Professional Documents
Culture Documents
Analgesic Activity
Dina H. Dawood,a Rabab S. Jasass,b Mohamed M. Amin,c Thoraya A. Farghaly,b,d and Eman M. H. Abbasa*
a
Department of Chemistry of Natural and Microbial Products, National Research Centre, Dokki, 12622 Giza, Egypt
b
Chemistry Department, Faculty of Applied Science, Umm Al-Qura University, Makkah Almukkarramah 21955,
Saudi Arabia
c
Department of Pharmacology, Medical Division, National Research Centre, 33 EL Bohouthst (former EL Tahrirst),
Dokki, 12622 Giza, Egypt
d
Department 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.
An increasing interest and an absolute requirement for The starting compounds 2a,b were prepared via the
finding of new, eclectic, and promising inhibitors with an reaction of benzylidene (1a,b) with thiourea in ethyl alco-
improved protection and efficacy profile has promoted us hol containing potassium hydroxide (Scheme 1).
toward layout unprecedented anti-inflammatory and analge- The latter compounds 2a,b have thiourea residue,
sic agents. The inflammation is a biotic rejoinder to a con- which is known to be an intermediate for the synthesis
catenation of biochemical reactions whose major function of several azoles and azines. Thus, the interaction of 2a,
is defense of the body from infection and settle of tissue b with hydrazonoyl chlorides 3 in dioxan in the existence
damage due to injury. Many heterocyclic compounds were of a base catalyst yielded only one isolated product. The
proved to have pharmacological significance as anti- spectroscopic information assured the reaction product
inflammatory and analgesic agents such as pyrimidines, 6a–h via s-alkylation to give the intermediate 4 then
qiunazolines, thiazoles, triazoles, and thiazines [1–12]. Ex- followed by Smiles rearrangement to give the intermediate
amples of the most reactive agents are proquazone and 5 with elimination of HCl and H2S molecules, respectively
fluproquazone [13,14] which have quinazoline ring (Fig. 1). (Scheme 2). Also, 1H NMR of 6 showed the absence of
The overall anti-inflammatory profile of proquazone any signals for NH protons.
is analogous with that of indomethacin. It is notewor- Furthermore, in order to synthesize fused thiazole ring
thy that proquazone is the first powerful anti- with quinazoline and cyclohepta-pyrimidine, the thione
inflammatory drug of a non-acidic kind. Also, derivatives 2a,b were reacted with diverse types of α-
meloxicam is an anti-inflammatory medication with haloketone or α-haloester, as represented in Schemes 3
analgesic and temperature-reducer effects (Fig. 1). In and 4. The structure of compounds 7, 9, 10, and 11 was
continuation of our efforts in synthesis of bioactive deduced by spectral information and elemental analyses
heterocyclic compounds [15–22], we became inter- (see the Experimental section).
ested here to design new polyheterocyclic ring sys- In addition, condensation of the thiazole derivatives 7a,b
tems having qiunazoline, thiazole, triazole, and/or with substituted benzaldehydes afforded product 8 (Scheme
thiazine rings to investigate their anti-inflammatory 3). The formation of compounds 8a–h was assured by alter-
and analgesic activities which are expected to have nate synthesis via multi-component reaction of compounds
potent activity. 2a,b, chloroacetic acid, and benzaldehyde derivatives.
activity (response time at 1 and 2 h; 40.43 and 51.36 s), 12a,b (response time at 1 h: 25.35 and 27.12 s and at
while the potency was not affected in case of the 2 h: 35.41 and 35.31 s, respectively).
heptenyl analogue 7b. The conversion of compounds The anti-inflammatory activity. Table 3 reveals the
7a,b to their arylidene analogues 8a–h retained the high percentage of inflammation inhibition after 4 h post-
analgesic activity (response time at 1 h: 25.61–43.77 s at compound administration using indomethacin as a
2 h: 34.51–52.51 s). The most potent activity was reference standard. The starting derivatives 2a,b exhibited
obtained by the p-fluorophenylquinazoline derivative 8b marked inhibition of inflammation of 54.54% and 46.56%,
representing response time at 1 h: 43.77 s and at 2 h: respectively, while the reference indomethacin exhibited
52.51 s. The replacement of the arylidene side chains 30.59% inflammatory inhibition. Similar to the analgesic
with CH3 as compounds 11a,b slightly reduced the data, the triazolo[3,4-b]quinazolines 6a,b,e,f displayed
response time (1 h: 31.73 and 26.11 s at 2 h: 40.2 and, more potent anti-inflammatory activity than the cyclohepta
35.35 s, respectively). Also, similar slight reduction in [d]triazolo[4,3-a]pyrimidines 6c,d,g,h (inhibition % 6a,b,e,
the potency was observed upon conversion the carbonyl f: 51.99–54.65, inhibition % 6c,d,g,h: 45.67–47.89). A
group at the thiazolidine-C4 to CH3 as compounds 9a,b remarkable increase in the inflammatory inhibition by the
and 10a,b. Further attenuation in the activity was trifused tetrahydro-thiazolo[2,3-b]quinazoline7a reached to
observed upon replacement of the five-member thiazole 64.63%, while the inhibition % of the heptenyl analogue
moiety with the six-member thiazine ring as compounds 7b reached to 47.11%. Also, significant anti-inflammatory
activity was gained by the 2-arylidenetetrahydro- recorded on GCMS-QP 1000EX Shimadzu Gas
thiazolo[2,3-b]quinazoline derivatives 8a–d (inhibition %; Chromatography MS Spectrometer. The IR spectra, mass
51.10–64.85), while the inhibition % of the heptenyl spectra, and the elemental analyses were performed at
derivatives 8e–h ranged from 46.23 to 65.63. Furthermore, Micro-analytical Laboratory, Central Services Laboratory,
the activity clarified to be significant by the rest of the Faculty of Science, Cairo University, Egypt. The reactions
compounds 9, 10, 11, and 12 (inhibition %; 48.33–53.43). were pursued by TLC (aluminum sheets, Merck), and the
It could be concluded that the new hexahydroquinazoline spots were disclosed by exposure to UV lamp. 2,6-
derivatives produced more potent anti-inflammatory and an- Bis-(3,4-dimethoxy-benzylidene)-cyclohexanone (1a) and
algesic activity than their cyclohepta[d]pyrimidine ana- 2,7-bis-(3,4-dimethoxy-benzylidene)-cycloheptanone (1b)
logues and could be considered as new nuclei for more were prepared as previously described [23].
