,
C3,C4,C5 cyclohexane-H), 1.74-1.78 (m, 2H, C2eq,C6eq cyclohex-
ane-H), 2.07-2.09 (m, 2H, C2ax,C6ax cyclohexane-H), 2.16 (s,
3H, C5-Me), 2.31 (s, 3H, 3′-Me), 3.72-3.78 (m, 1H, SCH), 4.00
(s, 2H, CH2Ar), 7.02-7.04 (m, 3H, 2′,4′,6′-H Ar), 7.15-7.18 (m,
1H, 5′-H Ar), 8.20 (s, 1H, C4-H). Anal. (C19H24N2S, 312.47)
C, H, S.
2-(Cycloh exylt h io)-4-m et h oxy-5-m et h yl-6-(3′-m et h yl-
ben zyl)p yr im id in e (15e) a n d 2-(Cycloh exylth io)-3,4-d i-
h yd r o-3,5-d im e t h yl-6-(3′-m e t h ylb e n zyl)-4-oxop yr im i-
d in e (15f). A mixture of 3c (0.20 g, 0.61 mmol), methyl iodide
(0.13 g, 0.057 mL, 0.91 mmol), and potassium carbonate (0.13
g, 0.91 mmol) in anhydrous N,N-dimethylformamide (1 mL)
was stirred at room temperature for 2 h and then poured on
cold water (100 mL) and extracted with ethyl acetate (3 × 50
mL). The organic layers were collected, washed with brine (3
× 50 mL), dried, and evaporated to afford a mixture of 15e,f,
which were separated by column chromatography on silica gel
eluting with chloroform.
Drug-Resistant HIV and HIV-1 rRTa
b
c
IC50
EC50
HIV-1/
H9/IIIB
HIV-1
rRT
compd
6d
HIV-2
>100
NevR
MC639R
>100
8.1
>100 >100
>100 >100
>100 >100
>100 >100
>100 >100
>100 >100
>100 >100
>100 >100
>100 >100
>100 >100
>100
2.1
10b
>100
>100
>100
>100
>100
>100
>100
>100
10e
10j
48.7
22.5
45.0
7.4
33.1
29.7
0.9
15.3
6.0
10k
11a
16.2
4.1
11c
11d
3c
nevirapine
AZT
20.0
17.8
>100
0.31
0.003
0.27 >100
0.015
>20
0.013
a
Data represent mean values for three separate experiments.
b
Standard errors average e10% of the respective means. Com-
pound concentration (µM) required to inhibit the HIV-1 rRT
activity by 50%. c Compound dose (µM) required to achieve 50%
protection of C8166 (HIV-2) or MT-4 (NevR, MC639R) cells from
the HIV-induced cytopathogenicity or to decrease the virus titer
by 1 log (HIV-1 in chronically infected H9/IIIB cells).
15e: 1H-NMR (CDCl3) δ 1.26-1.53 (m, 6H, C3,C4,C5 cyclo-
hexane-H), 1.75-1.82 (m, 2H, C2eq,C6eq cyclohexane-H), 2.05
(s, 3H, C5-Me), 2.07-2.14 (m, 2H, C2ax,C6ax cyclohexane-H),
2.30 (s, 3H, 3′-Me), 3.72-3.78 (m, 1H, SCH), 3.93 (s, 3H,
OCH3), 3.97 (s, 2H, CH2Ar), 7.00-7.05 (m, 3H, 2′,4′,6′-H Ar),
7.12-7.18 (m, 1H, 5′-H Ar). Anal. (C20H26N2OS, 342.50)
C,H,N,S.
diphosphetane 2,4-disulfide (Lawesson’s Reagent) (0.37 g, 0.92
mmol) in anhydrous benzene (50 mL) was refluxed for 1 h.
