Synthesis and hypnotic activity of new 4-thiazolidinone and 2-thioxo- 4,5-imidazolidinedione derivatives

Article abstract of DOI:10.1002/(SICI)1521-4184(199910)332:10<343::AID-ARDP343>3.0.CO;2-0

Conveniently accessible 4-[(2-(3,4-dimethoxyphenyl)ethyl]-3- thiosemicarbazide (2) was converted to new 1-substituted benzylidene/furfurylidene-4-[2-(3,4-dimethoxyphenyl)ethyl]-3- thiosemicarbazides (3) which furnished 2-(substituted benzylidene/furfurylidene)hydrazono-3-[2-(3,4- dimethoxyphenyl)ethyl]thiazolidin-4-ones (4) and 1-(substituted benzylidene/furfurylidene)amino-3-[2-(3,4-dimethoxyphenyl)ethyl]-2-thioxo- 4,5-imidazolidinediones (5) on reaction with chloroacetic acid and oxalyl chloride, respectively. The structure of 5 was confirmed by X-ray diffraction studies performed on 5a. 4 and 5 were evaluated for their potentiating effects on pentobarbital induced hypnosis. Most of the compounds caused remarkable increases in pentobarbital sleeping time.

Full text of DOI:10.1002/(SICI)1521-4184(199910)332:10<343::AID-ARDP343>3.0.CO;2-0

4-Thiazolidinones and 2-Thioxo-4,5-imidazolidinediones
343
Synthesis and Hypnotic Activity of New 4-Thiazolidinone and
2-Thioxo-4,5-imidazolidinedione Derivatives
a)
a)*
a)
a)
b)
c)
Nedime Ergenç , Gültaze Çapan , Nur Sibel Günay , Sumru Özk1r1ml1 , Mehmet Güngör , Süheyla Özbey , and
c)
Engin Kendi
a) Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Istanbul, 34452 Beyaz1t, Istanbul, Turkey
b) Department of Pharmacology, Istanbul Faculty of Medicine, 34390 Istanbul, Turkey
c) Department of Physics Engineering, Hacettepe University, 06532 Beytepe, Ankara, Turkey
Key Words: Arylidenethiosemicarbazides; 4-thiazolidinones; 2-thioxo-4,5-imidazolidinediones; hypnotic activity
ethyl]-3-thiosemicarbazides (3). Cyclization of 3 with chlo-
roacetic acid and oxalyl chloride furnished 2-(substituted
benzylidene)/furfurylidenehydrazono-3-[2-(3,4-dimethoxy-
phenyl)ethyl]thiazolidin-4-ones (4) and 1-(substituted ben-
zylidene)/furfurylideneamino-3-[2-(3,4-dimethoxyphenyl)-
ethyl]-2-thioxo-4,5-imidazolidinediones (5), respectively
(Scheme 1 and Table 1). The structures of 3–5 were deter-
Summary
Conveniently accessible 4-[(2-(3,4-dimethoxyphenyl)ethyl]-3-
thiosemicarbazide (2) was converted to new 1-substituted ben-
zylidene/furfurylidene-4-[2-(3,4-dimethoxyphenyl)ethyl]-3-thio-
semicarbazides (3) which furnished 2-(substituted benzylidene/
furfurylidene)hydrazono-3-[2-(3,4-dimethoxyphenyl)ethyl]thiaz-
olidin-4-ones (4) and 1-(substituted benzylidene/furfurylidene)-
amino-3-[2-(3,4-dimethoxyphenyl)ethyl]-2-thioxo-4,5-imidazol-
idinediones (5) on reaction with chloroacetic acid and oxalyl
chloride, respectively. The structure of 5 was confirmed by X-ray
diffraction studies performed on 5a. 4 and 5 were evaluated for
their potentiating effects on pentobarbital induced hypnosis. Most
of the compounds caused remarkable increases in pentobarbital
sleeping time.
1
13
mined by spectroscopic methods (IR, H-NMR, C-NMR,
EIMS) and elemental analysis.
