Synthesis and anti-arrhythmic activity of some piperidine-based 1,3-thiazole, 1,3,4-thiadiazole, and 1,3-thiazolo[2,3-c]-1,2,4-triazole derivatives

Article abstract of DOI:10.1007/s00706-008-0053-y

The reaction of 1-[4-(piperidin-1-yl)benzylidene]thiosemicarbazide with hydrazonoyl chlorides afforded 1,3-thiazole derivatives. Cyclization of two compounds of the latter 1,3-thiazole by means of bromine in the presence of sodium acetate at room temperature gave 1,3-thiazolo[2,3-c]-1,2,4-triazole derivatives. The reaction of 2-cyano-3-(4-piperidin-1-ylphenyl)prop-2- enethioamide with hydrazonoyl chlorides under reflux in ethanol in the presence of triethylamine yielded 1,3-thiazoles. Treatment of 3-oxo-3-(piperidin-1-yl) propanenitrile with phenyl isothiocyanate in DMF, in the presence of KOH, at ambient temperature, resulted in the formation of 3-anilino-3-mercapto-2- (piperidin-1-ylcarbonyl)acrylonitrile which was reacted with hydrazonoyl chlorides to yield the corresponding 1,3,4-thiadiazole derivatives. Some of the newly synthesized compounds had significant anti-arrhythmic activity.

Full text of DOI:10.1007/s00706-008-0053-y

Monatsh Chem (2009) 140:431–437
DOI 10.1007/s00706-008-0053-y
ORIGINAL PAPER
Synthesis and anti-arrhythmic activity of some piperidine-based
1,3-thiazole, 1,3,4-thiadiazole, and 1,3-thiazolo[2,3-c]-1,2,4-
triazole derivatives
Hatem A. Abdel-Aziz Æ Bakr F. Abdel-Wahab Æ
Marwa A. M. Sh. El-Sharief Æ Mohamed M. Abdulla
Received: 29 July 2008 / Accepted: 3 August 2008 / Published online: 30 September 2008
ꢀ Springer-Verlag 2008
Abstract Thereactionof1-[4-(piperidin-1-yl)benzylidene]
thiosemicarbazide with hydrazonoyl chlorides afforded
1,3-thiazole derivatives. Cyclization of two compounds
of the latter 1,3-thiazole by means of bromine in the pres-
ence of sodium acetate at room temperature gave 1,3-
thiazolo[2,3-c]-1,2,4-triazole derivatives. The reaction of
2-cyano-3-(4-piperidin-1-ylphenyl)prop-2-enethioamide with
hydrazonoyl chlorides under reflux in ethanol in the presence
of triethylamine yielded 1,3-thiazoles. Treatment of 3-oxo-
3-(piperidin-1-yl)propanenitrile with phenyl isothiocyanate
in DMF, in the presence of KOH, at ambient temperature,
resulted in the formation of 3-anilino-3-mercapto-2-(piper-
idin-1-ylcarbonyl)acrylonitrile which was reacted with
hydrazonoyl chlorides to yield the corresponding 1,3,4-
thiadiazole derivatives. Some of the newly synthesized
compounds had significant anti-arrhythmic activity.
heterocycles had antihypertensive [1], antibacterial [2–4],
antifungal [5], and anti-arrhythmic [6] activities. On the
other hand, piperidines are an important class of hetero-
cycles found in numerous natural products and medicinal
structures [7], such as raloxifene [8] and thioridazine [9].
The piperidine moiety is also part of the well known
vasodilator minoxidil (Fig. 1), which is used to treat high
blood pressure and androgenetic alopecia in men [10].
Furthermore, 1,3-thiazole has interesting pharmacological
properties [11] and is a key structural component of several
drugs. For example, clomethiazole (Fig. 1) is a potent
sedative and hypnotic drug [12] containing the 1,3-thiazole
moiety.
Moreover, some 1,3,4-thiadiazole derivatives are highly
potent inhibitors of HIV-1 [13] and useful as anti-inflam-
matory agents [14]. In addition, 1,3,4-thiadiazole is a
common structural feature in many biologically active
molecules, for example methazolamide (Fig. 1), which is
used clinically in the treatment of some forms of epilepsy
[15]. In the light of previous information, we wish to report
herein the utility of 4-piperidin-1-ylbenzaldehyde (1) and
3-oxo-3-(piperidin-1-yl)propanenitrile (11) in the synthesis
of some piperidine-based polyfunctional 1,3-thiazole,
1,3,4-thiadiazole, and 1,3-thiazolo[2,3-c]-1,2,4-triazole
derivatives to evaluate their anti-arrhythmic activity.