derivatization and optimization to get new anti- Synthesis of compounds 2a,b. Thiourea (1.52 gm,
inflammatory and analgesic candidates of more potency 20 mmol) was added to a mixture of compounds 1a,b
than the known marketed drugs. (20 mmol) in ethyl alcohol (100 mL) containing potassium
hydroxide (1 g) in water (0.5 mL). The reaction mixture
was heated under reflux for 5 h then allowed to cool, and
EXPERIMENTAL the solid formed was filtered off, dissolved in water, and
precipitated by HCl. The solid formed was filtered off and
Chemistry. All melting points were uncorrected and crystallized from methanol to afford compounds 2a,b.
measured using Electrothermal IA 9000 apparatus. 8-(3,4-Dimethoxybenzylidene)-4-(3,4-dimethoxyphenyl)-3,4,5,
Infrared spectra were measured by Nexus 670 FT-IR FT- 6,7,8-hexahydroquinazoline-2(1H)-thione (2a) was prepared as
Raman spectrometer using KBr discs. The NMR spectra previously described [24].
were determined using Varian mercury (300 MHz, for 1H 9-(3,4-Dimethoxybenzylidene)-4-(3,4-dimethoxyphenyl)-1,2,
NMR and 100 MHz for 13C NMR) spectrometer using 3,4,5,6,7,8,9-octahydro-2H-cyclohepta[d]pyrimidine-2-thione
TMS as the internal standard. The mass spectra were (2b). White solid, mp = 233–235°C, yield (85%).
Analysis for C26H30N2O4S (466.59); Calcd.: %C, 66.93; dioxane (30 mL). The reaction mixture was refluxed for
H, 6.48; N, 6.00; S, 6.87. Found: %C, 66.98; H, 6.52; N, 12 h. The solvent was evaporated, and the residue was
6.04; S, 6.95. IR (cm1): 3437, 3188 (2NH). 1H NMR treated with methanol. The precipitate formed was filtered
(DMSO-d6, δ ppm): 1.88–2.53 (m, 8H, 4CH2), 3.74– off and crystallized from the chloroform to give
3.77 (m, 12H, 4OCH3), 4.66 (s, 1H, pyrimidine-H), compounds 6a–h.
6.74–7.01 (m, 7H, Ar-Hs + benzylic proton), 8.84, 9.15 1-[9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-1-
(2 s, 2H, 2NH). MS m/z, (%): 466 (M+, 67), 329 (55), phenyl-1,5,6,7,8,9-hexahydro-[1,2,4]triazolo[3,4-b]quinazolin-
315 (21), 151(100). 3-yl]-ethanone (6a). Yellow solid, mp = 130–132°C, yield
Reaction of thione 2a,b with hydrazonoyl chlorides 3 to (75%). Analysis for C34H34N4O5 (578.66), Calcd.: %C,
give compounds 6a–h. Triethylamine was added 70.57; H, 5.92; N, 9.68. Found: %C, 70.61; H, 5.98; N,
(1.51 mL, 15 mmol) to a mixture of equimolar amounts 9.73. IR (cm1): 1694 (C = O) and 1592 (C = N). 1H
of pyrimidine-2-thione derivatives 2a,b and the NMR (DMSO-d6, δ ppm): 1.88–2.65 (m, 6H, 3CH2),
appropriate hydrazonoyl halides 3 (15 mmol of each) in 2.47 (s, 3H, COCH3), 3.70–3.77 (m, 12H, 4OCH3), 6.12
Table 2
Anti-inflammatory effect of different compounds in albino rats.
