Synthesis of some azoles incorporating a sulfonamide moiety as anticonvulsant agents

Article abstract of DOI:10.1002/ardp.201200014

Many derivatives of heterocyclic compounds containing a sulfonamide thiazole moiety were synthesized through the reaction of 2-(cyano or chloro)-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide with isocyanate followed by halogenated compounds, arylidene, 2

Full text of DOI:10.1002/ardp.201200014

Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
1
Full Paper
Synthesis of Some Azoles Incorporating a Sulfonamide
Moiety as Anticonvulsant Agents
Awatef A. Farag1,2, Safaa N. Abd-Alrahman2, Gihan F. Ahmed2, Ramy M. Ammar3,
Yousry A. Ammar4,5, and Samir Y. Abbas6
1 Faculty of Science, Chemistry Department, Al-Azhar University (Girls), Cairo, Egypt
2 Faculty of Education (Khourma), Chemistry Department, Taif University, Saudi Arabia
3 Faculty of Pharmacy, Pharmacology and Toxicology, Sinai University, Sina, Egypt
4 Faculty of Science, Chemistry Department, King Khaled University, Abha, Saudi Arabia
5 Faculty of Science, Chemistry Department, Al-Azhar University, Cairo, Egypt
6 National Research Centre, Organometallic and Organometalloid Chemistry Department, Dokki,
Cairo, Egypt
Many derivatives of heterocyclic compounds containing a sulfonamide thiazole moiety were
synthesized through the reaction of 2-(cyano or chloro)-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-
acetamide with isocyanate followed by halogenated compounds, arylidene, 2-hydroxy benzaldehydes,
active methylene compounds, and heterocyclic amines. The anticonvulsant activity for 15 of the
synthesized compounds was evaluated and 6 compounds showed protection against picrotoxin-
induced convulsion. 4-(6-Amino-3,5-dicyano-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-N-(thiazol-2-yl)-
benzenesulfonamide (11b) exhibited significant anticonvulsive effects, abolished the tonic extensor
phase and offered 100% protection.
Keywords: Acetamide / Anticonvulsant agents / Cynaoacetamide / Sulfathiazole / Sulfonamide / Thiazole
Received: January 10, 2012; Revised: April 20, 2012; Accepted: April 25, 2012
DOI 10.1002/ardp.201200014
Introduction
triazole anticonvulsant with broad-spectrum activity.
Loreclezole potentiates GABA-A receptor-mediated Clꢀ cur-
rents through a site present on the b2 and b3 (but not b1)
subunits of GABA-A receptors [4, 5]. Another structure among
the azoles that was studied for anticonvulsant activity is
the imidazole nucleus. Nafimidone and denzimole are the
examples of imidazole analogs that possess a profile of
activity similar to that of phenytoin or carbamazepine but
distinct from those of barbiturates or valproic acid [6–9]. In
addition, several thiazole derivatives possess important
pharmacological activities and therefore they are useful
materials in drug research. Since the past few decades, the
literature has been enriched with progressive findings about
the anticonvulsant activities of various substituted thiazole
derivatives [10, 11]. They are of interest as potential neuro-
protective agents [12, 13]. Sulfonamides were known to
inhibit carbonic anhydrase and they are the most important
class of carbonic anhydrase inhibitors [14]. Acetazolamide
and methazolamide are old members of this class, which
have shown anticonvulsant activity [15].
The improvement in the treatment of epilepsy over the past
decade is mainly associated with the development of new
antiepileptic drugs (AEDs), taking advantage of the pharma-
cophoric requirement specifically on a single target [1]. There
is currently a need for improved agents for the treatment of
seizure disorders, as there is a significant group of patients
who develop refractory epilepsy or are resistant to the avail-
able antiepileptic drugs. Moreover, the current drug therapy
is associated with adverse side effects such as drowsiness,
ataxia, gastrointestinal disturbance, gingival hyperplasia,
hirsutism, and megaloblastic anemia [2, 3].
One of the important core fragments of anticonvulsants is
defined by a nitrogen heteroatomic system (azoles). In recent
years, loreclezole has emerged as a structurally novel 1,2,4-
Correspondence: Dr. Samir Y. Abbas, National Research Centre,
Organometallic and Organometalloid Chemistry Department, Dokki, Cairo,
12622, Egypt.
E-mail: samiryoussef98@yahoo.com
Fax: þ202 33370931
In view of these observations, it was thought worthwhile to
synthesize some newer derivatives of sulfonamide thiazole
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2
A. A. Farag et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
and preliminarily evaluate their anticonvulsant properties
with a hope to get better anticonvulsant drugs without side
effects.
secondary amino group to the carbonyl group of chloroace-
tone to yield the cyclic product 5. Similarly, the novel thiazo-
lidinone 6 was synthesized from reaction of 2 with phenyl
isothiocyanate in the presence of potassium hydroxide
followed by in situ heterocyclization of the resulting adduct
with ethyl chloroacetate. In addition, treatment of the potass-
ium salt 3 with chloroacetonitrile furnished the correspond-
ing 4-amino-thiazolidine derivative 7. Elemental analysis and
spectroscopic data accorded well with the proposed structures
(Scheme 1). When cyanoacetanilide 2 was left to react with
phenyl isothiocyanate in the presence of (CH3)2SO4 in alkaline
medium, the corresponding acrylamide 8 was afforded.
Cyclocondensation of the acrylamide 8 with hydrazine deriva-
tives in ethanol under reflux furnished the corresponding
5-aminopyrazole derivatives 9a and b. Presumably, formation
of the aminopyrazole 9 is assumed to proceed via Michael
addition of the hydrazino amino group to the ethylenic bond
side chain in 8 with elimination of the SCH3 group, followed
by intramolecular cyclization at the cyano group.
