Synthesis and Anti-inflammatory Activity of Some New 1,2,3-Benzotriazine Derivatives Using 2-(4-Oxo-6-phenylbenzo[d][1,2,3]triazin-3(4H)-yl)acetohydrazide as a Starting Material

Article abstract of DOI:10.1002/jhet.3213

In continuation to our search for new heterocyclic system-based anti-inflammatory activity, a series of novel 1,2,3-benzotriazine derivatives were synthesized. The pharmacological screening showed that many of these compounds have good anti-inflammatory activity. The structure assignments of the new synthesized compounds are based on spectroscopic data, and pharmacological properties are reported.

Full text of DOI:10.1002/jhet.3213

Month 2018
Synthesis and Anti-inflammatory Activity of Some New 1,2,3-
Benzotriazine Derivatives Using 2-(4-Oxo-6-phenylbenzo[d][1,2,3]triazin-
3
(4H)-yl)acetohydrazide as a Starting Material
a
b
b
Yasser A. Selim, *
Mohamed H. M. Abd El-Azim, and Ahmed F. El-Farargy
a
Faculty of Specific Education, Zagazig University, Zagazig 44519, Egypt
b
Chemistry Department, Faculty of Science, Zagazig University, Zagazig 44519, Egypt
*
E-mail: y2selem@yahoo.com
Received March 6, 2018
DOI 10.1002/jhet.3213
Published online 00 Month 2018 in Wiley Online Library (wileyonlinelibrary.com).
In continuation to our search for new heterocyclic system-based anti-inflammatory activity, a series of
novel 1,2,3-benzotriazine derivatives were synthesized. The pharmacological screening showed that many
of these compounds have good anti-inflammatory activity. The structure assignments of the new synthesized
compounds are based on spectroscopic data, and pharmacological properties are reported.
J. Heterocyclic Chem., 00, 00 (2018).
INTRODUCTION
program work on pyrimidine of expected anti-
inflammatory activity, we tried to synthesize new fused
substituted benzotriazinones of expected biological
activity. Numerous publications have appeared describing
the synthesis of 1,2,3-benzotriazines possessing a variety
of pharmacological activities, such as anti-inflammatory
activity [2–5], cardiovascular activity [6–9], central
nervous system activity [10–15], and antimicrobial
activities [16]. On the other hand, the prepared 1,2,3-
triazine compounds showed antitumor activity, partly by
increasing free radicals production and partly by
depletion of intracellular catalase, glutathione peroxidase,
glutathione reductase, and reduced glutathione. Recently,
some new 1,2,3-benzotriazine and their derivatives have
been synthesized and used as local anesthetics activity
in vivo and exhibited a good activity comparable or
superior to that of lidocaine [17]. In addition, developed
1,2,3-benzotriazine is linked to beta-lactam as an
effective low-molecular-weight synthetic inhibitor of
human leukocyte elastase-induced lung damage in
Heterocyclic compounds constitute a large group of
organic molecules exhibiting a wide range of biological
activities that are the basis of life and society. The
majority of pharmaceutical products that mimic natural
products with biological activity are heterocyclic in
nature. 1,2,3-Benzotriazin-4-one is a commonly used
motif in a variety of pharmaceutical and agrochemical
compounds [1]. For example, azinphos-methyl and
azinphos-ethyl are widely used broad-spectrum
insecticides and acaricides in crop protection [2]. 1,2,3-
Benzotriazine derivatives bearing 2-cyanoiminothia
zolidin-4-one moieties had significant inhibitory activities
against Meloidogyne incognita, which can be utilized as
lead compounds [3]. 1,2,3-Triazine represents a widely
used lead structure with multitude of interesting
applications in the numerous pharmacological fields;
thus, various pharmacological activities have been
reported and explored till date [4]. In connection with our
©
2018 Wiley Periodicals, Inc.