Groups 1h 2h 3h 4h
Control positive 9.13 ± 0.15 10.09 ± 0.3 10.31 ± 0.11 9.02 ± 0.24
Indomethacin 7.21 ± 0.18* 8.19 ± 0.09* 7.69 ± 0.13* 6.26 ± 0.1*
2a 4.22 ± 0.05** 6.35 ± 0.03** 5.15 ± 0.07** 4.1 ± 0.04**
2b 4.51 ± 0.06** 6.66 ± 0.15** 5.75 ± 0.07** 4.82 ± 0.16**
6a 4.4 ± 0.1** 6.11 ± 0.02** 5.38 ± 0.06** 4.16 ± 0.01**
6b 4.17 ± 0.06** 6.27 ± 0.02** 5.2 ± 0.1** 4.33 ± 0.01**
6c 4.8 ± 0.01** 6.86 ± 0.1** 5.56 ± 0.02** 4.86 ± 0.08**
6d 4.55 ± 0.05** 6.59 ± 0.03** 5.93 ± 0.08** 4.81 ± 0.02**
6e 4.21 ± 0.08** 6.34 ± 0.09** 5.25 ± 0.04** 4.09 ± 0.07**
6f 4.41 ± 0.07** 6.39 ± 0.03** 5.42 ± 0.04** 4.15 ± 0.09**
6g 4.73 ± 0.02** 6.61 ± 0.05** 5.81 ± 0.01** 4.7 ± 0.04**
6h 4.65 ± 0.09** 6.91 ± 0.06** 5.7 ± 0.04** 4.9 ± 0.07**
7a 3.11 ± 0.09** 4.16 ± 0.07** 3.1 ± 0.08** 3.19 ± 0.1**
7b 4.88 ± 0.05** 6.95 ± 0.03** 5.58 ± 0.09** 4.77 ± 0.04**
8a 4.22 ± 0.03** 6.42 ± 0.04** 5.3 ± 0.09** 4.26 ± 0.05**
8b 3.14 ± 0.1** 4.09 ± 0.05** 3.2 ± 0.02** 3.17 ± 0.01**
8c 4.33 ± 0.1** 6.15 ± 0.08** 5.36 ± 0.07** 4.41 ± 0.02**
8d 4.27 ± 0.01** 6.11 ± 0.1** 5.28 ± 0.03** 4.17 ± 0.09**
8e 3.22 ± 0.03** 4.18 ± 0.08** 3.31 ± 0.01** 3.15 ± 0.06**
8f 4.61 ± 0.07** 6.52 ± 0.01** 5.69 ± 0.06** 4.82 ± 0.02**
8g 4.92 ± 0.08** 6.71 ± 0.1** 5.59 ± 0.03** 4.85 ± 0.07**
8h 3.09 ± 0.05** 4.15 ± 0.04** 3.21 ± 0.02** 3.1 ± 0.09**
9a 4.32 ± 0.03** 6.41 ± 0.05** 5.06 ± 0.01** 4.26 ± 0.1**
9b 4.78 ± 0.08** 6.89 ± 0.01** 5.66 ± 0.02** 4.55 ± 0.06**
10a 4.4 ± 0.08** 6.3 ± 0.1** 5.11 ± 0.05** 4.2 ± 0.02**
10b 4.81 ± 0.1** 6.92 ± 0.04** 5.58 ± 0.07** 4.6 ± 0.09**
11a 4.31 ± 0.03** 6.24 ± 0.01** 5.1 ± 0.06** 4.29 ± 0.04**
11b 4.63 ± 0.01** 6.52 ± 0.06** 5.74 ± 0.05** 4.59 ± 0.02**
12a 4.32 ± 0.09** 6.41 ± 0.1** 5.15 ± 0.03** 4.62 ± 0.08**
12b 4.96 ± 0.1** 6.71 ± 0.07** 5.88 ± 0.01** 4.66 ± 0.06**
Ethyl 9-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1- (m, 12H, 4OCH3), 4.30 (q, J = 7 Hz, 2H, CH2), 6.30 (s,
p-tolyl-1,5,6,7,8,9-hexahydro-[1,2,4]triazolo[3,4-b]quinazoline- 1H, pyrimidine-H), 6.90–7.84 (m, 12H, Ar-Hs + benzylic
3-carboxylate (6f). Yellow solid, mp = 120–122°C, yield proton). MS m/z, (%): 622 (M+, 0.7), 366 (1), 218 (6),
(73%). Analysis for C36H38N4O6, MW (622.71); Calcd.: 135 (12), 77 (34), 43 (100).
%C, 69.44; H, 6.15; N, 9.00. Found: %C, 69.51; H, Ethyl 10-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1-
6.20; N, 9.06. IR (cm1): 1731(C = O) and 1608 (C = p-tolyl-5,6,7,8,9,10-hexahydro-1H-cyclohepta[d][1,2,4]triazolo
N). 1H 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), mp = 84–86°C, yield (80%). Analysis for C37H40N4O6,
3.72–3.78 (m, 12H, 4OCH3), 4.34 (q, J = 7 Hz, 2H, MW (636.74); Calcd.: %C, 69.79; H, 6.33; N, 8.80. Found:
CH2), 6.11 (s, 1H, pyrimidine-H), 6.87–8.02 (m, 11H, %C, 69.82; H, 6.37; N, 8.86. IR (cm1): 1732 (C = O) and
Ar-Hs + benzylic proton). MS m/z, (%): 622 (M+, 3), 1599 (C = N). 1H NMR (DMSO-d6, δ ppm): 1.20 (t,
485 (4), 406 (8), 151 (75), 165 (35), 91 (100). J = 7 Hz, 3H, CH3), 1.87–2.66 (m, 8H, 4CH2), 2.26 (s,
Ethyl 10-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-1- 3H, CH3), 3.72–3.81 (m, 12H, 4OCH3), 4.33(q, J = 7 Hz,
phenyl-5,6,7,8,9,10-hexahydro-1H-cyclohepta[d][1,2,4]triazolo 2H, CH2), 6.32 (s, 1H, pyrimidine-H), 6.92–7.86 (m,
[4,3-a]pyrimidine-3-carboxylate (6 g). Yellow solid, 11H, Ar-Hs + benzylic proton). MS m/z, (%):636 (M+,
mp = 89–91°C, yield (77%). Analysis for C36H38N4O6, 11), 579 (10), 486 (3), 366 (10), 270 (12), 194 (16), 136
MW (622.71); Calcd.: %C, 69.44; H, 6.15; N, 9.00. Found: (3), 91 (13), 44 (100).