Results and discussion
Chemistry
One reason of our interest in amines is related to the con-
version possibility of their NH2 group to the NHCOCH2CN
group which leads to cyanoacetanilides with further useful
functionalization at this position [16, 17]. Cyanoacetanilide 2
was synthesized by thermal fusion of sulfathiazole (1) with
ethyl cyanoacetate. The reactivity of cyanoacetanilide 2 toward
isothiocyanate was investigated. Thus, when 2 was left to react
with phenyl isothiocyanate in the presence of potassium
hydroxide at room temperature and then chloroacetone
was added, the corresponding 4-methylthiazole derivative 5
was obtained as a final product in good yield without afford-
ing the expected thiophene structure of type 4. Probably the
reaction mechanism is assumed to proceed via initial alkyl-
ation for the intermediate potassium salt 3 followed by in situ
heterocyclization through nucleophilic addition of the
It was of interest to synthesize some new pyridines carry-
ing a thiazolyl and sulfonamido moieties for evaluation as
potential anticonvulsant agents. Thus, condensation of the
COCH3
H2N
O
S
O
O
S
O
N
S
N
S
H
N
H
S
H
N
N
NH2
O
NHPh
CH3
O
S
Cl
1
4
5
H3C
O
O
S
O
N
CN
N
S
Ph
H
N
O
O
S
O
N
S
NHCOCH2CN
H
N
H
N
CN
2
O
S
KOH /
O
N
PhNCS
KS
O
NHPh
CN
Ph
O
S
O
O
S
O
N
S
N
S
H
N
ClCH2COOC2H5
H
N
H
N
H
N
CN
O
3
8
6
NH2
(CH3)2SO4
H3CS
NHPh
CN
S
N
O
H
N
S
Ph
H
O
S
O
N
S
ClCH2CN
H
N
H
N
N
S
N
O
CN
O
7
O
PhHN
N
O
S
O
N
S
H
N
H
N
Ar
ArNHNH2
N
NH2
O
9a Ar = H 9b Ar = Ph
Scheme 1.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
Synthesis of Some Biologically Active Compounds
3
cyanoacetanilide 2 with aromatic aldehydes namely benzal-
dehyde, p-anisaldehyde, and p-nitrobenzaldehyde furnished
the corresponding arylidene derivatives 10a–c. Pyridin-2(1H)-
ones 11a–c were obtained through the reaction of the aryli-
dene derivatives 10a–c with malononitrile in ethanol con-
taining piperidine as catalyst. One-pot reactions of the
cyanoacetanilide derivative 2 with malononitrile and the
same aldehydes (1:1:1 molar ratio) at reflux temperature in
the presence of piperidine afforded the 2-pyridone deriva-
tives 11a–c. On the other hand, the 2-pyridone derivatives
11a–c were also obtained via reaction of cyanoacetanilide 2
with arylidene malononitrile upon heating under reflux in
the presence of piperidine as catalyst. In addition, when the
cyanoacetanilide 2 was thermally fused with acetylacetone or
benzoylacetone in the presence of a catalytic amount of
piperidine, the cyclocondensation reaction occurred and
the 2-pyridinone derivatives 12a and b were smoothly
afforded. It can be postulated that the reaction initially
proceeds via a nucleophilic attack to form the Michael adduct
which in turn cyclized and eliminated two water molecules,
affording the final products (Scheme 2).
2-iminochromene 15 with high yield. Chromen-2-one 16
was synthesized via interaction of 2 with 7-hydroxy-5-meth-
oxycoumarin-6-carboxaldehyde in the presence of AcOH/
AcONa. Compound 16 was also obtained upon treatment
of compound 15 with ethanol containing hydrochloric acid
(Scheme 3).
The present work was extended to synthesize some pyrrole
derivatives. The starting material 2-chloroacetamide deriva-
tive 17 was synthesized from the reaction of sulfathiazole (1)
with chloroacetyl chloride in dioxane containing a few drops
of triethylamine. The reactivity of compound 17 toward
active methylene compounds was investigated. In order to
optimize the reaction conditions, ethyl cyanoacetate and 17
were taken as model reactants. Thus, when compound 17 was
heated under reflux with ethyl cyanoacetate in DMF contain-
ing anhydrous potassium carbonate, two possible structures
18 and 20 can be formed. Structure 18 was readily excluded
on the basis of analytical and spectral data. The formation of
compound 20 can be explained on the basis of initial alkyl-
ation of ethyl cyanoacetate to give the intermediate dihydro-
pyrroles 19 followed by intramolecular cyclization which
oxidized under the reaction conditions to yield the novel
pyrrole derivative 20 (Scheme 4). In a similar manner, ethyl
acetoacetate and diethyl malonate were reacted with com-
pound 17 to yield the pyrrole derivatives 21a and b.
The present work describes the preparation of sulfonamide
thiazole containing a chromene nucleus. Cyclocondensation
of cyanoacetanilide 2 with salicylaldehyde in ethanolic
ammonium acetate afforded 2-iminochromene 13 in high
yield. On the other hand, by interaction of 2 with salicylal-
dehyde in the presence of AcOH/AcONa, chromenone 14 was
obtained in reasonably good yield. The structure of com-
pound 14 was further confirmed through its synthesis upon
hydrolysis of 13 with ethanolic HCl. Similarly, compound 2
was allowed to react with 7-hydroxy-5-methoxycoumarin-6-
carboxaldehyde in ethanolic ammonium acetate giving
In addition, 2-chloroacetamide 17 was reacted with
ammonium thiocyanate to give the intermediate 2-thiocya-
natoacetamide 22 which cyclized to the corresponding 2-
imino-4-thiazolidinone 23. Finally, our investigation was
extended to include the reactivity of compound 17 toward
amino compounds as nucleophilic reagents. Thus, the novel
acetanilides 24–27 were obtained when compound 17 was
O
CN
ArCHO
O
S
O
N
S
H
N
NH
Ar
_
10a c
O
S
O
N
S
H
N
NHCOCH2CN
NC CN
NC CN
O
N
CN
CN
2
O
S
N
H
Ar
H
O
O
N
Ar
ArCHO
+
or NC CN
S
R
CH3
O
10,11a
10,11b
10,11c
, Ar = C6H5
_
H2N
11a c
, Ar = C6H4OCH3
, Ar = C6H4NO2
CN
OH
CH3
CN
H
N
O
O
CN
CH3
OH
O
S
O
O
N
S
O
S
O
_
H
N
O
S
O
N
N
H
H2O
H
NH
O
N
N
CH3
N
S
H
S
R
OH
R
R
12a
12b
, R = C6H5
, R = CH3
Scheme 2.
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A. A. Farag et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
O
O
H
N
S
CH3COONH4
AcOH/AcONa
N
S
N
H
CHO
OH
O
13
HCl
O
HN
O
S
O
N
H
N
NHCOCH2CN
S
O
O
2
O
S
O
N
H
N
N
H
S
O
OCH3
O
14
OHC
HO
O
O
O
CH3
OCH3
O
S
O
N
S
CH3COONH4
H
N
N
H
O
O
CH3
HN
AcOH/AcONa
15
O
O
O
OCH3
O
S
O
N
S
H
N
HCl
N
H
O
O
CH3
16
Scheme 3.
heated under reflux with some heterocyclic amines in DMF
containing anhydrous potassium carbonate (Scheme 5).
latency of death were analyzed using the paired Student’s
t-test. A p-value of <0.05 was considered as statistically sig-
nificant. Anticonvulsant activity was screened for some
selected synthesized compounds, i.e. 2, 6, 9a, 10c, 11b, 11c,
12a, 13, 15, 16, 21a, 23, 24, 26, and 27 (15 compounds).
Anticonvulsant activity
Anticonvulsant activity was determined according to the
picrotoxin (PIC) method [18–20]. The following parameters
were recorded during these sessions: latency, status of animal
after 30 min, the number of protected animals, and the effect
of each compound on the mortality rate was calculated. The
results of onset of seizures in PIC-induced seizures and
Effect of synthesized compounds on picrotoxin induced
convulsion
PIC (10 mg/kg; i.p.) produced generalized seizure in all
groups. Only six compounds showed protection against
O
S
O
1
N
S
H
N
NH2
O
COOC2H5
NH2
O
S
O
N
S
ClCH2COCl
H
N
N
CN
O
CN
18
O
O
H
O
S
O
N
S
N
S
H
N
COOC2H5
N
S
O
NHCOCH2Cl
NH
O
OC2H5
17
19
O
O
S
O
N
S
H
N
N
O
R
CN
O
H
20
N
S
O
COOC2H5
N
S
O
N
R
O
21a R = COCH3
21b R = COOC2H5
Scheme 4.