Introduction
[1]
4-Thiazolidinones are reported to possess anticonvulsant
and hypnotic properties
[2,3]
. Hypnotic activity of cyclic
ureides, exemplified by barbiturates which exert their effects
mainly by potentiating and/or prolonging the action of the
inhibitory transmitter GABA by influencing conductance at
the chloride channel associated with the GABA receptor, is
[4,5]
well known
. We have previously reported on the anticon-
vulsant and hypnotic activities of 4-thiazolidinone and 2-thi-
[6–8]
oxo-4,5-imidazolidinedione derivatives
. To further
investigate the CNS depressant properties of these ring sys-
tems in an attempt to find new hypnotics with improved
pharmacological and safety profiles, we prepared 2,3-disub-
stituted 4-thiazolidinones (4) and 1,3-disubstituted 2-thioxo-
4,5-imidazolidinediones (5) and evaluated their potentiating
effects on pentobarbital induced hypnosis.
Results and Discussion
Chemistry
The target compounds were obtained as outlined in
Scheme 1. Thus 4-[(2-(3,4-dimethoxyphenyl)ethyl]-3-thio-
[9]
semicarbazide (2) obtained from a one-pot reaction was
condensed with appropriate aldehydes to afford 1-substitut-
ed benzylidene/furfurylidene-4-[2-(3,4-dimethoxyphenyl)-
Scheme 1. Synthesis of 2–5.
Arch. Pharm. Pharm. Med. Chem.
© WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1999
0365-6233/99/1010/0343 $17.50 +.50/0

344
Çapan and co-workers
Table 1. Physicochemical and MS data of 3–5.
————————————————————————————————————————————————
Compd.
R
Molecular Formula*
(MW)
Mp
Yield
(%)
MS (M+)
(°C)
m/z (%)
————————————————————————————————————————————————
3a
3b
3c
3d
3e
3f
4-BrC6H4
3-ClC6H4
4-FC6H4
C18H20BrN3O2S (422.33)
154
52
44
57
40
32
44
13
45
51
50
26
45
16
33
43
27
18
91
6
421 (53)
.
C18H20ClN3O2S H2O (395.90)
172–175
164
C18H20FN3O2S (361.42)
C19H21N3O4S (387.44)
C18H21N3O3S (359.43)
C18H20N4O4S (388.43)
C16H19N3O3S (333.39)
C20H20BrN3O3S (462.35)
C20H20ClN3O3S (417.90)
C20H20FN3O3S (401.44)
C21H21N3O5S (427.46)
C18H19N3O4S (373.41)
C20H18BrN3O4S (476.33)
361 (8)
387 (4)
4-COOHC6H4
2-OHC6H4
2-NO2C6H4
2-furyl
216–219
198–200
160–163
120–123
158–159
154–157
138–139
246
388 (15)
333 (42)
461 (2)
3g
4a
4b
4c
4d
4e
5a
5b
5c
5d
5e
5f
4-BrC6H4
3-ClC6H4
4-FC6H4
401 (1)
427 (2)
373 (20)
475 (25)
4-COOHC6H4
2-furyl
183–185
176–179
187–190
138–140
161–163
170
4-BrC6H4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-FC6H4
.
C20H18ClN3O4S 2.5 H2O (476.92)
.
C20H18ClN3O4S 1.5H2O (458.90)
C20H18ClN3O4S (431.88)
C20H18FN3O4S (415.42)
C21H19N3O6S (441.44)
415 (96)
441 (1)
4-COOHC6H4
2-OHC6H4
2-NO2C6H4
2-furyl
198
.
5g
5h
5i
C20H19N3O5S 3 H2O (467.48)
190–193
189–192
164–166
C20H18N4O6S (442.43)
C18H17N3O5S (387.40)
13
58
442 (77)
387 (72)
—————————————————————————————————————————————————————
* Satisfactory microanalysis obtained.
The IR spectra of 3 showed N-H and C=N stretching bands
–1
in the 3367–3115 and 1717–1592 cm regions, respectively.
Compound 3displayed the N4-H resonance in theδ 8.10–8.69
ppm region. N2-H resonated at about δ 11.56–11.75 ppm. In
3a and 3c this proton exchanged with the solvent and could
not be observed. The CH=N group displayed a singlet in the
δ 7.97–8.59 ppm region.
