Synthesis and morphine enhancement activity of N-[5-(2-phenoxyphenyl)-1,3, 4-oxadiazole-2-yl]-N′-phenylurea derivatives

Article abstract of DOI:10.1002/ardp.200300822

The synthesis of N-[5-(2-phenoxyphenyl)-1,3,4-oxadiazole-2-yl]-N′- phenylurea derivatives is reported. The structures of these compounds are supported by their IR, ¹H-NMR and mass spectra. Conformational analysis and superimposition of energy minima conformers of these compounds on L-365,260, a known 3-ureido-1,4-benzodiazepine CCK-B antagonist, showed that the aromatic rings fell in the same contour. Morphine analgesia enhancement evaluation of the synthesized compounds in comparison with a control group showed that compounds 8a, 8c, 8h-8j, 8l, 8o have significant effects.

Full text of DOI:10.1002/ardp.200300822

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 193−200
N-[5-(2-phenoxyphenyl)-1,3,4-oxadiazole-2-yl]-NЈ-phenylurea Derivatives 193
Ali Almasi Rada,
Synthesis and Morphine Enhancement Activity
of N-[5-(2-phenoxyphenyl)-1,3,4-oxadiazole-2-yl]-
NЈ-phenylurea Derivatives
Majid Sheikhhaa,
Rohollah Hosseinib,
Sayyed Abbas Tabatabaic,
Abbas Shafieea
a Department of Medicinal
Chemistry and
The synthesis of N-[5-(2-phenoxyphenyl)-1,3,4-oxadiazole-2-yl]-NЈ-phenylurea
derivatives is reported. The structures of these compounds are supported by
1
their IR, H-NMR and mass spectra. Conformational analysis and superimpo-
Pharmaceutical Sciences
Research Center, Faculty of
Pharmacy, Tehran University
of Medical Sciences,
Tehran, Iran
sition of energy minima conformers of these compounds on L-365,260, a known
3-ureido-1,4-benzodiazepine CCK-B antagonist, showed that the aromatic rings
fell in the same contour. Morphine analgesia enhancement evaluation of the
synthesized compounds in comparison with a control group showed that com-
pounds 8a, 8c, 8hϪ8j, 8l, 8o have significant effects.
b Department of Pharmacology
and Toxicology and
Keywords: 1,3,4-Oxadiazole; L-365,260, CCK-B antagonist; Morphine
Pharmaceutical Sciences
Research Center, Faculty of
Pharmacy, Tehran University
of Medical Sciences,
Tehran, Iran
enhancement; Analgesia
Received: June 13, 2003; Accepted: November 25, 2003 [FP822]
DOI 10.1002/ardp.200300822
c Department of Medicinal
Chemistry, Faculty of
Pharmacy, Shaheed Beheshti
University of Medical
Sciences,
Tehran, Iran
Introduction
Cholecystokinin (CCK) is a major gastrointestinal hor-
mone and also one of the most widely distributed
neuropeptides in the brain; it is considered a putative
central nervous system transmitter. The peripheral
effects of CCK are mediated mainly through CCK- A
receptor subtype, while the central effects are corre-
lated with the CCK-B receptor subtype. The CCK-B
receptor is involved in many pathological situations.
Among these, anxiety, panic and schizophrenia are
particularly relevant targets for therapeutic inter-
ventions [1Ϫ5]. Radioimmunoassay and immunohisto-
chemical studies have shown that CCK-B and the
opioid peptides, enkephalins, have a similar distri-
bution within many areas of the CNS and it has been
shown that CCK behaves as an antagonist of opiate
analgesia. Thus, the administration of CCK receptor
antagonists or active immunization against CCK, en-
hances the antinociception produced by exogenous
opiates [6Ϫ8]. 3-Ureido benzodiazepines are one of
the most important groups of nonpeptide CCK recep-
tor antagonists. L-365,260 (Figure 1), a selective CCK-
B receptor antagonist, enhances morphine analgesia
in the animal models [9]. In previous studies, we de-
signed and synthesized a new group of flexible benzo-
diazepine agonists with 1,2,4-triazole [10] and 1,3,4-
oxadiazole (unpublished data) rings, compound 1 (Fig-
ure 1), with all benzodiazepine main pharmacophores.
