Synthesis and anti-inflammatory activity of 5-(6-methyl-2-substituted 4-pyrimidinyloxymethyl)-1,3,4-oxadiazole-2-thiones and their 3-morpholinomethyl derivatives

Article abstract of DOI:10.1016/S0014-827X(02)00022-8

The synthesis of 5-(6-methyl-2-substituted 4-pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-thiones and their 3-morpholinomethyl derivatives and the results of anti-inflammatory activity in vivo are described. Most of the tested compounds exhibited anti-inflammatory activity and some of them were more active than acetylsalicylic acid.

Full text of DOI:10.1016/S0014-827X(02)00022-8

Il Farmaco 58 (2003) 323ꢀ328
/
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Synthesis and anti-inflammatory activity of 5-(6-methyl-2-substituted
4-pyrimidinyloxymethyl)-1,3,4-oxadiazole-2-thiones and their 3-
morpholinomethyl derivatives
Virginija Jakubkiene a,*, Milda Malvina Burbuliene a, Giedrute Mekusˇkiene a,
˙
˙
˙
˙
˙
Emilija Udrenaite a, Povilas Gaidelis b, Povilas Vainilavicˇius a
˙
a Faculty of Chemistry, Vilnius University, Naugarduko 24, 2006 Vilnius, Lithuania
ˇ
Faculty of Medicine, Vilnius University, M.K. Ciurlionio 21, 2009 Vilnius, Lithuania
b
Received 8 July 2002; accepted 12 October 2002
Abstract
The synthesis of 5-(6-methyl-2-substituted 4-pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-thiones and their 3-morpho-
linomethyl derivatives and the results of anti-inflammatory activity in vivo are described. Most of the tested compounds exhibited
anti-inflammatory activity and some of them were more active than acetylsalicylic acid.
´
# 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
Keywords: 1,3,4-Oxadiazole-2-thiones; Aminomethylation; Anti-inflammatory activity
1. Introduction
2. Chemistry
Among derivatives of 1,3,4-oxadiazole-2-thione there
is a large amount of compounds exhibiting anti-inflam-
The ester 1 was chosen as a starting compound [12]
(Fig. 1). 2-Alkylsulfanyl group is prone to be substituted
with nucleophiles [13], thus the starting compound 1 was
treated with different amines in order to synthesize
matory activity [1ꢀ6]. 1,3,4-Oxadiazole-2-thiones con-
/
taining the pyrimidine substituents in the 5th position of
the oxadiazole ring possess the above-mentioned activity
[7,8]. Previously we have reported on the synthesis and
pharmacological properties of compounds containing
esters 3bꢀf. Unfortunately, from the resulting multi-
/
component slurry individual compounds were not iso-
lated. Likely, in this case the nucleophilic attack
occurred not only at the 2nd position of pyrimidine
ring, but also at the 4th position and at the carbonyl
group of ester too. When the direct synthesis of 2-amino
both the pyrimidine and 1,3,4-oxadiazole moieties [8ꢀ
/
11]. In continuation of our interest in the synthesis of
biologically and chemically valuable compounds, now
substituted esters 3bꢀf under treatment of the 2-
/
we report on the synthesis of compounds 5aꢀf in which
/
methylsulfanyl derivative with different amines was
unsuccessful, first we oxidized the 2-methylsulfanyl
group into methylsulfonyl (better leaving group) [14].
This method of oxidation, i.e. oxidation of 2-alkylsulfa-
the pyrimidine and the 1,3,4-oxadiazole rings are
separated by methyleneoxy group. We made an attempt
to ascertain dependence of anti-inflammatory activity
on the nature of various substituents, introduced into
nylpyrimidines with gaseous chlorine in waterꢀalcohol
/
the 2nd position of pyrimidine ring. For structureꢀ
activity correlation the corresponding morfolinomethyl
derivatives 6aꢀf were also synthesized.
/
solution into corresponding 2-alkylsulfonylpyrimidines,
is reported in literature [15]. Further, the compound 2
was allowed to react with amines in dimethyl sulfoxide
to give methyl (2-aminosubstituted 6-methyl-4-pyrimi-
/
dinyloxy)acetates (3bꢀ
tained under the treatment of esters 1, 3bꢀ
hydrazine hydrate. Refluxing of hydrazides 4aꢀ
/
f). Hydrazides 4aꢀ
/
f were ob-
f with
f with
/
* Corresponding author.