%C, 69.48; H, 6.20; N, 9.05. IR (cm1): 1725 (C = O) and Synthesis of compounds 7a,b. A solution of pyrimidin-
1601 (C = N). 1H NMR (DMSO-d6, δ ppm): 1.22 (t, 2-thione derivatives 2a,b (20 mmol) in absolute ethyl
J = 7 Hz, 3H, CH3), 1.87–2.71 (m, 8H, 4CH2), 3.71–3.77 alcohol (40 mL) was refluxed with ethyl bromoacetate
Table 3
Anti-inflammatory effect (%) of different compounds in albino rats after 4 h.
2-Benzylidene-9-(3,4-dimethoxybenzylidene)-5-(3,4- (m, 8H, 4CH2), 3.71–3.78 (m, 12H, 4OCH3), 5.53 (s, 1H,
dimethoxyphenyl)-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b] pyrimidine-H), 6.87–7.63 (m, 13H, Ar-Hs + benzylic pro-
quinazolin-3(2H)-one (8a). Brown solid, mp = 142–144°C, tons). MS m/z, (%): 594 (M+, 5), 457 (16), 215 (3), 151
yield (75%). Analysis for C34H32N2O5S, MW (580.69); (40), 134 (100), 77 (23).
Calcd.: %C, 70.32; H, 5.55; N, 4.82; S, 5.52. Found: 2-(4-Flourobenzylidene)-10-(3,4-dimethoxybenzylidene)-5-
%C, 70.38; H, 5.60; N, 4.87; S, 5.40. IR (cm1): 1704 (3,4-dimethoxyphenyl)-5,6,7,8,9,10-hexahydrocyclohepta[d]
(C = O) and 1615 (C = N). 1H NMR (DMSO-d6, δ thiazolo[3,2-a]pyrimidin-3(2H)-one (8f). Green solid,
ppm): 1.82–2.62 (m, 6H, 3CH2), 3.71–3.76 (m, 12H, mp = 105–107°C, yield (79%). Analysis for
4OCH3), 5.58 (s, 1H, pyrimidine-H), 6.89–7.60 (m, 13H, C35H33FN2O5S, MW (612.71); Calcd.: %C, 68.61; H,
Ar-Hs + benzylic protons). MS m/z, (%):580 (M+, 51), 5.43; N, 4.57; S, 5.23. Found: %C, 68.67; H, 5.48; N,
563 (M+, 17), 443 (100), 417 (11), 399 (7), 151 (49), 4.61; S, 5.41. IR (cm1): 1707 (C = O) and 1601 (C =
134 (63), 77(15). N).1H NMR (DMSO-d6, δ ppm): 1.72–2.62 (m, 8H,
9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-2- 4CH2) 3.72–3.77 (m, 12H, 4OCH3), 5.57 (s, 1H,
(4-fluoro-benzylidene)-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b] pyrimidine-H), 6.87–7.66 (m, 12H, Ar-Hs + benzylic pro-
quinazolin-3-one (8b). Green solid, mp = 100–102°C, tons). MS m/z, (%): 612 (M+, 5), 475 (14), 382 (51), 327
yield (77%). Analysis for C34H31FN2O5S, MW (598.68); (30), 299 (10), 152 (79), 77 (100).
Calcd.: %C, 68.21; H, 5.22; N, 4.68; S, 5.36. Found: %C, 2-(4-Chlorobenzylidene)-10-(3,4-dimethoxybenzylidene)-5-
68.26; H, 5.28; N, 4.71; S, 5.45. IR (cm1): 1710(C = O) (3,4-dimethoxyphenyl)-5,6,7,8,9,10-hexahydrocyclohepta[d]
and 1598 (C = N). 1H 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 mp = 90–92°C, yield (79%). Analysis for C35H33ClN2O5S,
(s, 1H, pyrimidine-H), 6.78–7.54 (m, 12H, Ar-Hs + MW (629.16); Calcd.: %C, 66.81; H, 5.29; N, 4.45; S,
benzylic protons). MS m/z, (%):599 ((M+1)+, 4), 462 (18), 5.10. Found: %C, 66.87; H, 5.33; N, 4.52; S, 5.19. IR
445 (10), 242 (15), 170 (20), 136 (11), 76 (14), 42 (100). (cm1): 1707 (C = O) and 1603 (C = N).1H NMR
2-(4-Chloro-benzylidene)-9-(3,4-dimethoxy-benzylidene)-5- (DMSO-d6, δ ppm): 1.72–2.62 (m, 8H, 4CH2), 3.72–3.78
(3,4-dimethoxy-phenyl)-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b] (m, 12H, 4OCH3), 5.58 (s, 1H, pyrimidine-H), 6.87–7.66
quinazolin-3-one (8c). Yellow solid, mp = 104–106°C, (m, 12H, Ar-Hs + benzylic protons). MS m/z, (%): 629
yield (77%). Analysis for C34H31ClN2O5S, MW (M+, 9), 597 (3), 342 (14), 315 (17), 273 (16), 136 (11),
(615.14); Calcd.: %C, 66.39; H, 5.08; N, 4.55; S, 5.21. 123 (22), 43 (100).