Some of them showed benzodiazepine activity com-
parable with diazepam [10].
Since addition of an ureido group to a suitable position
of the benzodiazepine structure generates CCK-B
selective antagonist, e.g. L-365,260, we also inserted
the same group into our 1,3,4-oxadiazole benzodia-
zepine ligands to produce a similar effect.
To clarify whether the designed compounds 8 (Figure
1) could mimic the structure of CCK antagonists, con-
formational analysis on designed molecules as well as
a known CCK-B antagonist, L-365,260 (Figure 1) was
performed followed by superimposition of energy min-
ima conformers. In this paper, the synthesis and evalu-
ation of morphine analgesia enhancement of these
compounds are reported.
Correspondence: Abbas Shafiee, Department of Medicinal
Chemistry and Pharmaceutical Sciences Research Center,
Faculty of Pharmacy, Tehran University of Medical Sciences,
P.O. Box: 14155-6451, Tehran, Iran. Phone: +98-21-640
6757, Fax: +98-21-646 1178, e-mail: ashafiee@ams.ac.ir
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194 Shafiee et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 193−200
Figure 1. Structures of L-365,260, compounds 1 and 8.
Figure 2. (i) N2H4.H2O, CH3CH2OH, room temp.; (ii) BrCN, NaHCO3, dioxane, room temp.
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 193−200
N-[5-(2-phenoxyphenyl)-1,3,4-oxadiazole-2-yl]-NЈ-phenylurea Derivatives 195
Scheme 1. (i) semicarbazide hydrochloride, CH3COONa, H2O, reflux; (ii) Br2, CH3COOH, CH3COONa; (iii) phenyl
isocyanate derivatives, CH3COOEt, DMF, reflux.
Chemistry
lowed by PM3 calculation by the program hyperchem
5.02 [18]. Among all energy minima conformers, the
global minimum of compound 8j was compared with
the global minimum of L-365,250, as a reference CCK-
B antagonist. Thus the superimposition of these con-
formers were performed (Figure 3) to confirm whether
the synthesized compounds could mimic the major
comformation of the reference structure, although
other minima conformers are well superimposible. The
overlapping of low energy conformers shows that the
aromatic rings, annelated benzene of the benzodia-
zepine skeletone in addition to two other phenyl
groups, fall in the same contour of the synthesized
compounds.
The designed compounds were synthesized according
to Figure 2 and Scheme 1. Compounds 2aϪb and 5
were prepared by the known procedures [11Ϫ13]. 2-
Phenoxybenzoic acid hydrazides (3aϪb) were pre-
pared from the reaction of hydrazine hydrate with
methyl 2-phenoxybenzoates (2aϪb). The intermediate
2-amino oxadiazoles (4aϪb) were synthesized by re-
acting 3aϪb with BrCN [14]. In order to prepare benz-
aldehyde semicarbazone 6, compound 5 was allowed
to react with semicarbazide hydrochloride in aqueous
solution of sodium acetate. Reaction of compound 6
with bromine in glacial acetic acid contating anhydrous
sodium acetate gave compound 7 [15]. The urea de-
rivatives 8aϪ8p listed in Table 1 were prepared by re-
action of the appropriate amino oxadiazoles (4aϪb, 7)
with substituted phenyl isocyanates in ethyl acetate or
ethyl acetate and DMF [16Ϫ17].
Pharmacology
Male NMRI mice (Pasteur Institute of Iran) weighting
25-30 g were used in the present study. The animals
were housed in groups of 8 in conditions of constant
temperature (20 1°C) and a 12 h light/dark schedule
and were allowed free access to food and water.