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
Synthesis of Some Biologically Active Compounds
5
O
O
O
S
O
O
S
O
S
N
S
N
S
H
N
H
N
N
NH CN
S
23
22
HN
S
NH4SCN
NH2
O
S
O
N
S
H
N
H
N
N
S
N
N
H
O
O
O
H
24
25
N
S
N
S
NHCOCH2Cl
H3C
S
N
O
NH2
17
O
S
O
N
S
H
H
CH3
S
N
N
N
N
H
H
N
NH2
N
O
S
O
N
H
H
N
N
N
N
H
S
N
H
CH3
O
26
H2N
N
O
N
Ph
CH3
O
S
O
N
H
H
CH3
CH3
N
N
N
S
H
O
N
27
O
N
Ph
Scheme 5.
Table 1. Effect of 15 newly synthesized compounds on PIC-induced convulsion in mice.
Compd.
no.
Latency
Death
Onset of
convulsion
(min)
No. of animals
convulsed/no. used
Protected
animals (%)
Death
latency (min)
Mortality
(%)
Control
2
6
9a
10c
11b
11c
12a
13
15
16
21a
23
24
26
27
6.98 ꢁ 0.90
9.25 ꢁ 1.63
8.15 ꢁ 0.58
6.25 ꢁ 0.87
11.4 ꢁ 1.22
–
5.15 ꢁ 0.33
6.97 ꢁ 0.53
6.54 ꢁ 0.50
6.06 ꢁ 0.48
5.50 ꢁ 0.23
7.15 ꢁ 1.46
5.26 ꢁ 0.04
11.3 ꢁ 0.88
7.34 ꢁ 1.16
6.23 ꢁ 1.09
15 ꢁ 0.90
6/6
6/6
6/6
5/6
3/6
0/6
5/6
6/6
6/6
6/6
6/6
6/6
4/6
3/6
6/6
6/6
1/6
0.00
0.00
0.00
16.67
50.00
100.00
16.67
0.00
0.00
0.00
0.00
0.00
33.33
50.00
0.00
0.00
83.33
11.9 ꢁ 1.19
14.8 ꢁ 2.48
12.7 ꢁ 1.04
10.8 ꢁ 1.22
19.5 ꢁ 3.71
–
9.2 ꢁ 0.89
13.3 ꢁ 0.62
11.7 ꢁ 1.88
11.8 ꢁ 2.90
9.6 ꢁ 0.60
10.3 ꢁ 0.42
8.3 ꢁ 0.78
20 ꢁ 1.34
12.5 ꢁ 1.18
11 ꢁ 1.87
–
100
100
100
83.3
50
0
83.3
100
100
100
100
100
66.7
50
100
100
0
Phenobarbital
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6
A. A. Farag et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
linked to GABA-A receptors, thus preventing the entry of
chloride ions into the brain. This process will, in turn, inhibit
GABA neurotransmission and activity in the brain.
Phenobarbital is believed to enhance GABAergic neurotrans-
mission by increasing the chloride ion flux through the
chloride-ion channels at GABA-A receptor sites. This hypothesis
may explain the observed protective effects and/or antagonistic
actions, of phenobarbital against PIC-induced seizures in the
mice used. So, the obtained results suggest that the six com-
pounds that showed protection against PIC-induced convulsion
may act by facilitating GABAergic transmission.
Experimental
Figure 1. Protection against PIC-induced convulsion by the synthe-
All melting points were determined on an electrothermal
Gallenkamp apparatus and are uncorrected. The IR spectra were
measured on a Mattson 5000 FTIR spectrometer in potassium
bromide discs. The NMR spectra were recorded in DMSO-d6 on a
Bruker WP spectrometer (500 MHz) and the chemical shifts d
downfield from TMS as an internal standard. The mass spectra
were recorded on a Finnegan MAT 212 instrument, the ionizing
voltage was 70 eV, at the Faculty of Science, Cairo University.
Elemental analyses were carried out by the Microanalytical Unit
of the Faculty of Science, Cairo University.
sized compounds and by phenobarbital as standard drug.
PIC-induced convulsion. Compound 11b exhibited significant
anticonvulsive effect and abolished the tonic extensor phase
and offered 100% protection. Compounds 10c and 24 not only
showed 50% protection but also both compounds signifi-
cantly delayed the onset of convulsion in the remaining
animals. Compound 23 showed 33.33% protection while
compounds 9a and 11c showed 16.67% protection.
Phenobarbital (reference drug) showed 83.33% protection
against PIC-induced convulsion and delayed the onset of
convulsion in the remaining animals (Table 1). The compari-
son between our potent synthesized compounds and pheno-
barbital as standard drug is presented in Fig. 1
2-Cyano-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-
acetamide (2)
Sulfathiazole (1) (0.01 mol) was fused with excess ethyl cyano-
acetate around 2108C in an oil bath for 40 min. Excess ethyl
cyanoacetate was evaporated under vacuum. The solid product
remained was triturated with ethanol (20 mL) then filtered.
The solid product obtained was filtered and crystallized from
ethanol to give 2 as pale yellow crystals, yield 80%; m.p. 140–
Effect on death latency and mortality rate
1418C; IR: n/cmꢀ1: 3279, 3204 (2NH), 2234 (CN), 1675 (C O), 1355,
–
The same compounds showed an effect on the mortality rate of
the treated animals. PIC showed 100% death rate. Compound
11b successfully protected all mice from death and showed 0%
death rate. Compounds 10c and 24 were able to protect 50% of
the animals from death and showed 50% death rate, also
compound 24 significantly delayed the death latency in the
remaining animals while compound 10c delayed the latency;
but this delay did not reach statistical significance. Compound
23 showed 66.67% death rate while compounds 9a and 11c
showed 83.33% death rate. Phenobarbital (reference drug)
protected 100% of the animals from death (Table 1).
–
1150 (SO2); 1H NMR: d/ppm: 4.15 (s, 2H, CH2), 6.82 (d, 1H,
J ¼ 4.5 Hz, C5-H thiazole), 7.25 (d, 1H, J ¼ 4.5 Hz, C4-H thiazole),
7.68 (d, 2H, J ¼ 6.5 Hz, Ar-H), 7.77 (d, 2H, J ¼ 6.5 Hz, Ar-H), 10.64,
12.12 (2s, 2H, 2NH; cancelled with D2O); 13C NMR: 24.46 (CH2),
108.12 137.06, 168.73 (3C thiazole), 115.66 (CN), 118.75, 118.83,
–
124.35, 124.35, 127.35, 141.42 (6C-Ar), 161.63 (C O); Anal. Calcd.
–
for C12H10N4O3S2 (322.36): C, 44.71; H, 3.13; N, 17.38. Found: C,
44.50; H, 3.20; N, 17.20%.
