Synthesis and evaluation of some novel quinazolinone derivatives as diuretic agents

Article abstract of DOI:10.1002/ardp.200400869

A new series of quinazolin-4(3H)-one derivatives containing either a thiazole or a 1,3,4-thiadiazole moiety were prepared in order to study the effect of such a heterocyclic combination on the expected diuretic activity. Synthesis of the target compounds (2, 4, and 6) has been achieved through an interaction of the starting 7-chloro-2-methyl-4H-3,1-benzoxazin-4-one 1 with different heterocyclic amines. Alkylation of 3-(2-mercapto-1,3,4-thiadiazol-5- yl)quinazolin-4(3H)-one derivative 4 with different alkyl halides or chloroacetic acid afforded the corresponding thioethers 5 while interaction of 2-methyl-3-(1,3,4-thiadiazol-5-yl or thiazol-5-yl)quinazolin-4(3H)-ones (2 and 6) with various aromatic aldehydes resulted in the formation of the arylvinyl analogs 3 and 7, respectively. On the other hand, 2-morpholinomethyl-3-(2- sulfamoyl or mercapto-1,3,4-thiadiazol-5-yl)quinazolin-4(3H)-one derivatives 10 have also been synthesized through an interaction of the sulfonamide or thiol analog 9 with the appropriate amine. Biological evaluation of some of the target compounds as diuretic agents was carried out. The results showed that 2-[2-(4-chlorophenyl)vinyl]-7-chloro-3-(2-sulfamoyl-1,3,4-thiadiazol-5-yl) quinazolin-4(3H)-one 7b exhibited significant diuretic activity. The detailed synthesis, spectroscopic and biological data are reported.

Full text of DOI:10.1002/ardp.200400869

Arch. Pharm. Pharm. Med. Chem. 2004, 337, 527−532
Novel Quinazolinone Derivatives as Diuretic Agents 527
Azza R. Maaroufa,
Synthesis and Evaluation of some Novel
Quinazolinone Derivatives as Diuretic Agents
Eman R. El-Bendarya,
Fatma E. Godab
a Medicinal Chemistry,
College of Pharmacy,
Mansoura University,
Mansoura 35516, Egypt
b Pharmaceutical Organic
Chemistry Departments,
College of Pharmacy,
Mansoura University,
Mansoura 35516, Egypt
A new series of quinazolin-4(3H)-one derivatives containing either a thiazole or
a 1,3,4-thiadiazole moiety were prepared in order to study the effect of such a
heterocyclic combination on the expected diuretic activity. Synthesis of the target
compounds (2, 4, and 6) has been achieved through an interaction of the
starting 7-chloro-2-methyl-4H-3,1-benzoxazin-4-one 1 with different heterocyclic
amines. Alkylation of 3-(2-mercapto-1,3,4-thiadiazol-5-yl)quinazolin-4(3H)-one
derivative 4 with different alkyl halides or chloroacetic acid afforded the corre-
sponding thioethers 5 while interaction of 2-methyl-3-(1,3,4-thiadiazol-5-yl or thi-
azol-5-yl)quinazolin-4(3H)-ones (2 and 6) with various aromatic aldehydes re-
sulted in the formation of the arylvinyl analogs 3 and 7, respectively. On the
other hand, 2-morpholinomethyl-3-(2-sulfamoyl or mercapto-1,3,4Ϫthiadiazol-5-
yl)quinazolin-4(3H)-one derivatives 10 have also been synthesized through an
interaction of the sulfonamide or thiol analog 9 with the appropriate amine. Bio-
logical evaluation of some of the target compounds as diuretic agents was
carried out. The results showed that 2-[2-(4-chlorophenyl)vinyl]-7-chloro-3-(2-
sulfamoyl-1,3,4-thiadiazol-5-yl)quinazolin-4(3H)-one 7b exhibited significant
diuretic activity. The detailed synthesis, spectroscopic and biological data are re-
ported.
Keywords: 4(3H)-Quinazolinones; Thiazolylquinazolinones; Thiadiazolylquin-
azolinones; Diuretic activity
Received: January 21, 2004; Accepted: May 25, 2004 [FP869]
DOI 10.1002/ardp.200400869
Introduction
that is used effectively in treatment of hypertension
[20]. In addition, thiadiazole and thiadiazoline sulfon-
Literature survey has revealed the value of some new
classes of condensed pyrimidines as biologically ver-
satile compounds possessing diuretic [1], antimicrobial
[2, 3], hypnotic and anticonvulsant [4], analgesic/anti-
inflammatory [5], antiviral and anti-tumor [6, 7] activi-
ties.
amides are carbonic anhydrase inhibitors representing
an important group of diuretic agents [21]. A series of
novel 2-substituted acetylamino-5-alkyl-1,3,4Ϫthia-
diazoles were proven to possess diuretic activity com-
pared to that of furosemide [22]. 2,5-Disubstituted-
1,3,4-thiadiazole derivatives were also reported to ex-
hibit carbonic anhydrase inhibiting activity [23]. The
extensive Japanese study [24] on the diuretic activity
of 219 polyazanaphthalenes concluded that morpho-
lino and 4-chlorophenyl moieties are the most prefer-
able substituents for the diuretic activity and the pres-
ence of a halogen (fluorine or chlorine in a biologically
active molecule is known to enhance its lipid solubility
and absorption). Moreover, it is well known that the
methyl group at position-2 of quinazoline ring system
possesses high reactivity and can be condensed with
many aldehydes to afford the corresponding 2-vinyl
derivatives [25].
Likewise, many fused pyrimidines such as quinazo-
lines and pyridopyrimidines have been reported to
exhibit diuretic [8, 9], anti-inflammatory [10, 11], anti-
microbial [12], and anticancer [13, 14] activities. More-
over, several quinazolinone derivatives were synthe-
sized as potential antimicrobial [15], anticancer [16],
and antimalarial [17] agents. Cohen et al [18] were the
first to report on the synthesis and diuretic activity of
quinazolinone sulfonamides. Quinethazone (a thiazide
with diuretic activity), in which the cyclic (SO2) was iso-
sterically replaced by (C=O) group [19], was reported
to be as effective as chlorothiazide [18]. Metolazone is
a 3-phenyl-substituted quinazolinone diuretic agent
Considering the above finding, it was thought worth-
while to prepare certain novel thiadiazolyl or thiazol-
ylquinazolinones (isosteres) as well as their vinyl anal-
ogs carrying sulfonamide residue, 4-chlorophenyl,
morpholino, or dimethylmorpholino moiety in order to
Correspondence: Azza R. Maarouf, Medicinal Chemistry
Department, College of Pharmacy, Mansoura University,
El Mansoura 35516, Egypt. Phone: +20 50 224-7496, Fax:
+20 50 224-7496, e-mail: azza rashad@hotmail.com
Ϫ
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528 Maarouf et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 527−532
Scheme 1. Synthesis of thiazolyl and thiadiazolyl quinazolin-4(3H)-one derivatives.
explore and to study the effect of such heterocyclic
combination on their expected diuretic activity. The de-
signed compounds were synthesized via application of
the reaction pathways shown in Schemes 1 and 2.
yields. Interaction of the starting 2-methylbenzoxazin-
4-one 1 with 5-amino-1,3,4Ϫthiadiazole-2-thiol re-
sulted in the formation of the 2-methylquinazolinone 4.
Mercaptoetherification of compound 4 with various
alkyl halides or chloroacetic acid in refluxing pyridine
furnished the thioethers 5aϪd. On the other hand,
heating of compound 1 with 5-amino-1,3,4Ϫthiadi-
azole-2-sulfonamide [27] in glacial acetic acid at reflux
temperature yielded the sulfonamide analog 6, which
upon condensation with the appropriate aromatic
aldehydes by fusion at 140Ϫ150°C, afforded the aryl-
vinyl derivatives 7a؊c (Scheme 1, Table 1). Further-
more, 7-chloro-2-morpholinomethyl or 2,6-dimethyl-
morpholinomethyl-3-(2-substituted-1,3,4-thiadiazol-5-
yl)quinazolin-4(3H)-ones 10aϪd were prepared
starting from 4-chloroanthranilic acid using the routes
depicted in Scheme II. 4-Chloroanthranilic acid was al-
lowed to react with chloroacetyl chloride in dichloro-
methane in the presence of triethylamine to afford the
chloroacetylamino intermediate [8] 8 that was cyclized
Results and discussion
Chemistry
Schemes I and II were adopted for the preparation of
the target quinazolinone derivatives. 7-Chloro-2-
methyl-4H-3,1-benzoxazin-4-one 1 was prepared ac-
cording to the directions of Desai and his co-workers
[26]. Compounds 2a,b were obtained by heating at
150Ϫ170°C an intimate mixture of benzoxazine 1 and
2-amino-1,3,4-thiadiazole or 2-amino-1,3-thiazole,
respectively. 2-Methyl-3-substituted-4-quinazolinones
2 were fused with different aromatic aldehydes at
140Ϫ150°C in the presence of anhydrous zinc chloride
to afford the 2-arylvinyl quinazolinones 3aϪh in good
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 527−532
Novel Quinazolinone Derivatives as Diuretic Agents 529
Scheme 2. Synthesis of morpholinomethyl thiadiazolyl quinazoline-4(3H)-one derivatives.
with 5-amino-1,3,4-thiadiazole-2-sulfonamide or 5-
amino 1,3,4-thiadiazole-2-thiol in toluene in the
presence of PCl3 to get the 3-(2-substituted thiadiazo-
lyl)quinazolinones 9a,b. Two equivalents of morph-
oline or its 2,6-dimethyl analog were then reacted
with 2-chloromethylquinazolinone derivatives 9a,b in
dichloromethane to afford the corresponding 2-morph-
olinomethyl analogs 10a-d (Scheme 2, Table 1). The
structure assignment of these compounds was estab-
lished by elemental analyses and spectral data.
steric residue incorporated at the 3-position. Only one
compound, the arylvinyl sulfonamide 7b was found to
produce a significant diuretic activity in the treated ani-
mals. A 75% increase in the urine volume compared
to control at the specified dose (100 mg/kg) was no-
ticed (Table 2). Compounds 4 and 6 showed moderate
activities with 14 and 30% increase in the urine vol-
ume, respectively. Regarding compound 2, the iso-
steric replacement of the thiadizole ring at the 3-posi-
tion of quinazolinone with a thiazole ring resulted in
the formation of a completely inactive analog. The ac-
tivities of compounds 3a, 5a, 5d, and 10b seem insig-
nificant while the other tested compounds are devoid
of any diuretic activity.
Biological screening
Ten of the newly synthesized compounds were tested
for their diuretic activity in rats at a dose 100 mg/kg
using furosemide as a reference standard [28] (Table
2). Our screening efforts were directed towards the
evaluation of the diuretic activities of the 4-quinazoli-
none derivatives with the thiazole or thiadiazole iso-
In general terms, the 4-quinazolinone derivatives with
unsubstituted thiazole or thiadiazole residue at the 3-
position were found to be inactive. On the other hand,
it seems that the replacement of sulfhydryl group at
the 5-position of the thiadiazolyl moiety in compound
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530 Maarouf et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 527−532
Table 1. Physical properties and molecular formulae of the synthesized compounds.
Comp.
Ar
R(X)
mp°C
Rec. Sol.† Yield (%)
Formulae‡
2a
2b
3a
3b
3c
3d
3e
3f
3g
3h
5a
5b
5c
5d
7a
7b
7c
Ϫ
(N)
(CH)
(N)
(N)
(N)
210Ϫ212
189Ϫ191
235Ϫ237
263Ϫ265
169Ϫ171
243Ϫ245
261Ϫ263
>300
E/W
E
C/E
C/E
E
73
62
70
68
60
65
87
74
67
63
77
70
61
69
57
62
49
68
66
59
43
73
56
C11H7ClN4OS
C12H8ClN3OS
Ϫ
4-Br-C6 H4
4-Cl-C6H4
3-pyridyl
2-thienyl
4-Br-C6 H4
4-Cl-C6H4
3-pyridyl
2-thienyl
Ϫ
C18H10BrClN4OS
C18H10Cl2N4OS
C17H10ClN5OS
C16H9ClN4OS2
C19H11Br ClN3OS
C19H11Cl2N3OS
C18H11ClN4OS
C17H10ClN3OS2
C18H13ClN4OS2
C15H15ClN4OS2
C14H11ClN4OS2
C13H9ClN4O3S2
C18H11BrClN5O3S2
C18H11Cl2N5O3S2
C17H11ClN6O3S2
C11H7Cl2N5O3S2
C11H6Cl2N4OS2
C15H15ClN6O4S2
C17H19ClN6O4S2
C15H14ClN5O2S2
C17H18ClN5O2S2
(N)
E
(CH)
(CH)
(CH)
(CH)
CH2C6H5
B/E
C/E
C/E
E
E/W
E
E/W
A
C/E
M
E
M
A
E
A
M
M
197Ϫ199
238Ϫ239
218Ϫ220
Ϫ
Ϫ
Ϫ
CH2(CH2)2CH3 271Ϫ272
CH2CH=CH2
CH2COOH
Ϫ
202-204
>300
>300
4-Br-C6H4
4-Cl-C6H4
3-pyridyl
Ϫ
Ϫ
Ϫ
291Ϫ293
215Ϫ216
269Ϫ271
231Ϫ233
191Ϫ193
148Ϫ150
125Ϫ127
150Ϫ152
9a
SO2NH2
SH
SO2NH2
SO2NH2
SH
9b
10a
10b
10c
10d
Ϫ
morpholino
2,6-(CH3)2-morpholino
morpholino
2,6-(CH3)2-morpholino
SH
†
Rec. Sol.: AϪAcetonitrile, BϪBenzene, CϪChloroform, EϪEthanol, WϪWater, MϪMethanol.
Analyzed for C, H, N; results were within 0.4% of the theoretical values for the formulae given.
‡
Table 2. Effect of the tested compounds on the
excretion of urine in rats.
4 by a sulfamoyl moiety potentiates the activity as re-
vealed from the better diuretic activity exhibited by
compound 6. The substantial improvement in activity
of the thiadiazolyl sulfonamide 7b may be attributed to
the nonpolar character of the p-chlorophenylvinyl
group that may facilitate the penetration and absorp-
tion of the compound through the cellular membranes.
Moreover, the presence of the chlorophenyl substitu-
ent in the diuretic molecule may enhance the activity
and increase the lipid solubility of the molecule as re-
vealed from the introductory part. It has been noticed
that the activity of 7b is inferior to that of the control
drug furosemide. The LD50 of the active compound 7b
was determined according to Lichfield and Wilcoxon
[29] and found to be 328 mg/kg.
Com-
Mean urine
volume (mL) SE
Percentage increase
in urinevolume
from control
pound†
Control
2b
3a
3c
3h
4
5a
5d
1.50
1.20
1.62
0.63
1.50
1.71
1.61
1.60
1.95
0.31
0.17
0.21
0.15
0.20
0.31
0.20
0.24
0.29
Ϫ
Ϫ
8
Ϫ
Ϫ
14
7.3
6.6
30
75
8.6
90
6
7b
2.62‡ 0.47
1.63 0.25
2.85‡ 0.14
Experimental
10b
Furosemide
Chemistry
†
Control (CMC, 0.5%), all compounds (100 mg/kg);
Furosemide (1 mg/kg)
Significantly different from the control (P < 0.05)
Melting points were determined on a Fischer-Johns appar-
atus (Fischer Scientific, Pettsberg, PA, USA) and are uncor-
rected. 1H-NMR spectra were recorded on a Varian EM-360
‡
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Arch. Pharm. Pharm. Med. Chem. 2004, 337, 527−532
Novel Quinazolinone Derivatives as Diuretic Agents 531
(90 MHz) and a FT-NMR (400 MHz) Lambda series (JNM-
LA) instrument (Varian Inc., Palo Alto, CA, USA) using TMS
as internal standard (Chemical shifts in ppm, d units). IR
spectra (KBr) were recorded on a Buck Scientific, Model 500
spectrophotometer (cmϪ1) (Buck Scientific, Norwalk, CT,
USA). The results of elemental analyses (C, H, N) were within
0.4% of the theoretical values. Thin-layer chromatography
was performed on silica gel GLF plates, 250 microns using
chloroform/methanol (9/1) as a mobile solvent. 7-Chloro-2-
methyl-4H-3,1-benzoxazin-4-one [26] 1, 5-amino-1,3,4-thiadi-
azole-2-sulfonamide [27] and 4-chloro-2-(chloroacetylamino)-
benzoic acid [8] 8 were prepared according to the reported
procedures.
7-Chloro-2-methyl-3-(2-substituted thio-1,3,4-thiadiazol-5-yl)-
quinazolin-4(3H)-ones 5aϪd
A mixture of 4 (0.62 g, 2 mmol), the appropriate alkyl halide
or chloroacetic acid (2 mmol), and pyridine (20 mL) was
heated at reflux temperature for 7 h. After cooling, the reac-
tion mixture was poured onto crushed ice/dil. HCl (100 g, 2:1
w/v) with constant shaking and refrigerated overnight. The
separated solid was collected by filtration, washed with cold
water, dried, and recrystallized. IR (KBr) 5aϪd: 1685 (C=O),
1560 (C=N), 5d: 3350 (OH); 1H-NMR (DMSO-d6): δ 2.17 (s,
3H, CH3), 4.65 (s, 2H, CH2), 7.38Ϫ8.41 (m, 8H, ArH). 5b: δ
0.95 (t, 3H, CH3), 1.32 (m, 2H, CH2), 1.69 (m, 2H, CH2), 2.10
(s, 3H, CH3), 2.95 (t, 2H, CH2), 7.35Ϫ8.24 (m, 3H, ArH). 5c:
δ 2.17 (s, 3H, CH3), 3.65 (d, 2H, CH2), 5.03Ϫ5.10 (d, 2H,
CH2), 5.90Ϫ5.94 (t, 1H, CH), 7.43Ϫ8.32 (m, 3H, ArH). 5d: δ
2.17 (s, 3H, CH3), 3.87 (s, 2H, CH2), 7.41Ϫ8.24 (m, 3H, ArH),
11.12 (s, 1H, OH).
7-Chloro-2-methyl-3-(1,3,4-thiadiazol-2-yl or thiazol-2-yl)-
quinazolin-4(3H)-ones 2a,b
An intimate mixture of the oxazine [26] 1 (1 g, 5 mmol) and
the appropriate heterocyclic amine (5 mmol) was heated at
150Ϫ170°C. The reaction mixture melted to a thick liquid and
resolidified within 30 minutes. After cooling, the residue was
dissolved in hot ethanol and filtered. The filtrate was evapo-
rated to dryness in vacuo and the residue was recrystallized.
IR (KBr) 2a, b: 1670 (C=O), 1550 (C=N); 1H-NMR(DMSO-d6)
2a: δ 2.15 (s, 3H, CH3), 7.80Ϫ8.39 (m, 3H, ArH), 8.62 (s, 1H,
ArH). 2b: δ 2.19 (s, 3H, CH3), 7.78Ϫ8.69 (m, 5H, ArH).
7-Chloro-2-methyl-3-(2-sulfamoyl-1,3,4-thiadiazol-5-yl)quin-
azolin-4(3H)-one 6
Compound 6 was prepared from 1 (1.95 g, 10 mmol) and 5-
amino-1,3,4Ϫthiadiazole-2-sulfonamide [27] (1.80
g ,10
mmol) following the same procedure applied for preparation
of 4. The product obtained was recrystallized from DMF/
methanol to give 2.35 g (66%) of 6, mp 293Ϫ295°C. Analy-
sis: C11H8ClN5O3S2 (C, H, N). IR (KBr): 3350 (NH2), 1685
(C=O), 1580 (C=N), 1315 (SO2); 1HϪNMR (DMSO-d6): δ
2.20 (s, 3H, CH3), 7.03Ϫ7.15 (br s, 2H, NH2), 8.40Ϫ8.57 (m,
3H, ArH).
2-(2-Arylvinyl)-7-chloro-3-(1,3,4-thiadiazol-2-yl or thiazol-2-
yl)quinazolin-4(3H)-ones 3aϪh
2-(2-Arylvinyl)-7-chloro-3-(2-sulfamoyl-1,3,4-thiadiazol-5-yl)-
quinazolin-4(3H)-ones 7aϪc
A mixture of 2 (10 mmol), the appropriate aldehyde (11
mmol), and anhyd. zinc chloride (0.1 g) was fused at
140Ϫ150°C for 2 h. After cooling, the reaction mixture was
treated with ice-cooled water to remove excess zinc chloride
and filtered. The residue was then washed with cold ethanol
and recrystallized. IR (KBr) 3aϪh: 1680 (C=O), 1560 (C=N),
980 (CH=CH). 1H-NMR (DMSO-d6) 3a: δ 6.63 (d, 1H, CH),
7.19Ϫ7.39 (m, 4H, ArH), 8.12 (d, 1H, CH), 8.20Ϫ8.52 (m,
3H, quinazolinone-H), 8.59 (s, 1H, ArH). 3b: δ 6.60 (d, 1H,
CH), 7.12Ϫ7.88 (m, 4H, ArH), 8.10 (d, 1H, CH), 8.39Ϫ8.60
(m, 3H, quinazolinone-H), 8.65 (s, 1H, ArH). 3c: δ 6.67 (d,
1H, CH), 7.35Ϫ7.94 (m, 4H, ArH), 8.21 (d, 1H, CH),
8.35Ϫ8.69 (m, 3H, quinazolinone-H), 8.75 (s, 1H, ArH). 3d:
δ 6.65 (d, 1H, CH), 7.10Ϫ7.55 (m, 3H, ArH), 8.15 (d, 1H, CH),
8.30Ϫ8.58 (m, 3H, quinazolinone-H), 8.67 (s, 1H, ArH) 3e: δ
6.54 (d, 1H, CH), 7.09Ϫ7.92 (m, 6H, ArH), 8.19 (d, 1H, CH),
8.56Ϫ8.75 (m, 3H, quinazolinone-H). 3f: δ 6.61 (d, 1H, CH),
7.11Ϫ8.09 (m, 6H, ArH), 8.52 (d, 1H, CH), 8.60Ϫ8.85 (m, 3H,
quinazolinone-H). 3g: δ 5.90 (d, 1H, CH), 7.35Ϫ8.60 (m, 9H,
ArH), 8.22 (d, 1H, CH). 3h: 6.55 (d, 1H, CH), 7.12Ϫ7.94 (m,
6H, ArH), 8.12 (d, 1H, CH), 8.32Ϫ8.64 (m, 3H, quinazoli-
none-H).
These compounds were prepared from 6 applying the same
procedures used for the preparation of compounds 3. IR
(KBr) 7a: 1685 (C=O), 3300 (NH2), 1550 (C=N), 1325 (SO2),
980 (CH=CH); 1H-NMR (DMSO-d6): δ 6.90 (d, 1H, CH),
7.21Ϫ7.29 (br s, 2H, NH2), 7.45Ϫ7.80 (m, 4H, ArH), 8.11 (d,
1H, CH), 8.41Ϫ8.59 (m, 3H, quinazolinone-H). 7b: δ 6.65 (d,
1H, CH), 7.20Ϫ7.26 (br s, 2H, NH2), 7.33Ϫ7.62 (m, 4H, ArH),
7.96 (d, 1H, CH), 8.40Ϫ8.55 (m, 3H, quinazolinone-H). 7c: δ
7.07 (d, 1H, CH), 7.31Ϫ7.40 (br s, 2H, NH2), 7.52Ϫ7.81 (m,
4H, Ar H), 8.20 (d, 1H, CH), 8.43Ϫ8.60 (m, 3H, quinazoli-
none-H).