Conformational analysis
Conformations of the synthesized compounds and
L-365,260 were optimized through MM+ force filed fol-
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196 Shafiee et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 193−200
Table 1. Physical properties of compounds 8aϪ8p.
Compound
No.
R
RЈ
Recrystallization
solvent
Yield
(%)
Mp
(°C)
Formula†
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
Cl
Cl
Cl
Cl
Cl
Cl
F
F
F
H
m-Cl
p-Cl
m-,p-Cl
m-CH3
p-CH3
H
m-Cl
p-Cl
m-CH3
p-CH3
H
m-Cl
p-Cl
petr.ether-CHCl3
dioxane-H2O
dioxane-H2O
dioxane-H2O
CHCl3
71
55
60
93
70
68
61
32
51
53
53
70
55
84
66
72
185Ϫ187
199Ϫ201
188Ϫ191
204Ϫ206
179Ϫ181
173Ϫ175
187Ϫ189
217Ϫ219
188Ϫ189
202Ϫ204
181Ϫ183
150Ϫ151
157Ϫ159
154Ϫ155
154Ϫ156
158Ϫ159
C21H15ClN4O3
C21H14Cl2N4O3
C21H14Cl2N4O3
C21H13Cl3N4O3
C22H17ClN4O3
C22H17ClN4O3
C21H15FN4O3
C21H14ClFN4O3
C21H14ClFN4O3
C22H17FN4O3
C22H17FN4O3
C21H15N5O5
petr.ether-CHCl3
THF
i-PrOH
i-PrOH
THF
THF
THF
i-PrOH
i-PrOH
THF
F
F
NO2
NO2
NO2
NO2
NO2
C21H14ClN5O5
C21H14ClN5O5
C22H17N5O5
m-CH3
p-CH3
THF
C22H17N5O5
†
All Compounds were analyzed for C, H, N. Analytical results obtained for these elements were within 0.4%
of the calculated value for the formula shown.
The animals were tested for thermal analgesia using
a standard hot-plate method. Briefly, each mouse was
placed on hot-plate surface maintained at 55 0.1°C.
The mouse was removed from the hot plate as soon
as it licked a hind paw, and the time from hot-plate
placement to hind paw lick was recorded. Before drug
administration, the animal was placed on the hot plate
twice and the mean latency to response was recorded
and served as the control latency for that animal. Maxi-
mal analgesia was observed 20 min following mor-
phine injection.
In this study, the vehicle (containing 2.5% DMSO,
75% propylene glycol and 22.5% distilled water), or
test compounds (0.1, 0.15, 0.3, 0.5, 1.25, 2.5, 4.0, 6.0,
10.0 mg/kg) were injected to the animals 10 min prior
to i.p. injection of vehicle of morphine (normal saline)
or 4 mg/kg morphine. Lick latencies were measured
20 min after the second injection [9]. Statistics were
performed with one-way analysis of variance
(ANOVA), which was followed by Newman Kelaus
test. All data are presented as mean SEM (Table 2).
The animals were removed from the hot plate if no
response was seen within 45 seconds, and were as-
signed a maximal analgesic score of 100%. The re-
sults were expressed as the percentage of the maxi-
mal possible effect (% MPE) as following. % MPE =
[(post drug latency-predrug latency)/(cut off time-pre-
drug latency)] ϫ 100.
Results and discussion
The designed compounds were screened for mor-
phine analgesia enhancement effect in mice. Com-
pounds 8a, 8c, 8hϪ8j, 8l, and 8o showed significant
activity in comparison with the control group (Table 2).
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 193−200
N-[5-(2-phenoxyphenyl)-1,3,4-oxadiazole-2-yl]-NЈ-phenylurea Derivatives 197
Figure 3. The superimposition of the energy minima conformers of L-365,260 (top left) and compound 8j (top
right).
Table 2. Morphine enhancement activity of N-[5-(2-phenoxyphenyl)-1,3,4-oxadiazole-2-yl]-NЈ-phenylurea derivatives.