Synthesis of thiazole derivatives 5–7
To a stirred suspension of finely powdered potassium hydroxide
(0.01 mol) in dry DMF (10 mL), cyanoacetanilide 2 (0.01 mol), and
(0.01 mol) phenyl isothiocyanate were added slowly. After com-
plete addition, stirring of the reaction mixture was continued for
an additional 5 h to give the potassium salt 3. Then chloroace-
tone, ethyl chloroacetate, or chloroacetonitrile (0.01 mol) was
added to the mixture and the reaction mixture was stirred for
2 h. The reaction mixture was poured into crushed ice. The
resulting precipitate was filtrated off, dried, and crystallized
from ethanol to give 5–7, respectively.
The present study examined the anticonvulsant effects of
newly synthesized compounds using the PIC model. PIC, a
potent, selective GABA-A receptor antagonist, produces seiz-
ures by blocking the effect of GABA at central GABA-A recep-
tors, which have been associated with epilepsy. Postsynaptic
GABA-A receptors are functionally linked to benzodiazepine
receptors, barbiturate receptors, and chloride ion channels to
form the GABA–chloride ionophore complex, which is intimately
involved in the modulation of GABAergic neurotransmission
epilepsy. According to Nicoll, PIC, a GABA-A receptor antagon-
ist, produces seizures by blocking the chloride-ion channels
2-Cyano-2-(4-methyl-3-phenylthiazol-2(3H)-ylidene)-
N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (5)
Yield 75%; m.p. 245–2468C; IR: n/cmꢀ1: 3289, 3108 (2NH), 2200
1
(CN), 1673 (C O), 1354, 1147 (SO ); H NMR: d/ppm: 1.56 (s, 3H,
–
–
2
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
Synthesis of Some Biologically Active Compounds
7
CH3) 4.87 (s, 1H, C5-H thiazole), 6.78–7.87 (m, 11H, Ar-H), 9.12,
11.23 (2s, 2H, 2NH; cancelled with D2O); 13C NMR: 19.14 (CH3),
78.38, 102.32, 108.45, 115.12, 116.56, 117.34, 119.43, 120.23,
120.32, 125.56, 125.76, 128.56, 129.23, 129.29, 137.34, 141.56,
142.23, 145.45, 163.23, 168.12, 169.34 (21C); Anal. Calcd.
for C22H17N5O3S3 (495.60): C, 53.32; H, 3.46; N, 14.13. Found:
C, 53.20; H, 3.60; N, 14.00%.
(455.51): C, 50.10; H, 3.76; N, 21.52. Found: C, 50.20; H, 3.80;
N, 21.40%.
5-Amino-1-phenyl-3-(phenylamino)-N-(4-(N-thiazol-2-
ylsulfamoyl)phenyl)-1H-pyrazole-4-carboxamide (9b)
Yield 77%; m.p. 223–2258C; IR: n/cmꢀ1: 3410, 3356, 3223, 3176
(NH , NH), 1665 (C O), 1350, 1143 (SO ); 1H NMR: d/ppm: 4.45
–
–
2
2
(br, 2H, NH2), 6.76–7.89 (m, 16H, Ar-H), 9.78, 11.43, 12.54 (3s, 3H,
3NH; cancelled with D2O); MS, m/z 531 (Mþ; 1%), 372 (6.61), 298
(3.62), 285 (2.10), 270 (2.42), 217 (5.13), 190 (7.8), 107 (100), 93
(40.39), 80 (35.35), 77 (10.88) and 63 (44.84); Anal. Calcd.
for C25H21N7O3S2 (531.61): C, 56.48; H, 3.98; N, 18.44. Found:
C, 56.30; H, 3.70; N, 18.20%.
2-Cyano-2-(4-oxo-3-phenylthiazolidin-2-ylidene)-
N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (6)
Yield 68%; m.p. 234–2358C; IR: n/cmꢀ1: 3322, 3106 (2NH), 2201
1
(CN), 1745, 1687 (2C O), 1314, 1143 (SO ); H NMR: d/ppm: 3.96
–
–
2
(s, 2H, CH2), 6.90 (d, 1H, J5,4 ¼ 4.5 Hz, C5-H thiazole), 7.38 (d, 1H,
J4,5 ¼ 4.5 Hz, C4-H thiazole),7.44–7.73 (m, 9H, Ar-H), 9.79, 12.72
(2s, 2H, 2NH; cancelled with D2O); 13C NMR: 31.93 (CH2), 61.39,
78.38, 106.70, 113.14, 120.19, 120.31, 126.56, 126.60, 127.07,
127.56, 128.56, 129.23, 129.43, 130.48, 135.09, 136.34, 141.42,
163.39, 166.88, 173.37 (20C); Anal. Calcd. for C21H15N5O4S3
(497.57): C, 50.69; H, 3.04; N, 14.08. Found: C, 50.40; H, 3.10;
N, 14.20%.
Synthesis of arylidenes 10a–c
A mixture of the cyanoacetanilide 2 (0.01 mol) and the appropriate
aldehyde (namely benzaldehyde, p-anisaldehyde, and p-nitroben-
zaldehyde) (0.01 mol) in ethanol (30 mL) containing piperidine
(0.5 mL) was heated under reflux for 1 h. The obtained product
was filtered and recrystallized from ethanol to give 10a–c.
2-(4-Amino-3-phenylthiazol-2(3H)-ylidene)-2-cyano-N-
(4-(N-thiazol-2-ylsulfamoyl)phenyl)acetamide (7)
2-Cyano-3-phenyl-N-(4-(N-thiazol-2-ylsulfamoyl)-
phenyl)acrylamide (10a)
Yield 75%; m.p. 208–2108C; IR: n/cmꢀ1: 3423, 3314, 3224, 3156
Yield (67%); m.p. 280–2828C; IR: n/cmꢀ1: 3320, 3276 (2NH), 2218
1
–
(NH2 þ 2NH), 2218 (CN), 1680 (C O), 1343, 1156 (SO ); H NMR:
–
2
(CN), 1658 (C O), 1334, 1158 (SO ). 1H NMR: d/ppm: 6.78–7.98
–
–
2
d/ppm: 5.45 (hump, 2H, NH2), 6.12 (s, 1H, C-H thiazole), 6.76–7.89
(m, 11H, Ar-H), 9.23, 11.45 (2s, 2H, 2NH; cancelled with D2O);
Anal. Calcd. for C21H16N6O3S3 (496.59): C, 50.79; H, 3.25; N, 16.92.
Found: C, 50.90; H, 3.10; N, 16.70%.
(m, 12H, 11Ar-H and CH ), 8.84, 9.54 (2s, 2H, 2NH); 13C NMR:
–
–
105.13, 116.34, 120.65, 120.87, 126.45, 126.97, 127.34, 127.76,
128.34, 129.12, 129.56, 129.87, 130.32, 135.65, 136.45, 141.43,
156.21, 166.76, 172.56 (19C); Anal. Calcd. for C19H14N4O3S2
(410.47): C, 55.60; H, 3.44; N, 13.65. Found: C, 55.70; H, 3.20;
N, 13.70%.