E-mail address: virginija.jakubkiene@chf.vu.lt (V. Jakubkiene).
˙
/
´
0014-827X/03/$ - see front matter # 2003 Editions scientifiques et me´dicales Elsevier SAS. All rights reserved.
doi:10.1016/S0014-827X(02)00022-8

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ture the gaseous chlorine was bubbled till the starting
compound dissolved and the reaction product precipi-
tated. Then the solid was filtered off, washed with 1%
solution of Na2S2O3, water and dissolved in chloroform.
The solution was dried with Na2SO4 and evaporated,
the residue was recrystallized.
1H NMR (CDCl3): 2.57 (s, 3H, CH3), 3.25 (s, 3H,
SO2CH3), 3.77 (s, 3H, OCH3), 4.99 (s, 2H, OCH2), 6.86
(s, 1H, CH).
3.1.2. Methyl (2-aminosubstituted 6-methyl-4-
pyrimidinyloxy)acetates (3bꢀf)
/
To a suspension of 2.6 g (0.01 mol) of compound 2 in
3 ml of anh. DMSO 0.02 mol of corresponding amine
(in the case of 3c-solution of dimethylamine in anh.
DMSO) was added. The reaction mixture was stirred at
50ꢀ70 8C temperature for 0.5 h, then cooled and poured
/
into 100 ml of cold water. The solid was filtered off,
washed with water and recrystallized.
1H NMR, 3b (CCl4): 2.08 (s, 3H, CH3), 3.44 (s, 3H,
OCH3), 4.43 (d, Jꢂ/6 Hz, 2H, NHCH2), 4.55 (s, 2H,
OCH2), 5.78 (s, 1H, CH), 7.1 (s, 6H, ArÃ
/H, NH).
Compound 3c (CDCl3): 2.26 (s, 3H, CH3), 3.09 [s, 6H,
N(CH3)2], 3.73 (s, 3H, OCH3), 4.78 (s, 2H, OCH2), 5.91
(s, 1H, CH).
Compound 3d (CDCl3): 1.6ꢀ
/
2.06 [m, 4H, (CH2)2],
Fig. 1.
2.26 (s, 3H, CH3), 3.25ꢀ3.65 [m, 4H, N(CH2)2], 3.73 (s,
/
3H, OCH3), 4.79 (s, 2H, OCH2), 5.93 (s, 1H, CH).
Compound 3e (CCl4): 1.5 [s, 6H, (CH2)3], 2.1 (s, 3H,
CH3), 3.55 [s, 7H, OCH3, N(CH2)2], 4.53 (s, 2H, OCH2),
5.69 (s, 1H, CH).
Compound 3f (CCl4): 2.15 (s, 3H, CH3), 3.56 [s, 11H,
OCH3, N(CH2)2, O(CH2)2], 4.58 (s, 2H, OCH2), 5.81 (s,
1H, CH).
potassium O-ethylxanthate produced 1,3,4-oxadiazole-
2-thiones 5aꢀf. The latter were reacted with formalde-
hyde and morpholine in ethanol at 40 8C to give
compounds 6aꢀf. The structure of new compounds 2,
3bꢀf, 4bꢀf, 5aꢀf, 6aꢀ
f was proved by the data of IR, 1H
/
/
/
/
/
/
NMR spectra and elemental analysis.
3. Experimental
3.1.3. (2-Aminosubstituted 6-methyl-4-
pyrimidinyloxy)acethydrazide (4bꢀ
/
f)
3.1. Chemistry
To a hot solution of 0.01 mol of ester 3bꢀf in 10 ml of
/
isopropanol 1.5 g (0.03 mol) of 99% hydrazine hydrate
was added. The reaction mixture was stirred at reflux for
1 h and allowed to warm to room temperature (r.t.). The
solid was filtered off, washed with ether and recrystal-
lized.