Keywords Heterocycles Á Cyclizations Á 1,3-Thiazole Á
1,3,4-Thiadiazole Á Anti-arrhythmic activity
Introduction
In the course of our research efforts towards the prepara-
tion of new biologically active heterocycles [1–6]
specifically 1,3-thiazoles [1] and 1,3,4-thiadiazoles [2], we
have reported that some of the newly synthesized
Results and discussion
H. A. Abdel-Aziz Á B. F. Abdel-Wahab Á
M. A. M. Sh. El-Sharief (&)
Chemistry
Applied Organic Chemistry Department,
National Research Centre, Dokki, Cairo, Egypt
e-mail: marwaelsharif@yahoo.com
4-Piperidin-1-ylbenzaldehyde (1) was prepared by reaction
of 4-fluorobenzaldehyde and piperidine in DMSO, in the
presence of K2CO3 [16]. The reaction of the latter aldehyde
with thiosemicarbazide in ethanol under reflux afforded
M. M. Abdulla
Research Units, Hi-Care Pharmaceutical Co., Cairo, Egypt
123

432
H. A. Abdel-Aziz et al.
treatment with bromine in acetic acid, in the presence of
sodium acetate, at room temperature, formed the non-iso-
lable intermediate hydrazonoyl bromides 6a and 6b, which
underwent in-situ dehydrobromination under reaction con-
ditions to give the corresponding 1,3-thiazolo[2,3-c]-1,2,4-
triazole derivatives 8a and 8b as end products (Scheme 1).
Next, the catalytic condensation reaction of 4-piperi-
din-1-ylbenzaldehyde (1) with 2-cyanoethanethioamide
afforded 2-cyano-3-(4-piperidin-1-ylphenyl)prop-2-enethi-
oamide (9) in moderate yield by use of either potassium
hydroxide at ambient temperature or piperidine in ethanol
under reflux. The IR spectrum of compound 9 exhibited
characteristic broad amino bands at 3,362 and 3,272 cm-1
NH2
N O
NH2
Me
(CH2)2 Cl
N
N
N
S
Clomethiazole
Minixodil
Me
N
N
N R
COMe
H2N-SO2
N
S
1, R= C6H4-CHO
11, R= -COCH2CN
Methazolamide
while the sharp nitrile band was observed at 2,207 cm-1
.
1
Fig. 1 Structures of some compounds mentioned in the ‘‘Introduction’’
Its H NMR spectrum contained a D2O-exchangeable sig-
nal of the amino function at 9.15 ppm and the singlet signal
of an olefinic proton at 8.03 ppm, in addition to the signals
of piperidine protons in the regions d 1.57–1.60 (6H) and d
3.44–3.47 (4H) ppm. Also it showed the two doublets of
the A2B2 system for the p-substituted benzene ring at 7.03
and 7.86 ppm with J = 9.0 Hz. Treatment of 2-cyano-3-(4-
piperidin-1-ylphenyl)prop-2-enethioamide (9) with the
hydrazonoyl chlorides 3a–3c in ethanol under reflux, in the
presence of triethylamine, afforded the corresponding 1,3-
thiazole derivatives 10a–10c (Scheme 1). The IR spectra of
10a–10c showed, in each case, the sharp absorption band
near 2,200 cm-1 of the nitrile function, and their mass
spectra revealed, in each case, a peak corresponding to
their molecular ion.
1-[4-(piperidin-1-yl)benzylidene]thiosemicarbazide (2)
[17]. Compound 2 reacted with hydrazonoyl chloride 3a–3d
in ethanol under reflux, in the presence of a catalytic amount
of triethylamine, to yield products formulated as 5a–5d
through the non-isolable intermediate 4a–4d (Scheme 1).