Found: %C, 66.44; H, 5.14; N, 4.61; S, 5.29. IR 2-(4-Dimethylamino-benzylidene)-10-(3,4-dimethoxybenzylidene)-
(cm1): 1709(C = O) and 1602 (C = N). 1H NMR 5-(3,4-dimethoxy-phenyl)-5,6,7,8,9,10-hexahydrocyclohepta[d]
(DMSO-d6, δ ppm): 1.82–2.62 (m, 6H, 3CH2), 3.68– thiazolo[3,2-a]pyrimidin-3(2H)-one (8h). Reddish brown
3.72 (m, 12H, 4OCH3), 5.61 (s, 1H, pyrimidine-H), solid, mp = 150–152°C, yield (79%). Analysis for
6.78–7.54 (m, 12H, Ar-Hs + benzylic protons). MS m/z, C37H39N3O5S, MW (637.79); Calcd.: %C, 69.68; H,
(%): 615 (M+, 3), 614 (M1+, 8), 477 (9), 329 (13), 267 6.16; N, 6.59; S, 5.03. Found: %C, 69.74; H, 6.20; N,
(3), 170 (16), 151 (61), 136 (10), 77 (16), 64 (100). 6.64; S, 5.12. IR (cm1): 1700 (C = O) and 1586 (C =
9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-2- N).1H NMR (DMSO-d6, δ ppm): 1.72–2.62 (m, 8H,
(4-dimethylamino-benzylidene)-6,7,8,9-tetrahydro-5H-thiazolo 4CH2), 3.01 (s, 6H, 2CH3), 3.72–3.78 (m, 12H, 4OCH3),
[2,3-b]quinazolin-3-one (8d). Reddish brown solid, 5.54 (s, 1H, pyrimidine-H), 6.76–7.53 (m, 12H, Ar-Hs + -
mp = 143–145°C, yield (79%). Analysis for C36H37N3O5S, benzylic protons). MS m/z, (%): 637 (M+, 0.7), 577 (6),
MW (623.76); Calcd.: %C, 69.32; H, 5.98; N, 6.74; S, 471 (23), 313 (33), 262 (48), 239 (31), 57(100).
5.14. Found: %C, 69.37; H, 5.94; N, 6.79; S, 5.23. IR Synthesis of compounds 9a,b. A solution of the
(cm1): 1698 (C = O) and 1587 (C = N). 1H NMR pyrimidin-2-thione derivatives 2a,b (20 mmol) in absolute
(DMSO-d6, δ ppm): 1.82–2.62 (m, 6H, 3CH2), 3.01(s, ethyl alcohol (40 mL) was refluxed with chloroacetone
6H, 2 CH3), 3.72–3.77 (m, 12H, 4OCH3), 5.60 (s, 1H, (1.85 mL, 20 mmol) and fused NaOAc (3.28 g, 40 mmol)
pyrimidine-H), 6.73–7.55 (m, 12H, Ar-Hs + benzylic pro- for 7 h. The reaction mixture was then left to cool and was
tons). MS m/z, (%): 623 (M+, 1), 486 (8), 177 (100), 151 poured into ice-cold water; the product that was separated
(31), 134 (44), 77 (25). was filtered, dried, and crystallized from methanol to give
2-Benzylidene-10-(3,4-dimethoxybenzylidene)-5-(3,4-dimetho- compounds 9a,b
xyphenyl)-5,6,7,8,9,10-hexahydrocyclohepta[d]thiazolo[3,2-a]pyri- 9-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-3-
midin-3(2H)-one (8e). Brown solid, mp = 90–92°C, yield methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazoline (9a).
(77%). Analysis for C35H34N2O5S, MW (594.72); Calcd.: Yellow solid, mp = 145–147°C, yield (78%). Analysis for
%C, 70.68; H, 5.76; N, 4.71; S, 5.39. Found: %C, 70.73; C28H30N2O4S, MW (490.61); Calcd.: %C, 68.55; H,
H, 5.80; N, 4.75; S, 5.44. IR (cm1): 1706 (C = O) and 6.16; N, 5.71; S, 6.53. Found: %C, 68.47; H, 6.25; N,
1603 (C = N).1H NMR (DMSO-d6, δ ppm): 1.72–2.62 5.80; S, 6.58. IR (cm1): 1597 (C = N). 1H NMR
(DMSO-d6, δ ppm): 1.60–2.62 (m, 6H, 3CH2), 1.87 (s, 3H, mixture was poured into ice-cold water; the product that
CH3), 3.71–3.74 (m, 12H, 4OCH3), 5.60 (s, 1H, was separated was filtered, dried, and crystallized from
pyrimidine-H), 5.98 (s, 1H, CH), 6.78–7.22 (m, 7H, Ar- methanol to give compounds 11a,b
Hs + benzylic proton). MS m/z, (%): 490 (M+, 23), 391 9-(3,4-Dimethoxy-benzylidene)-5-(3,4-dimethoxy-phenyl)-2-
(8), 353 (95), 339 (62), 239 (29), 165 (83), 151 (60), 137 methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazolin-3(2H)-
(28), 57 (100). one (11a). White crystals, mp = 175–177°C, yield
10-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-3- (80%). Analysis for C28H30N2O5S, MW (506.61);
methyl-5,6,7,8,9,10-hexahydrocyclohepta[d]thiazolo[3,2-a]py- Calcd.: %C, 66.38; H, 5.97; N, 5.53; S, 6.33. Found:
rimidine (9b). Yellow solid, mp = 155–157°C, yield %C, 66.45; H, 6.04; N, 5.58; S, 6.45. IR (cm1): 1724
(75%). Analysis for C29H32N2O4S, MW (504.64); Calcd.: (C = O) and 1603 (C = N). 1H NMR (DMSO-d6, δ
%C, 69.02; H, 6.39; N, 5.55; S, 6.35. Found: %C, 69.07; ppm): 1.50 (d, J = 8 Hz, 3H, CH 3), 1.81–2.65 (m, 6H,
H, 6.45; N, 5.61; S, 6.48. IR (cm1): 1593 (C = N). 1H 3CH2), 3.69–3.71 (m, 12H, 4OCH3), 4.35 (q, J = 8 Hz,
NMR (DMSO-d6, δ ppm): 1.72–2.62 (m, 8H, 4CH2), 1H, CH), 5.39 (s, 1H, pyrimidine-H), 6.89–7.22 (m,
1.84 (s, 3H, CH3), 3.73–3.76 (m, 12H, 4OCH3), 5.52 (s, 7H, Ar-Hs + benzylic proton). MS m/z, (%):506 (M+,
1H, pyrimidine-H), 5.98 (s, 1H, CH), 6.73–7.12 (m, 7H, 65), 369 (100), 341 (37), 151 (25), 77 (7).