Melting points (m.p.) were determined in open
capillaries and are uncorrected. The IR spectra were
measured on a Carl Zeiss Jena spectrofotometer Spe-
cord M 8O in Nujol, 1H NMR spectra were recorded on
a BS 567A (80 MHz, Tesla) with HMDSO as an internal
standard. Chemical shifts (d) are reported in ppm. The
experimental values of microanalyses for compounds 2,
1H NMR, 4b (CF3COOH): 2.07 (s, 3H, CH3), 4.33 (d,
Jꢂ
/
5 Hz, 2H, NHCH2), 4.84 (s, 2H, OCH2), 5.99 (s, 1H,
H).
CH), 6.89 (s, 5H, ArÃ
/
3bꢀ
/
f, 4bꢀ
/
f, 5aꢀ
/
f, 6aꢀ/f agreed with the calculated ones.
Compound 4c (DMSO-d6): 2.18 (s, 3H, CH3), 3.04 [s,
6H, N(CH3)2], 4.25 (s, 2H, NH2), 4.64 (s, 2H, OCH2),
5.93 (s, 1H, CH), 9.38 (s, 1H, NH).
Compound 4d (DMSO-d6): 1.86 [s, 4H, (CH2)2], 2.17
(s, 3H, CH3), 3.34 [s, 4H, N(CH2)2], 4.25 (s, 2H, NH2),
4.64 (s, 2H, OCH2), 5.93 (s, 1H, CH), 9,29 (s, 1H, NH).
Compound 4e (CF3COOH): 1.33 [s, 6H, (CH2)3], 2.01
(s, 3H, CH3), 3.36 [s, 4H, N(CH2)2], 4.84 (s, 2H, OCH2),
5.84 (s, 1H, CH).
The properties of compounds are presented in Table 1.
Compounds 1 and 4a were synthesized as reported
previously [12,16].
3.1.1. Methyl (6-methyl-2-methylsulfonyl-4-
pyrimidinyloxy)acetate (2)
To a stirred suspension of 2.28 g (0.01 mol) of
compound 1 in 30 ml 70% methanol at ꢁ5 8C tempera-
/

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325
˙
Table 1
Properties of the compounds 2ꢀ
/6
Comp. Formula (molecular weight)
M.p. (8C) (solvent)
Yield (%)
IR, n (cmꢁ1
)
NH
CÄ
/
O
CÄ
/
N
CÄS
/
2
C9H12N2O5S (260.3)
C15H17N3O3 (287.3)
C10H15N3O3 (225.2)
109ꢀ
88ꢀ
38ꢀ
73ꢀ
59ꢀ
93ꢀ
156ꢀ
143ꢀ
151ꢀ
151ꢀ
186ꢀ
180ꢀ
166ꢀ
183ꢀ
191ꢀ
163ꢀ
169ꢀ
125ꢀ
120ꢀ
115ꢀ
127ꢀ
98ꢀ
128ꢀ
/
110 (benzene)
87
85
58
84
88
86
76
83
76
68
80
72
67
56
52
73
69
74
57
66
61
74
74
1760 1596
1756 1580
1752 1592
1752 1564
1756 1564
1744 1564
1648 1576
1676 1588
1672 1588
1680 1580
1672 1564
1576
3b
3c
3d
3e
3f
/
89 (hexane)
40 (hexane)
75 (hexane)
60 (hexane)
94 (hexane)
3256
/
C
12H17N3O3 (251.3)
/
C13H19N3O3 (265.3)
C12H17N3O4 (267.3)
/
/
4b
4c
4d
4e
4f
C
14H17N5O2 (287.3)
/
158 (isopropanol)
145 (isopropanol)
153 (isopropanol)
152 (isopropanol)
188 (isopropanol)
182 (isopropanol/water)
168 (isopropanol/water)
185 (isopropanol/water)
193 (isopropanol/water)
165 (isopropanol/water)
170 (isopropanol/water)
127 (ethanol)
3296
C9H15N5O2 (225.3)
C13H17N5O2 (275.3)
C12H19N5O2 (265.3)
/
3304, 3264, 3200
3312, 3212
3312, 3208
/
/
C
11H17N5O3 (267.3)
/
3304, 3216
5a
5b
5c
5d
5e
5f
C9H10N4O2S2 (270.3)
C15H15N5O2S (329.4)
C10H13N5O2S (267.3)
/
1312
1316
1324
1328
1320
1308
1304
1316
1312
1316
1324
1344
/
3192
1588
/
1596, 1572
C
C
12H15N5O2S (293.4)
13H17N5O2S (307.4)
/
1576, 1540
1568, 1540
1590, 1576
1580, 1546
1564
/
C12H15N5O3S (309.4)
14H19N5O3S2 (369.5)
C20H24N6O3S (428.5)
15H22N6O3S (366.4)
C17H24N6O3S (392.5)
/
6a
6b
6c
6d
6e
6f
C
/
/
122 (ethanol)
3248
C
/
117 (ethanol)
1564
/
129 (ethanol)
1580, 1536
1576, 1528
1564
C
C
18H26N6O3S (406.5)
17H24N6O4S (408.5)
/
100 (ethanol)
/
130 (ethanol)
Compound 4f (CF3COOH): 2.05 (s, 3H, CH3), 3.56 [s,
8H, N(CH2)2, O(CH2)2], 4.86 (s, 2H, OCH2), 5.84 (s,
1H, CH).