The IR spectra of the isolated compounds revealed, in each
case, an absorption band of an NH function near 2,233–
1
3,219 cm-1 and their H NMR spectra contained, in each
case, a singlet in the region d 8.47–8.68 ppm due to the
–CH=N– proton, in addition to the D2O-exchangeable sig-
nal of NH protons in the region d 10.32–10.64 ppm. 1,5
Electrocyclization [18, 19] of hydrazone 5c or 5d by
Scheme 1
Cl
H
S
O
Me
N
S
N
Ar
NH2
NH2
Me
H2N
N
O
N
R
S
3a-3d
H
H2N
N
H
2
R-CHO
1
HN N
Ar
N N
TEA
R
4a-4d
S
- H2O
CN
KOH
H2N
R =
N
Me
N
Me
S
N
R
N
N
Ar
N
10 Ar
N
3a-3c
N
S
CN
R
CN
Ar
H
Ph
H2N
a
b
c
N
S
TEA
5a-5d
4-MeC6H4
4-ClC6H4
10a-10c
R
Ar
Ph
3-5
a
9
4-MeC6H4
4-ClC6H4
b
c
Br2/AcONa
4-NH2SO2C6H4
d
R
Me
N
Me
Me
N
NH
N
N
N
- HBr
R
N
N
R
N
N
N
Ar
Ar
N
N
Ar
N
S
S
N
H
S
Br
Br
8a-8b
6a-6b
7a-7b
8 Ar
4-ClC6H4
4-NH2SO2C6H4
a
b
123

Synthesis and anti-arrhythmic activity of some piperidine-based 1,3-thiazole derivatives
433
Pharmacological screening
The reaction of 3-oxo-3-(piperidin-1-yl)propanenitrile
(11) [20] with phenyl isothiocyanate at ambient tempera-
ture in dimethylformamide, in the presence of potassium
hydroxide, provided the non-isolable potassium salt 12.
Subsequent addition of the appropriate hydrazonoyl chlo-
ride 3a–3d yielded the corresponding 1,3,4-thiadiazole
derivatives 15a–15d (Scheme 2). Scheme 2 depicts the
possible structures proposed for the reaction products.
However, elemental analysis and spectral data of the
reaction products supported the 1,3,4-thiadiazole structure
15a–15d. These results indicate that the reaction of the
potassium salt 12 with hydrazonoyl chloride 3a–3d pro-
ceeds in each case, through the non-isolable intermediate
14a–14d which cyclized by loss of an aniline molecule to
form the isolable final product 1,3,4-thiadiazole derivatives
15a–15d [2].
Procaine amide, 5 mg/kg iv, and lidocaine, 5 mg/kg iv,
led to an increase in LD100 by 65%, which corresponds
to a LD100 of approximately 9 lg/100 mg. Table 1
shows compounds 2, 5a–5d, 9, and 10a–10c had no
Table 1 Anti-arrhythmic activity of the synthesized compounds
(5 mg/kg)
Compound
Percentage increase (LD100/%)
2
No effect
No effect
No effect
No effect
No effect
No effect
No effect
No effect
No effect
No effect
No effect
38 0.11
72 0.11
74 0.11
79 0.22
66 0.21
5a
5b
5c
5d
On the other hand, the potassium salt 12 could be con-
verted into 3-anilino-3-mercapto-2-(piperidin-1-ylcarbonyl)
acrylonitrile (13) upon neutralization with dilute hydro-
chloric acid (Scheme 2). The reaction of compound 13
with hydrazonoyl chloride 3a–3d in ethanol under reflux,
in the presence of catalytic amount of triethylamine,
resulted in the formation of the products identical in all
respects with those obtained from the method described
above. The IR spectra of compounds 15a–15d showed, in
each case, the appearance of two carbonyl absorption bands
in the region 1,741–1,630 cm-1 in addition to a charac-
teristic nitrile absorption band in the region 2,201–
2,190 cm-1. Their mass spectra revealed, in each case, a
peak corresponding to their molecular ion.
8a
8b
9
10a
10b
10c
13
15a
15b
15c
15d
All data were significantly different from the normal control value at
P B 0.05
Scheme 2
O
O
O
CN
SH
CN
PhNCS
CN
HCl
N
N
N
KOH
Ph N
Ph N
H
S K
11
H
13
12
Cl
H
3a-3d
TEA
Me
O
N
O
N
Ar
CN
S
O
N
3a-3d
Me
Ph N
H
N NH
..
Ar
15
a
Ar
Ph
14a-14d
4-MeC6H4
4-ClC6H4
4-NH2SO2C6H4
b
- H2O
- PhNH2
c
d
O
N
O
N
CN
N
CN
S
N
Ph
S
Ar
N
N
N
Me
Me
Ar
16a-16d
O
15a-15d
123

434
H. A. Abdel-Aziz et al.
1-[4-(Piperidin-1-yl)benzylidene]thiosemicarbazide (2)
mp = 105–106 ꢁC [Lit. mp = 105–106 ꢁC] [17]; the IR,
mass, and H NMR spectra of compound 2 were found to
Table 2 Acute toxicity (LD50) of compounds 13 and 15a–15d
Compound
LD50/mg kg-1
1
13
898.56 3.67
578.33 2.29
897.89 3.35
654.11 1.18
675.56 2.44
be identical with those described in Ref. [17].
