Synthesis of Some New Azoloazines with Potent Anti-inflammatory and Analgesic Activity

Article abstract of DOI:10.1002/jhet.2746

Starting from pyrimidine-2-thiones, a set of new fused triazoles, thiazoles, and thiazines has been obtained. The mechanistic pathway and structures of all the novel products were ascertained on the foundation of spectral information and elemental analyses. The analgesic and anti-inflammatory activities of all the prepared compounds were predestined. The outcomes disclosed that all of the examined samples revealed potent activity. Moreover, the relation between the structure and the activity has been researched.

Full text of DOI:10.1002/jhet.2746

Month 2016
Synthesis of Some New Azoloazines with Potent Anti-inflammatory and
Analgesic Activity
a
Dina H. Dawood,a Rabab S. Jasass,b Mohamed M. Amin,c Thoraya A. Farghaly,b,d and Eman M. H. Abbas
*
aDepartment of Chemistry of Natural and Microbial Products, National Research Centre, Dokki, 12622 Giza, Egypt
bChemistry Department, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah 21955,
Saudi Arabia
cDepartment of Pharmacology, Medical Division, National Research Centre, 33 EL Bohouthst (former EL Tahrirst),
Dokki, 12622 Giza, Egypt
dDepartment of Chemistry, Faculty of Science, Cairo University, Giza 12613, Egypt
*
E-mail: eman_m69@yahoo.com
Received April 12, 2016
DOI 10.1002/jhet.2746
Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com).
Starting from pyrimidine-2-thiones, a set of new fused triazoles, thiazoles, and thiazines has been ob-
tained. The mechanistic pathway and structures of all the novel products were ascertained on the foundation
of spectral information and elemental analyses. The analgesic and anti-inflammatory activities of all the pre-
pared compounds were predestined. The outcomes disclosed that all of the examined samples revealed po-
tent activity. Moreover, the relation between the structure and the activity has been researched.
J. Heterocyclic Chem., 00, 00 (2016).
INTRODUCTION
RESULTS AND DISCUSSION
An increasing interest and an absolute requirement for
finding of new, eclectic, and promising inhibitors with an
improved protection and efficacy profile has promoted us
toward layout unprecedented anti-inflammatory and analge-
sic agents. The inflammation is a biotic rejoinder to a con-
catenation of biochemical reactions whose major function
is defense of the body from infection and settle of tissue
damage due to injury. Many heterocyclic compounds were
proved to have pharmacological significance as anti-
inflammatory and analgesic agents such as pyrimidines,
qiunazolines, thiazoles, triazoles, and thiazines [1–12]. Ex-
amples of the most reactive agents are proquazone and
fluproquazone [13,14] which have quinazoline ring (Fig. 1).
The overall anti-inflammatory profile of proquazone
is analogous with that of indomethacin. It is notewor-
thy that proquazone is the first powerful anti-
The starting compounds 2a,b were prepared via the
reaction of benzylidene (1a,b) with thiourea in ethyl alco-
hol containing potassium hydroxide (Scheme 1).
The latter compounds 2a,b have thiourea residue,
which is known to be an intermediate for the synthesis
of several azoles and azines. Thus, the interaction of 2a,
b with hydrazonoyl chlorides 3 in dioxan in the existence
of a base catalyst yielded only one isolated product. The
spectroscopic information assured the reaction product
6a–h via s-alkylation to give the intermediate 4 then
followed by Smiles rearrangement to give the intermediate
5 with elimination of HCl and H2S molecules, respectively
1
(Scheme 2). Also, H NMR of 6 showed the absence of
any signals for NH protons.
Furthermore, in order to synthesize fused thiazole ring
with quinazoline and cyclohepta-pyrimidine, the thione
derivatives 2a,b were reacted with diverse types of α-
haloketone or α-haloester, as represented in Schemes 3
and 4. The structure of compounds 7, 9, 10, and 11 was
deduced by spectral information and elemental analyses
(see the Experimental section).
In addition, condensation of the thiazole derivatives 7a,b
with substituted benzaldehydes afforded product 8 (Scheme
3). The formation of compounds 8a–h was assured by alter-
nate synthesis via multi-component reaction of compounds
2a,b, chloroacetic acid, and benzaldehyde derivatives.
inflammatory drug of
a non-acidic kind. Also,
meloxicam is an anti-inflammatory medication with
analgesic and temperature-reducer effects (Fig. 1). In
continuation of our efforts in synthesis of bioactive
heterocyclic compounds [15–22], we became inter-
ested here to design new polyheterocyclic ring sys-
tems having qiunazoline, thiazole, triazole, and/or
thiazine rings to investigate their anti-inflammatory
and analgesic activities which are expected to have
potent activity.
© 2016 Wiley Periodicals, Inc.

D. H. Dawood, R. S. Jasass, M. M. Amin, T. A. Farghaly, and E. M. H. Abbas
Vol 000
and 12b) showed a moderate effect in comparison with
compounds 7a and 8b,e,h but still showing a more
pronounced effect than aspirin.
Anti-inflammatory effect. All of the tested derivatives
(Tables 2 and 3 and Figs 3 and 4) displayed a higher
anti-inflammatory effect than that of standard drug
(indomethacin). Moreover, the duration and the outset
of actions of the investigated samples were ascended
with time, and their activity was retained for 4 h after
compound administration. The highest potency was
presented by compounds 7a and 8b,e,h, while other
tested compounds (2a, 2b, 6a, 6b, 6c, 6d, 6e, 6f, 6g,
6h, 7b, 8a, 8c, 8d, 8f, 8g, 9a, 9b, 10a, 10b, 11a, 11b,
12a, and12b) showed a moderate effect in comparison
with compounds 7a and 8b,e,h but still showing a more
pronounced effect than standard drug (indomethacin).
Figure 1. Structure of proquazone, fluproquazone, and meloxicam.
When pyrimidine-2-thiones (2a,b) were allowed to react
with 3-bromopropanoic acid, they gave one isolable product
in each case, namely, 10-(3,4-dimethoxy-benzylidene)-6-
(3,4-dimethoxyphenyl)-2,3,7,8,9,10-hexahydro-4H,6H-[1,3]
thiazino[2,3-b]quinazolin-4-one (12a) and 11-(3,4-
dimethoxybenzylidene)-6-(3,4-dimethoxyphenyl)-
2,3,6,7,8,9,10,11-octahydro-4H-cyclohepta [4,5]pyrimido
[2,1-b][1,3]thiazin-4-one (12b), respectively (Scheme 5).
The structure of the products was deduced by spectral infor-
mation and elemental analyses. In the IR spectra of com-
pounds 12a,b, there are intense absorption bands near
1690 cmꢀ1 attributed to the carbonyl groups. Also, there
are multiple signals that appear at 2.95-3-06 for two CH2
groups in the thiazine ring in their 1H NMR spectra.
STRUCTURE ACTIVITY RELATIONSHIP
The analgesic activity. According to Table 1, which
represents the analgesic activity comparing with
aspirin, the starting derivatives hexahydroquinazoline
and cyclohepta[d]pyrimidine 2a and 2b showed
a
potent analgesic activity of long duration of action
(response time at 1 and 2h for 2a; 30.23 and 41.36 s
for 2b: 24.31 and 33.81s). It can be noticed that the
size increase of the cyclohexene ring of 2a to the
cycloheptene ring as compound 2b slightly decreased
the obtained potency. Furthermore, the trifused
analogues triazolo[3,4-b]quinazolines 6a,b,e,f and the
cyclohepta[d]triazolo[4,3-a]pyrimidines 6c,d,g,h exhibited
the same significant analgesia of long duration of action
representing response times ranging from 25.33 to
31.31s after 1 h and 33.60–40.50 s at 2h post-
compound administration, taking in consideration that
the cyclohexenyl derivatives are more potent than the
cycloheptenyl ones. The replacement of the triazole ring
with thiazolidinone ring to give the trifused tetrahydro-
thiazolo[2,3-b]quinazoline7a significantly improved the
Pharmacological activity.
All of the target products
were screened as anti-inflammatory and analgesic agents.
They displayed dual activity producing about 1.5 to 2-
folds higher potency than that acquired by aspirin and
indomethacin, the reference drugs used in this experiment.
Anti-nociceptive (analgesic) effect. All of the screened
derivatives (Table 1 and Fig. 2) displayed a higher
analgesic effect than that of standard drug (aspirin).
Moreover, the duration and the outset of actions of
the investigated samples were ascended with time, and
they retained activity for 2 h after compound
administration. Compounds 7a and 8b,e,h were
presented the highest analgesic effect, while other tested
derivatives (2a, 2b, 6a, 6b, 6c, 6d, 6e, 6f, 6g, 6h, 7b,
8a, 8c, 8d, 8f, 8g, 9a, 9b, 10a, 10b, 11a, 11b, 12a,
Scheme 1. Synthesis of compounds 2a,b.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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New Azoloazines with Potent Anti-inflammatory and Analgesic Activity
Scheme 2. Reaction of compounds 2a,b with hydrazonoyl chlorides 3.
activity (response time at 1 and 2 h; 40.43 and 51.36 s),
while the potency was not affected in case of the
heptenyl analogue 7b. The conversion of compounds
7a,b to their arylidene analogues 8a–h retained the high
analgesic activity (response time at 1h: 25.61–43.77 s at
2 h: 34.51–52.51 s). The most potent activity was
obtained by the p-fluorophenylquinazoline derivative 8b
representing response time at 1 h: 43.77 s and at 2 h:
52.51s. The replacement of the arylidene side chains
with CH3 as compounds 11a,b slightly reduced the
response time (1h: 31.73 and 26.11 s at 2 h: 40.2 and,
35.35s, respectively). Also, similar slight reduction in
the potency was observed upon conversion the carbonyl
group at the thiazolidine-C4 to CH3 as compounds 9a,b
and 10a,b. Further attenuation in the activity was
observed upon replacement of the five-member thiazole
moiety with the six-member thiazine ring as compounds
12a,b (response time at 1 h: 25.35 and 27.12 s and at
2 h: 35.41 and 35.31 s, respectively).
The anti-inflammatory activity.
Table 3 reveals the
percentage of inflammation inhibition after 4 h post-
compound administration using indomethacin as
a
reference standard. The starting derivatives 2a,b exhibited
marked inhibition of inflammation of 54.54% and 46.56%,
respectively, while the reference indomethacin exhibited
30.59% inflammatory inhibition. Similar to the analgesic
data, the triazolo[3,4-b]quinazolines 6a,b,e,f displayed
more potent anti-inflammatory activity than the cyclohepta
[d]triazolo[4,3-a]pyrimidines 6c,d,g,h (inhibition % 6a,b,e,
f: 51.99–54.65, inhibition % 6c,d,g,h: 45.67–47.89). A
remarkable increase in the inflammatory inhibition by the
trifused tetrahydro-thiazolo[2,3-b]quinazoline7a reached to
64.63%, while the inhibition % of the heptenyl analogue
7b reached to 47.11%. Also, significant anti-inflammatory
Journal of Heterocyclic Chemistry
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D. H. Dawood, R. S. Jasass, M. M. Amin, T. A. Farghaly, and E. M. H. Abbas
Vol 000
Scheme 3. Synthesis of thiazole derivative 7a,b and 8a–h.
activity was gained by the 2-arylidenetetrahydro-
thiazolo[2,3-b]quinazoline derivatives 8a–d (inhibition %;
51.10–64.85), while the inhibition % of the heptenyl
derivatives 8e–h ranged from 46.23 to 65.63. Furthermore,
the activity clarified to be significant by the rest of the
compounds 9, 10, 11, and 12 (inhibition %; 48.33–53.43).
It could be concluded that the new hexahydroquinazoline
derivatives produced more potent anti-inflammatory and an-
algesic activity than their cyclohepta[d]pyrimidine ana-
logues and could be considered as new nuclei for more
derivatization and optimization to get new anti-
inflammatory and analgesic candidates of more potency
than the known marketed drugs.
recorded on GCMS-QP 1000EX Shimadzu Gas
Chromatography MS Spectrometer. The IR spectra, mass
spectra, and the elemental analyses were performed at
Micro-analytical Laboratory, Central Services Laboratory,
Faculty of Science, Cairo University, Egypt. The reactions
were pursued by TLC (aluminum sheets, Merck), and the
spots were disclosed by exposure to UV lamp. 2,6-
Bis-(3,4-dimethoxy-benzylidene)-cyclohexanone (1a) and
2,7-bis-(3,4-dimethoxy-benzylidene)-cycloheptanone (1b)
were prepared as previously described [23].
Synthesis of compounds 2a,b.
Thiourea (1.52gm,
20mmol) was added to a mixture of compounds 1a,b
(20 mmol) in ethyl alcohol (100mL) containing potassium
hydroxide (1g) in water (0.5mL). The reaction mixture
was heated under reflux for 5h then allowed to cool, and
the solid formed was filtered off, dissolved in water, and
precipitated by HCl. The solid formed was filtered off and
crystallized from methanol to afford compounds 2a,b.
8-(3,4-Dimethoxybenzylidene)-4-(3,4-dimethoxyphenyl)-3,4,5,
6,7,8-hexahydroquinazoline-2(1H)-thione (2a) was prepared as
previously described [24].
EXPERIMENTAL
Chemistry.
All melting points were uncorrected and
measured using Electrothermal IA 9000 apparatus.
Infrared spectra were measured by Nexus 670 FT-IR FT-
Raman spectrometer using KBr discs. The NMR spectra
1
were determined using Varian mercury (300MHz, for H
9-(3,4-Dimethoxybenzylidene)-4-(3,4-dimethoxyphenyl)-1,2,
3,4,5,6,7,8,9-octahydro-2H-cyclohepta[d]pyrimidine-2-thione
NMR and 100MHz for 13C NMR) spectrometer using
TMS as the internal standard. The mass spectra were
(2b).
White solid, mp= 233–235°C, yield (85%).
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New Azoloazines with Potent Anti-inflammatory and Analgesic Activity
Scheme 4. Synthesis of compounds 9–11.
Scheme 5. Synthesis of compounds 12a,b.
Analysis for C26H30N2O4S (466.59); Calcd.: %C, 66.93;
H, 6.48; N, 6.00; S, 6.87. Found: %C, 66.98; H, 6.52; N,
dioxane (30mL). The reaction mixture was refluxed for
12 h. The solvent was evaporated, and the residue was
treated with methanol. The precipitate formed was filtered
off and crystallized from the chloroform to give
compounds 6a–h.
1
6.04; S, 6.95. IR (cmꢀ1): 3437, 3188 (2NH). H NMR
(DMSO-d6, δ ppm): 1.88–2.53 (m, 8H, 4CH2), 3.74–
3.77 (m, 12H, 4OCH3), 4.66 (s, 1H, pyrimidine-H),
6.74–7.01 (m, 7H, Ar-Hs + benzylic proton), 8.84, 9.15
(2 s, 2H, 2NH). MS m/z, (%): 466 (M+, 67), 329 (55),
315 (21), 151(100).
1-[9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-1-
phenyl-1,5,6,7,8,9-hexahydro-[1,2,4]triazolo[3,4-b]quinazolin-
3-yl]-ethanone (6a). Yellow solid, mp= 130–132°C, yield
(75%). Analysis for C34H34N4O5 (578.66), Calcd.: %C,
70.57; H, 5.92; N, 9.68. Found: %C, 70.61; H, 5.98; N,
Reaction of thione 2a,b with hydrazonoyl chlorides 3 to
give compounds 6a–h.
Triethylamine was added
1
(1.51mL, 15mmol) to a mixture of equimolar amounts
of pyrimidine-2-thione derivatives 2a,b and the
appropriate hydrazonoyl halides 3 (15 mmol of each) in
9.73. IR (cmꢀ1): 1694 (C = O) and 1592 (C = N). H
NMR (DMSO-d6, δ ppm): 1.88–2.65 (m, 6H, 3CH2),
2.47 (s, 3H, COCH3), 3.70–3.77 (m, 12H, 4OCH3), 6.12
Journal of Heterocyclic Chemistry
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D. H. Dawood, R. S. Jasass, M. M. Amin, T. A. Farghaly, and E. M. H. Abbas
Vol 000
Table 1
134.96, 138.22, 141.69, 146.96, 148.0, 149.25, 187.90.
MS m/z, (%): 578 (M+, 8), 548 (13), 423 (20), 243 (51),
135 (82), 59 (100).
Anti-nociceptive (analgesic) effect of different compounds in albino mice.
E (s)
1-[9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-1-
p-tolyl-1,5,6,7,8,9-hexahydro-[1,2,4]triazolo[3,4-b]quinazolin-
Groups
Zero time
60 min
120 min
3-yl]-ethanone (6b).
Yellow solid, mp = 122–124°C,
Control
Aspirin
2a
2b
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
8a
8b
8c
11.20 0.21
11.32 0.28
11.17 0.17
11.25 0.19
11.24 0.04
11.21 0.11
11.26 0.2
11.23 0.07
11.3 0.24
11.13 0.06
11.22 0.09
11.11 0.18
11 0.05
11.21 0.16
10.85 0.25
11.22 0.27
11.12 0.14
11.29 0.2
11.15 0.09
11.19 0.1
10.98 0.1
10.96 0.12
11.28 0.16
11.16 0.13
11.1 0.25
11.05 0.05
11.23 0.23
11.12 0.08
11.15 0.14
11.18 0.15
11.18 0.25
11.22 0.16
yield (80%). Analysis for C35H36N4O5, MW (592.68);
Calcd.: %C, 70.93; H, 6.12; N, 9.45. Found: %C, 70.98;
H, 6.17; N, 9.51. IR (cmꢀ1): 1691 (C = O) and 1608 (C
16.29 0.12*
30.23 0.2**
24.31 0.11**
29.15 0.26**
31.31 0.25**
25.33 0.33**
26.08 0.17**
31.1 0.22**
30.41 0.08**
25.55 0.24**
27.21 0.23**
40.43 0.32**
25.73 0.18**
32.15 0.19**
43.77 0.36**
30.27 0.24**
31.83 0.31**
34.37 0.41**
25.61 0.08**
25.93 0.28**
36.7 0.35**
29.45 0.11**
24.85 0.26**
30.51 0.28**
23.95 0.2**
31.73 0.21**
26.11 0.13**
25.35 0.08**
27.12 0.2**
20.73 0.21*
41.36 0.09**
33.81 0.22**
39.42 0.35**
39.26 0.42**
33.6 0.11**
34.75 0.05**
40.5 0.16**
40.33 0.19**
35.86 0.31**
35.19 0.14**
51.36 0.41**
35.41 0.29**
41.34 0.07**
52.51 0.11**
40.66 0.2**
39.71 0.22**
47.28 0.33**
34.92 0.24**
34.51 0.15**
45.66 0.51**
40.31 0.19**
34.25 0.26**
39.16 0.31**
35.14 0.23**
40.25 0.29**
35.35 0.3**
35.41 0.17**
35.31 0.28**
1
= N). H NMR (DMSO-d6, δ ppm): 1.64–2.72 (m, 6H,
3CH2), 2.21 (s, 3H, CH3), 2.46 (s, 3H, COCH3), 3.72–
3.79 (m, 12H, 4OCH3), 6.13 (s, 1H, pyrimidine-H),
6.87–8.15 (m, 11H, Ar-Hs + benzylic proton). MS m/z,
(%): 592 (M+, 3), 455 (13), 417 (11), 165 (12), 138 (12),
91 (36), 43 (100).
1-(10-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1-
phenyl-5,6,7,8,9,10-hexahydro-1H-cyclohepta[d][1,2,4]triazolo
[4,3-a]pyrimidin-3-yl)ethan-1-one (6c).
Yellow solid,
mp = 85–87°C, yield (80%). Analysis for C35H36N4O5,
MW (592.68); Calcd.: %C, 70.93; H, 6.12; N, 9.45. Found:
%C, 70.97; H, 6.17; N, 9.50. IR (cmꢀ1): 1693 (C = O) and
1597 (C = N). 1H NMR (DMSO-d6, δ ppm): 1.85–2.69 (m,
8H, 4CH2), 2.45 (s, 3H, COCH3), 3.71–3.77 (m, 12H,
4OCH3), 6.12 (s, 1H, pyrimidine-H), 6.90–7.89 (m, 12H,
Ar-Hs +benzylic proton). MS m/z, (%): 592 (M+, 0.7),
444 (1), 180 (11), 43 (100).
8d
8e
8f
8 g
8 h
9a
9b
10a
10b
11a
11b
12a
12b
1-(10-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1-p-
tolyl-5,6,7,8,9,10-hexahydro-1H-cyclohepta[d][1,2,4]triazolo[4,3-
a]pyrimidin-3-yl)ethan-1-one (6d). Yellow solid, mp= 95–
97°C, yield (74%). Analysis for C36H38N4O5, MW
(606.71); Calcd.: %C, 71.27; H, 6.31; N, 9.23. Found: %
C, 71.31; H, 6.34; N, 9.28. IR (cmꢀ1): 1698 (C = O) and
Values were expressed as means SE of six animals.
*As compared with normal control group (one-way ANOVA followed by
Tukey post hoc test) at P < 0.05.
**As compared with standard group (one-way ANOVA followed by
Tukey post hoc test) at P < 0.05.
1
1632 (C = N). H NMR (DMSO-d6, δ ppm): 1.85–2.67
(m, 8H, 4CH2), 2.24 (s, 3H, CH3), 2.44 (s, 3H, COCH3),
3.72–3.79 (m, 12H, 4OCH3), 6.14 (s, 1H, pyrimidine-H),
6.92–7.76 (m, 11H, Ar-Hs + benzylic proton). MS m/z,
(%): 606 (M+, 10), 537 (12), 469 (22), 431 (13), 151
(93), 43 (100).
Ethyl 9-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1-
phenyl-1,5,6,7,8,9-hexahydro-[1,2,4]triazolo[3,4-b]quinazoline-
3-carboxylate (6e).
Yellow solid, mp= 115–117°C, yield
(72%). Analysis for C35H36N4O6, MW (608.68); Calcd.: %
C, 69.06; H, 5.96; N, 9.20. Found: %C, 69.14; H, 5.99; N,
1
9.25. IR (cmꢀ1): 1727 (C = O) and 1593 (C = N). H
NMR (DMSO-d6, δ ppm): 1.25 (t, J=7Hz, 3H, CH3),
1.88–2.66 (m, 6H, 3CH2), 3.71–3.77 (m, 12H, 4OCH3),
4.30 (q, J=7Hz, 2H, CH2), 6.09 (s, 1H, pyrimidine-H),
6.76–8.28 (m, 12H, Ar-Hs + benzylic proton). 13C NMR
(DMSO-d6, δ ppm): 14.34, 22.88, 27.31, 27.53, 55.93,
56.01, 61.98, 62.98, 111.15, 112.15, 112.56, 113.61, 119.39,
122.29, 124.12, 126.23, 128.01, 129.66, 130.21, 133.79,
134.74, 137.91, 138.26, 146.70, 147.99, 148.91, 148.98,
149.34, 153.0, 156.51, 169.93. MS m/z, (%): 608 (M+, 26),
471 (100), 399 (11), 281 (18), 151 (34).
Figure 2. The most active compounds that exert analgesic effect at zero
time and after 60 and 120 min from administration. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
(s, 1H, pyrimidine-H), 6.77–8.34 (m, 12H, Ar-Hs +
benzylic proton). 13C NMR (DMSO-d6, δ ppm): 22.91,
26.55, 27.34, 27.53, 55.91, 56.04, 59.07, 61.79, 112.0,
112.17, 112.49, 113.0, 113.61, 119.38, 119.55, 122.29,
123.99, 126.40, 128.20, 129.71, 131.26, 133.81, 134.90,
Journal of Heterocyclic Chemistry
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Month 2016
New Azoloazines with Potent Anti-inflammatory and Analgesic Activity
Table 2
Anti-inflammatory effect of different compounds in albino rats.
Edema paw thickness (mm)
Groups
1 h
2 h
3 h
4 h
Control positive
Indomethacin
2a
2b
6a
6b
6c
6d
6e
9.13 0.15
10.09 0.3
10.31 0.11
7.69 0.13*
5.15 0.07**
5.75 0.07**
5.38 0.06**
5.2 0.1**
9.02 0.24
6.26 0.1*
7.21 0.18*
4.22 0.05**
4.51 0.06**
4.4 0.1**
8.19 0.09*
6.35 0.03**
6.66 0.15**
6.11 0.02**
6.27 0.02**
6.86 0.1**
6.59 0.03**
6.34 0.09**
6.39 0.03**
6.61 0.05**
6.91 0.06**
4.16 0.07**
6.95 0.03**
6.42 0.04**
4.09 0.05**
6.15 0.08**
6.11 0.1**
4.18 0.08**
6.52 0.01**
6.71 0.1**
4.15 0.04**
6.41 0.05**
6.89 0.01**
6.3 0.1**
4.1 0.04**
4.82 0.16**
4.16 0.01**
4.33 0.01**
4.86 0.08**
4.81 0.02**
4.09 0.07**
4.15 0.09**
4.7 0.04**
4.9 0.07**
3.19 0.1**
4.77 0.04**
4.26 0.05**
3.17 0.01**
4.41 0.02**
4.17 0.09**
3.15 0.06**
4.82 0.02**
4.85 0.07**
3.1 0.09**
4.26 0.1**
4.55 0.06**
4.2 0.02**
4.6 0.09**
4.29 0.04**
4.59 0.02**
4.62 0.08**
4.66 0.06**
4.17 0.06**
4.8 0.01**
4.55 0.05**
4.21 0.08**
4.41 0.07**
4.73 0.02**
4.65 0.09**
3.11 0.09**
4.88 0.05**
4.22 0.03**
3.14 0.1**
4.33 0.1**
4.27 0.01**
3.22 0.03**
4.61 0.07**
4.92 0.08**
3.09 0.05**
4.32 0.03**
4.78 0.08**
4.4 0.08**
4.81 0.1**
4.31 0.03**
4.63 0.01**
4.32 0.09**
4.96 0.1**
5.56 0.02**
5.93 0.08**
5.25 0.04**
5.42 0.04**
5.81 0.01**
5.7 0.04**
3.1 0.08**
5.58 0.09**
5.3 0.09**
3.2 0.02**
5.36 0.07**
5.28 0.03**
3.31 0.01**
5.69 0.06**
5.59 0.03**
3.21 0.02**
5.06 0.01**
5.66 0.02**
5.11 0.05**
5.58 0.07**
5.1 0.06**
5.74 0.05**
5.15 0.03**
5.88 0.01**
6f
6g
6h
7a
7b
8a
8b
8c
8d
8e
8f
8g
8h
9a
9b
10a
10b
11a
11b
12a
12b
6.92 0.04**
6.24 0.01**
6.52 0.06**
6.41 0.1**
6.71 0.07**
Values were expressed as means SE of six animals.
*As compared with normal control group (one-way ANOVA followed by Tukey post hoc test) at P < 0.05.
**As compared with standard group (one-way ANOVA followed by Tukey post hoc test) at P < 0.05.
Ethyl 9-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1-
p-tolyl-1,5,6,7,8,9-hexahydro-[1,2,4]triazolo[3,4-b]quinazoline-
3-carboxylate (6f). Yellow solid, mp = 120–122°C, yield
(73%). Analysis for C36H38N4O6, MW (622.71); Calcd.:
%C, 69.44; H, 6.15; N, 9.00. Found: %C, 69.51; H,
6.20; N, 9.06. IR (cmꢀ1): 1731(C = O) and 1608 (C =
(m, 12H, 4OCH3), 4.30 (q, J = 7 Hz, 2H, CH2), 6.30 (s,
1H, pyrimidine-H), 6.90–7.84 (m, 12H, Ar-Hs + benzylic
proton). MS m/z, (%): 622 (M+, 0.7), 366 (1), 218 (6),
135 (12), 77 (34), 43 (100).
Ethyl 10-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1-
p-tolyl-5,6,7,8,9,10-hexahydro-1H-cyclohepta[d][1,2,4]triazolo
1
N). H NMR (DMSO-d6, δ ppm): 1.20 (t, J= 7 Hz, 3H,
[4,3-a]pyrimidine-3-carboxylate (6 h).
Yellow solid,
CH3), 1.88–2.60 (m, 6H, 3CH2), 2.22 (s, 3H, CH3),
3.72–3.78 (m, 12H, 4OCH3), 4.34 (q, J =7 Hz, 2H,
CH2), 6.11 (s, 1H, pyrimidine-H), 6.87–8.02 (m, 11H,
Ar-Hs + benzylic proton). MS m/z, (%): 622 (M+, 3),
485 (4), 406 (8), 151 (75), 165 (35), 91 (100).
mp = 84–86°C, yield (80%). Analysis for C37H40N4O6,
MW (636.74); Calcd.: %C, 69.79; H, 6.33; N, 8.80. Found:
%C, 69.82; H, 6.37; N, 8.86. IR (cmꢀ1): 1732 (C = O) and
1599 (C = N). 1H NMR (DMSO-d6, δ ppm): 1.20 (t,
J = 7Hz, 3H, CH3), 1.87–2.66 (m, 8H, 4CH2), 2.26 (s,
3H, CH3), 3.72–3.81 (m, 12H, 4OCH3), 4.33(q, J = 7 Hz,
2H, CH2), 6.32 (s, 1H, pyrimidine-H), 6.92–7.86 (m,
11H, Ar-Hs +benzylic proton). MS m/z, (%):636 (M+,
11), 579 (10), 486 (3), 366 (10), 270 (12), 194 (16), 136
(3), 91 (13), 44 (100).
Ethyl 10-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1-
phenyl-5,6,7,8,9,10-hexahydro-1H-cyclohepta[d][1,2,4]triazolo
[4,3-a]pyrimidine-3-carboxylate (6 g).
Yellow solid,
mp = 89–91°C, yield (77%). Analysis for C36H38N4O6,
MW (622.71); Calcd.: %C, 69.44; H, 6.15; N, 9.00. Found:
%C, 69.48; H, 6.20; N, 9.05. IR (cmꢀ1): 1725 (C = O) and
1601 (C = N). 1H NMR (DMSO-d6, δ ppm): 1.22 (t,
J =7 Hz, 3H, CH3), 1.87–2.71 (m, 8H, 4CH2), 3.71–3.77
Synthesis of compounds 7a,b. A solution of pyrimidin-
2-thione derivatives 2a,b (20mmol) in absolute ethyl
alcohol (40mL) was refluxed with ethyl bromoacetate
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. H. Dawood, R. S. Jasass, M. M. Amin, T. A. Farghaly, and E. M. H. Abbas
Vol 000
Table 3
Anti-inflammatory effect (%) of different compounds in albino rats after 4 h.
Groups
Edema %
Inhibition %
Potency %
Control positive
100
—
—
Indomethacin
2a
2b
6a
6b
6c
6d
6e
6f
6g
6h
7a
7b
8a
69.41
45.46
53.44
46.12
48.01
53.89
53.33
45.35
46.01
52.11
54.33
35.37
52.89
47.23
35.15
48.9
46.24
34.93
53.44
53.77
34.37
47.23
50.45
46.57
51
30.59
54.54
46.56
53.88
51.99
46.11
46.67
54.65
53.99
47.89
45.67
64.63
47.11
52.77
64.85
51.1
53.76
65.07
46.56
46.23
65.63
52.77
49.55
53.43
49
100
178.29
152.20
176.13
169.95
150.73
152.56
178.65
176.49
156.55
149.29
211.27
154
172.50
211.99
167.04
175.74
212.71
152.20
151.12
214.54
172.50
161.98
174.66
160.18
171.39
160.54
159.46
157.99
Figure 4. The percentage of the most active compounds that exert anti-in-
flammatory effect after 4 h from administration. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
N, 5.69; S, 6.51. Found: %C, 65.89; H, 5.80; N, 5.80; S,
6.64. IR (cmꢀ1): 1725 (C = O) and 1602 (C = N). 1H NMR
(DMSO-d6, δ ppm): 1.56–2.64 (m, 6H, 3CH2), 3.73–3.75
(m, 12H, 4OCH3), 4.03 (s, 2H, CH2), 5.43 (s, 1H,
pyrimidine-H), 6.76–7.30 (m, 7H, Ar-Hs + benzylic proton).
MS m/z, (%): 492 (M+, 43), 417 (10), 355 (100), 327 (11),
151 (41), 77 (7).
10-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-
5,6,7,8,9,10-hexahydrocyclo-hepta[d]thiazolo[3,2-a]pyrimidin-
3(2H)-one (7b). Yellow solid, mp=188–190°C, yield (80%).
Analysis for C28H30N2O5S, MW (506.61); Calcd.: %C,
66.38; H, 5.97; N, 5.53; S, 6.33. Found: %C, 66.44; H, 6.04;
N, 5.60; S, 6.51. IR (cmꢀ1): 1717(C = O) and 1624 (C =
N).1H NMR (DMSO-d6, δ ppm): 1.66–2.55 (m, 8H, 4CH2),
3.67–3.74 (m, 12H, 4OCH3), 4.00 (s, 2H, CH2), 5.34 (s, 1H,
pyrimidine-H), 6.81–6.91 (m, 7H, Ar-Hs+benzylic proton).
13C NMR (DMSO-d6, δ ppm): 26.01, 27.20, 29.0, 29.45,
55.92, 56.01, 60.34, 112.05, 112.19, 113.25, 119.32, 120.45,
121.80, 129.63, 130.50, 133.37, 134.11, 137.29, 138.10,
140.0, 148.93, 149.06, 149.35, 149.69, 152.44, 171.90. MS
m/z, (%): 506 (M+, 3), 504 ((M-2)+, 17), 470 (15), 428 (27),
335 (33), 303 (31), 162 (41), 85 (100).
8b
8c
8d
8e
8f
8g
8h
9a
9b
10a
10b
11a
11b
12a
12b
47.57
50.89
51.22
51.67
52.43
49.11
48.78
48.33
Synthesis of compounds 8a–h
Method A.
A mixture of pyrimidin-2-thione deriva-
tives 2a,b (20mmol), chloroacetic acid (1.89g, 20mmol),
fused AcONa (3.28, 40mmol) in glacial acetic acid
(20mL), acetic anhydride (10mL), and the appropriate aro-
matic aldehyde (20mmol) was refluxed for 5 h. The reaction
mixture was cooled, poured onto cold water, and the solid
formed was filtered, dried, and crystallized from acetic acid
to give compounds 8a–h.
Figure 3. The most active compounds that exert anti-inflammatory effect
after 1, 2, 3, and 4 h from administration. [Color figure can be viewed in
the online issue, which is available at wileyonlinelibrary.com.]
(3.34mL, 20mmol) and fused NaOAc (3.28g, 40mmol) for
8h. Upon cooling, the precipitate formed was filtered,
washed, dried, and crystallized from methanol to give
compounds 7a,b.
9-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-
6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3(2H)-one (7a).
Yellow solid, mp = 90–92°C, yield (82%). Analysis for
C27H28N2O5S, MW (492.59); Calcd.: %C, 65.83; H, 5.73;
Method B.
The appropriate aromatic aldehyde
(20 mmol) was added to a mixture of 7a,b (20mmol), acetic
anhydride (10mL), and fused AcONa (3.28, 40mmol) in
acetic acid (20mL). The latter solution was refluxed for
3 h, then after the solution was cooled, it was poured onto
cold water. The solid formed was collected by filtration
and crystallized from acetic acid to give compounds 8a–h.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
New Azoloazines with Potent Anti-inflammatory and Analgesic Activity
2-Benzylidene-9-(3,4-dimethoxybenzylidene)-5-(3,4-
dimethoxyphenyl)-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]
quinazolin-3(2H)-one (8a). Brown solid, mp = 142–144°C,
yield (75%). Analysis for C34H32N2O5S, MW (580.69);
Calcd.: %C, 70.32; H, 5.55; N, 4.82; S, 5.52. Found:
%C, 70.38; H, 5.60; N, 4.87; S, 5.40. IR (cmꢀ1): 1704
(C = O) and 1615 (C = N). 1H NMR (DMSO-d6, δ
ppm): 1.82–2.62 (m, 6H, 3CH2), 3.71–3.76 (m, 12H,
4OCH3), 5.58 (s, 1H, pyrimidine-H), 6.89–7.60 (m, 13H,
Ar-Hs+ benzylic protons). MS m/z, (%):580 (M+, 51),
563 (M+, 17), 443 (100), 417 (11), 399 (7), 151 (49),
134 (63), 77(15).
(m, 8H, 4CH2), 3.71–3.78 (m, 12H, 4OCH3), 5.53 (s, 1H,
pyrimidine-H), 6.87–7.63 (m, 13H, Ar-Hs+benzylic pro-
tons). MS m/z, (%): 594 (M+, 5), 457 (16), 215 (3), 151
(40), 134 (100), 77 (23).
2-(4-Flourobenzylidene)-10-(3,4-dimethoxybenzylidene)-5-
(3,4-dimethoxyphenyl)-5,6,7,8,9,10-hexahydrocyclohepta[d]
thiazolo[3,2-a]pyrimidin-3(2H)-one (8f).
Green solid,
Analysis for
mp = 105–107°C,
yield
(79%).
C35H33FN2O5S, MW (612.71); Calcd.: %C, 68.61; H,
5.43; N, 4.57; S, 5.23. Found: %C, 68.67; H, 5.48; N,
4.61; S, 5.41. IR (cmꢀ1): 1707 (C = O) and 1601 (C =
N).1H NMR (DMSO-d6, δ ppm): 1.72–2.62 (m, 8H,
4CH2) 3.72–3.77 (m, 12H, 4OCH3), 5.57 (s, 1H,
pyrimidine-H), 6.87–7.66 (m, 12H, Ar-Hs + benzylic pro-
tons). MS m/z, (%): 612 (M+, 5), 475 (14), 382 (51), 327
(30), 299 (10), 152 (79), 77 (100).
9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-2-
(4-fluoro-benzylidene)-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]
quinazolin-3-one (8b).
Green solid, mp= 100–102°C,
yield (77%). Analysis for C34H31FN2O5S, MW (598.68);
Calcd.: %C, 68.21; H, 5.22; N, 4.68; S, 5.36. Found: %C,
68.26; H, 5.28; N, 4.71; S, 5.45. IR (cmꢀ1): 1710(C = O)
2-(4-Chlorobenzylidene)-10-(3,4-dimethoxybenzylidene)-5-
(3,4-dimethoxyphenyl)-5,6,7,8,9,10-hexahydrocyclohepta[d]
1
and 1598 (C = N). H NMR (DMSO-d6, δ ppm): 1.82–
thiazolo[3,2-a]pyrimidin-3(2H)-one (8g).
Yellow solid,
2.65 (m, 6H, 3CH2), 3.68–3.72 (m, 12H, 4OCH3), 5.60
(s, 1H, pyrimidine-H), 6.78–7.54 (m, 12H, Ar-Hs +
benzylic protons). MS m/z, (%):599 ((M+1)+, 4), 462 (18),
445 (10), 242 (15), 170 (20), 136 (11), 76 (14), 42 (100).
2-(4-Chloro-benzylidene)-9-(3,4-dimethoxy-benzylidene)-5-
(3,4-dimethoxy-phenyl)-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]
mp = 90–92°C, yield (79%). Analysis for C35H33ClN2O5S,
MW (629.16); Calcd.: %C, 66.81; H, 5.29; N, 4.45; S,
5.10. Found: %C, 66.87; H, 5.33; N, 4.52; S, 5.19. IR
(cmꢀ1): 1707 (C = O) and 1603 (C = N).1H NMR
(DMSO-d6, δ ppm): 1.72–2.62 (m, 8H, 4CH2), 3.72–3.78
(m, 12H, 4OCH3), 5.58 (s, 1H, pyrimidine-H), 6.87–7.66
(m, 12H, Ar-Hs +benzylic protons). MS m/z, (%): 629
(M+, 9), 597 (3), 342 (14), 315 (17), 273 (16), 136 (11),
123 (22), 43 (100).
quinazolin-3-one (8c).
Yellow solid, mp = 104–106°C,
yield (77%). Analysis for C34H31ClN2O5S, MW
(615.14); Calcd.: %C, 66.39; H, 5.08; N, 4.55; S, 5.21.
Found: %C, 66.44; H, 5.14; N, 4.61; S, 5.29. IR
(cmꢀ1): 1709(C = O) and 1602 (C = N). 1H NMR
(DMSO-d6, δ ppm): 1.82–2.62 (m, 6H, 3CH2), 3.68–
3.72 (m, 12H, 4OCH3), 5.61 (s, 1H, pyrimidine-H),
6.78–7.54 (m, 12H, Ar-Hs + benzylic protons). MS m/z,
(%): 615 (M+, 3), 614 (M1+, 8), 477 (9), 329 (13), 267
(3), 170 (16), 151 (61), 136 (10), 77 (16), 64 (100).
9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-2-
(4-dimethylamino-benzylidene)-6,7,8,9-tetrahydro-5H-thiazolo
2-(4-Dimethylamino-benzylidene)-10-(3,4-dimethoxybenzylidene)-
5-(3,4-dimethoxy-phenyl)-5,6,7,8,9,10-hexahydrocyclohepta[d]
thiazolo[3,2-a]pyrimidin-3(2H)-one (8h).
Reddish brown
solid, mp = 150–152°C, yield (79%). Analysis for
C37H39N3O5S, MW (637.79); Calcd.: %C, 69.68; H,
6.16; N, 6.59; S, 5.03. Found: %C, 69.74; H, 6.20; N,
6.64; S, 5.12. IR (cmꢀ1): 1700 (C = O) and 1586 (C =
N).1H NMR (DMSO-d6, δ ppm): 1.72–2.62 (m, 8H,
4CH2), 3.01 (s, 6H, 2CH3), 3.72–3.78 (m, 12H, 4OCH3),
5.54 (s, 1H, pyrimidine-H), 6.76–7.53 (m, 12H, Ar-Hs + -
benzylic protons). MS m/z, (%): 637 (M+, 0.7), 577 (6),
471 (23), 313 (33), 262 (48), 239 (31), 57(100).
[2,3-b]quinazolin-3-one (8d).
Reddish brown solid,
mp = 143–145°C, yield (79%). Analysis for C36H37N3O5S,
MW (623.76); Calcd.: %C, 69.32; H, 5.98; N, 6.74; S,
5.14. Found: %C, 69.37; H, 5.94; N, 6.79; S, 5.23. IR
(cmꢀ1): 1698 (C = O) and 1587 (C = N). 1H NMR
(DMSO-d6, δ ppm): 1.82–2.62 (m, 6H, 3CH2), 3.01(s,
6H, 2 CH3), 3.72–3.77 (m, 12H, 4OCH3), 5.60 (s, 1H,
pyrimidine-H), 6.73–7.55 (m, 12H, Ar-Hs + benzylic pro-
tons). MS m/z, (%): 623 (M+, 1), 486 (8), 177 (100), 151
(31), 134 (44), 77 (25).
2-Benzylidene-10-(3,4-dimethoxybenzylidene)-5-(3,4-dimetho-
xyphenyl)-5,6,7,8,9,10-hexahydrocyclohepta[d]thiazolo[3,2-a]pyri-
midin-3(2H)-one (8e). Brown solid, mp=90–92°C, yield
(77%). Analysis for C35H34N2O5S, MW (594.72); Calcd.:
%C, 70.68; H, 5.76; N, 4.71; S, 5.39. Found: %C, 70.73;
H, 5.80; N, 4.75; S, 5.44. IR (cmꢀ1): 1706 (C = O) and
1603 (C = N).1H NMR (DMSO-d6, δ ppm): 1.72–2.62
Synthesis of compounds 9a,b.
A solution of the
pyrimidin-2-thione derivatives 2a,b (20mmol) in absolute
ethyl alcohol (40mL) was refluxed with chloroacetone
(1.85mL, 20mmol) and fused NaOAc (3.28g, 40mmol)
for 7h. The reaction mixture was then left to cool and was
poured into ice-cold water; the product that was separated
was filtered, dried, and crystallized from methanol to give
compounds 9a,b
9-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-3-
methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazoline (9a).
Yellow solid, mp = 145–147°C, yield (78%). Analysis for
C28H30N2O4S, MW (490.61); Calcd.: %C, 68.55; H,
6.16; N, 5.71; S, 6.53. Found: %C, 68.47; H, 6.25; N,
5.80; S, 6.58. IR (cmꢀ1): 1597 (C = N). 1H NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

D. H. Dawood, R. S. Jasass, M. M. Amin, T. A. Farghaly, and E. M. H. Abbas
Vol 000
(DMSO-d6, δ ppm): 1.60–2.62 (m, 6H, 3CH2), 1.87 (s, 3H,
CH3), 3.71–3.74 (m, 12H, 4OCH3), 5.60 (s, 1H,
pyrimidine-H), 5.98 (s, 1H, CH), 6.78–7.22 (m, 7H, Ar-
Hs+ benzylic proton). MS m/z, (%): 490 (M+, 23), 391
(8), 353 (95), 339 (62), 239 (29), 165 (83), 151 (60), 137
(28), 57 (100).
mixture was poured into ice-cold water; the product that
was separated was filtered, dried, and crystallized from
methanol to give compounds 11a,b
9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-2-
methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3(2H)-
one (11a).
White crystals, mp = 175–177°C, yield
10-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-3-
methyl-5,6,7,8,9,10-hexahydrocyclohepta[d]thiazolo[3,2-a]py-
(80%). Analysis for C28H30N2O5S, MW (506.61);
Calcd.: %C, 66.38; H, 5.97; N, 5.53; S, 6.33. Found:
%C, 66.45; H, 6.04; N, 5.58; S, 6.45. IR (cmꢀ1): 1724
(C = O) and 1603 (C = N). 1H NMR (DMSO-d6, δ
ppm): 1.50 (d, J = 8 Hz, 3H, CH3), 1.81–2.65 (m, 6H,
3CH2), 3.69–3.71 (m, 12H, 4OCH3), 4.35 (q, J = 8 Hz,
1H, CH), 5.39 (s, 1H, pyrimidine-H), 6.89–7.22 (m,
7H, Ar-Hs + benzylic proton). MS m/z, (%):506 (M+,
65), 369 (100), 341 (37), 151 (25), 77 (7).
rimidine (9b).
Yellow solid, mp = 155–157°C, yield
(75%). Analysis for C29H32N2O4S, MW (504.64); Calcd.:
%C, 69.02; H, 6.39; N, 5.55; S, 6.35. Found: %C, 69.07;
1
H, 6.45; N, 5.61; S, 6.48. IR (cmꢀ1): 1593 (C = N). H
NMR (DMSO-d6, δ ppm): 1.72–2.62 (m, 8H, 4CH2),
1.84 (s, 3H, CH3), 3.73–3.76 (m, 12H, 4OCH3), 5.52 (s,
1H, pyrimidine-H), 5.98 (s, 1H, CH), 6.73–7.12 (m, 7H,
Ar-Hs + benzylic proton). MS m/z, (%): 504 (M+, 7), 367
(45), 353 (38), 165 (46), 151 (55), 57 (100).
10-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-2-
methyl-5,6,7,8,9,10-hexahydrocyclohepta[d]thiazolo[3,2-a]pyri-
Synthesis of compounds 10a,b.
A solution of the
midin-3(2H)-one (11b).
White crystals, mp=160–162°C,
pyrimidin-2-thione derivatives 2a,b (20mmol) in absolute
ethyl alcohol (40mL) was refluxed with ethyl-2-chloro
acetoacetate (3.29mL, 20 mmol) and fused NaOAc(3.28g,
40mmol) for 9h. The reaction mixture was then left to
cool and was poured into ice-cold water; the product that
was separated was filtered, dried, and crystallized from
methanol to give compounds 10a,b.
Ethyl 9-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-3-
methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazoline-2-carbox-
ylate (10a). Buff crystals, mp= 148–150°C, yield (78%).
Analysis for C31H34N2O6S, MW (562.68); Calcd.: %C,
66.17; H, 6.09; N, 4.98; S, 5.70. Found: %C, 66.23; H,
6.15; N, 5.04; S, 5.86. IR (cmꢀ1): 1721 (C = O) and
1604 (C = N). 1H NMR (DMSO-d6, δ ppm): 1.49 (t,
J =7 Hz, 3H, CH3), 1.79–2.62 (m, 6H, 3CH2), 2.46 (s,
3H, CH3), 3.69–3.72 (m, 12H, 4OCH3), 3.99 (q, J =7 Hz,
2H, CH2), 5.40 (s, 1H, pyrimidine-H), 6.84–7.25 (m, 7H,
Ar-Hs + benzylic proton). MS m/z, (%): 562 (M+, 0.7),
492 (28), 355 (100), 151 (45), 77 (19).
yield (80%). Analysis for C29H32N2O5S, MW (520.64);
Calcd.: %C, 66.90; H, 6.20; N, 5.38; S, 6.16. Found: %C,
66.96; H, 6.27; N, 5.43; S, 6.26. IR (cmꢀ1): 1722 (C = O)
and 1623 (C = N).1H NMR (DMSO-d6, δ ppm): 1.53 (d,
J=8Hz, 3H, CH3), 1.68–2.59 (m, 8H, 4CH2), 3.71–3.77
(m, 12H, 4OCH3), 4.35 (q, J=8Hz, 1H, CH), 5.35 (s, 1H,
pyrimidine-H), 6.83–7.22 (m, 7H, Ar-Hs+benzylic proton).
13C NMR (DMSO-d6, δ ppm): 19.31, 25.78, 26.40, 29.03,
29.44, 42.31, 56.0, 60.40, 100.0, 112.13, 112.29, 113.19,
120.0, 120.21, 121.79, 122.52, 129.66, 130.53, 130.40,
137.10, 138.0, 147.56, 148.36, 148.91, 149.19, 150.10,
174.50. MS m/z, (%): 520 (M+, 90), 489 (17), 383 (100),
369 (61), 355 (40), 151 (84).
Synthesis of compounds 12a,b.
A
mixture of
pyrimidin-2-thione derivatives 2a,b (20mmol), 3-
bromopropanoic acid (3.06 g, 20 mmol), and fused
AcONa (3.28 g, 40 mmol) in glacial acetic acid (20mL)
and acetic anhydride (10mL), was refluxed for 6h. The
reaction mixture was cooled, poured onto cold water,
and the solid formed was collected and crystallized from
acetic acid to give compounds 12a,b
10-(3,4-Dimethoxybenzylidene)-6-(3,4-dimethoxyphenyl)-
2,3,7,8,9,10-hexahydro-4H,6H-[1,3]thiazino[2,3-b]quinazolin-
4-one (12a). Buff crystal, mp =110–112°C, yield (82%).
Analysis for C28H30N2O5S, MW (506.61); Calcd.: %C,
66.38; H, 5.97; N, 5.53; S, 6.33. Found: %C, 66.42; H,
6.01; N, 5.57; S, 6.39. IR (cmꢀ1): 1692 (C = O) and 1561
(C = N).1H NMR (DMSO-d6, δ ppm): 1.68–2.62 (m, 6H,
3CH2), 2.98–3.06 (m, 4H, 2CH2), 3.71–3.76 (m, 12H,
4OCH3), 5.91 (s, 1H, pyrimidine-H), 6.78–7.15 (m, 7H,
Ar-Hs +benzylic proton). MS m/z, (%): 506 (M+, 48), 406
(39), 369 (28), 315 (26), 236 (22), 174 (54), 151 (100).
11-(3,4-Dimethoxybenzylidene)-6-(3,4-dimethoxyphenyl)-
2,3,6,7,8,9,10,11-octahydro-4H-cyclohepta[4,5]pyrimido[2,1-b]
Ethyl 10-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-3-
methyl-5,6,7,8,9,10-hexahydrocyclohepta[d]thiazolo[3,2-a]py-
rimidine-2-carboxylate (10b). Buff crystals, mp=135–137°C,
yield (78%). Analysis for C32H36N2O6S, MW (576.70);
Calcd.: %C, 66.64; H, 6.29; N, 4.86; S, 5.56. Found: %C,
66.70; H, 6.34; N, 4.93; S, 5.70. IR (cmꢀ1): 1721 (C = O)
1
and 1617 (C = N). H NMR (DMSO-d6, δ ppm): 1.23(t,
J=7Hz, 3H, CH3), 1.73–2.58 (m, 8H, 4CH2), 2.49 (s, 3H,
CH3), 3.71–3.77 (m, 12H, 4OCH3), 3.99 (q, J=7Hz, 2H,
CH2), 5.37 (s, 1H, pyrimidine-H), 6.83–7.22 (m, 7H,
Ar-Hs + benzylic proton). MS m/z, (%): 576 (M+, 5), 551
(8), 367 (9), 339 (17), 151 (24), 135 (25), 57 (100).
Synthesis of compounds 11a,b.
A solution of the
pyrimidin-2-thione derivatives 2a,b (20mmol) in
absolute ethyl alcohol (40mL) was refluxed with ethyl-2-
bromopropionate (3.62mL, 20mmol) and fused AcONa
(3.28 g, 40 mmol) for 7 h. Upon cooling, the reaction
[1,3]thiazin-4-one (12b).
Buff crystal, mp = 86–88°C,
yield (80%). Analysis for C29H32N2O5S, MW (520.64);
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2016
New Azoloazines with Potent Anti-inflammatory and Analgesic Activity
Calcd.: %C, 66.90; H, 6.20; N, 5.38; S, 6.16. Found: %C,
66.94; H, 6.23; N, 5.41; S, 6.31. IR (cmꢀ1): 1690 (C = O)
and 1566 (C = N).1H NMR (DMSO-d6, δ ppm): 1.63–2.63
(m, 8H, 4CH2), 2.95–3.04 (m, 4H, 2CH2), 3.71–3.78 (m,
12H, 4OCH3), 5.91 (s, 1H, pyrimidine-H), 6.66–7.18 (m,
7H, Ar-Hs +benzylic proton). MS m/z, (%): 520 (M+, 5),
369 (10), 329 (7), 315 (8), 151 (46), 77 (14), 55 (100).
Latency to show analgesic response, like licking the paws
or jumping out the hot plate, was recorded at 60 and
120 min after 1 h from i.p. administration of 28 different
compounds (10 mg/kg) after dissolving in DMSO, aspirin
(200 mg/kg; positive control), and DMSO (negative con-
trol) [28]. Response time for thermal pain was recorded
before administration of different compounds and aspirin
(0 time).
Anti-inflammatory test. This test was carried out by
carrageenan, an induced rat paw edema [27,29] for
testing the anti-inflammatory properties of the different
compounds. Rats were divided into 30 groups (n = 6), i.p.
administration of 28 different compounds (10 mg/kg) and
DMSO (negative control), while indomethacin(20 mg/kg;
positive control) was administered once orally by gastric
tube [30]. All the rats were injected with 0.1 mL of 1%
carrageenan solution in saline at the sub-planter area of
the right hind paw after 1 h from different compounds
and indomethacin administration. Each rat’s paw
thickness was measured by planimeter before carrageenan
administration. After administration of carrageenan, the
paw thickness of each rat was measured by planimeter
every 1 h for 4h. Edema rate, inhibition, and potency
were calculated as follows [31]:
PHARMACOLOGICAL SCREENING
Material and methods
Material
Animals.
Adult male albino Sprague Dawely rats
and mice weighing 100–120 and 20–30 g, respectively,
were purchased from the National Research Centre An-
imal Laboratory (Giza, Egypt) and were housed in stan-
dard polypropylene cages and kept under constant
environmental conditions and equal light–dark cycles.
The animals were fed commercially rat normal standard
diet pellets and water ad libitum.
Ethics statement. This experiment was carried out in
according to recommendations in the Guide for the Care
and Use of Laboratory Animals of the National Institutes
Control thickness mean - treated thickness mean
Edema ð%Þ ¼
ꢁ 100
Control thickness mean
Control edema ð%Þ mean - treated edema ð%Þ mean
Inhibition ð%Þ ¼
Potency ð%Þ ¼
ꢁ 100
Control edema ð%Þ
Inhibition ð%Þ indomethacine - inhibition ð%Þ treated group
Inhibition ð%Þ indomethacine
ꢁ 100
of Health (NIH publication no. 85–23, revised 1996) and
under regulations of Animal Care and Use of National Re-
search Centre in Egypt.
Statistical analysis.
The differences between groups
were tested for significance using analysis of variance,
followed by Tukey post hoc test determined by SPSS
software program, version 21.Values are expressed as
mean SE. The level of statistical significance was taken
at P< 0.05.
Drugs
Standard drugs used as
a
control.
Indomethacin
(Indocid) was obtained from El Kahera pharmaceutical in-
dustrial company, Giza, Egypt. Aspirin (Aspirin) was ob-
tained from Bayer Limited Egypt LLC, Cairo, Egypt.
REFERENCES AND NOTES
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for determination of different compound effect [25].
Thirty groups of mice (n = 6) were adapted for three con-
secutive days before the test by putting them in a hot plate
device adapted at room temperature for 15 min [26,27].
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