Compound 5f (CF3COOH): 2.08 (s, 3H, CH3), 3.63 [s,
8H, N(CH2)2, O(CH2)2], 5.13 (s, 2H, OCH2), 5.91 (s,
1H, CH).
3.1.5. 5-(2-Aminosubstituted 6-methyl-4-
pyrimidinyloxymethyl)-3-morpholinomethyl-2,3-dihydro-
3.1.4. 5-(2-Aminosubstituted 6-methyl-4-
pyrimidinyloxymethyl)-2,3-dihydro-1,3,4-oxadiazole-2-
1,3,4-oxadiazole-2-thiones (6aꢀ
/
f)
thiones (5aꢀ
/
f)
To a solution of 0.01 mol of compound 5aꢀ
/f in 100 ml
A mixture of 0.01 mol of compound 4aꢀ
/
f and 1.6 g
of ethanol at 40 8C 1.13 ml (0.015 mol) of formalin and
0.87 g (0.01) of morpholine was added. The reaction
mixture was stirred at this temperature for 1 h and
cooled. The solid was filtered off, washed with ether and
recrystallized.
(0.01 mol) of potassium O-ethylxanthate in 70 ml
ethanol was refluxed for 12 h. The solvent was
evaporated, the residue was dissolved in 30 ml of water.
The solution was acidified with concentrated HCl to pH
5. The solid formed was filtered off, washed with water
and recrystallized.
1H NMR, 5a (DMSO-d6): 2.29 (s, 3H, CH3), 2.44 (s,
3H, SCH3), 5.46 (s, 2H, OCH2), 6.55 (s, 1H, CH).
Compound 5b (CF3COOH): 2.04 (s, 3H, CH3), 4.29
1H NMR, 6a (CDCl3): 2.39 (s, 3H, CH3), 2.52 (s, 3H,
SCH3), 2.63ꢀ
/
2.94 [m, 4H, N(CH2)2], 3.52ꢀ3.84 [m, 4H,
/
O(CH2)2], 4.96 (s, 2H, NCH2), 5.39 (s, 2H, OCH2), 6.34
(s, 1H, CH).
Compound 6b (CDCl3): 2.27 (s, 3H, CH3), 2.56ꢀ
[m, 4H, N(CH2)2], 3.53ꢀ3.88 [m, 4H, O(CH2)2], 4.62 (d,
Jꢂ6 Hz, 2H, NHCH2), 4.86 (s, 2H, NCH2), 5.24 (s, 2H,
OCH2), 5.5ꢀ5.8 (m, 1H, NH), 5.98 (s, 1H, CH), 7.29 (s,
5H, ArÃH).
Compound 6c (CDCl3): 2.27 (s, 3H, CH3), 2.62ꢀ
[m, 4H, N(CH2)2], 3.12 [s, 6H, N(CH3)2], 3.5ꢀ3.88 [m,
/2.94
(d, Jꢂ
/
5 Hz, 2H, NHCH2), 5.06 (s, 2H, OCH2), 5.88 (s,
H).
Compound 5c (DMSO-d6): 2.12 (s, 3H, CH3), 3.04 [s,
/
1H, CH), 6.85 (s, 5H, ArÃ
/
/
/
6H, N(CH3)2], 5.37 (s, 2H, OCH2), 6.01 (s, 1H, CH).