Compound
No.†
studied doses
(mg/kg)
effective
doses
MPE (%)‡
Value§
derivatives
8a
8c
8h
8i
0.1, 0.3, 0.5
1.25, 2.5, 10
0.1, 0.15, 0.3, 0.5
0.3, 0.5, 1.25, 4,
6.30, 10
0.1, 0.3
10.0
0.3, 0.5
1.25, 4.0
6.0, 10
45.60 15.09, 53.45 19.15
69.83 14.31
77.27 10.04, 80.8 9.17
52.58 10.22, 71.98 17.16
58.62 12.07, 62.28 17.06
P <0.05, P <0.05
P <0.001
P <0.001, p <0.001
P <0.05, P <0.01
P <0.05, P <0.01
8j
8l
0.1, 0.15, 0.3, 0.5
0.15, 0.3, 0.5 53.45 21.23, 56.90 16.62, P <0.05, P <0.05, P <0.05
66.06 20.98
0.1, 0.15, 0.3, 0.5
0.15, 0.3, 0.5 79.74 9.63, 49.20 18.10,
77.83 10.50
P <0.001, p <0.05, p <0.001
8o
0.15, 0.3, 0.5, 1.25 1.25
54.20 19.70
P <0.01
†
only effective compounds are reported.
MPE(%) for control group was 6.07 3.93.
as compared to the control group (n = 8).
‡
§
In addition, 8a, 8h, 8j, 8l had activity comparable with
L-365,260 in a similar study [9]. Superimposition of en-
ergy minima conformers shows that the aromatic rings
of synthesized compounds and L-365,260 are well
matched, but substitutions of the phenyl ring could in-
crease or decrease their effects. Because of partial
structural similarity between our compounds and typi-
cal benzodiazepine CCK-B antagonists, it is likely that
the designed structures show this effect through CCK-
B antagonistic activity.
Experimental
Chemicals were purchased from Merck chemical company
(Darmstadt, Germany). Melting points were taken on a Kofler
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198 Shafiee et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 193−200
hot stage apparatus (Reichert, Vienna, Austria) and are un-
corrected. 1H-NMR spectra were obtained using a Bruker FT-
80 spectrometer (Bruker, Rheinstetten, Germany). Tetra-
methylsilane was used as an internal standard. Mass spectra
were obtained using a Finnigan MAT TSQ-70 spectrometer
at 70 eV (Finnigan, Bremen, Germany). The IR spectra were
obtained using a Nicolet FT-IR Magna 550 spectrographs
(KBr disks) (Nicolet, Madison, WI, USA). Elemental analyses
were within 0.4% of theoretical values for C, H and N.
2-Amino-5-[2-(2-nitrophenoxy)phenyl]-1,3,4-oxadiazole (7)
To a stirring suspension of 6 (10 g, 33 mmol) and anhydrous
sodium acetate (10.9 g, 133 mmol) in glacial acetic acid (120
mL), bromine (1.9 mL, 73 mmol) in glacial acetic acid (20 mL)
was added dropwise. The mixture was stirred for 2h at room
temperature and then poured into ice-water. An oil was col-
lected, dissolved in glacial acetic acid, treated with activated
carbon, and heated at 50°C for 5 min. After filtration, water
(l00 mL) was added to filtrate. The precipitate was collected
and crystallized from EtOH-water to give 4.1 g of 7 (41%),
mp 128Ϫ129°C. Ϫ IR (KBr): ν cmϪ1 3403, 3323 (NH2), 1653
(NH2), 1520, 1348 (NO2). 1H NMR (CDCl3): δ = 8.04 (dd, J =
8.0, 2.4 Hz, 1H, aromatic), 7.89 (dd, J = 7.3, J = 2.3 Hz, 1H,
aromatic), 7.48Ϫ7.06 (m, 5H, aromatic), 6.73 (d, J = 8.20 Hz,
1H, aromatic), 5.63 (bs, 2H, NH2). Ϫ MS: m/z (%) 298 (M+,
19), 254 (100), 196 (19), 182 (67), 168 (43), 139 (47).