After cooling, the solvent was removed to afford 15a , which
was purified by passing through a silica gel column eluting
with chloroform: IR ν 3100, 1600 cm-1
;
1H-NMR (CDCl3) δ
1.27-1.48 (m, 6H, C3,C4,C5 cyclohexane-H), 1.72-1.76 (m, 2H,
C2eq,C6eq cyclohexane-H), 1.96-2.01 (m, 2H, C2ax,C6ax cyclohex-
ane-H), 2.32 (s, 3H, 3′-Me), 2.39 (s, 3H, C5-Me), 3.75-3.80 (m,
1H, SCH), 3.93 (s, 2H, CH2Ar), 7.03-7.04 (m, 3H, 2′,4′,6′-H
Ar), 7.15-7.20 (m, 1H, 5′-H Ar). Anal. (C19H24N2S2, 344.53)
C, H, S.
15f: IR ν 1640 cm-1; 1H-NMR (CDCl3) δ 1.26-1.46 (m, 6H,
C3,C4,C5 cyclohexane-H), 1.72-1.78 (m, 2H, C2eq,C6eq cyclohex-
ane-H), 1.98-2.04 (m, 2H, C2ax,C6ax cyclohexane-H), 2.14 (s,
3H, C5-Me), 2.32 (s, 3H, 3′-Me), 3.44 (s, 3H, NCH3), 3.72-3.83
(m, 1H, SCH), 3.83 (s, 2H, CH2Ar overlapped signal), 7.00-
7.08 (m, 3H, 2′,4′,6′-H Ar), 7.15-7.18 (m, 1H, 5′-H Ar). Anal.
(C20H26N2OS, 342.50) C,H,N,S.
4-Am in o-2-(cycloh exylth io)-5-m eth yl-6-(3′-m eth ylben -
zyl)p yr im id in e (15g). A mixture of 15c (0.40 g, 1.15 mmol)
in ethanol (5 mL) and ammonium hydroxide (5.0 N, 60 mL)
was heated with stirring in a sealed tube at 120 °C for 10 h.
After cooling, the reaction mixture was diluted with water (300
mL) and extracted with ethyl acetate (3 × 50 mL). The organic
layers were collected, washed with brine (100 mL), dried, and
evaporated to give 15g, which was purified by recrystallization
from diethyl ether: IR ν 3460, 3290 cm-1; 1H-NMR (CDCl3) δ
1.33-1.51 (m, 6H, C3,C4,C5 cyclohexane-H), 1.73-1.77 (m, 2H,
C2eq,C6eq cyclohexane-H), 1.98 (s, 3H, C5-Me), 2.05-2.10 (m,
2H, C2ax,C6ax cyclohexane-H), 2.30 (s, 3H, 3′-Me), 3.71-3.81
(m, 1H, SCH), 3.94 (s, 2H, CH2Ar), 4.76 (br s, 2H, NH2), 6.98-
7.05 (m, 3H, 2′,4′,6′-H Ar), 7.11-7.19 (m, 1H, 5′-H Ar). Anal.
(C19H25N3S, 327.49) C,H,N,S.
2-(Cycloh exylth io)-5-m eth yl-6-(3′-m eth ylben zyl)-4-[(2-
m eth ylp r op yl)th io]p yr im id in e (15b). A mixture of 15a (40
mg, 0.120 mmol), 2-iodobutane (24.3 mg, 0.015 mL, 0.132
mmol) and potassium carbonate (18.2 mg, 0.132 mmol) in
anhydrous N,N-dimethylformamide (1 mL) was stirred at room
temperature for 8 h. The reaction content was poured on cold
water (100 mL), and extracted with ethyl acetate (3 × 50 mL).
The organic layers were collected, washed with brine (3 × 50
mL), dried, and evaporated to furnish crude 15b which was
then purified by column chromatography on silica gel (eluent:
n-hexane/ethyl acetate, 10/1): 1H-NMR (CDCl3) δ 1.02-1.07
(t, 3H, CH2CH3), 1.28-1.55 (m, 6H, C3,C4,C5 cyclohexane-H),
1.40-1.42 (d, 3H, CHCH3, overlapped signal), 1.70-1.81 (m,
4H, C2eq,C6eq cyclohexane-H, CH2CH3), 2.09-2.19 (m, 2H,
C2ax,C6ax cyclohexane-H), 2.09 (s, 3H, C5-Me overlapped signal),
2.32 (s, 3H, 3′-Me), 3.74-3.80 (m, 1H, SCH cyclohexane), 3.96-
4.02 (m, 1H, CHCH3), 3.98 (s, 2H, CH2Ar overlapped signal),
7.00-7.06 (m, 3H, 2′,4′,6′-H Ar), 7.16-7.19 (m, 1H, 5′-H Ar).