The IR spectra of 4 displayed the C=O absorbance in the
–1
1
1711–1721 cm region. H-NMR spectra supported cycliza-
tion to 4 as they displayed additional resonances assigned to
the SCH group of the thiazolidinone ring at about δ 3.90–
2
[6]
4.14 ppm together with the NCH triplet . The CH=N
2
proton in these structures was observed in the δ 7.86–8.72
ppm region.
–1
New C=O peaks (1760–1785 cm ) observed in IR spectra
of 5 characteristic for 2-thioxo-4,5-imidazolidinediones pro-
1
vided confirmatory evidence for ring closure. H-NMR spec-
tra supported these findings as the CH=N resonance showed
a downfield shift and absorbed in the δ 8.97–9.67 ppm re-
[7,8]
gion
presumably due to the anisotropy of the thiocar-
bonyl or carbonyl groups when the molecule adopts the E
[10]
configuration
. An independent proof of the correct struc-
ture of 5 was also achieved by single crystal X-ray diffraction
analysis of compound 5a (Figure 1).
Figure 1. ORTEP diagram of 5a.
Arch. Pharm. Pharm. Med. Chem. 332, 343–347 (1999)

4-Thiazolidinones and 2-Thioxo-4,5-imidazolidinediones
345
Table 2. Potentiating effects of 4 and 5 on pentobarbital induced hypnosis.
X-Ray Structure of 5a
———————————————————————————
Technical details of the structure determination are given in
the experimental part. An ORTEP
Compound
Sleeping Time (min)
[11]
diagram of 5a showing
Mean ± SE
the molecular configuration and atom labeling scheme is
depicted in Figure 1. The imidazole moiety deviates slightly
from planarity [maximum deviation 0.035(6) Å for N2]. The
S atom attached to C1 is situated –0.143(3) Å below the
best-plane P1 defined by the imidazole ring atoms and the O2
and O3 atoms deviate from P1 by only –0.081(6) and
0.010(5) Å, and so lie nearly in this plane. The dihedral angles
between the plane P1 and the mean plane P2 (defined by C6,
C7, C8, C9, C10, C11) on one side, P1 and the mean plane
P3 (C15, C16, C17, C18, C19, C20) on the other side, are
respectively 169.8(4) and 149.0(2)°, while the dihedral angle
between P2 and P3 is 22.8(2)°. The N3=C14 bond in the
amine group [1.267(8) Å] is slightly shortened by compari-
———————————————————————————
4a
2.57 ± 2.50
12.71 ± 5.10
30.00 ± 8.00
68.50 ± 12.10
51.30 ±7.70
26.20 ± 5.66
23.20 ± 8.00
38.30 ± 7.09
30.60 ± 2.67
19.20 ± 6.69
37.00 ± 7.30
15.30 ± 4.80
26.20 ± 7.20
13.20 ± 5.30
8.20 ± 3.70
4b
4c
4d
4e
5a
5b
5c
5d
5e
2
son with a normal Csp =N distance (1.28 Å). The interatomic
5f
distances for the C-N bonds in the imidazole moiety are in
the range 1.35–1.41 Å . Introduction of several substituents
on the imidazole ring adds steric and electronic effects and
causes further distortion of the ring structure. The torsion
angles C1-N1-C4-C5 and C1-N2-N3-C14 are 90.5(8) and
152.6(7) °.
5g
5h
5i
Control
———————————————————————————
Experimental Part
Pharmacology
Chemistry
The hypnotic activity of 4 and 5 was evaluated by determi-
Melting points were determined with a Büchi (Tottoli) melting point
apparatus in open capillaries and are uncorrected. IR (KBr), 1H-NMR,
13C-NMR (proton decoupled-DEPT135) ([d6]DMSO)*, and mass spectra
were recorded on a Perkin-Elmer 1600 FT-IR, Bruker AC 200 (200 MHz),
ARX-300 (1H: 300 MHz, 13C: 75.5 MHz) and VG Zab Spec (EI, 70eV)
instruments, respectively. TLC was carried on precoated plates (silica gel 60
F254 Merck Art. 5735) employing the solvent system C6H6:CH3COCH3
(30:70).
nation of their potentiating effects on pentobarbital induced
[12]
hypnosis in mice
. When administered at a dose of
100 mg/kg the test compounds did not induce any drowsi-
ness, ataxia, or sleep. The duration of sleep in pentobarbital
sodium injected control mice (equivalent to pentobarbital
base, 40 mg/kg) was 8.20 ± 3.70 min. As can be seen in
Table 2, the majority of the compounds prolonged pentobar-
bital sleeping time significantly. The most active compounds
4-[(2-(3,4-Dimethoxyphenyl)ethyl]-3-thiosemicarbazide 2 [9]
To an ethanolic solution of 1 (0.1 mol) was slowly added 16.5 ml of
concentrated NH3 solution. After the mixture had cooled below 30 °C , CS2
(7.5 ml) was added dropwise over 20 min and the mixture was allowed to
stand at room temperature for 1 h. To this mixture was added an aqueous
solution of ClCH2COONa (0.1 mol/20 ml). This resulted in an exothermic
reaction, and NH2NH2.H2O (0.1 mol, 80%) was then added to the warm
solution. The reaction mixture was cooled overnight and the crude thiosemi-
carbazide which separated out was filtered and used without further purifi-
cation.
were 4d and 4e the 4-COOHC H and the 2-furyl substituted
6
4
derivatives. Compounds 4c, 5c, 5d, and 5f (4-FC6H4, 3-
ClC H , 4-ClC H , and 4-COOHC H substituted entries,
6
4
6
4
6 4
respectively) also caused remarkable enhancements in pen-
tobarbital induced hypnosis. Although no clear correlation
between structure and activity emerged from compounds 4 or
5, the active compounds may be regarded as promising seda-
tive-hypnotic candidates which may lead to compounds that
approximate the ideal sedative-hypnotic after structural
modification keeping in mind the importance of the 4-
1-Substituted Benzylidene/furfurylidene-4-[2-(3,4-dimethoxyphenyl)ethyl]-
3-thiosemicarbazides 3
An ethanolic (20 ml) solution of 2 (0.01 mol) was added to a boiling
ethanolic (20 ml) solution of an appropriate aldehyde (0.011 mol) and re-
fluxed for 2 h on a water bath. The solid mass which separated out on cooling
was filtered, dried, and recrystallized from C2H5OH.
COOHC H group which is represented by potent com-
6
4
pounds in both series.
Spectral dataof3a: IR: ν = 3334, 3149 (N-H), 1700(C=N)cm–1.–1H-NMR
(300 MHz): δ = 2.67 (t, J = 7.50 Hz, 2H, CH2), 3.51–3.61 (m, 8H, 2OCH3
and NCH2), 6.57–6.70 (m, 3H, ar), 7.41 (d, J = 8.50 Hz, 2H, ar), 7.52 (d, J=
8.50 Hz, 2H, ar), 7.83 (s, 1H, N=CH), 8.34 (t, J= 5.80 Hz, 1H, N4-H).–
13C-NMR: δ = 34.6 (CH2), 45.4 (NCH2), 55.7 (OCH3), 112.3 (=CH), 112.8
Acknowledgements
We thank Professor Belk1s Gözler for the measurement of 1H-NMR and
13C-NMR spectra. This work was supported in part by Istanbul University
Research Fund (Project Number: Ö-89/240495).
———
* Some =CH and/or C=C signals coincided.
Arch. Pharm. Pharm. Med. Chem. 332, 343–347 (1999)

346
Çapan and co-workers
(=CH), 120.8 (=CH), 123.3 (C=C), 130.2 (=CH), 132.0 (=CH), 133.8 (C=C),
140.9 (CH=N), 147.6 (C=C); 147.9 (C=C), 149.0 (C=C), 171.3 (C=S).– MS
m/z (%): 423 [M+2]+ (52) , 421 [M+] (53), 242, 240 (25, 25), 238 (48), 224
(7), 206 (9), 196 (13), 191 (12), 184, 182 (33, 34), 165 (95), 164 (95), 157,
155 (24, 24), 151 (100), 149 (60), 137 (18), 121 (22), 107 (29), 103 (24), 91
(24), 89 (30), 77 (21), 65 (17).
(CH2), 42.6 (NCH2), 55.3 (OCH3), 111.9 (=CH), 112.3 (=CH), 120.4 (=CH),
129.0 (C=C), 130.0 (=CH), 131.6 (C=C), 132.1 (=CH), 147.4 (C=C), 148.6
(C=C), 151.6 (C=C), 154.5 (C=S/C=O), 160.8 (CH=N), 178.2 (C=S/C=O).–
MS m/z (%): 477 [M+2]+ (25), 475 [M+] (25), 294 (10), 264 (5), 222 (1), 206
(2), 184, 182 (6), 165 (25), 164 (100), 151 (61), 149 (20), 135 (4), 121 (6),
107 (10),103 (6), 91 (8), 89 (10),78 (27), 63 (30).
Spectral data of 3c: IR: ν = 3337, 3148 (N-H), 1706 (C=N) cm–1.–
1H-NMR (300 MHz): δ = 3.04 (t, J = 7.90 Hz, 2H, CH2), 3.89–3.96 (m, 8H,
2OCH3 and NCH2), 6.98–7.09 (m, 3H, ar), 7.45 (t, J = 8.90 Hz, 2H, ar), 8.03
(dd J = 8.60 Hz, 5.70 Hz, 2H, ar), 8.23 (s, 1H, N=CH), 8.69 (t, 1H, N4-H).–
13C-NMR: δ = 34.6 (CH2), 45.4 (NCH2), 55.7 (OCH3), 55.8 (OCH3), 112.5
(=CH), 115.6 (=CH), 115.9 (=CH), 120.5 (=CH), 129.4 (=CH), 130.8 (C=C),
131.7 (C=C), 140.7 (CH=N), 147.4 (C=C), 148.7 (C=C), 177.0 (C=S).– MS
m/z (%): 361 [M+] (8), 245 (13), 238 (4), 180 (2), 165 (14), 164 (100), 152
(7), 151 (14), 149 (11), 122 (6), 107 (7), 95 (6), 91 (6), 77 (6).
Spectral data of 5e: IR: ν = 1772 (C=O) cm–1. 1H-NMR (300 MHz): δ =
2.88 (t, J = 7.55 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 4.04
(t, J = 7.50 Hz, 2H, NCH2), 6.76–6.90 (m, 3H, ar), 7.40 (t, J = 8.35 Hz, 2H,
ar), 8.00 (t, J = 8.30 Hz, 2H, ar), 9.13 (s, 1H, N=CH).– 13C-NMR: δ = 32.8
(CH2), 43.0 (NCH2), 55.8 (OCH3), 112.3 (=CH), 112.8 (=CH), 116.6 (=CH),
116.9 (=CH), 120.9 (=CH), 129.4 (C=C), 130.5 (C=C), 131.2 (=CH), 131.3
(=CH), 147.9 (C=C), 149.1 (C=C), 152.1 (C=C), 155.0 (C=S/C=O), 161.9
(CH=N), 178.7 (C=S/C=O).– MS m/z (%): 415 [M+] (96), 294 (12), 264 (15),
222 (3), 206 (8), 181 (3), 165 (63), 164 (75), 151 (100), 149 (48), 135 (11),
122 (20), 121 (27), 108 (25), 107 (32), 103 (16), 91 (19), 78 (50), 63 (47).
Spectral data of 5i: IR: ν = 1772 (C=O) cm–1.– 1H-NMR (200 MHz): δ =
2.88 (t, J = 7.43 Hz, 2H, CH2), 3.72 (s, 3H, OCH3), 3.75 (s, 3H, OCH3), 4.03
(t, J = 7.43 Hz, 2H, NCH2), 6.74–6.90 (m, 4H, furan H4 and ar), 7.33 (d, J =
3.40 Hz, 1H, furan H3), 8.03 (s, 1H, furan H5), 8.92 (s, 1H, N=CH).– MS
m/z (%): 387 [M+] (70), 371 (5), 309 (2), 294 (13), 264 (33), 222 (2), 206 (5),
193 (3), 164 (100), 151 (74), 135 (7), 121 (15), 107 (20), 91 (20), 77 (8), 65
(7).
Spectral data of 3g: IR: ν = 3283, 3136 (N-H), 1619 (C=N) cm–1.–
1H-NMR (200 MHz): δ = 2.83 (t, J = 7.30 Hz, 2H, CH2), 3.72–3.80 (m, 8H,
2OCH3 and NCH2), 6.62 (dd, J = 3.18, 1.70 Hz, 1H, furan H4), 6.73–6.90
(m, 4H, furan H3 and ar), 7.79 (d, J = 1.10 Hz, 1H, furan H5), 7.97 (s, 1H,
N=CH), 8.10 (t, J = 5.60 Hz, 1H, N4-H), 11.40 (s, 1H, N2-H).– MS m/z (%):
333 [M+] (41), 298 (18), 238 (33), 244 (4), 206 (7), 196 (9), 180 (5), 164
(100), 151 (57), 135 (7), 121 (14), 108 (27), 94 (21), 80 (27), 65 (7).
2-(Substituted Benzylidene/furfurylidene)hydrazono-3-[2-(3,4-dimethoxy-
phenyl)ethyl]thiazolidin-4-ones 4
Crystal Data and X-Ray Structure Analysis of 5a
3 (0.005 mol), ClCH2COOH (0.005 mol), and CH3COONa (0.0075 mol)
were suspended in CH3COOH (14 ml), and refluxed for 3–6 h on a water
bath. The reaction mixture thus obtained was poured over ice-water and
refrigerated overnight. The solid mass which separated out was filtered,
washed with H2O, and recrystallized from C2H5OH or washed with
C2H5OH.
A yellow prismatic crystal of C20H18N3O4SBr with approximate dimen-
sions of 0.30 × 0.008 × 0.64 mm was used for all X-ray experiments which
were carried out on Enraf-Nonius CAD4 diffractometer at 293 K with MoKα
radiation (λ = 0.71073Å). The lattice parameters of the crystal were refined
using 24 reflections in the range θ = 8–18. The data collection with ω–2θ
scan between θ = 2–25 resulted in 4081 intensity values. During the collec-
tions three intensity control reflections were monitored every 2 h, showing
no loss of intensity. The data were corrected for absorption using the ψ-scan
Spectral data of 4a: IR: ν = 1711 (C=O) cm–1.– 1H-NMR (300 MHz): δ =
2.90 (t, 2H, CH2), 3.70 (s, 3H, OCH3), 3.78 (s, 3H, OCH3), 3.90–4.00 (m,
4H, NCH2 and SCH2), 6.70–6.90 (m, 3H, ar), 7.65–7.77 (m, 4H, ar), 8.50 (s,
1H, N=CH).– 13C-NMR: δ = 32.5 (CH2/SCH2), 32.6 (CH2/SCH2), 44.4
(NCH2), 56.0 (OCH3), 112.3 (=CH), 112.5 (=CH), 113.0 (=CH), 121.1
(=CH), 130.1 (=CH), 130.8 (=CH), 131.0 (C=C), 132.5 (=CH), 148.0 (C=C),
157.1 (CH=N), 162.2 (C=C), 164.4 (C=C), 165 (C=N), 172.4(C=O).– MS
m/z (%): 463 [M+2]+ (2), 461 [M+] (2), 183, 181 (2,2), 165 (22), 164 (100),
151 (13), 149 (17), 121 (5), 107 (5), 103 (5), 91 (5), 89 (7), 78 (70), 63 (79).
Spectral data of 4c: IR: ν = 1721 (C=O) cm–1.– 1H-NMR (300 MHz ): δ
= 3.08 (t, J = 7.50 Hz, 2H, CH2), 3.91 (s, 3H, OCH3), 3.95 (s, 3H, OCH3),
4.09–4.14 (m, 4H, NCH2 and SCH2), 6.91–7.08 (m, 3H, ar); 7.52 (t, J = 7.80
Hz, 2H, ar), 8.06 (t, J = 7.80 Hz, 2H, ar), 8.72 (s, 1H, N=CH).– 13C-NMR:
δ = 32.3 (CH2/SCH2), 32.4 (CH2/SCH2), 44.1 (NCH2), 55.8 (OCH3), 112.3
(=CH), 112.8 (=CH), 116.1 (=CH), 116.4 (=CH), 120.9 (=CH), 130.2 (=CH),
130.8 (=CH), 131.0 (C=C), 147.8 (C=C), 149.0 (C=C), 156.8 (CH=N), 162.2
(C=C), 164.4 (C=C), 165.0 (C=N), 172.2 (C=O).– MS m/z (%): 401 [M+]
(1), 200 (1), 165 (11), 164 (100), 151 (6), 149 (10), 121 (4), 107 (6).