15a
15b
15c
15d
General procedure for reaction of thiosemicarbazone 2
with hydrazonoyl chlorides 3a–3d
To 2.7 g compound 2 (10 mmol) dissolved in 50 cm3
absolute ethanol, the appropriate hydrazonoyl chloride 3a–
3d (10 mmol) and 0.5 cm3 triethylamine were added. The
reaction mixture was heated under reflux for 2 h. The solid
formed was isolated by filtration, washed with ethanol, and
recrystallized from EtOH–DMF to afford the correspond-
ing 1,3-thiazole derivatives 5a–5d.
All data were significantly different from the normal control value at
P B 0.05
anti-arrhythmic activity, whereas compound 13 had anti-
arrhythmic activity less than that of procaine amide or
lidocaine. Compounds 15a–15d were more active than
procaine amide or lidocaine.
4-Methyl-2-{[2-(4-(piperidin-1-yl)benzylidene)
hydrazino]}-5-Phenylazo-1,3-thiazole (5a, C22H24N6S)
Structure–activity relationship
mp 215–217 ꢁC; yield: 2.83 g (70%) starting from 1.97 g
(10 mmol) 3a; IR (KBr): m = 3,219 (NH), 1,604 (C=N)
ꢀ
1,3,4-Thiadiazole and piperidine moieties are essential for
anti-arrhythmic activity in 15a–15d. The chlorinated 1,3,4-
thiadiazole derivative 15c had a higher anti-arrhythmic
effect than the other derivatives.
cm-1; 1H NMR (300 MHz, DMSO-d6): d = 1.57–1.60 (m,
6H, piperidine), 2.57 (s, 3H, CH3), 3.32–3.35 (m,
4H, piperidine), 7.1–7.73 (m, 9H, Ar-H), 8.52 (s, 1H,
–CH=N–), 10.61 (s, D2O-exchangeable, 1H, NH) ppm; MS
(70 eV): m/z = 405 (M??1, 14.6), 404 (M?, 100), 281
(24.7), 125 (47.2).
Determination of acute toxicity (LD50)
The LD50 was determined by using rats. They were
injected with different, increasing doses of the synthesized
compounds. The dose that killed 50% of the animals was
calculated according to Austen and Brocklehurst [21]
(Table 2).
4-Methyl-2-{[2-(4-(piperidin-1-yl)benzylidene)
hydrazino]}-5-(4-tolylazo)-1,3-thiazole (5b, C23H26N6S)
mp 211–213 ꢁC; yield: 3.10 g (74%) starting from 2.11 g
ꢀ
(10 mmol) 3b; IR (KBr): m = 3,233 (NH), 1,601 (C=N)
cm-1; 1H NMR (300 MHz, DMSO-d6): d = 1.52–1.60 (m,
6H, piperidine), 2.22 (s, 3H, CH3), 2.52 (s, 3H, CH3), 3.31–
3.35 (m, 4H, piperidine), 7.00–7.68 (m, 8H, Ar-H), 8.68 (s,
1H, –CH=N–), 10.64 (s, D2O-exchangeable, 1H, NH) ppm;
MS (70 eV): m/z = 419 (M??1, 35.2), 418 (M?, 100),
221 (31.5).
Experimental
Chemistry
Melting points were taken on Electrothermal IA 9000
series digital melting point apparatus. Elemental analytical
data were obtained from the microanalytical unit, Cairo
University, Cairo, Egypt, their results were found to be in
good agreement with the calculated values. The IR spectra
(KBr) were recorded on a Shimadzu CVT-04 spectropho-
tometer. The NMR spectra were recorded on a Varian
4-Methyl-2-{[2-(4-(piperidin-1-yl)benzylidene)
hydrazino]}-5-[(4-chlorophenyl)azo]-1,3-thiazole
(5c, C22H23ClN6S)
mp 233–235 ꢁC; yield: 3.16 g (72%) starting from 2.13 g
ꢀ
(10 mmol) 3c; IR (KBr): m = 3,215 (NH), 1,600 (C=N)
cm-1; 1H NMR (300 MHz, DMSO-d6): d = 1.58–1.60 (m,
6H, piperidine), 2.57 (s, 3H, CH3), 3.33–3.35 (m,
4H, piperidine), 7.0–7.70 (m, 8H, Ar-H), 8.50 (s, 1H,
–CH=N–), 10.53 (s, D2O-exchangeable, 1H, NH) ppm; MS
(70 eV): m/z = 440 (M??2, 3.53), 439 (M??1, 16.85),
438 (M?, 35.73), 281 (100), 125 (30.58).