Ar-Hs + benzylic proton). MS m/z, (%): 504 (M+, 7), 367 10-(3,4-Dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-2-
(45), 353 (38), 165 (46), 151 (55), 57 (100). 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 (20 mmol) in absolute yield (80%). Analysis for C29H32N2O5S, MW (520.64);
ethyl alcohol (40 mL) was refluxed with ethyl-2-chloro Calcd.: %C, 66.90; H, 6.20; N, 5.38; S, 6.16. Found: %C,
acetoacetate (3.29 mL, 20 mmol) and fused NaOAc(3.28 g, 66.96; H, 6.27; N, 5.43; S, 6.26. IR (cm1): 1722 (C = O)
40 mmol) for 9 h. The reaction mixture was then left to and 1623 (C = N).1H NMR (DMSO-d6, δ ppm): 1.53 (d,
cool and was poured into ice-cold water; the product that J = 8 Hz, 3H, CH3), 1.68–2.59 (m, 8H, 4CH2), 3.71–3.77
was separated was filtered, dried, and crystallized from (m, 12H, 4OCH3), 4.35 (q, J = 8 Hz, 1H, CH), 5.35 (s, 1H,
methanol to give compounds 10a,b. pyrimidine-H), 6.83–7.22 (m, 7H, Ar-Hs + benzylic proton).
Ethyl 9-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-3- 13
C NMR (DMSO-d6, δ ppm): 19.31, 25.78, 26.40, 29.03,
methyl-6,7,8,9-tetrahydro-5H-thiazolo[2,3-b]quinazoline-2-carbox- 29.44, 42.31, 56.0, 60.40, 100.0, 112.13, 112.29, 113.19,
ylate (10a). Buff crystals, mp = 148–150°C, yield (78%). 120.0, 120.21, 121.79, 122.52, 129.66, 130.53, 130.40,
Analysis for C31H34N2O6S, MW (562.68); Calcd.: %C, 137.10, 138.0, 147.56, 148.36, 148.91, 149.19, 150.10,
66.17; H, 6.09; N, 4.98; S, 5.70. Found: %C, 66.23; H, 174.50. MS m/z, (%): 520 (M+, 90), 489 (17), 383 (100),
6.15; N, 5.04; S, 5.86. IR (cm1): 1721 (C = O) and 369 (61), 355 (40), 151 (84).
1604 (C = N). 1H NMR (DMSO-d6, δ ppm): 1.49 (t, Synthesis of compounds 12a,b. A mixture of
J = 7 Hz, 3H, CH3), 1.79–2.62 (m, 6H, 3CH2), 2.46 (s, pyrimidin-2-thione derivatives 2a,b (20 mmol), 3-
3H, CH3), 3.69–3.72 (m, 12H, 4OCH3), 3.99 (q, J = 7 Hz, bromopropanoic acid (3.06 g, 20 mmol), and fused
2H, CH2), 5.40 (s, 1H, pyrimidine-H), 6.84–7.25 (m, 7H, AcONa (3.28 g, 40 mmol) in glacial acetic acid (20 mL)
Ar-Hs + benzylic proton). MS m/z, (%): 562 (M+, 0.7), and acetic anhydride (10 mL), was refluxed for 6 h. The
492 (28), 355 (100), 151 (45), 77 (19). reaction mixture was cooled, poured onto cold water,
Ethyl 10-(3,4-dimethoxybenzylidene)-5-(3,4-dimethoxyphenyl)-3- and the solid formed was collected and crystallized from
methyl-5,6,7,8,9,10-hexahydrocyclohepta[d]thiazolo[3,2-a]py- acetic acid to give compounds 12a,b
rimidine-2-carboxylate (10b). Buff crystals, mp = 135–137°C, 10-(3,4-Dimethoxybenzylidene)-6-(3,4-dimethoxyphenyl)-
yield (78%). Analysis for C32H36N2O6S, MW (576.70); 2,3,7,8,9,10-hexahydro-4H,6H-[1,3]thiazino[2,3-b]quinazolin-
Calcd.: %C, 66.64; H, 6.29; N, 4.86; S, 5.56. Found: %C, 4-one (12a). Buff crystal, mp = 110–112°C, yield (82%).