2-Cyano-3-(methylthio)-3-(phenylamino)-N-(4-(N-
thiazol-2-ylsulfamoyl)phenyl)acrylamide (8)
To suspension of potassium hydroxide (0.01 mol) in dry DMF
(10 mL) cyanoacetanilide 2 (0.01 mol) was added during stirring,
phenyl isothiocyanate (0.01 mol) was dropped slowly to the
reaction mixture. After complete addition, stirring of the reac-
tion was continued for 5 h and dimethylsulfate (0.01 mol) was
added. The reaction mixture was stirred for 2 h, then poured into
crushed ice. The resulting precipitate was filtrated off, dried, and
crystallized from toluene to give 8 as pale yellow crystals, yield
2-Cyano-3-(4-methoxyphenyl)-N-(4-(N-thiazol-2-
ylsulfamoyl)phenyl)acrylamide (10b)
Yield (67%); m.p. 289–2918C; IR: n/cmꢀ1: 3276, 3232 (2NH), 2216
1
(CN), 1664 (C O), 1336, 1153 (SO ); H NMR: d/ppm: 3,87 (s, 3H,
–
–
2
–
OCH ), 6.86–7.67 (m, 11H, 10Ar-H, CH ), 8.43, 9.47 (2s, 2H, 2NH);
–
3
13C NMR: 62.32 (OCH3), 104.12, 116.87, 120.45, 120.76, 126.34,
126.67, 127.23, 127.87, 128.56, 129.34, 130.12, 131.34, 135.65,
136.45, 141.54, 153.34, 161.45, 166.76, 172.56 (19C); Anal. Calcd.
for C20H16N4O4S2 (440.50): C, 54.53; H, 3.66; N, 12.72. Found: C,
54.70; H, 3.40; N, 12.80%.
73%; m.p. 238–2408C; IR: n/cmꢀ1: 3375, 3210, 3101, (3NH), 2194
1
(CN), 1654 (C O), 1362, 1139 (SO ); H NMR: d/ppm: 2.76 (s, 3H,
–
–
2
SCH3), 6.82 (d, 1H, J5,4 ¼ 4.5 Hz, C5-H thiazole), 7.25 (d, 1H,
J4,5 ¼ 4.5 Hz, C4-H thiazole), 7.20–7.80 (m, 9H, Ar-H), 9.92,
11.51, 12.70 (3s, 3H, 3NH; cancelled with D2O); Anal. Calcd.
for C20H17N5O3S3 (471.58): C, 50.94; H, 3.63; N, 14.85. Found:
C, 50.70; H, 3.40; N, 14.70%.
2-Cyano-3-(4-nitrophenyl)-N-(4-(N-thiazol-2-
ylsulfamoyl)phenyl)acrylamide (10c)
Yield (62%); m.p. >3008C; IR: n/cmꢀ1: 3310, 3243 (2NH), 2222 (CN),
1
1663 (C O), 1337, 1152 (SO ); H NMR: d/ppm: 6.78–7.98 (m, 11H,
–
–
2
10 Ar-H, CH ), 8.87, 9.56 (2s, 2H, 2NH); 13C NMR: 103.65, 116.45,
–
Synthesis of pyrazoles 9a and b
–
A mixture of 8 (0.01 mol) and hydrazine derivatives (0.012 mol)
in ethanol (30 mL) was heated under reflux for 3 h and allowed
to cool. The solid product obtained was filtered and crystallized
from ethanol.
120.56, 120.98, 126.23, 126.76, 127.54, 127.85, 128.12, 129.23,
130.56, 131.65, 135.45, 136.23, 141.12, 149.45, 155.43, 162.45,
172.523 (19C); Anal. Calcd. for C19H13N5O5S2 (455.47): C, 50.10; H,
2.88; N, 15.38. Found: C, 50.20; H, 2.60; N, 15.40%.
5-Amino-3-(phenylamino)-N-(4-(N-thiazol-2-
ylsulfamoyl)phenyl)-1H-pyrazole-4-carboxamide (9a)
Yield 67%; m.p. 178–1808C; IR: n/cmꢀ1: 3449, 3329, 3245, 3159
Synthesis of pyridines 11a–c
Method A
A mixture of 10 (0.01 mol) and malononitrile (0.01 mol) in
ethanol (30 mL) containing piperidine (0.5 mL) was heated
under reflux for 3 h. The obtained product was filtered and
recrystallized from ethanol to give 11a–c.
(NH , NH), 1684 (C O), 1352, 1135 (SO ); 1H NMR: d/ppm: 4.89
(br, 2H, NH2), 6.82–7.80 (m, 11H, Ar-H), 9.92, 10.45, 11.51, 12.70
(4s, 4H, 4NH; cancelled with D2O); Anal. Calcd. for C19H17N7O3S2
–
–
2
2
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www.archpharm.com

8
A. A. Farag et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
Method B
4-(3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)-N-
(thiazol-2-yl)benzenesulfonamide (12a)
Equimolar amounts of 2 (0.01 mol) and the appropriate 2-
(arylidene)-malononitrile (namely 2-(benzylidene)-malononitrile,
2-(4-methoxybenzylidene)-malononitrile, and 2-(4-nitrobenzyli-
dene)-malononitrile) (0.01 mol) in ethanol (30 mL) was treated
with piperidine (0.5 mL) and the reaction mixture was heated
under reflux for 3 h. The resulting solid was filtered off and
recrystallized (m.p. and mixed m.p.).
Yield (71%); m.p. >3008C; IR: n/cmꢀ1: 3225 (NH), 2218 (CN), 1675
1
(C O), 1334, 1154 (SO ); H NMR: d/ppm: 1.72, 1.75 (2s, 6H, 2CH ),
–
–
2
3
5.87 (s, 1H, 5-H-pyridyl), 6.75, 7.65 (2d, 2H, 2H-thiazole), 7.98, 8.01
(2d, 4H, Ar-H), 9.43 (s, 1H, NH); 13C NMR: 14.67, 23.12 (2CH),
100.12, 100.32, 102.12, 108.45, 117.23, 120.34, 120.65, 125.43,
125.89, 135.43, 138.45, 143.12, 161.54, 166.76, 172.34 (15C); Anal.
Calcd. for C17H14N4O3S2 (386.45): C, 52.84; H, 3.65; N, 14.50.
Found: C, 52.60; H, 3.40; N, 14.60%.
Method C
A mixture of 2 (0.01 mol), the appropriate aldehyde (namely benzal-
dehyde, p-anisaldehyde, and p-nitrobenzaldehyde) (0.01 mol), piper-
idine (0.01mol), and malononitrile (0.01mol) in ethanol (30 mL)
was heated under reflux for 3 h (m.p. and mixed m.p.).
4-(3-Cyano-4-methyl-2-oxo-6-phenylpyridin-1(2H)-yl)-
N-(thiazol-2-yl)benzenesulfonamide (12b)
Yield (70%); m.p. 235–2378C; IR: n/cmꢀ1: 3232 (NH), 2220 (CN),
1
1670 (C O), 1335, 1151 (SO ); H NMR: d/ppm: 1.84 (s, 3H, CH ),
–
–
2
3
6.04 (s, 1H, 5-H-pyridyl), 6.86–8.12 (m, 11H, Ar-H), 9.32 (s, 1H, NH).
Anal. Calcd. for C22H16N4O3S2 (448.52): C, 58.91; H, 3.60; N, 12.49.
Found: C, 58.70; H, 3.40; N, 12.70%.
4-(6-Amino-3,5-dicyano-2-oxo-4-phenylpyridin-1(2H)-
yl)-N-(thiazol-2-yl)benzenesulfonamide (11a)
Yield (61%); m.p. 180–1818C; IR: n/cmꢀ1: 3456, 3307, 3154
–
(NH2 þ NH), 2211 (2CN), 1677 (C O), 1335, 1176 (SO2);
–
1H NMR: d/ppm: 6.85–7.86 (m, 11H, Ar-H), 8.98, 10.32 (2s, 3H,
NH and NH2); 13C NMR: 73.45, 101.21, 107.14, 116.34, 117.32,
120.15, 120.37, 125.32, 126.32, 126.94, 127.36, 128.23, 129.12,
129.97, 134.34, 136.45, 137.63, 138.76, 156.34, 165.45, 166.87,
172.34 (22C); Anal. Calcd. for C22H14N6O3S2 (474.51): C, 55.69; H,
2.97; N, 17.71. Found: C, 55.70; H, 2.70; N, 17.50%.
Synthesis of chromene-3-carboxamides 13 and 15
A mixture of equimolar amounts of 2 (0.01 mol), salicyaldehyde
(0.01 mol), or 7-hydroxy-5-methoxy-coumarin-6-carboxaldehyde
(0.01 mol) and ammonium acetate (0.015 mol) in ethanol
(30 mL) was heated under reflux for 2 h. The solid product
formed was collected by filtration and recrystallized from diox-
ane to give 13 and 15.
4-(6-Amino-3,5-dicyano-4-(4-methoxyphenyl)-2-
oxopyridin-1(2H)-yl)-N-(thiazol-2-
2-Imino-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-2H-
chromene-3-carboxamide (13)
yl)benzenesulfonamide (11b)
Yield (63%); m.p. 188–1908C; IR: n/cmꢀ1: 3443, 3312, 3149
Yield (76%); m.p. >3008C; IR: n/cmꢀ1: 3365, 3265, 3198 (3NH),
1
1676 (C O), 1343, 1154 (SO ); H NMR: d/ppm: 6.65–7.98 (m, 10H,
–
–
2
–
(NH2 þ NH), 2210 (2CN), 1679 (C O), 1339, 1178 (SO2);
–
Ar-H), 8.51 (s, 1H, H-4), 9.12, 10.32, 12.6 (3s, 3H, 3NH); Anal. Calcd.
for C19H14N4O4S2 (426.47): C, 53.51; H, 3.31; N, 13.14. Found: C,
53.70; H, 3.40; N, 13.30%.
1H NMR: d/ppm: 3.65 (s, 3H, OCH3), 6.63–7.98 (m, 10H, Ar-H),
8.76, 10.12 (2s, 3H, NH, NH2); 13C NMR: 54.87 (OCH3), 68.21,
101.04, 107.98, 114.76, 114.98, 116.87, 117.43, 120.23, 120.67,
125.65, 126.76, 127.87, 129.23, 129.87, 134.56, 137.63, 138.45,
156.43, 161.54, 165.34, 166.76, 172.34 (22C); MS, m/z 504 (Mþ;
5.8%), 366 (10.55), 241 (7.04), 224 (11.79), 210 (8.6), 161 (14.48),
135 (10.94), 121 (30.06), 112 (10.23), 107 (22.90), 93 (24.37), 84
(30.96), 77 (16.62), 64 (18.73), 55 (100); Anal. Calcd.
for C23H16N6O4S2 (504.54): C, 54.75; H, 3.20; N, 16.66. Found:
C, 54.50; H, 3.40; N, 16.50%.
2-Imino-5-methoxy-8-methyl-6-oxo-N-(4-(N-thiazol-2-
ylsulfamoyl)phenyl)-2,6-dihydropyrano[3,2-
g]chromene-3-carboxamide (15)
Yield (67%); m.p. 286–2888C; IR: n/cmꢀ1: 3312, 3200, 3107 (3NH),
1
1692, 1657 (2C O), 1362, 1141 (SO ); H NMR: d/ppm: 2.22 (s, 3H,
–
–
2
CH3), 3.95 (s, 3H, OCH3), 6.42 (s, 1H, H-7), 6.81 (s, 1H, H-10), 7.23–
7.56 (m, 6H, Ar-H), 8.52 (s, 1H, H-4), 9.5, 10.43, 12.8 (3s, 3H, 3NH);
MS, m/z 538 (Mþ; 1.39%), 342 (1.62), 332 (38.59), 269 (10.34), 248
(10.69), 232 (31.15), 191 (12.08), 177 (17.66), 153 (37.3), 140 (8.73),
138 (15.6), 135 (100), 107 (89.67) and 91 (12.53); Anal. Calcd.
for C24H18N4O7S2 (538.55): C, 53.52; H, 3.37; N, 10.40. Found:
C, 53.70; H, 3.40; N, 10.30%.
4-(6-Amino-3,5-dicyano-4-(4-nitrophenyl)-2-
oxopyridin-1(2H)-yl)-N-(thiazol-2-
yl)benzenesulfonamide (11c)
Yield (65%); m.p. >3008C; IR: n/cmꢀ1: 3412, 3323, 3176 (NH, NH2),
1
–
2223 (2CN), 1665 (C O), 1338, 1165 (SO ); H NMR: d/ppm: 6.75–
–
2
8.12 (m, 10H, Ar-H), 8.98, 10.56 (2s, 3H, NH, NH2); 13C NMR: 68.65,
102.43, 108.76, 116.34, 117.56, 120.54, 120.78, 125.45, 126.65,
127.23, 129.65, 129.87, 134.56, 136.41, 138.45, 142.43, 148.43,
156.43, 161.54, 165.34, 166.76, 172.34 (22C); Anal. Calcd.
for C22H13N7O5S2 (519.51): C, 50.86; H, 2.52; N, 18.87. Found:
C, 50.50; H, 2.60; N, 18.60%.
Synthesis of chromene-3-carboxamides 14 and 16
Method A
To a solution of 2 (0.01mol) in acetic acide (30 mL) containing
0.5 g of fused sodium acetate, o-hydroxyaldehyde (0.01 mol) was
added. The mixture was heated under reflux for 2 h and the solid
product obtained after cooling was collected by filtration and
recrystallized from acetic acid to give 14 or 16.
Synthesis of pyridines 12a and b
Method B
A mixture of 2 (0.01 mol), acetylacetone or benzoylacetone
(0.01 mol), and piperidine (0.5 mL) was fused in an oil bath at
1508C for 0.5 h to give a product which was crystallized from
ethanol.
The iminochromene derivatives 13 and 15 (0.01mol) were dis-
solved in boiling dioxane (40 mL) and treated with 5 mL HCl. The
reaction mixture was heated under reflux for 2 h. Left to cool,
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
Synthesis of Some Biologically Active Compounds
9
the obtained products were filtered off, washed with cold water,
and air-dried.
(s, 3H, CH3), 6.67, 7.75 (2d, 2H, thiazol-H), 7.67, 7.68 (2d, 4H, Ar-H),
8.34 (s, 1H, pyrrole-H), 9.45 (s, 1H, NH); 13C NMR 25.33 (CH3), 108.12
138.34, 168.76 (3C thiazole), 120.34, 120.56, 125.56, 125.67, 137.45,
143.64 (6C-Ar), 141.65, 151.43 162.64, 162.76 (4C-pyrrole), 187.54
2-Oxo-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-2H-
chromene-3-carboxamide (14)
–
(C O-acetyl); Anal. Calcd. for C H N O S (377.39): C, 47.74; H,
–
2.94; N, 11.13. Found: C, 47.63; H, 2.78; N, 11.36%.
15 11
3 5 2
Yield (73%); m.p. 245–2468C; IR: n/cmꢀ1: 3287, 3235 (2NH), 1712,
1669 (2C O), 1361, 1134 (SO ); 1H NMR: d/ppm: 6.75–7.86
–
–
2
Ethyl 2,5-dioxo-1-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-
2,5-dihydro-1H-pyrrole-3-carboxylate (21b)
(m, 10H, Ar-H), 8.67 (s, 1H, H-4), 9.54, 11.32 (2s, 2H, 2NH);
Anal. Calcd. for C19H13N3O5S2 (427.45): C, 53.39; H, 3.07; N,
9.83. Found: C, 53.50; H, 3.20; N, 9.70%.
Yield (73%); m.p. 241–2438C; IR: n/cmꢀ1: 3287 (NH), 1735, 1678
(C O), 1343, 1152 (SO ); 1H NMR: d/ppm: 1.45 (t, 3H, CH3), 4.12
–
–
2
(q, 2H, CH2), 6.87, 7.56 (2d, 2H, thiazole-H), 7.72, 7.74 (2d, 4H, Ar-H),
8.12 (s, 1H, pyrrole-H), 9.34 (s, 1H, NH); 13C NMR: 14.34, 61.23 (C2H5),
108.02, 138.25, 168.56 (3C thiazole), 120.12, 120.67, 125.23, 125.45,
137.67, 143.23 (6C-Ar), 141.34, 145.43, 162.34, 162.45 (4C-pyrrole),
5-Methoxy-8-methyl-2,6-dioxo-N-(4-(N-thiazol-2-
ylsulfamoyl)phenyl)-2,6-dihydropyrano[3,2-g]-
chromene-3-carboxamide (16)
Yield (58%); m.p. 256–2588C; IR: n/cmꢀ1: 3325, 3245 (2NH), 1712,
–
168.50 (C O-ester); Anal. Calcd. for C16H13N3O6S2 (407.42): C, 47.17;
–
H, 3.22; N, 10.31. Found: C, 47.30; H, 3.00; N, 10.40%.
1
1678, 1662 (3C O), 1362, 1156 (SO ); H NMR: d/ppm: 2.33 (s, 3H,
–
–
2
CH3), 3.95 (s, 3H, OCH3), 6.16 (s, 1H, pyranochromene H-7), 6.83
(s, 1H, pyranochromene H-10), 7.17–7.80 (m, 6H, Ar-H), 8.55 (s, 1H,
pyranochromene H-4), 10.61, 12.83 (2s, 2H, 2NH). Anal. Calcd.
for C24H17N3O8S2 (539.54): C, 53.43; H, 3.18; N, 7.79. Found: C,
53.60; H, 3.30; N, 7.80%.
4-(2-Imino-4-oxothiazolidin-3-yl)-N-(thiazol-2-yl)-
benzenesulfonamide (23)
Chloroacetanilide 17 (0.01 mol) and ammonium thiocyanate
(0.012 mol) in 50 mL of acetone was heated under reflux in a
water bath for 3 h, left overnight, and poured into cold water.
The solid product was filtered and crystallized from ethanol.
2-Chloro-N-(4-(N-thiazol-2-ylsulfamoyl)phenyl)-
acetamide (17)
Chloroacetyl chloride (0.012 mol) was added to a solution of
sulfathiazole (1) (0.01 mol) in dioxane (20 mL) containing
2 mL of triethyl amine. The solution was heated under reflux
for 2 h then left to cool. The precipitated product was filtered off
Yield (76%); m.p. >3008C; IR: n/cmꢀ1: 3266, 3185 (2NH), 1687
1
(C O), 1602 (C N), 1322, 1136 (SO ); H NMR: d/ppm: 3.94 (s, 2H,
–
–
–
–
2
CH2), 6.76 (d, 1H, J5,4 ¼ 4.50 Hz, C5-H thiazole), 7.34 (d, 1H,
J4,5 ¼ 4.51 Hz, C4-H thiazole), 7.83 (d, 2H, J ¼ 6.5 Hz, Ar-H),
7.85 (d, 2H, J ¼ 6.5 Hz, Ar-H), 9.43, 10.56 (2s, 2H, 2NH);
13C NMR: 33.56 (CH2), 109.56 137.54, 168.75 (3C thiazole),
120.45, 120.78, 125.56, 125.89, 137.34,þ142.45 (6C-Ar), 162.64
and recrystallized from ethanol, yield (84%); m.p. 220–2228C; IR:
1
n/cmꢀ1: 3322, 3292 (2NH), 1702 (C O), 1324, 1135 (SO ); H NMR:
–
–
2
d/ppm: 4.29 (s, 2H, CH2), 6.81, 6.82, 7.24, 7.25 (2d, 2H, thiazole-H),
7.71, 7.73, 776, 7.78 (AB, 4H, Ar-H), 10.63, 12.70 (2s, 2H, 2NH);
13C NMR: 43.42 (CH2), 108.03, 136.93, 168.64 (3C thiazole),
118.86, 124.28, 126.93, 126.36, 136.93, 141.49 (6C-Ar), 165.05
–
–
–
(C NH), 169.54 (C O); MS, m/z 354 (M ; 30.74%), 290 (63.54),
–
255 (51.45), 239 (56.30), 205 (29.39), 165 (25.77), 128 (38.82),
108 (32.54), 100 (31.21), 90 (32.42), 79 (36.23), 69 (32.07) and
55 (100); Anal. Calcd. for C12H10N4O3S3 (354.43): C, 40.67; H,
2.84; N, 15.81. Found: C, 40.70; H, 2.50; N, 15.50%.
–
(C O); Anal. Calcd. for C11H10ClN3O3S2 (331.80): C, 39.82; H,
–
3.04; N, 12.66. Found: C, 39.60; H, 3.30; N, 12.70%.
Synthesis of acetamides 24–27
Synthesis of pyrroles 20 and 21a and b
A mixture of compounds 17 (0.01 mol) and the appropriate amino
compound (namely 2-aminothiazole, 2-amino-6-methyl-benzo[d]-
thiazole, 2-aminobenzo[d]imidazole, and antipyrine) (0.01 mol) in
ethanol (50 mL) containing anhydrous potassium carbonate (0.5 g)
was heated under reflux for 3 h, then left to cool. The precipitated
product was filtered off and recrystallized from dioxane.
A mixture of compound 17 (0.01 mol) and ethyl cyanoacetate, ethyl
acetoacetate, or diethyl malonate (0.01 mol) in dimethylform-
amide (20 mL) containing anhydrous potassium carbonate (0.5 g)
was heated under reflux for 2 h, then left to cool to r.t. The
precipitated product was filtered off and recrystallized from DMF.
4-(3-Cyano-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-
(thiazol-2-yl)benzenesulfonamide (20)
2-(Thiazol-2-ylamino)-N-(4-(N-thiazol-2-ylsulfamoyl)-
phenyl)acetamide (24)
Yield (67%); m.p. >3008C; IR: n/cmꢀ1: 3265 (NH), 2218 (CN), 1697
Yield (67%); m.p. >3008C; IR: n/cmꢀ1: 3324, 3264, 3156 (3NH),
1
(C O); and 1354, 1155 (SO ); H NMR: d/ppm: 6.88, 7.65 (2d, 2H,
–
–
2
1
–
1664 (C O), 1335, 1146 (SO ); H NMR: d/ppm: 4.12 (s, 2H, CH ),
–
2
2
thiazole-H), 7.67, 7.85 (AB, 4H, Ar-H), 7.98 (s, 1H, pyrrole-H), 9.43
(s, 1H, NH); 13C NMR 108.02, 138.25, 168.56 (3C thiazole), 117.56
(CN), 120.34, 120.54, 125.34, 125.65, 137.45, 142.24 (6C-Ar),
118.23, 149.67 162.56, 162.78 (4C-pyrrole); Anal. Calcd.
for C14H8N4O4S2 (360.37): C, 46.66; H, 2.24; N, 15.55. Found: C,
46.30; H, 2.40; N, 15.40%.
6.76–7.87 (m, 8H, Ar-H), 9.65, 10.45, 11.23 (3s, 3H, 3NH); 13C NMR:
56.34 (CH2), 109.34, 109.56, 120.45, 120.67, 125.34, 125.854,
137.54, 138.34, 141.23, 142.45, 168.75, 169.32 (12C-Ar), 172.54
–
(C O); Anal. Calcd. for C14H13N5O3S3 (395.48): C, 42.52; H, 3.31; N,
–
17.71. Found: C, 42.70; H, 3.40; N, 17.50%.
4-(3-Acetyl-2,5-dioxo-2,5-dihydro-1H-pyrrol-1-yl)-N-
(thiazol-2-yl)benzenesulfonamide (21a)
2-(6-Methylbenzo[d]thiazol-2-ylamino)-N-(4-(N-thiazol-
2-ylsulfamoyl)phenyl)acetamide (25)
Yield (84%); pale brown; m.p. >3008C; IR: n/cmꢀ1: 3354 (NH),
Yield (63%); m.p. >3008C; IR: n/cmꢀ1: 3325, 3260, 3153 (3NH),
1712, 1667 (C O), 1345, 1154 (SO ); 1H NMR: d/ppm: 2.35
1
1659 (C O), 1333, 1156 (SO ); H NMR: d/ppm: 2.43 (s, 3H, CH ),
–
–
–
–
2
2
3
ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

10
A. A. Farag et al.
Arch. Pharm. Chem. Life Sci. 2012, 000, 1–10
4.74 (s, 2H, CH2), 6.90–7.50 (m, 10H, Ar-H and 1NH), 10.49, 10.89
(2s, 2H, 2NH); Anal. Calcd. for C19H17N5O3S3 (459.56): C, 49.66; H,
3.73; N, 15.24. Found: C, 49.40; H, 3.50; N, 15.50%.
[5] D. Ashton, J. Fransen, J. Heeres, G. H. Clincke, P. A. Janssen,
Epilepsy Res. 1992, 11, 27–36.
[6] K. A. M. Walker, M. B. Wallach, D. R. Hirschfeld, J. Med. Chem.
1981, 24, 67–74.
2-(1H-Benzo[d]imidazol-2-ylamino)-N-(4-(N-thiazol-2-
ylsulfamoyl)phenyl)acetamide (26)
[7] M. N. Serradell, P. Blancafort, J. Castaner, Drugs Fut. 1983, 8,
689.
Yield (61%); m.p. >3008C; IR: n/cmꢀ1: 3376, 3312, 3265, 3187
[8] D. Nardi, A. Tajana, A. Leonardi, R. Pennini, F. Portioli,
M. J. Magistretti, A. Subissi, J. Med. Chem. 1981, 24, 727–
731.
1
(4NH), 1663 (C O), 1345, 1163 (SO ); H NMR: d/ppm: 4.04 (s, 2H,
–
–
2
CH2), 6.85–7.97 (m, 10H, Ar-H), 8.76, 9.65, 10.78, 11.43 (4s, 4H,
4NH); Anal. Calcd. for C18H16N6O3S2 (428.49): C, 50.45; H, 3.76;
N, 19.61. Found: C, 50.70; H, 3.60; N, 19.50%.
[9] G. Graziani, P. Cazzulini, C. Luca, G. Nava, R. Testa, Arzneim.-
Forsch./Drug Res. 1983, 33, 1161–1167.
[10] M. Bachir, J. P. Riffaud, J. Lacolle, J. Lemoine, A. D. Almeida,
P. Houziaux, B. Danree, Eur. J. Med. Chem. 1990, 25, 71–74.
2-(1,5-Dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-
pyrazol-4-ylamino)-N-(4-(N-thiazol-2-ylsulfamoyl)-
phenyl)acetamide (27)
[11] G. B. DeSarro, M. Zapalla, S. Grasso, A. Chimirri, A. DeSarro,
Gen. Pharmacol. 1993, 24, 877–884.
Yield (66%); m.p. >3008C; IR: n/cmꢀ1: 3345, 3234, 3193 (3NH),
[12] M. J. Wilby, P. J. Hutchinson, CNS Drug Rev. 2004, 10, 281–294.
1
1666 (C O), 1354, 1153 (SO ); H NMR: d/ppm: 2.12, 2.75 (2s, 6H,
–
–
2
[13] J. J. Harnett, V. Roubert, C. Dolo, C. Charnet, B. Spinnewyn,
S. Cornet, A. Rolland, J. G. Marin, D. Bigg, P. E. Chabrier,
Bioorg. Med. Chem. Lett. 2004, 14, 157–160.
2CH3), 3.98 (s, 2H, CH2), 6.76–7.78 (m, 11H, Ar-H), 8.76, 9.65, 10.78
(3s, 3H, 3NH); Anal. Calcd. for C22H22N6O4S2 (498.58): C, 53.00; H,
4.45; N, 16.86. Found: C, 53.20; H, 4.50; N, 16.90%.
[14] T. Mann, D. Keilin, Nature 1940, 146, 164–165.
[15] B. Malawska, Curr. Top. Med. Chem. 2005, 5, 69–85.
The authors have declared no conflict of interest.
[16] Y. A. Ammar, N. M. Saleh, J. A. Micky, H. S. Abas, M. S. A. El-
Gaby, Indian J. Chem. 2004, 43B, 2203–2211.
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ß 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com