1
Mercury VX-300 NMR spectrometer. H spectra were run
at 300 MHz in deuterated dimethylsulfoxide (DMSO-d6).
Mass spectra were measured on a Varian MAT CH-5
spectrometer (70 eV). Hydrazonoyl chlorides 3a–3c [22]
and 3d [23] were prepared according to reported methods.
4-Methyl-2-{[2-(4-(piperidin-1-yl)benzylidene)
hydrazino]}-5-[(4-aminosulfonylphenyl)azo]-1,3-thiazole
(5d, C22H25N7O2S2)
4-Piperidin-1-ylbenzaldehyde (1)
mp = 65–66 ꢁC [Lit. mp = 62–64 ꢁC] [16]; the IR, mass,
and H NMR spectra of compound 1 were found to be
identical with those described in Ref. [16].
1
mp 290–292 ꢁC; yield: 3.77 g (78%) starting from 2.76 g
ꢀ
(10 mmol) 3d; IR (KBr): m = 3,307, 3,265, 3,183 (NH,
123

Synthesis and anti-arrhythmic activity of some piperidine-based 1,3-thiazole derivatives
1
435
NH2), 1,596 (C=N), 1,332, 1,151 (SO2) cm-1; H NMR
(300 MHz, DMSO-d6): d = 1.58–1.61 (m, 6H, piperidine),
2.58 (s, 3H, CH3), 3.31–3.34 (m, 4H, piperidine), 7.25 (d,
2H, J = 7.6 Hz, Ar-H), 7. 44 (d, 2H, J = 7.6 Hz, Ar-H),
7.58 (d, 2H, J = 8.7 Hz, Ar-H), 7.82 (d, 2H, J = 8.7 Hz,
Ar-H), 7.26 (s, D2O-exchangeable, 2H, NH2), 8.47 (s, 1H,
–CH=N–), 10.32 (s, D2O-exchangeable, 1H, NH) ppm; MS
(70 eV): m/z = 484 (M??1, 26.3), 483 (M?, 100).
recrystallized from ethanol to give compound 9 in 75%
yield.
Method B: To 1.89 g 4-piperidin-1-ylbenzaldehyde (1)
(10 mmol) and 1.0 g 2-cyanoethanethioamide (10 mmol)
in 30 cm3 absolute ethanol, 0.5 cm3 piperidine was added
and the reaction mixture was gently heated under reflux for
1 h, then left to cool. The solid formed was isolated by
filtration and crystallization from ethanol afforded a
product identical in all respects with that obtained from
method A, above, in 68% yield, mp 220–222 ꢁC; IR (KBr):
General procedure for synthesis of [1,3]thiazolo[2,
3-c][1,2,4]triazole derivatives 8a and 8b
1
m = 3,362, 3,272 (NH2), 2,207 (C:N) cm-1; H NMR
ꢀ
(300 MHz, DMSO-d6): d = 1.57–1.60 (m, 6H, piperidine),
3.44–3.47 (m, 4H, piperidine), 7.03 (d, 2H, J = 9.0 Hz, Ar-
H), 7.86 (d, 2H, J = 9.0 Hz, Ar-H), 8.03 (s, 1H, –CH=N–),
9.15 (s, D2O-exchangeable, 2H, NH2) ppm; MS (70 eV):
m/z = 272 (M??1, 23.7), 271 (M?, 100), 270 (80.3), 236
(41.9), 187 (14.6).
Bromine (0.44 g, 5.5 mmol) in 5 cm3 acetic acid was
added drop-wise to a stirred mixture of the appropriate
hydrazone 5c or 5d (5 mmol) and 1.2 g sodium acetate
(15 mmol) in 30 cm3 acetic acid. The reaction mixture was
stirred for 12 h at room temperature. The mixture was then
poured on to 250 cm3 ice-cold water. The solid that pre-
cipitated was isolated by filtration, washed with 50 cm3 5%
sodium bicarbonate solution and then with water, dried,
and crystallized from EtOH–DMF to give the 1,3-thiazol-
o[2,3-c]-1,2,4-triazole derivatives 8a and 8b.