/
Compound 5d (DMSO-d6): 1.71ꢀ/1.99 [m, 4H,
/2.94
(CH2)2], 2.2 (s, 3H, CH3), 3.06ꢀ3.75 [m, 4H,
/
/
N(CH2)2], 5.37 (s, 2H, OCH2), 6.01 (s, 1H, CH).
Compound 5e (CF3COOH): 1.35 [s, 6H, (CH2)3], 2.01
(s, 3H, CH3), 3.39 [s, 4H, N(CH2)2], 5.1 (s, 2H, OCH2),
5.78 (s, 1H, CH).
4H, O(CH2)2], 4.94 (s, 2H, NCH2), 5.31 (s, 2H, OCH2),
5.88 (s, 1H, CH).
Compound 6d (CDCl3): 1.69ꢀ/2.07 [m, 4H, N(CH2)2],
2.27 (s, 3H, CH3), 2.58ꢀ2.9 [m, 4H, N(CH2)2], 3.31ꢀ
/
/3.83

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˙
[m, 8H, N(CH2)2, O(CH2)2], 4.94 (s, 2H, NCH2), 5.31 (s,
2H, OCH2), 5.89 (s, 1H, CH).
Compound 6e (CDCl3): 1.59 [s, 6H, (CH2)3], 2.25 (s,
measured with an electronic onkograph immediately
before and 1, 2, 3 and 5 h after the carrageenin injection.
3H, CH3), 2.6ꢀ
8H, N(CH2)2, O(CH2)2], 4.94 (s, 2H, NCH2), 5.28 (s,
2H, OCH2), 5.86 (s, 1H, CH).
/
2.85 [m, 4H, N(CH2)2], 3.54ꢀ3.85 [m,
/
3.2.2. Bentonite test
Bentonite test was analogously produced (0.1 ml 5%
solution) according to [18].
Compound 6f (CDCl3): 2.27 (s, 3H, CH3), 2.63ꢀ
/
2.88
[m, 4H, CH2ÃN(CH2)2], 3.54ꢀ3.95 {m, 12H, N(CH2)2,
/
/
3.2.3. Acute toxicity
The tests of acute toxicity of the compounds were
2[O(CH2)2]}, 4.94 (s, 2H, NCH2), 5.28 (s, 2H, OCH2),
5.95 (s, 1H, CH).
done on male BALB/C strain mice weighing 18ꢀ22 g.
/
Groups of six mice were treated perorally with the test
compound at various dose levels. The animals were
watched for mortality and symptoms until 8th day [19].
3.2. Pharmacology
For anti-inflammatory tests adult male and female
Wistar strain rats weighing 140ꢀ150 g were used. All test
/
compounds and the reference drug were administered
orally suspended in 1% carboxymethylcellulose with one
drop of Twin-80 solution. The effect of test compounds
on decrease of rats paw oedema was compared with that
of control rats. The anti-inflammatory activity was
expressed as a decrease of rats paw oedema and is given
in percentage. The data were evaluated statistically using
4. Results and discussion
Anti-inflammatory activity was studied by carragee-
nin- and bentonite-induced paw oedema in rats. The
inhibition of the oedema was measured after 1, 2, 3 and
5 h from the administration of test compounds. The
data in the Table 2 are given as an arithmetical means of
these measurements. As a reference substance in experi-
ments an acetylsalicylic acid was used. Compounds 5f
and 6a were the most active of all the tested ones. They
showed anti-inflammatory activity higher than that of
acetylsalicylic acid, i.e. they decreased carrageenin-
induced oedema, 29.7 and 32.6% and bentonite-induced,
26.4 and 23.4%, respectively. Both of compounds have
morpholine fragment as a substituent in the 2nd
position of pyrimidine (5f) or in the 3rd position of
oxadiazole ring (6a). Compound 6f containing morpho-
line moiety in both above mentioned positions showed
similar activity in bentonite test (decreased oedema
Student’s t-test. A level of P B0.05 was adopted as the
/
test of significance.