Anal. (C23H32N2S2, 400.64) C, H, S.
4-Ch lor o-2-(cycloh exylth io)-5-m eth yl-6-(3′-m eth ylben -
zyl)p yr im id in e (15c). A mixture of anhydrous N,N-dimeth-
ylformamide (0.20 g, 0.21 mL, 2.74 mmol) and phosphorus
oxychloride (0.42 g, 0.25 mL, 2.74 mmol) was stirred at room
temperature for 1 h; then a solution of 3c (0.60 g, 1.83 mmol)
in anhydrous chloroform (10 mL) was added. The resulting
mixture was stirred at room temperature for a further 5 h;
then the reaction was quenched with aqueous sodium hydro-
gen carbonate (50 mL), and the phases were separated. The
aqueous layer was extracted twice with fresh chloroform (20
mL), and the organic extracts were collected, washed with
brine (2 × 50 mL), dried, and evaporated to give pure 15c:
1H-NMR (CDCl3) δ 1.27-1.52 (m, 6H, C3,C4,C5 cyclohexane-
H), 1.74-1.78 (m, 2H, C2eq,C6eq cyclohexane-H), 2.06-2.10 (m,
2H, C2ax,C6ax cyclohexane-H), 2.27 (s, 3H, C5-Me), 2.32 (s, 3H,
3′-Me), 3.72-3.78 (m, 1H, SCH), 4.05 (s, 2H, CH2Ar), 7.00-
7.06 (m, 3H, 2′,4′,6′-H Ar), 7.16-7.20 (m, 1H, 5′-H Ar). Anal.
(C19H23ClN2S, 346.92) C,H,Cl,S.
2-(Cycloh e xylt h io)-5-m e t h yl-6-(3′-m e t h ylb e n zyl)-4-
t h iosem ica r b a zid op yr im id in e (15h ). A mixture of 15c
(0.13 g, 0.36 mmol) and thiosemicarbazide (0.06 g, 0.72 mmol)
in anhydrous ethanol (2 mL) was refluxed for 2 h. After
cooling, the reaction mixture was diluted with water (50 mL)
and extracted with ethyl acetate (3 × 20 mL). The organic
layers were collected, washed with brine (3 × 50 mL), dried,
and evaporated to give a residue which was purified by column
chromatography on silica gel (eluent: chloroform/ethyl acetate,
1
1/1): IR ν 3400-3200, 1600 cm-1; H-NMR (CDCl3) δ 1.26-
1.53 (m, 6H, C3,C4,C5 cyclohexane-H), 1.60-1.68 (m, 2H,
C2eq,C6eq cyclohexane-H), 1.87-2.01 (m, 2H, C2ax,C6ax cyclohex-
ane-H), 1.92 (s, 3H, C5-Me overlapped signal), 2.23 (s, 3H, 3′-
Me), 3.75-3.83 (m, 4H, SCH, NHCSNH2), 3.97 (s, 2H, CH2Ar),
4.65 (br s, 1H, PyNH), 6.91-7.06 (m, 3H, 2′,4′,6′-H Ar), 7.11-
7.19 (m, 1H, 5′-H Ar). Anal. (C20H27N5S2, 401.59) C,H,S.
Gen er a l P r oced u r e for th e P r ep a r a tion of Der iva tives
13b-l. Exa m p le: Eth yl 2-[(2-P h en ylth io)a cetyl]p r op i-
on a te (13j). Triethylamine (14.6 mL, 100.0 mmol) and then
magnesium chloride (7.05 g, 74.0 mmol) were added with
stirring to a cooled (10-15 °C) suspension of potassium ethyl
2-methylmalonate (12b) (11.7 g, 63.5 mmol) in dry acetonitrile
2-(C y c lo h e x y lt h io )-5-m e t h y l-6-(3′-m e t h y lb e n zy l)-
p yr im id in e (15d ). Zinc dust (1.0 g, 15.3 mmol) and 28%
ammonium hydroxide (20 mL) were added to a solution of 15c