2-(2-Chlorophenoxy)benzoic acid hydrazide (3a)
To a stirring solution of compound 2a (9.5 g, 36 mmol) in 17
mL ethanol, at room temperature hydrazine hydrate (9 mL,
180 mmol) was added. After 2 h the contents were poured
on water (40 mL) and filtered. The precipitate was crystallized
from ethanol to give 8.0g (84%) of 3a; mp 122Ϫ124°C.- IR
(KBr): ν cmϪ1 3315, 3203 (NH2, NH), 1630 (C=O). Ϫ 1H-NMR
(CDCl3): δ = 8.68 (bs, 1H, NH), 8.23(dd, J = 7.2, 2.5 Hz, 1H,
aromatic), 7.57Ϫ7.00 (m, 6H, aromatic), 6.66 (dd, J = 8.8,
1.6 Hz, 1H, aromatic), 4.18 (bs, 2H, NH2).
General Procedure for the prepartion of N-[5-(2-phenoxy-
phenyl)]-1,3,4-oxadiazole-2-yl]-NЈ-phenylurea
(8aϪ8p)
derivatives
A solution of amino oxadiazole 4a, 4b or 7 (1.2 mmol) and
substituted phenyl isocyanate (1.40 mmol) in dry EtOAc or
EtOAc-DMF was heated under reflux until isocyanate was no
longer monitored by tlc. After cooling, the precipitate was col-
lected and washed with cold EtOAc and crystallized from a
suitable solvent. In some cases several recrystallizations
were required to remove the symmetrical urea also formed
as a by-product.
2-(2-Fluorophenoxy)benzoic acid hydrazide (3b)
This compound was prepared similar to 3a in 93% yield, mp
114-115°C. Ϫ IR (KBr): ν cmϪ1 3313, 3201 (NH2, NH), 1644
1
(C=O). Ϫ H-NMR (CDCl3): δ = 8.74 (bs, 1H, NH), 8.22 (dd,
J = 8.8, 2.27 Hz, 1H, aromatic), 7.39Ϫ7.17 (m, 6H, aromatic),
6.72 (d, J = 7.7 Hz, 1H, aromatic), 3.97 (bs, 2H, NH2).Ϫ MS:
m/z (%), 247 (M+1, 31), 215 (100), 159 (32), 133 (40).
Melting points, crystallization solvents, and yield for ureas
8aϪ8p are reported in Table 1.
2-Amino-5-[2-(2-chlorophenoxy)phenyl]-1,3,4-oxadiazole (4a)
N-[5-(2-(2-Chlorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
phenyurea (8a)
To a stirring solution of 3a (6.8 g, 25.9 mmol) in 60 mL of
dioxane, sodium bicarbonate (2.17 g, 25.8 mmol) in water (40
mL) was added at room temperature. After the mixture was
stirred at room temperature for 5 min cyanogen bromide (2.75
g, 26 mmol) was added. After 3hrs water (200 mL) was added
to the mixture and the precipitate was removed by filtration
and crystallized from ethanol to give 6.0 g (80%) of 3a; mp
144Ϫ146°C. Ϫ IR (KBr): ν cmϪ1 3335, 3124 (NH2). Ϫ 1H-
NMR (CDCl3): δ = 7.98 (dd, 1H, J = 7.3, 2.1 Hz, aromatic),
7.50-6.78 (m, 7H, aromatic), 5.54 (bs, 2H, NH2). Ϫ MS: m/z
(%), 287 (M+, 60), 252 (100), 209 (9), 182 (25), 152 (27).
IR (KBr): ν cmϪ1 3286, 3222 (NH), 1680 (C=O). Ϫ 1H-NMR
(CDCl3): δ = 10.20 (bs, 1H, NH), 9.30 (bs, 1H, NH), 8.00 (d,
J = 8.0 Hz, 1H, aromatic), 7.60Ϫ7.00 (m, 11H, aromatic), 6.75
(d, J = 8.0 Hz, 1H, aromatic). Ϫ MS: m/z (%) 406 (M+, 13),
288 (40), 287 (62), 252 (100), 182 (25).