Y. A. Selim, M. H. M. Abd El-Azim, and A. F. El-Farargy
Vol 000
ꢀ
1
1
hamsters. In view of this observation and in continuation of
our previous work, we synthesized some new 1,2,3-
benzotriazine derivatives and tested their anti-
inflammatory activity.
two carbonyl groups at 1680 and 1662 cm . The H
NMR spectrum showed NH2 and NH signals (D O
2
13
exchangeable) at 4.3 and 9.5 ppm. The C NMR and
mass spectrometry (MS) data of 2 were found to be in
full agreement with the proposed structure (cf.
Experimental section). The hydrazide derivative
2
RESULTS AND DISCUSSION
prompted us to use it as key starting material for
synthesis of some interesting heterocyclic compounds.
When compound 2 was reacted with 5,5-dimethyl-1,3-
cyclohexanedione (dimedone) in the presence of toluene,
the corresponding triazine-acetohydrazide derivative 3
Treatment of diazonium salt of methyl-4-aminophenyl-
-carboxylate with ethyl glycinate gave the corresponding
3
benzotriazine derivative 1 (Scheme 1). The IR spectrum
of 1 displayed strong absorption bands of two carbonyl
1
was formed (Scheme 1). The H NMR showed these
ꢀ
1
of ester and amide at 1739 and 1680 cm . The acid
hydrazide has been in the center of attention of
researchers over many years because of its high reactivity
in heterocyclic synthesis as key starting various classes of
biologically and pharmacologically active conditions
singlet signals for the three CH groups at 2.1, 2.2, and
2
5.1 ppm besides the two methyl groups at 0.97 ppm. The
13
C NMR spectrum showed the presence of three
carbonyl groups at 155.5, 168.4, and 196.1 ppm. The MS
revealed their exact molecule masses (cf. Scheme 1 and
Experimental section).
[
18]. In addition, substituted hydrazides are characterized
by low toxicity [19]. The addition of hydrazine hydrate in
the presence of ethanol to compound 1 gave the
corresponding acetohydrazide derivative 2 (Scheme 1).
The structure of 2 was deduced from their analytical and
spectral data where, IR spectrum showed absorption
Furthermore, the new diazepinone derivative 4 was
prepared via the reaction of enaminone 3 with 2-(4-
nitrobenzylidene)malononitrile
in
ethanol
and
trimethylamine (Scheme 1). Mechanistically, the reaction
is believed to take place via nucleophilic attack of
methine group of enaminone 3 on the double bond of
malononitrile followed by cyclization (Fig. 1). IR
ꢀ
1
bands ranging from 3311 to 3300 cm assignable for
NH and NH groups besides two absorption bands for the
2
Scheme 1. Synthetic pathway of diazepinone derivative 4. [Color figure can be viewed at wileyonlinelibrary.com]
Figure 1. The suggested reaction mechanism for the synthesis of compound 4.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
New 1, 2, 3-Benzotriazine Derivatives
showed two absorption bands, one for NH at 3258 cm
ꢀ
1
spectrum showed new absorption bands at 3446–
ꢀ
1
ꢀ1
ꢀ1
1
3
341 cm for NH and NH and at 2184 cm for CN.
and the other for C═O at 1688 cm . The H NMR
2
1
H NMR showed a singlet signal at 0.8 for two methyl
showed a singlet signal at 5.8 ppm for CH , aromatic
2
groups, two singlet signals at 2.1 and 2.2 for 2 CH of
dimedone ring, a singlet signal at 4.45 ppm for CH of
protons ranging from 6.9 to 8.3 ppm, and a singlet signal
at 10 ppm for NH of pyrrole thion ring. The MS showed
the molecular mass m/z = 410.
On the other hand, a mixture of compound 6 with
phenacylbromide in the presence of fused sodium acetate
2
dimedone ring, a singlet signal at 6.63 ppm for NH , and
2
1
a singlet signal at 11.2 ppm for NH. Also, the H NMR
spectrum showed two CH signals of diazepinone ring at
13
4.33 (d, J = 1.7, Hz) and 4.93 (d, J = 2.4, Hz) ppm.
C
in alcohol gave 3,4-diphenylthiazole derivative
8
NMR showed a signal at 117.3 ppm for CN and signals
at 157.5, 171.4, and 191.3 ppm for three carbonyl
groups. The MS showed the molecular mass m/z = 616,
which is in full agreement with the assigned structure.
On treatment of compound 2 with p-nitrobenzaldehyde,
(Scheme 2). IR showed the presence of an absorption
ꢀ
1
1
band of NH group at 3242 cm . The H NMR showed
13
the olefinic hydrogen of thiazole at 4.9 ppm. The
C
NMR and MS showed the expected structure. The
mechanism is proposed on the basis of the observed
results as shown in Scheme 2; initially, the loss of HBr is
followed by intramolecular cyclization to give the
expected compound as in Figure 2.
4-nitrobenzylidene acetohydrazide derivative 5 was
obtained (Scheme 2). The IR spectrum showed the
absence of NH group and presence of amidic C═O at
2
ꢀ
1 1
1
639 cm . H NMR spectrum showed NH signal (D O
The 1,3,4-oxadiazole derivative 9 was synthesized
2
oxide exchangeable) at 12.1 ppm and CH2 signal at
