Synthesis of 2-Amino-5-sulfanyl-1,3,4-thiadiazoles
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 6 935
N-[5-(4-Nitr o-ben zylsu lfa n yl)-1,3,4-th ia d ia zol-2-yl]-a c-
eta m id e (5c). From 3e. Yield 87%; mp 263-265 °C (EtOH).
1H NMR (DMSO) δ 2.2 (s, 3H, COCH3); 3.35 (bs, 1H, NH);
4.65 (s, 2H, SCH2); 7.6-8.4 (m, 4H, arom.). Anal. C11H10N4O3S2
(310.35) C, H, N.
2.75 (s, 3H, SCH3); 3.8 (s, 3H, NCH3). Anal. C6H9N3OS2
(203.28) C, H, N.
N-Met h yl-N-[5-isop r op ylsu lfa n yl)-1,3,4-t h ia d ia zol-2-
yl]-a ceta m id e (6b). From 5b by the same procedure described
1
for 6a . Yield 51%; mp 44-45 °C (EtOH). H NMR (CDCl3) δ
N-[5-(4-Meth oxy-ben zylsu lfa n yl)-1,3,4-th ia d ia zol-2-yl]-
a ceta m id e (5d ). From 3f. Yield 77%; mp 177-179 °C (EtOH).
1H NMR (CDCl3) δ 2.5 (s, 3H, COCH3); 3.8 (s, 3H, OCH3); 4.4
(s, 2H, SCH2); 6.8-7.5 (dd, 4H, arom.); 13.4 (bs, 1H, NH). Anal.
1.45 (d, 6H, CH(CH3)2); 2.4 (s, 3H, COCH3); 3.8 (s, 3H, NCH3).
Anal. C8H13N3OS2 (231.33) C, H, N.
P h a r m a cology. An im a ls. Male albino Swiss mice 25-30
g were used in the despair test and in the experimental
procedures adopted for side effects detection.
C
12H13N3O2S2 (295.37) C, H, N.
N-[5-(4-Ch lor o-b en zylsu lfa n yl)-1,3,4-t h ia d ia zol-2-yl]-
Male Sprague-Dawley rats 200-250 g were used in the
despair test and social interaction test.
a ceta m id e (5e). From 3g. Yield 86%; mp 213-215 °C (EtOH).
1H NMR (DMSO) δ 2.2 (s, 3H, CH3CO); 4.5 (s, 2H, SCH2); 7.45
(dd, 4H, arom.); 12.5 (bs, 1H, NH). Anal. C11H10ClN3OS2
(299.79) C, H, N.
N-[5-(4-Met h yl-b en zylsu lfa n yl)-1,3,4-t h ia d ia zol-2-yl]-
a ceta m id e (5f). From 3h . Yield 85%; mp 212-213 °C (EtOH).
1H NMR (DMSO) δ 2.2 (s, 3H, CH3CO); 2.3 (s, 3H, CH3); 4.5
(s, 2H, SCH2); 7.25 (dd, 4H, arom.); 13.0 (bs, 1H, NH). Anal.
C12H13N3OS2 (279.37) C, H, N.
N-[5-Ben zylsu lfa n yl)-1,3,4-th ia d ia zol-2-yl]-a ceta m id e
(5g). From 3d . Yield 96%; mp 170 °C (H2O). 1H NMR (CDCl3)
δ 2.4 (s, 3H, CH3CO); 4.4 (s, 2H, SCH2); 7.35 (m, 5H, arom);
13.4 (bs, 1H, NH). Anal. C11H11N3OS2 (265.35) C, H, N.
N-[5-(3,4,5-Tr im eth oxyben zylsu lfa n yl)-1,3,4-th ia dia zol-
2-yl]-a ceta m id e (5h ). From 3m . Yield 88%; mp 200-201 °C
(EtOH). 1H NMR (CDCl3) δ 2.5 (s, 3H, CH3CO); 3.9 (s, 9H,
3,4,5-OCH3); 4.45 (s, 2H, SCH2); 6.7 (s, 2H, arom.); 13.45 (s,
1H, NH). Anal. C14H17N3O4S2 (355.43) C, H, N.
Desp a ir Test. As described by Porsolt et al.13,14 the animals
were forced to swim inside a plexiglass cylinder containing
water, and the total duration of immobility during a 5 min
test was recorded. Antidepressants decrease the duration of
immobility.
Test compounds were injected intraperitoneally 1 h before
evaluation of the mice, while acute administration in the rat
was performed in three ip injections 24, 5, and 1 h before the
test and repeated administration once a day for 1 week.
Socia l In ter a ction Test. The method was based on that
described by File et al.15 The test arena consisted of a white
open-topped box (55 × 55 × 30 cm3) with a 100 W lamp 50 cm
above the box floor. The behavior of pairs of rats was observed
over a 10 min test period, and the time spent in social
interaction (following, sniffing, crawling, tumbling, boxing,
grooming) was recorded. Such increases in social interaction
are considered to be predictive of anxiolytic activity. The
compounds were administered ip 1 h before the test.
Sp on ta n eou s Motor Activity. Each mouse was placed in
a cage (40 × 40 × 20 cm3) designed for horizontal motor
activity detection (Activity Cages-U.Basile) 1 h after treatment
and allowed to explore its environment. The movements were
recorded every 5 min for a total period of 15 min.
Eth a n ol P oten tia tion Test. Mice were treated with the
test compound and 1 h later with ethanol 2.5 g/kg ip. This
dose of ethanol did not induce lateral position in the control
animals. The number of animals that were in the lateral
position after receiving ethanol in each group was then
determined.