N-[5-(2-(2-Chlorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(3-chlorophenyl)urea (8b)
IR (KBr): ν cmϪ1 3260, 3235 (NH), 1680 (C=O). Ϫ 1H-NMR
(CDCl3): δ = 11.1 (bs, 1H, NH), 9.69 (bs, 1H, NH), 7.95 (d,
J = 8.0 Hz, 1H, aromatic), 7.76Ϫ6.91 (m, 11H, aromatic). Ϫ
MS: m/z (%) 441 (M+, 15), 313(14), 288 (40), 287 (20), 278
(70), 252 (100), 168 (28), 155 (30), 153 (91), 129 (22), 127
(80).
2-Amino-5-[2-(2-fluorophenoxy)phenyl]-1,3,4-oxadiazole (4b)
This compound was prepared similar to 4a in 94% yield; mp
208Ϫ210°C. Ϫ IR (KBr): ν cmϪ1 3288, 3114 (NH2). Ϫ 1H-
NMR (CDCl3): δ = 7.92 (dd, 1H, J = 7.4, 2.0 Hz, aromatic),
7.58Ϫ7.12 (m, 6H, aromatic), 6.85 (d, J = 7.96 Hz, 1H, aro-
matic), 6.43 (bs, 2H, NH2). Ϫ MS: m/z (%) 271 (M+, 100),
214 (10), 198 (30), 170 (20).
N-[5-(2-(2-Chlorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(4-chlorophenyl)urea (8c)
IR (KBr): ν cmϪ1 3278, 3209 (NH), 1685 (C=O).- 1H-NMR
(CDCl3): δ = 11.1 (bs, 1H, NH), 9.53 (bs, 1H, NH), 7.82 (dd,
J = 8.0, 2.2 Hz, 1H, aromatic), 7.98Ϫ7.11 (m, 10H, aromatic),
6.87 (d, J = 8.0 Hz, 1H, aromatic). Ϫ MS: m/z (%) 441 (M+,
13), 313(78), 286 (100), 229 (14), 214 (31), 168 (30).
2-(2-Nitrophenoxy)benzaldehyde semicarbazone (6)
A mixture of aldehyde 5 (9.0g, 37 mmol), semicarbazide hy-
drochloride (18 g, 156 mmol) and sodium acetate trihydrate
(27 g, 198 mmol) in 300 mL water was refluxed for 2 h. After
cooling, the precipitate was filtered and washed with water
and petroleum ether, then crystallized from water to give 10.4
g of 6 (93%); mp 151Ϫ154°C. Ϫ IR (KBr): ν cmϪ1 3490,
N-[5-(2-(2-Chlorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(3,4-dichlorophenyl) urea (8d)
1
3350 (NH2, NH), 1673 (C=O), 1520, 1355 (NO2). Ϫ H NMR
(CDCl3): δ = 9.25 (bs, 1H, NH), 8.04 (s, 1H) 8.00Ϫ7.85 (m,
2H, aromatic), 7.59Ϫ6.82 (m, 6H, aromatic), 5.6 (bs, 2H,
NH2): Ϫ MS: m/z (%) 300 (M+, 10), 195(10), 181 (43), 152
(24), 122 (100).
IR (KBr): ν cmϪ1 3277, 3205 (NH), 1700 (C=O). Ϫ 1H-NMR
(CDCl3): δ = 10.50 (bs, 1H, NH), 9.80 (bs, 1H, NH), 7.94-7.28
(m, 10H, aromatic), 6.97 (d, J = 8.0 Hz, 1H, aromatic). Ϫ MS:
m/z (%) 475 (M+, 15), 287(100), 246 (65), 216 (40).