Spectral data of 4e: IR: ν = 1725 (C=O) cm–1.– 1H-NMR (200 MHz): δ =
2.91 (t, J = 7.50 Hz, 2H, CH2), 3.71 (s, 6H, 2OCH3), 3.93–4.06 (m, 4H, NCH2
and SCH2), 6.67–6.89 (m, 4H, furan H4 and ar), 7.35 (d, J = 3.30 Hz, 1H,
furan H3), 7.86 (s, 2H, furan H5 and N=CH).– MS m/z (%): 373 [M+] (20),
278 (2), 264 (4), 257 (7), 222 (2), 209 (6), 186 (10), 179 (4), 165 (100), 151
(70), 149 (85), 135 (14), 121 (35), 108 (15), 107 (31), 94 (29), 91 (34), 80
(10), 77 (25), 70 (5), 65 (10).
data. The structure was solved by direct methods using SIR in MolEN [13]
.
Refinements were carried out by full-matrix least square techniques and
non-hydrogen atoms were anisotropically refined. All H atoms were geomet-
rically located 0.95 Å from their parent atoms and included using a riding
model; displacement parameters were fixed at 1.3 Ueq of the parent atoms.
The current R factor was 0.047 and weighted factor wR 0.052. The data for
5a were as follows : C20H18N3O4SBr, Mr = 476.36, a = 15.138(2), b =
7.422(1), c = 19.649(1) Å, β = 109.33 (1), V = 2082.9(3) Å3, Z = 4, space
group = P 21/c, monoclinic, Dc = 1.52 g cm–3, µ = 20.8 cm–1, F(000) = 968,
R(F) = 0.047, wR = 0.052, S = 0.71. The refinement of the structure used
1818 observed reflections [I > 2 (I)]. Parameters refined = 262 ; final (∆σ)max
= 0.000. ∆ρ in the final difference map within +0.52 and –0.243 e Å–3
.
Supplementary data on final atomic coordinates, equivalent isotropic thermal
parameters for all non-hydrogen atoms and selected geometric parameters
may be obtained from the authors on request.
Potentiation of Pentobarbital Induced Hypnosis
The method of winter[12] was employed to investigate the ability of 4 and
5 to potentiate pentobarbital induced hypnosis. Male BALB-c mice, weigh-
ing 20–25 g were divided into groups of ten animals. One group was used
for each compound, and one for the control. The test compounds were
suspended in % 0.5 carboxymethylcellulose (CMC) to give a concentration
of % 1 (w/v) and were injected to the animals at a dose of 100 mg/kg ip 1 h
prior to the injection of pentobarbital sodium (equivalent to pentobarbital
base 40 mg/kg/H2O). The animals were observed for sleep as evidenced by
the loss of the righting reflex. The degree of potentiation produced by the test
compounds was calculated by the mean sleeping time observed in mice.
1-(Substituted Benzylidene/furfurylidene)amino-3-[2-(3,4-dimethoxy-
phenyl)-ethyl]-2-thioxo-4,5-imidazolidinediones 5
Compound 3 (0.0035 mol) was suspended in anhydrous C2H5OC2H5
(30 ml). To this suspension oxalyl chloride (0.007 mol) was added and the
reaction mixture was refluxed for 2–6 h on a water bath at 60 °C with constant
stirring. The solid mass thus obtained was filtered, washed with petroleum
benzene to remove excess oxalyl chloride, dried and purified by recrystalli-
zation from C2H5OH , C2H5OH/CHCl3 or washing with C2H5OC2H5.
Spectral data of 5a: IR: ν = 1769 (C=O) cm–1. 1H-NMR (300 MHz): δ =
2.69 (t, J = 7.60 Hz, 2H, CH2), 3.53 (s, 3H, OCH3), 3.57 (s, 3H, OCH3), 3.84
(t, J = 7.90 Hz, 2H, NCH2), 6.56–6.70 (m, 3H, ar), 7.58 (d, J = 8.40 Hz, 2H,
ar), 7.68 (d, J = 8.40 Hz, 2H, ar), 8.97 (s, 1H, N=CH). 13C-NMR: δ = 32.3
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