3.2.1. Carrageenin test
Carrageenin-induced hind paw oedema in rats was
produced by the method of Winter et al. [17]. Carra-
geenin solution (1.0% in sterile 0.9% NaCl solution) was
injected subcutaneously into the subplanar region of the
hind paw (in a volume of 0.1 ml to each paw) 1 h after
administration of the test compound. Control rats
received only solution of 0.5% carboxymethylcellulose
with one drop of Twin-80. The hind paw volume was
Table 2
Anti-inflammatory activity (50 mg kgꢁ1 p.o.) and acute toxicity (LD50) data for compounds 5ꢀ
6
/
Comp.
0.1 ml of 1% carrageenin solution
0.1 ml of 5% bentonite suspension
LD50 (mg
kgꢁ1
)
Cross-section of rat paw Inhibition of rat paw oedema Cross-section of rat paw Inhibition of rat paw oedema
(%) over control
(relative units)
(%) over control
(relative units)
Control
5a
95.3
96.3
110.4
77.9
125.7
95.0
65.6
62.7
109.3
89.0
90.6
78.6
77.5
77.2
0
0
94.8
106.9
107.5
76.5
75.5
94.6
68.9
71.4
59.2
84.1
73.9
70.8
67.5
74.7
0
ꢃ
ꢃ
18.3
19.3
0
/
12.1 a
12.2 a
5b
5c
ꢃ
/
15.1 a
/
17.4
30.4 a
ꢀ/1000
5d
5e
ꢃ
/
0
5f
6a
29.7
32.6
26.4
23.4
33.6
10.7
20.9
24.0
27.3
21.6
800
1000
ꢀ
/
6b
6c
ꢃ
6.3
0
/
14.0 a
6d
6e
16.7
17.8
19.8
750
1000
1216
6f
ꢀ
/
Acetylsalicylic
acid
a
Increase oedema.

V. Jakubkiene et al. / Il Farmaco 58 (2003) 323ꢀ
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327
˙
Table 3
Data of elemental analysis of compounds
Calculated / Found, %
C
Compound
Brutto formula
C9H12N2O5S
Mol. Weight
H
N
2
260.3
287.3
225.2
251.3
265.3
267.3
287.3
225.3
275.3
265.3
267.3
270.3
329.4
267.3
293.4
307.4
309.4
369.5
428.5
366.4
392.5
406.5
408.5
41.53 / 41.97
62.70 / 62.76
53.32 / 53.37
57.36 / 57.40
58.85 / 58.82
53.92 / 53.82
58.52 / 58.38
47.99 / 48.10
52.58 / 52.64
54.32 / 54.41
49.43 / 49.22
39.99 / 40.19
54.70 / 54.73
44.93 / 45.21
49.13 / 49.35
50.80 / 51.10
46.59 / 46.72
45.51 / 45.62
56.06 / 55.80
49.17 / 49.28
52.03 / 51.94
53.18 / 53.35
49.99 / 50.09
4.64 / 4.65
5.96 / 6.02
6.71 / 6.67
6.82 / 7.02
7.21 / 7.28
6.41 / 6.28
5.96 / 6.12
6.71 / 6.70
6.82 / 7.06
7.21 / 7.28
6.41 / 6.37
3.73 / 3.45
4.59 / 4.45
4.90 / 4.81
5.15 / 5.18
5.57 / 5.88
4.89 / 4.92
5.18 / 5.14
5.65 / 5.64
6.05 / 5.89
6.16 / 5.91
6.45 / 6.76
5.92 / 5.85
10.76 / 10.94
14.62 / 14.92
18.65 / 18.69
16.72 / 16.93
15.83 / 15.69
15.72 / 15.72
24.37 / 24.25
31.09 / 31.14
27.87 / 28.61
26.39 / 26.49
26.20 / 26.22
20.73 / 21.00
21.26 / 21.30
26.20 / 26.37
23.87 / 23.74
22.78 / 22.79
22.64 / 22.57
18.96 / 19.06
19.61 / 19.45
22.93 / 22.87
21.41 / 21.50
20.67 / 20.60
20.57 / 20.56
3b
3c
3d
3e
3f
C
C
15H17N3O3
10H15N3O3
C12H17N3O3
C13H19N3O3
C
12H17N3O4
4b
4c
4d
4e
4f
C14H17N5O2
C9H15N5O2
C13H17N5O2
C
12H19N5O2
C11H17N5O3
C9H10N4O2S2
C15H15N5O2S
5a
5b
5c
5d
5e
5f
C
10H13N5O2S
C12H15N5O2S
C13H17N5O2S
C
12H15N5O3S
C14H19N5O3S2
20H24N6O3S
C15H22N6O3S
17H24N6O3S
C18H26N6O3S
17H24N6O4S
6a
6b
6c
6d
6e
6f
C
C
C
[2] R. Kalsi, K. Pande, J.P. Barthwal, Synthesis of formazans of