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 193−200
N-[5-(2-phenoxyphenyl)-1,3,4-oxadiazole-2-yl]-NЈ-phenylurea Derivatives 199
N-[5-(2-(2-Chlorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(3-methylphenyl)urea (8e)
(%) 417 (M+, 12), 298 (9), 252 (100), 196 (20), 182 (65),
139 (46).
IR (KBr): ν cmϪ1 3260, 3231 (NH), 1700 (C=O). Ϫ 1H-NMR
(CDCl3): δ = 10.50 (bs, 1H, NH), 9.23 (bs, 1H, NH), 7.83 (dd,
J = 8.0, 2.2 Hz, 1H, aromatic), 7.89Ϫ6.81 (m, 11H, aromatic),
2.31 (s, 3H, CH3). Ϫ MS: m/z (%) 420 (M+, 17), 314 (20),
285 (100), 231 (77), 215 (52), 77 (95).
N-[5-(2-(2-Nitrophenoxyphenyl)-1,3,4-oxadiazole-2-yl]-NЈ-(3-
chlorophenyl)urea (8m)
IR (KBr): ν cmϪ1 3264, 3210 (NH), 1693 (C=O), 1348, 1547
(NO2). Ϫ 1H-NMR (DMSO-d6): δ = 11.20 (bs, 1H, NH), 9.82
(bs, 1H, NH), 8.12-7.98 (m, 2H, aromatic), 7.70Ϫ7.25 (m, 9H,
aromatic), 6.90 (d, J = 8.5 Hz, 1H, aromatic). Ϫ MS: m/z (%)
451(M+, 12), 252 (10), 182 (8), 153 (100), 127 (50).
N-[5-(2-(2-Chlorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(4-methylphenyl)urea (8f)
IR (KBr): ν cmϪ1 3260, 3205 (NH), 1683 (C=O). Ϫ 1H-NMR
(CDCl3): δ = 10.1 (bs, 1H, NH), 9.15 (bs, 1H, NH), 7.96 (d, J =
8.0 Hz, 1H, aromatic), 7.50Ϫ7.00 (m, 10H, aromatic), 6.80 (d,
J = 8.0 Hz, 1H, aromatic), 2.31 (s, 3H, CH3). Ϫ MS: m/z (%)
420 (M+, 14), 313(4), 215 (19), 186 (24), 137 (100), 123 (71)
77 (50).
N-[5-(2-(2-Nitrophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(4-chlorophenyl)urea (8n)
IR (KBr): ν cmϪ1 3264, 3202 (NH), 1686 (C=O), 1540, 1328
(NO2). Ϫ 1H-NMR (DMSO-d6): δ = 11.30 (bs, 1H, NH), 9.95
(bs, 1H, NH), 8.80Ϫ7.90 (m, 2H, aromatic), 7.58Ϫ6.90 (m,
10H, aromatic). Ϫ MS: m/z (%) 451 (M+, 15), 324 (15), 294
(24), 252 (66), 182 (38), 152 (100), 127 (92).
N-[5-(2-(2-Fluorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
phenylurea (8g)
N-[5-(2-(2-Nitrophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(3-methylphenyl)urea (8o)
IR (KBr): ν cmϪ1 3278, 3236 (NH), 1685 (C=O). Ϫ 1H-NMR
(DMSO-d6): δ = 11.03 (bs, 1H, NH), 9.57 (bs, 1H, NH), 7.92
(dd, J = 8.0, J = 2.6 Hz, 1H, aromatic), 7.78Ϫ6.88 (m, 12H,
aromatic). Ϫ MS: m/z (%) 390 (M+, 10), 297(18), 271 (100),
199 (28), 170 (24).
IR (KBr): ν cmϪ1 3280, 3231 (NH), 1686 (C=O), 1534, 1347
1
(NO2). Ϫ H-NMR (CDCl3): δ = 11.13 (bs, 1H, NH), 9.87 (bs,
1H, NH), 8.09Ϫ7.90 (m, 2H, aromatic), 7.61Ϫ6.90 (m, 10H,
aromatic), 2.34 (s, 1H, CH3). Ϫ MS: m/z (%) 431 (M+, 15),
324 (20), 298 (20), 252 (100), 182 (50),139 (50), 133 (55).