Rota r od Test. The disruptive effects on motor coordination
were assessed using the Rotarod Treadmills mouse test
(U.Basile). The animals were placed on a rotating rod (24 rpm)
and then observed for 5 min. Each daily session consisted of
two trials to evaluate predrug performance (T1) and postdrug
performance (T2) 1 h after ip administration of the test
compound. Animals that fell from the rod three times during
the first trial were excluded. The number of mice in each single
dose group that fell from the rod is taken to calculate the ataxic
properties of the test compound, and the impairment of motor
coordination was defined as
N-[5-(3-Meth oxy-ben zylsu lfa n yl)-1,3,4-th ia d ia zol-2-yl]-
a ceta m id e (5k ). From 3k . Yield 82%; mp 172-173 °C
1
(EtOAc). H NMR (DMSO) δ 2.25 (s, 3H, CH3CO); 3.8 (s, 3H,
OCH3); 4.45 (s, 2H, SCH2); 7.5-7.7 (m, 4H, arom.); 11.0-13.0
(bs, 1H, NH). Anal. C12H13N3O2S2 (295.37) C, H, N.
N-[5-(3-Ch lor o-b en zylsu lfa n yl)-1,3,4-t h ia d ia zol-2-yl]-
a ceta m id e (5i). From 3i. Yield 93%; mp 184-186 °C (EtOAc).
1H NMR (DMSO) δ 2.25 (s, 3H, CH3CO); 2.8-3.6 (bs, 1H, NH);
4.5 (s, 2H, SCH2); 7.4-7.5 (m, 4H, arom.). Anal. C11H10ClN3-
OS2 (299.79) C, H, N.
N-[5-(3-Nitr o-ben zylsu lfa n yl)-1,3,4-th ia d ia zol-2-yl]-a c-
eta m id e (5j). From 3j. Yield 69%; mp 223-224 °C (EtOH).
1H NMR (DMSO) δ 2.2 (s, 3H, CH3CO); 3.2-4.0 (bs, 1H, NH);
4.7 (s, 2H, SCH2); 7.6-8.5 (m, 4H, arom.). Anal. C11H10N4O3S2
(310.35) C, H, N.
N-[5-Ben zylsu lfa n yl)-1,3,4-t h ia d ia zol-2-yl]-p r op ion a -
m id e (5l). From 3d and propionic anhydride. Yield 65%; mp
1
162-163 °C (EtOH). H NMR (CDCl3) δ 1.3 (t, 3H, CH3); 2.8
(q, 2H, CH2CO); 4.5 (s, 2H, SCH2); 7.4 (m, 5H, arom.); 13.2 (s,
1H, NH). Anal. C12H13N3OS2 (279.37) C, H, N.
Hep ta n oic Acid N-[5-Ben zylsu lfa n yl)-1,3,4-th ia d ia zol-
2-yl]a m id e (5m ). From 3d and heptanoic anhydride. Yield
71%; mp 123-124 °C (EtOH). 1H NMR (CDCl3) 0.7-2.0 (m,
10H, (CH2)5); 2.75 (t, 3H, CH3); 4.5 (s, 2H, C6H5CH2): 7.5 (m,
5H, arom.); 13.3 (s, 1H, NH). Anal. C16H11N3OS2 (335.48) C,
H, N.
[(T1 - T2 )/T1] × 100
N -[5-B e n zy ls u lfa n y l)-1,3,4-t h ia d ia zo l-2-y l]-b e n za -
m id e (5n ). 2-Amino-5-benzylsulfanyl-1,3,4,thiadiazole (3d )
(0.2 mol, 26.62 g) was dissolved in distilled water (25 mL) with
stirring, and pure benzoyl chloride was dropped into the
solution while mantaining the temperature at 0-5 °C. After
30 min, water (125 mL) was added, and a white precipitate
was formed. Filtration of the precipitate and recrystallization
from EtOH afforded compound 5n (yield 67%): mp 193-194
°C. 1H NMR (CDCl3) δ 4.4 (s, 2H, SCH2); 7.2-8.5 (m, 10H,
arom.); 12.8 (bs, 1H, NH). Anal. C16H13N3OS2 (327.42) C, H,
N.
P a ssive Avoid a n ce Test. The method followed that de-
scribed by Bammer et al.16 Briefly, rats were placed individu-
ally into the lit compartment of a two-compartment box. When
they crossed to the darker compartment they received a light
foot-shock (1 mA) and then were immediately removed (S1).
After 24 h they were again placed in the lighted compartment,
and the time interval before the rats crossed into the dark
compartment (step-through) was measured with a cutoff time
of 180 s (S2). An increase in the S2 step-through interval
compared with S1 would indicate that the rat remembered
having received a shock in the dark compartment 24 h
previously. A decrease in the S2 latency in rats that had
received the test compound compared to control group would
indicate an amnesia-inducing effect. The experiment was
performed using 10 rats per group. The test compound was
administered ip 1 h before S1 at 0.5, 1, or 2 mg/kg.
N-Met h yl-N-[5-m et h ylsu lfa n yl)-1,3,4-t h ia d ia zol-2-yl]-
a ceta m id e (6a ). To a solution of compound 5a (0.2 mol) in
DMF (50 mL) was added K2CO3 (1 g, 0.007 mol) under stirring,
and then methyl iodide (0.2 mol, 28.4 g) was added dropwise.
After 30 min, water (150 mL) was added, and a white
precipitate was formed. This was removed by filtration then
recrystallized from EtOH, affording compound 6a (yield
Sta tistica l An a lysis. Data from the despair test, the social
interaction test, passive avoidance, and motor activity were
1
41%): mp 72-74 °C. H NMR (CDCl3) δ 2.4 (s, 3H, COCH3);