66.70; H, 6.34; N, 4.93; S, 5.70. IR (cm1): 1721 (C = O) Analysis for C28H30N2O5S, MW (506.61); Calcd.: %C,
and 1617 (C = N). 1H NMR (DMSO-d6, δ ppm): 1.23(t, 66.38; H, 5.97; N, 5.53; S, 6.33. Found: %C, 66.42; H,
J = 7 Hz, 3H, CH3), 1.73–2.58 (m, 8H, 4CH2), 2.49 (s, 3H, 6.01; N, 5.57; S, 6.39. IR (cm1): 1692 (C = O) and 1561
CH3), 3.71–3.77 (m, 12H, 4OCH3), 3.99 (q, J = 7 Hz, 2H, (C = N).1H NMR (DMSO-d6, δ ppm): 1.68–2.62 (m, 6H,
CH2), 5.37 (s, 1H, pyrimidine-H), 6.83–7.22 (m, 7H, 3CH2), 2.98–3.06 (m, 4H, 2CH2), 3.71–3.76 (m, 12H,
Ar-Hs + benzylic proton). MS m/z, (%): 576 (M+, 5), 551 4OCH3), 5.91 (s, 1H, pyrimidine-H), 6.78–7.15 (m, 7H,
(8), 367 (9), 339 (17), 151 (24), 135 (25), 57 (100). Ar-Hs + benzylic proton). MS m/z, (%): 506 (M+, 48), 406
Synthesis of compounds 11a,b. A solution of the (39), 369 (28), 315 (26), 236 (22), 174 (54), 151 (100).
pyrimidin-2-thione derivatives 2a,b (20 mmol) in 11-(3,4-Dimethoxybenzylidene)-6-(3,4-dimethoxyphenyl)-
absolute ethyl alcohol (40 mL) was refluxed with ethyl-2- 2,3,6,7,8,9,10,11-octahydro-4H-cyclohepta[4,5]pyrimido[2,1-b]
bromopropionate (3.62 mL, 20 mmol) and fused AcONa [1,3]thiazin-4-one (12b). Buff crystal, mp = 86–88°C,
(3.28 g, 40 mmol) for 7 h. Upon cooling, the reaction yield (80%). Analysis for C29H32N2O5S, MW (520.64);
Calcd.: %C, 66.90; H, 6.20; N, 5.38; S, 6.16. Found: %C, Latency to show analgesic response, like licking the paws
66.94; H, 6.23; N, 5.41; S, 6.31. IR (cm1): 1690 (C = O) or jumping out the hot plate, was recorded at 60 and
and 1566 (C = N).1H NMR (DMSO-d6, δ ppm): 1.63–2.63 120 min after 1 h from i.p. administration of 28 different
(m, 8H, 4CH2), 2.95–3.04 (m, 4H, 2CH2), 3.71–3.78 (m, compounds (10 mg/kg) after dissolving in DMSO, aspirin
12H, 4OCH3), 5.91 (s, 1H, pyrimidine-H), 6.66–7.18 (m, (200 mg/kg; positive control), and DMSO (negative con-
7H, Ar-Hs + benzylic proton). MS m/z, (%): 520 (M+, 5), trol) [28]. Response time for thermal pain was recorded
369 (10), 329 (7), 315 (8), 151 (46), 77 (14), 55 (100). before administration of different compounds and aspirin
(0 time).
Anti-inflammatory test. This test was carried out by
PHARMACOLOGICAL SCREENING carrageenan, an induced rat paw edema [27,29] for
testing the anti-inflammatory properties of the different
Material and methods compounds. Rats were divided into 30 groups (n = 6), i.p.
Material administration of 28 different compounds (10 mg/kg) and
Animals. Adult male albino Sprague Dawely rats DMSO (negative control), while indomethacin(20 mg/kg;
and mice weighing 100–120 and 20–30 g, respectively, positive control) was administered once orally by gastric
were purchased from the National Research Centre An- tube [30]. All the rats were injected with 0.1 mL of 1%
imal Laboratory (Giza, Egypt) and were housed in stan- carrageenan solution in saline at the sub-planter area of
dard polypropylene cages and kept under constant the right hind paw after 1 h from different compounds
environmental conditions and equal light–dark cycles. and indomethacin administration. Each rat’s paw
The animals were fed commercially rat normal standard thickness was measured by planimeter before carrageenan
diet pellets and water ad libitum. administration. After administration of carrageenan, the
Ethics statement. This experiment was carried out in paw thickness of each rat was measured by planimeter
according to recommendations in the Guide for the Care every 1 h for 4 h. Edema rate, inhibition, and potency
and Use of Laboratory Animals of the National Institutes were calculated as follows [31]:
of Health (NIH publication no. 85–23, revised 1996) and Statistical analysis. The differences between groups
under regulations of Animal Care and Use of National Re- were tested for significance using analysis of variance,
search Centre in Egypt. followed by Tukey post hoc test determined by SPSS
Drugs software program, version 21.Values are expressed as
Standard drugs used as a control. Indomethacin mean ± SE. The level of statistical significance was taken
(Indocid) was obtained from El Kahera pharmaceutical in- at P < 0.05.
dustrial company, Giza, Egypt. Aspirin (Aspirin) was ob-
tained from Bayer Limited Egypt LLC, Cairo, Egypt.