N-[5-(2-(2-Fluorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(3-chlorophenyl)urea (8h)
N-[5-(2-(2-Nitrophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(4-methylphenyl)urea (8p)
IR (KBr): ν cmϪ1 3290, 3237 (NH), 1690 (C=O). Ϫ 1H-NMR
(DMSO-d6): δ = 11.05 (bs, 1H, NH), 9.71 (bs, 1H, NH), 7.94
(d, J = 8.0 Hz, 1H, aromatic), 7.59Ϫ6.91 (m, 11H, aromatic).
Ϫ MS: m/z (%) 424 (M+, 10), 298 (14), 270 (43), 62 (100).
IR (KBr): ν cmϪ1 3266, 3220 (NH), 1693 (C=O), 1534, 1341
1
(NO2). Ϫ H-NMR (CDCl3): δ = 10.95 (bs, 1H, NH), 9.82 (bs,
1H, NH), 8.15Ϫ7.90 (m, 2H, aromatic), 7.59Ϫ6.93 (m, 10H,
aromatic), 2.31 (s, 3H, CH3). Ϫ MS: m/z (%) 431 (M+, 17),
298 (24), 252 (43), 182 (19),139 (19), 133 (100), 106 (52).
N-[5-(2-(2-Fluorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(4-chlorophenyl)urea (8i)
IR (KBr): ν cmϪ1 3285, 3201 (NH), 1695 (C=O). Ϫ 1H-NMR
(DMSO-d6): δ = 11.08 (bs, 1H, NH), 9.66 (bs, 1H, NH), 7.95
(dd, J = 8.0, 2.3 Hz, 1H, aromatic), 7.70Ϫ6.92 (m, 11H, aro-
matic). Ϫ MS: m/z (%) 424 (M+, 10), 296 (83), 271 (100), 199
(32), 170 (43), 75 (43).
References
[1] H. Ito, H. Sogabe, Y. Satoh, Drug Fut. 1995, 20,
587Ϫ599.
N-[5-(2-(2-Fluorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(3-methylphenyl)urea (8j)
[2] E. Lattmann, J. Sattayasai, D. C. Billington, D. R.
Poyner, P. Puapairoj, S. Tiamkao, W. Airarat, H. Singh,
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IR (KBr): ν cmϪ1 3319, 3222 (NH), 1695 (C=O). Ϫ 1H-NMR
(DMSO-d6): δ = 11.01 (bs, 1H, NH), 9.56 (bs, 1H, NH), 7.90
(d, J = 8.0, 1H, aromatic), 7.52Ϫ6.86 (m, 11H, aromatic), 2.28
(s, 3H, CH3). Ϫ MS: m/z (%) 404 (M+, 15), 296 (17), 271
(32), 199 (32), 170 (41), 77 (100).
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N-[5-(2-(2-Fluorophenoxy)phenyl)-1,3,4-oxadiazole-2-yl]-NЈ-
(4-methylphenyl)urea (8k)
IR (KBr): ν cmϪ1 3278, 3220 (NH), 1695 (C=O). Ϫ 1H-NMR
(CDCl3): δ = 10.10 (bs, 1H, NH), 9.99 (bs, 1H, NH), 8.01 (dd,
J = 8.2, 2.1 Hz, 1H), 7.50Ϫ6.81 (m, 11H, aromatic), 2.30 (s,
3H, CH3). Ϫ MS: m/z (%) 404 (M+, 10), 296 (28), 270 (100),
198 (46), 168 (51), 133 (81).
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79Ϫ93.
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phenylurea (8l)
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(NO2). Ϫ 1H-NMR (DMSO-d6): δ = 9.71 (bs, 1H, NH), 11.02
(bs, 1H, NH), 8.15-7.96 (m, 2H, aromatic), 7.76Ϫ7.10 (m,
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 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim