May 2004
653
Hydrazine hydrate 8.6 g (0.2 mol) was added dropwise to a 6.9—7.5 (m, 4H, ArH), 8.4—8.5 (s, 1H, NH); MS (m/z) 294
ꢂ
stirred methyl N-(2-methoxycarbonylphenyl)dithiocarbamate (M ). Anal. Calcd for C H N OS , C, 48.97; H, 4.76; N,
1
2
14
4
2
4.82 g (0.02 mol) in cold condition. After the completion of 19.05. Found: C, 49.05; H, 4.69; N, 19.09.
addition, stirring was continued for 1.5 h at 50 °C and the 1,1-Diethyl-3-(2-methlylthio-4-oxo-3H-quinazolin-3-
ꢀ1
mixture was poured into ice-water. The solid obtained was yl)thiourea (A3) IR (KBr) cm : 3330 (NH), 1670 (cyclic
1
filtered, washed with water, dried and recrystallized from di- CꢁO), 1630 (CꢁN), 1310 (C–N), 1130 (CꢁS); H-NMR
methylformamide and ethanol, yieldꢁ90%, mp 236— (CDCl ) d: 1.1 (m, 4H, –N(CH CH ) ), 1.3 (m, 6H,
3
2
3 2
ꢀ1
2
(
37 °C; IR (KBr) cm ; 3300, 3220 (NH ), 2560 (SH), 1680 –N(CH CH ) , 2.5—2.7 (s, 3H, –SCH ), 6.6—7.2 (m, 4H,
2 2 3 2 3
ꢂ
1
CꢁO); H-NMR (CDCl ) d: 3.21 (s, 1H, SH), 5.12 (s, 2H, ArH), 8.3—8.4 (s, 1H, NH); MS (m/z) 322 (M ). Anal.
3
NH , D O exchangeable), 7.14 (m, 4H, ArH). Anal. Calcd Calcd for C H N OS , C, 52.17; H, 5.59; N, 17.39. Found:
2
2
14 18
4
2
for C H N OS: C, 49.74; H, 3.65; N, 21.77. Found: C, 49.26; C, 52.23; H, 5.63; N, 17.31.
8
7
3
H, 3.72; N, 21.94.
1-(Pyrrolidinyl)-3-(2-methlylthio-4-oxo-3H-quinazolin-
ꢀ1
Synthesis of 3-Amino-2-methylthioquinazolin-4(3H)- 3-yl)thiourea (A4) IR (KBr) cm : 3320 (NH), 1680
one A solution of 3-amino-2-mercaptoquinazolin-4(3H)- (cyclic CꢁO), 1620 (CꢁN), 1330 (C–N), 1110 (CꢁS); H-
1
one 1.93 g (0.01 mol) in sodium hydroxide 10 ml (20% w/v) NMR (CDCl ) d: 1.6 (m, 4H, –N(CH CH ) , 2.7 (m, 4H,
3
2
2 2
was obtained by warming on a water bath. It was clarified by –N(CH CH ) , 3.0—3.2 (s, 3H, –SCH ), 6.7—7.3 (m, 4H,
2
2 2
3
ꢂ
filteration while in warm condition, cooled and treated with ArH), 8.5—8.6 (s, 1H, NH); MS (m/z) 320 (M ). Anal.
dimethylsulphate 1.26 g (0.01 mol) under constant stirring. Calcd for C H N OS , C, 52.50; H, 5.00; N, 17.50. Found:
1
4
16
4
2
The solution was stirred at room temperature for 12 h. The C, 52.59; H, 5.13; N, 17.42.
solid obtained was filtered, washed with cold water, dried and 1-(Morpholinyl)-3-(2-methlylthio-4-oxo-3H-quinazolin-
recrystallized from chloroform–ethanol, yieldꢁ90%, mp 3-yl)thiourea (A5) IR (KBr) cm : 3300 (NH), 1670
ꢀ1
ꢀ
1
1
1
(
2
55—159 °C; IR (KBr) cm : 3400, 3320 (NH ), 1700 (cyclic CꢁO), 1630 (CꢁN), 1340 (C–N), 1120 (CꢁS); H-
2
1
CꢁO); H-NMR (DMSO-d ) d: 2.51 (s, 3H, SCH ), 6.6 (s, NMR (CDCl ) d: 2.5 (m, 4H, –(N(CH CH ) –O), 3.0 (m,
6
3
3
2
2 2
H, NH , D O exchangeable), 7.5—7.8 (m, 4H, ArH). Anal. 4H, –(N(CH CH ) –O), 3.3—3.4 (s, 3H, –SCH ), 6.9—7.5
2 2 2 2 2 3
ꢂ
Calcd for C H N OS: C, 52.22; H, 4.38; N, 20.3. Found: C, (m, 4H, ArH), 8.5—8.6 (s, 1H, NH); MS (m/z) 336 (M ).
9
9
3
5
2.46; H, 3.98; N, 20.52.
Anal. Calcd for C H N O S , C, 50.00; H, 4.76; N, 16.66.
14 16 4 2 2
Synthesis of (2-Methylthio-4-oxo-3H-quinazolin-3-yl)- Found: C, 51.01; H, 4.47; N, 16.70.
dithiocarbamic acid methyl ester To a vigorously stirred
solution of 3-amino-2-methylthioquinazolin-4(3H)-one 3.86 g PHARMACOLOGY
(0.02 mol) in dimethyl sulfoxide (10 ml) at room temperature
carbondisulphide (1.6 ml, 0.026 mol) and sodium hydroxide
The synthesized compounds were evaluated for analgesic,
1.2 ml, 20 mol solution) were added dropwise during anti-inflammatory and antimicrobial activities. Student-t-test
(
30 min, it was allowed to stirr for 30 min more. Dimethyl sul- was performed for all the activities to ascertain the signifi-
phate 2.5 g (0.02 mol) was added at 5—10 °C, stirring was cance of the exhibited activities. The test compounds and the
continued for 3 h and the reaction mixture was poured into standard drugs were administered in the form of a suspension
ice water, the solid, so obtained was filtered, washed with (1% carboxyl methyl cellulose as vehicle) in the same route
water, dried and recrystallized from ethanol, yieldꢁ73%, mp of administration. Each group consisted of six animals.
ꢀ
1
9
1
3
8
5—97 °C, IR (KBr) cm : 3330 (NH), 1680 (cyclic CꢁO),
Animals The animals were procured from “National Bi-
1
610 (CꢁN), 1160 (CꢁS); H-NMR (CDCl ) d: 2.6—2.7 (s, ological Center,” Madurai, India, and were maintained in
H, CH ), 3.0—3.1 (s, 3H, CH ), 6.6—7.1 (m, 4H, ArH), colony cages at 25ꢃ2 °C, relative humidity of 45—55%,
.5—8.7 (s, 1H, NH); MS (m/z) 297 (M ). Anal. Calcd for maintained under 12 h light and dark cycle and were fed with
3
3
3
ꢂ
C H N OS : C, 44.44; H, 3.70; N, 14.14. Found: C, 44.30; standard animal feed. All the animals were acclimatized for a
1
1
11
3
3
H, 3.66; N, 14.05.
Synthesis of 1-Methyl-3-(2-methlylthio-4-oxo-3H-quina-
week before use.
Analgesic Activity
8,9)
Test for analgesic activity was
zolin-3-yl)thiourea (A1) A mixture of (2-methylthio-4- performed by tail-flick technique using Wistar albino mice
oxo-3H-quinazolin-3-yl)dithiocarbamic acid methyl ester (25—35 g) of either sex selected by random sampling tech-
3.27 g (0.01 mol) and methylamine 0.62 g (0.02 mol) in N,N- nique Diclofenac sodium at a dose level of 10 and 20 mg/kg
dimethyl formamide (20 ml) was refluxed for 20 h cooled and was administered orally as reference drug for comparison.
poured into ice water, the solid obtained was filtered, dried The test compounds at two dose levels (10, 20 mg/kg) were
and recrystallized from ethanol, yieldꢁ71%, mp 166— administered orally. The reaction time was recorded at
ꢀ
1
1
1
69 °C, IR (KBr) cm : 3350 (NH), 1670 (cyclic CꢁO), 30 min, 1, 2 and 3 h after the treatment. The cut off time was
1
620 (CꢁN), 1310 (C–N), 1130 (CꢁS); H-NMR (CDCl ) 10 s. The percent analgesic activity (PAA) was calculated by
3
d: 2.3—2.5 (s, 3H, –NCH ), 2.7—3.0 (s, 3H, –SCH ), 6.5— the following formula,
3
3
ꢂ
7
.0 (m, 4H, ArH), 8.2—8.3 (s, 1H, NH); MS (m/z) 280 (M ).
T ꢀT
2 1
Anal. Calcd for C H N OS , C, 47.14; H, 4.28; N, 20.00.
Found: C, 47.26; H, 4.21; N, 19.91. Adopting this procedure
compounds A2—A11 were prepared.
1
1
12
4
2
PAAꢁ
ꢄ100
10ꢀT
1
1
,1-Dimethyl-3-(2-methlylthio-4-oxo-3H-quinazolin-3- Where T is the reaction time (s) before treatment, T is the
1 2
ꢀ
1
yl)thiourea (A2) IR (KBr) cm : 3310 (NH), 1680 (cyclic reaction time (s) after treatment.
CꢁO), 1640 (CꢁN), 1330 (C–N), 1120 (CꢁS); H-NMR
CDCl ) d: 2.2 (s, 6H, –N(CH ) ), 2.6—2.8 (s, 3H, –SCH ), was performed by carrageenan-induced paw oedema test in
1
Anti-inflammatory Activity Anti-inflammatory activity
(
3
3 2
3