Reaction of thioamide 9 with hydrazonoyl chlorides
10a–10c
This reaction was carried out by the same procedure
described for the synthesis of compounds 5a–5d using
thioamide 9 instead of thiosemicarbazone 2 and using
hydrazonoyl chlorides 3a–3c. After heating under reflux
for 5 h, the solid product was isolated by filtration and
recrystallized from aqueous DMF to afford the corre-
sponding 1,3-thiazole derivatives 10a–10c.
6-[(4-Chlorophenyl)azo]-5-methyl-3-[4-(piperidin-1-
yl)phenyl][1,3]thiazolo[2,3-c][1,2,4]triazole
(8a, C22H21ClN6S)
mp 209–211 ꢁC; yield: 1.3 g (60%) starting from 2.2 g
1
(5 mmol) 5c; IR (KBr): m = 1,609 (C=N) cm-1; H NMR
ꢀ
(300 MHz, DMSO-d6): d = 1.57–1.60 (m, 6H, piperidine),
2.58 (s, 3H, CH3), 3.31–3.36 (m, 4H, piperidine), 7.1–7.68
(m, 8H, Ar-H), ppm; MS (70 eV): m/z = 338 (M??2,
7.37), 437 (M??1, 14.22), 436 (M?, 100).
2-[4-Methyl-5-(phenylazo)-1,3-thiazol-2-yl]-3-[4-
(piperidin-1-yl)phenyl]acrylonitrile (10a, C24H23N5S)
mp 202–204 ꢁC; yield: 2.61 g (63%) starting from 1.97 g
ꢀ
(10 mmol) 3a; IR (KBr): m = 2,202 (C:N), 1,598 (C=N)
cm-1; 1H NMR (300 MHz, DMSO-d6): d = 1.56–1.60 (m,
6H, piperidine), 2.55 (s, 3H, CH3), 3.43–3.45 (m, 4H,
piperidine), 6.98–7.88 (m, 9H, Ar-H), 8.10 (s, 1H, –CH=N–)
ppm; MS (70 eV): m/z = 414 (M??1, 16.4), 413 (M?,
100), 235 (28.6), 187 (27.1).
6-[(4-Aminosulfonylphenyl)azo]-5-methyl-3-[4-(piperidin-
1-yl)phenyl][1,3]thiazolo[2,3-c][1,2,4]triazole
(8b, C22H23N7O2S2)
mp 215–217 ꢁC; yield: 1.54 g (64%) starting from 2.4 g
ꢀ
(5 mmol) 5d; IR (KBr): m = 3,414, 3,205 (NH2), 1,616
(C=N), 1,314, 1,160 (SO2) cm-1 1H NMR (300 MHz,
;
2-[4-Methyl-5-(4-tolylazo)-1,3-thiazol-2-yl]-3-[4-
(piperidin-1-yl)phenyl]acrylonitrile (10b, C25H25N5S)
mp 210–212 ꢁC; yield: 1.17 g (64%) starting from 2.11 g
DMSO-d6): d = 1.58–1.61 (m, 6H, piperidine), 2.58 (s,
3H, CH3), 3.31–3.34 (m, 4H, piperidine), 7.27 (d, 2H,
J = 7.0 Hz, Ar-H), 7. 40 (d, 2H, J = 7.3 Hz, Ar-H), 7.58 (d,
2H, J = 8.7 Hz, Ar-H), 7.81 (d, 2H, J = 9.0 Hz, Ar-H),
7.26 (s, D2O-exchangeable, 2H, NH2) ppm; MS (70 eV):
m/z = 482 (M??1, 8.6), 481 (M?, 100).
ꢀ
(10 mmol) 3b; IR (KBr): m = 2,199 (C:N), 1,600 (C=N)
cm-1; 1H NMR (300 MHz, DMSO-d6): d = 1.55–1.60 (m,
6H, piperidine), 2.51 (s, 3H, CH3), 2.55 (s, 3H, CH3), 3.42–
3.45 (m, 4H, piperidine), 7.01–7.83 (m, 8H, Ar-H), 8.10 (s,
1H, –CH=N–) ppm; MS (70 eV): m/z = 428 (M??1,
21.1), 427 (M?, 58.5), 226 (100), 196 (11.5).