Methods REFERENCES AND NOTES
Anti-nociceptive (analgesic) test. This test was carried
[1] Amir, M.; Javed, S. A.; Kumar, H.; Indian, J. Pharmaceut Sci
out by hot plate (UgoBasile, Italy) method at 52°C (±0.1°C) 2007, 69, 337.
for determination of different compound effect [25]. [2] Sondhi, S. M.; Sharma, V. K.; Verma, R. P.; Singhal, N.;
Thirty groups of mice (n = 6) were adapted for three con- Shukla, R.; Raghubir, R.; Dubey, M. P. Synthesis-Stuttgart 1999, 878,
1999.
secutive days before the test by putting them in a hot plate [3] Baba, A.; Kawamura, N.; Makino, H.; Ohta, Y.; Taketomi, S.;
device adapted at room temperature for 15 min [26,27]. Sohda, T. J Med Chem 1996, 39, 5176.
[4] Mohamed, M. S.; Kamel, M. M.; Kassem, E. M. M.; Abotaleb, [18] Farghaly, T. A.; Abdallah, M. A.; Masaret, G. S.; Muhammad,
N.; Khedr, M.; Ahmed, M. F. Acta Pol Pharm Drug Res 2011, 68, 665. Z. A. Eur J Med Chem 2015, 97, 320.
[5] Smits, R. A.; Adami, M.; Istyastono, E. P.; Zuiderveld, O. P.; [19] Farghaly, T. A.; Mahmoud, H. K. J Heterocyclic Chem 2015,
Van Dam, C. M. E.; DeKanter, F. J. J Med Chem 2010, 53, 2390. 52, 86.
[6] Rostom, S. A. F.; El-Ashmawy, I. M.; Abd El Razik, H. A.; [20] Abbas, E. M. H.; Gomha, S. M.; Farghaly, T. A. Arabian J
Badr, M. H.; Ashour, H. M. A. Bioorg Med Chem 2009, 17, 882. Chem 2014, 7, 623.
[7] Kalkhambkar, R. G.; Kulkarni, G. M.; Shivkumar, H.; Rao, N. [21] Farghaly, T. A.; Abbas, E. M. H.; Dawood, K. M.; El-Naggar,
R. Eur J Med Chem 2007, 42, 1272. T. B. A. Molecules 2014, 19, 740.
[8] Holla, B. S.; Malini, K. V.; Rao, B. S.; Sarojini, B. K.; Kumari, [22] Shawali, A. S.; Farghaly, T. A.; Hussein, S. M.; Abdalla, M.
N. S. Eur J Med Chem 2003, 38, 313. M. Arch Pharm Res 2013, 36, 694.
[9] Kumar, A.; Rajput, C. S.; Bhati, S. K. Bioorg Med Chem [23] Singh, N.; Pandey, J.; Yadav, A.; Chaturvedi, V.; Bhatnagar,
2007, 15, 3089. S.; Gaikwad, A. N.; Sinha, S. K.; Kumar, A.; Shukla, P. K.; Tripathi, R.
[10] Jupudi, S.; Talari, S.; Karunakaram, D.; Govindarajan, R.; In- P. Eur J Med Chem 2009, 44, 1705.
ternational, J. Res Pharm Chem 2013, 3, 213. [24] Darehkordi, A.; Reentan, J.; Ramezani, M. J Iran Chem Soc
[11] Sanjeeva, R. C.; Nagara, A. J Iranian Chem Soc 2008, 5(2), 262. 2013, 10, 385.
[12] Bhalgat, C. M.; Ali, M. I.; Ramesh, B.; Ramu, G. Arabian J [25] Woolfe, C.; Macdonald, A. D. J Pharmacol Exp Ther 1944, 80,
Chem 2014, 7, 986. 300.
[13] Coombs, R. V.; Danna, R. P.; Denzer, M.; Hardtmann, G. E.; [26] Koriem, K. M.; Asaad, G. F.; Megahed, H. A.; Zahran, H.;
Huegi, B.; Koletar, G.; Koletar, J.; Ott, H.; Jukniewicz, E.; Perrine, J. W.; Arbid, M. S. Int J Toxicol 2012, 31, 294.
Takesue, E. J.; Trapold, J. H. J Med Chem 1973, 16, 1237. [27] Amin, M. M.; Arbid, M. S. Asian Pac J Trop Biomed 2015, 5,
[14] Perrine, J. W.; Houlihan, W. J.; Takesue, E. I. Arzneim 619.
Forsch/Drug Res 1984, 34, 879. [28] Eddy, N. B.; Touchberry, C. F.; Lieberman, J. E. J Pharmacol
[15] Farghaly, T. A.; Abdallah, M. A.; Muhammad, Z. A. Curr Org Exp Ther 1950, 98, 121.
Synth 2016, 13, 291. [29] Winter, C. A.; Risley, E. A.; Nuss, G. W. Proc Soc Exp Biol
[16] Dawood, D. H.; Batran, R. Z.; Farghaly, T. A.; Khedr, M. A.; Med 1962, 111, 544.
Abdulla, M. M. Arch Pharm Chem Life Sci 2015, 348, 875. [30] Prempeh, A. B. A.; Mensah-Attipoe, J. Ghana Med J 2009, 43,
[17] Farghaly, T. A.; Abdallah, M. A.; Muhammad, Z. A. Res 77.
Chem Inter Med 2015, 41, 3937. [31] Sudjarwo, S. A. Folia Med Indones 2005, 41, 190.