7-Chloro-2-chloromethyl-3-(2-substituted-1,3,4-thiadiazol-5-
yl)quinazolin-4(3H)Ϫones 9a,b
A solution of phosphorous trichloride (1 mL) in dry toluene
(5 mL) was added dropwise, while stirring, to a mixture of 4-
chloro-2-chloroacetylaminobenzoic acid [8] 8 (0.5 g, 2 mmol)
and the appropriate heterocyclic amine (2 mmol) in dry tolu-
ene (10 mL). The reaction mixture was stirred at reflux tem-
perature for 3 h. The solvent was removed in vacuo and the
residue was treated with a 5% solution of sodium carbonate
(50 mL). The formed solid was filtered, washed with water,
dried, and recrystallized. 1H-NMR (DMSO-d6) 9a: δ 3.10 (s,
2H, CH2), 7.17Ϫ7.20 (br s, 2H, NH2), 7.89Ϫ8.49 (m, 3H,
quinazolinone-H). 9b: δ 3.04 (s, 2H, CH2), 7.85Ϫ8.42 (m, 3H,
quinazolinone-H), 10.91 (s, 1H, SH).
7-Chloro-3-(2-mercapto-1,3,4-thiadiazol-5-yl)-2-methylquin-
azolin-4(3H)-one 4
A mixture of 1 (3.9 g, 20 mmol), 5-amino-1,3,4-thiadiazole-2-
thiol (2.66 g, 20 mmol), and glacial acetic acid (40 mL) was
refluxed for 6 h. The reaction mixture was concentrated in
vacuo, cooled, poured onto ice water (30 mL), and filtered.
The separated solid was recrystallized from ethanol/ether to
7-Chloro-2-(morpholinomethyl or 2,6Ϫdimethylmorpholino-
methyl)-3-(2-substituted-1,3,4-thiadiazol-5-yl)quinazolin-
4(3H)-ones 10aϪd
give 2.2
g (71%) of 4, mp 280Ϫ281°C. Analysis,
C11H7ClN4OS2 (C, H, N). IR (KBr): 3250 (SH), 1670 (C=0),
1570 (C=N); 1H NMR (DMSO-d6): δ 2.19 (s, 3H, CH3),
7.90Ϫ8.44 (m, 3H, ArH), 10.42 (br.s, 1H, SH).
A mixture of 9 (3 mmol) and the required amine (6 mmol) in
dichloromethane (30 mL) was heated under reflux for 3Ϫ5 h.
 2004 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

532 Maarouf et al.
Arch. Pharm. Pharm. Med. Chem. 2004, 337, 527−532
The solution was concentrated to half the volume by evapor-
ation in vacuo, and then filtered. The separated solid was
washed with water, dried, and recrystallized. 1HϪNMR
(DMSO-d6) 10a: δ 2.35-2.38 (t, 4H, 2CH2), 3.42 (s, 2H, CH2),
3.65Ϫ3.69 (t, 4H, 2CH2), 5.43Ϫ5.47 (s, 2H, NH2), 7.75Ϫ8.41
(m, 3H, quinazolinone-H). 10b: δ 1.08Ϫ1.18 (d, 6H, 2CH3),
1.71Ϫ2.26 (m, 2H, 2CH), 3.26Ϫ3.34 (d, 4H, 2CH2), 3.39 (s,
2H, CH2), 5.32Ϫ5.36 (s, 2H, NH2), 7.90Ϫ8.39 (m, 3H, quin-
azolinone-H). 10c: δ 2.22Ϫ2.24 (t, 4H, 2CH2), 3.18Ϫ3.21 (t,
4H, 2CH2), 3.41 (s, 2H, CH2), 7.95Ϫ8.45 (m, 3H, quinazoli-
none-H), 10.97 (s, 1H, SH). 10d: δ 1.10Ϫ1.15 (d, 6H, 2CH3),
2.21Ϫ2.45 (m, 2H, 2CH), 3.25Ϫ3.33 (d, 4H, 2CH2), 3.37 (s,
2H, CH2), 7.91Ϫ8.47 (m, 3H, quinazolinone-H), 10.75 (s,
1H, SH).
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Albino rats of both sexes weighing about 200 g were used in
this study. Prior to the experiment, the rats were allowed food
and water ad libitum. The animals were divided into 12
groups each consists of 4 rats. During the experiment, each
rat was housed in a separate improved metabolic cage to
ensure adequate separation of urine from faeces. One group
was used as untreated control group and received the vehicle
only, (0.5 mL of 0.5% carboxymethylcellulose (CMC) solu-
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have received the 10 test compounds suspended in CMC
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