2-Cyano-3-(4-piperidin-1-ylphenyl)prop-2-enethioamide
(9, C15H17N3S)
2-{4-Methyl-5-[4-chlorophenyl)azo]-1,3-thiazol-2-yl}-3-[4-
(piperidin-1-yl)phenyl]acrylonitrile (10c, C24H22ClN5S)
mp 238–240 ꢁC; yield: 1.17 g (60%) starting from 2.31 g
Method A: 4-Piperidin-1-ylbenzaldehyde (1) (1.89 g,
10 mmol) and 1.0 g 2-cyanoethanethioamide (10 mmol)
were dissolved in 30 cm3 ethanol. After the addition of
0.5 cm3 10% KOH solution, the mixture was set aside for
2 h. The orange crystals were isolated by filtration and
ꢀ
(10 mmol) 3c; IR (KBr): m = 2,202 (C:N), 1,603 (C=N)
cm-1
;
1H NMR (300 MHz, DMSO-d6): d = 1.54–1.60
123

436
H. A. Abdel-Aziz et al.
(m, 6H, piperidine), 2.54 (s, 3H, CH3), 3.42–3.45 (m,
4H, piperidine), 7.00–7.83 (m, 8H, Ar-H), 8.10 (s, 1H,
–CH=N–) ppm; MS (70 eV): m/z = 448 (M??2, 10.4),
447 (M??1, 13.5), 409 (M?, 100), 236 (54.8).
2-(5-Acetyl-3-phenyl-1,3,4-thiadiazol-2(3H)-ylidene)-3-
oxo-3-piperidin-1-ylpropanenitrile (15a, C18H18N4O2S)
mp 198–200 ꢁC; yield: 2.41 g (68%) starting from 1.97 g
(10 mmol) 3a; IR (KBr): ꢀm = 2,198 (C:N), 1,675, 1,628
1
(2C=O), 1,596 (C=N) cm-1; H NMR (300 MHz, DMSO-
3-Oxo-3-(piperidin-1-yl)propanenitrile (11)
d6): d = 2.35 (s, 3H, CH3), 1.47–1.49 (m, 6H, piperidine),
4.16–4.35 (m, 4H, piperidine), 6.50–7.72 (m, 5H, Ar-H)
ppm; MS (70 eV): m/z = 355 (M??1, 22.5), 354
(M?, 100).
mp = 88 ꢁC [Lit. mp = 87 ꢁC] [20]; the IR, mass, and 1H
NMR spectra of compound 11 were found to be identical
with those described in Ref. [20].
3-Anilino-3-mercapto-2-(piperidin-1-ylcarbonyl)
acrylonitrile (13, C15H17N3OS)
2-[5-Acetyl-3-(4-tolyl)-1,3,4-thiadiazol-2(3H)-ylidene]-3-
oxo-3-piperidin-1-ylpropanenitrile (15b, C19H20N4O2S)
mp 216–218 ꢁC; yield: 2.7 g (73%) starting from 2.11 g
To a stirred solution of 0.56 g potassium hydroxide
(10 mmol) in 20 cm3 dimethylformamide, 1.52 g 3-oxo-
3-(piperidin-1-yl)propanenitrile (11) (10 mmol) was added.
After stirring for 30 min, 1.35 g phenyl isothiocyanate
(10 mmol) was added to the resulting mixture and stirring
was continued for 3 h. The mixture was then poured on to
crushed ice and neutralized with hydrochloric acid. The
solid product that formed was isolated by filtration, washed
with water, dried, and finally crystallized from ethanol to
afford compound 13 as greenish yellow crystals in 78%
ꢀ
(10 mmol) 3b; IR (KBr): m = 2,190 (C:N), 1,666, 1,630
1
(2C=O), 1,596 (C=N) cm-1; H NMR (300 MHz, DMSO-
d6): d = 1.49–1.67 (m, 6H, piperidine), 2.47 (s, 3H, CH3),
2.33 (s, 3H, CH3), 4.11–4.36 (m, 4H, piperidine), 7.22 (d,
2H, J = 8.7 Hz, Ar-H), 7.94 (d, 2H, J = 9.0 Hz, Ar-H)
ppm; MS (70 eV): m/z = 368 (M?, 2.2), 261 (100), 208
(21.3), 132 (20.6), 106 (44.9).
2-[5-Acetyl-3-(4-chlorophenyl)-1,3,4-thiadiazol-2(3H)-
ylidene]-3-oxo-3-piperidin-1-ylpropanenitrile
(15c, C18H17ClN4O2S)
ꢀ
yield, mp 160–162 ꢁC; IR (KBr): m = 3,238 (NH), 2195
1
(C:N), 1634 (C=O) cm-1; H NMR (300 MHz, DMSO-
d6): d = 1.47–1.67 (m, 6H, piperidine), 4.12–4.36 (m, 4H,
piperidine), 6.50–7.78 (m, 5H, Ar-H), 11.95 (s, D2O-
exchangeable, 1H, NH), 12.71 (s, D2O-exchangeable, 1H,
SH) ppm; MS (70 eV): m/z = 288 (M??1, 20.7), 287
(M?, 27.8), 254 (32.3), 152 (100), 111 (18.2).