substituted oxadiazole-2(3H)-thiones, Indian J. Chem. 27B (1988)
27.3%), however, it was less active in carrageenin test
(decreased oedema 17.8%). Compounds 5b,d and 6b
showed the contrary effect. They increased the carra-
gennin-induced oedema in rat’s paw 15.1, 30.4 and
14.0%, respectively. Compounds 5a,b showed the ana-
logous results in bentonite test (increased oedema 12.1
and 12.2%, respectively). It may be stated, that intro-
duction of benzylamino group into 2nd position of
pyrimidine ring (compounds 5b and 6b) is unfavorable
for anti-inflammatory effect. Morpholinomethyl deriva-
tives 6a,e exhibit stronger anti-inflammatory activity
than corresponding oxadiazolethiones 5a,e, while mor-
pholinomethylated 6c is less active than oxadiazo-
lethione 5c. Thus, the influence of morpholinomethyl
substituent of oxadiazoles 6 towards anti-inflammatory
activity is not clear expressed.
197ꢀ199.
/
[3] I.P. Singh, A.K. Saxena, K. Shankar, Synthesis and anti-
inflammatory activity of oxadiazoline thione hydrochlorides,
Eur. J. Med. Chem.*
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Chim. Ther. 21 (1986) 267ꢀ269.
/
[4] R. Nigam, S. Swarup, V.K. Saxena, H.K. Singh, Synthesis and
pharmacological screening of some new 2-thioxo-3-(substituted
aminomethyl)-5-(3,5-dinitrophenyl)-1,3,4-oxadiazoles, J. Indian
Chem. Soc. 69 (1992) 692ꢀ693.
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[5] S. Saxena, M. Verma, A.K. Saxena, K. Shanker, 1,3,4-Oxadia-
zolethiones as inflammation inhibitors, Indian J. Pharm. Sci. 54
(1992) 1ꢀ3.
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[6] D.H. Boschelli, D.T. Connor, C.R. Kostlan, J.B. Kramer, M.D.
Mullican, J.C. Sircar, Preparation of (3,5-di-tert-butyl-4-hydro-
xyphenylthio)-1,3,4-thiadiazoles, oxadiazoles and analogs as anti-
inflammatory agents, EP 449211 (1991) (C. A. 116 (1992) 6570).
[7] T.R. Belliotti, D.T. Connor, C.R. Kostlan, Preparation of 2-
diazolyl-4,6-ditertiary-butyl-5-hydroxypyrimidines as cyclooxy-
genase and 5-lipoxygenase inhibitors, WO 9213844 (1992) (C.
A. 118 (1993) 6990).
Compounds with higher expressed anti-inflammatory
activity (5c,f, 6a,e,f) were evaluated for their acute
toxicity. The tests indicated, that compounds possess
toxicity comparable to that of acetylsalicylic acid (Table
2).
[8] M.M. Burbuliene, E. Udrenaite, P. Gaidelis, P. Vainilavicius,
Reactions of 5-(2-dimethylamino-6-methyl-4-pyrimidinylsulfanyl-
methyl)-1,3,4-oxadiazole-2-thione with carbon electrophiles, Pol.
J. Chem. 76 (2002) 557ꢀ563.
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[9] G. Mekuskiene, P. Vainilavicius, A. Hetzheim, R. Sematovic,
Synthesis of 5-(4,6-dimethyl-2-pyrimidinyl)-1,3,4-oxadiazole-2-
thione, Khim. Geterotsikl. Soedin. (1993) 700ꢀ
A. 120 (1994) 8554).
[10] V. Jakubkiene, P. Vainilavicius, Reaction of 6-methyl-2-
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705 (Russ.) (C.
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