mp 250–252 ꢁC; yield: 2.72 g (70%) starting from 2.31 g
ꢀ
(10 mmol) 3c; IR (KBr): m = 2,192 (C:N), 1,679, 1,634
1
(2C=O), 1,601 (C=N) cm-1; H NMR (300 MHz, DMSO-
d6): d = 1.51 (m, 6H, piperidine), 1.64 (m, 4H, piperidine),
2.37 (s, 3H, CH3), 7.10 (d, 2H, J = 9.0 Hz, Ar-H), 7.73 (d,
2H, J = 9.0 Hz, Ar-H) ppm; MS (70 eV): m/z = 389
(M??1, 41.5), 388 (M?, 100), 311 (12.8), 249 (24.1).
Synthesis of 2-(5-acetyl-3-aryl-1,3,4-thiadiazol-2(3H)-
ylidene)-3-oxo-3-piperidin-1-ylpropanenitrile 15a–15d
2-[5-Acetyl-3-(4-aminosulfonylphenyl)-1,3,4-thiadiazol-
2(3H)-ylidene]-3-oxo-3-piperidin-1-ylpropanenitrile
(15d, C18H19N5O4S2)
Method A: To a stirred solution of 0.06 g potassium
hydroxide (1 mmol) in 20 cm3 dimethylformamide, 1.52 g
3-oxo-3-(piperidin-1-yl)propanenitrile (11) (10 mmol) was
added. After stirring for 30 min, 0.14 g phenyl isothiocya-
nate (1 mmol) was added to the resulting mixture. Stirring
was continued for 3 h then the appropriate hydrazonoyl
chloride 3a–3d (1 mmol) was added portion-wise over a
period of 30 min. When addition was complete, the reaction
mixture was stirred for 12 h while the hydrazonoyl chloride
dissolved and a yellowish colored product precipitated. The
solid product was isolated by filtration, washed with etha-
nol, and finally recrystallized from EtOH–DMF to afford
the corresponding 1,3,4-thiadiazole derivative 15a–15d.
Method B: To 0.29 g compound 13 (1 mmol) in 30 cm3
ethanol the appropriate hydrazonoyl chloride 3a–3d
(1 mmol) and 0.5 cm3 triethylamine were added. The
mixture was heated under reflux for 2 h, and the solid
formed was isolated by filtration, washed with water, and
dried. Crystallization from EtOH–DMF afforded com-
pounds 15a–15d.
mp 220–222 ꢁC; yield: 2.95 g (68%) starting from 2.78 g
ꢀ
(10 mmol) 3c; IR (KBr): m = 3,421, 3,210 (NH2), 2,192
(C:N), 1,741, 1,680 (2C=O), 1,597 (C=N), 1,420, 1,276
1
(SO2) cm-1; H NMR (300 MHz, DMSO-d6): d = 1.47–
1.56 (m, 6H, piperidine), 2.29 (s, 3H, CH3), 3.92–3.93 (m,
4H, piperidine), 7.63 (s, D2O-exchangeable, 2H, NH2),
7.66 (d, 2H, J = 8.7 Hz, Ar-H), 7.70 (d, 2H, J = 8.7 Hz,
Ar-H), ppm; MS (70 eV): m/z = 434 (M??1, 13.6), 433
(M?, 45.5), 339 (100), 285 (64.6).
Anti-arrhythmic activity [24–29]
The plant alkaloid aconitine persistently activates sodium
channels. Infusion of aconitine into anesthetized rats
causes ventricular arrhythmias. Drugs considered to have
anti-arrhythmic properties can be tested in aconitine-
intoxicated rats.
123

Synthesis and anti-arrhythmic activity of some piperidine-based 1,3-thiazole derivatives
437
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Male Ivanovas rats weighing 300–350 g were used. The
animals were anesthetized by intraperitoneal injection of
1.25 g/kg urethane, 5 mg/kg aconitine dissolved in 0.1 N
HNO3 was administered by continuous infusion into the
saphenous vein at 0.1 cm3/min, and the ECG in lead II was
recorded every 30 s. The test compound was injected iv at
a screening dose of 3 mg/kg 5 min before the start of
aconitine infusion. Twenty-four animals were used per
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Evaluation
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infusion) which induces:
•
•
•
ventricular extra systoles,
ventricular tachycardia,
ventricular fibrillation.
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123