through one-pot reaction of compound
6
with
5
.3 ppm. The MS showed exact molecular mass m/z = 428.
When a mixture of compound 2 refluxed with phenyl
dicyclohexylcarbodiimide in the presence of toluene
(Scheme 2). IR spectrum showed strong absorption bands
ꢀ
1
isothiocyanate, compound 6 was obtained (Scheme 2). IR
spectrum showed absorption bands for 3 (str, NH) and
the absence of amino group. The H NMR showed
at 3083 and 1673 cm
respectively. The H NMR spectrum showed a band for
attributed to NH and C═O,
1
1
13
NH (exchange with D O) at 10.5 ppm. The C NMR
2
signals for 3 NH at 10 and 10.5 ppm. The MS and NMR
are in full agreement with the assigned structure. The
cyclization of compound 6 using different media has
and MS showed the expected structure.
Treatment of compound 2 with 2,5-hexanedione in acetic
acid at room temperature afforded the pyrrole derivative 10
(Scheme 3). The IR spectrum displayed bands for NH and
been discussed. Heating compound 6 with conc. H SO4
2
ꢀ
1
1
gave thioxopyrrole derivative 7 (Scheme 2). IR spectrum
C═O at 3284 and 1681 cm , respectively. The H NMR
Scheme 2. Synthesis of novel 1,2,3-benzotriazine derivatives.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. A. Selim, M. H. M. Abd El-Azim, and A. F. El-Farargy
Vol 000
Figure 2. The suggested reaction mechanism for the synthesis of compound 8.
Scheme 3. Synthesis of pyrrole, pyrazole, and dioxoisoindoline 1,2,3-triazine derivatives.
exhibited signals for NH at 11.14 ppm and doublet of
doublet for 2 C═H at 5.6 and 4.9 ppm.
attack of nitrogen followed by elimination of water to
give the target product 12, as shown in Figure 3. The IR
ꢀ
1
Treatment of 2 with acetyl acetone and benzoyl acetone
afforded 11a, b as shown in Scheme 3. Compound 11a
spectrum showed strong absorption bands at 3197 cm
ꢀ
1
for NH and a broad band at 1672–1694 cm for four
C═O groups. The H NMR spectrum showed a band for
ꢀ
1
1
exhibited IR absorption bands at 1680 and 1632 cm for
1
amidic C═O. H NMR showed a singlet signal at
CH at 5.3 ppm and at 11.2 ppm for NH. MS; m/z = 425.
2
5
.3 ppm for CH , two singlet signals at 2.3 and 2.5 ppm
The reaction of 6-phenylbenzo[d][1,2,3]triazin-4(3H)-
one and 2-chloro-N-(2-methoxyphenyl)acetamide in
dimethylformamide (DMF) afforded compound 13
2
for CH , and a singlet signal at 6.3 ppm for ═CH. The
3
1
3
C NMR and MS showed the expected structure. Also
compound 11b exhibited IR absorption bands at 1690
ꢀ
1
(Scheme 4). IR showed a band at 3233 cm for NH str
ꢀ
1
1
and 1672 cm for amidic C═O. H NMR showed a
singlet signal at 2.3 ppm for CH , a singlet signal at
and two bands at 1687 (C═O) and 1633 (amidic C═O)
ꢀ
1 1
cm . H NMR exhibited a singlet signal at 3.8 ppm for
CH , a singlet signal at 5.3 ppm for CH , and a broad
3
5.9 ppm for CH , and a singlet signal at 5.6 ppm for
3
2
2
13
singlet signal at 9.8 ppm for NH. C NMR and MS
showed the expected structure.
═
CH. MS; m/z = 421.
The reaction of 2 with phthalic anhydride afforded the
dioxoisoindolinyl derivative 12 (Scheme 3). The reaction
is believed to take place via the initial opening phthalic
anhydride and formation of an amide intermediate. The
amide intermediate was cyclized by internal nucleophilic
Anti-inflammatory activity assay. Carrageenan-induced
rat paw edema model is a suitable test for evaluating anti-
inflammatory drugs, which has frequently been used to
assess the antiedematous effect of the drug. Carrageenan
Figure 3. The suggested reaction mechanism for the synthesis of compound 12.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
New 1, 2, 3-Benzotriazine Derivatives
Scheme 4. Synthesis of [1,2,3]-benzotriazin-3(4H)-yl)acetamide 13.
is a strong chemical used for the release of inflammatory
and proinflammatory mediators (prostaglandins and TNF-
α, etc.) in carrageen paw edema, for measurement of rat
paw volume, and for the calculation of the percentage of
rat paw volume that assists in the intensity of the edema.
It was obvious from our results that the maximum
volume of edema was observed in the control group after
using sheets precoated with the UV, fluorescent silica gel,
60 F254 (Merck), and spots were visualized by iodine vapor
or by irradiation with UV light. Elemental analysis was
carried out on a PerkinElmer EA1110 CHNS/O analyzer
(Life Technologies Ltd., Paisley, UK).
Ethyl
2-(4-oxo-6-phenylbenzo[d][1,2,3]triazin-3(4H)-yl)
acetate (1).
Methyl 4-aminobiphenyl-3-carboxylate
4
h of carrageen injection, which is in accordance with
(0.039 mol, 6 g) was dissolved in an ice-cooled solution
of dilute hydrochloric acid and then diazotized by
solution of sodium nitrite (4.25 g) in water (10 mL). A
solution of ethyl glycinate hydrochloride (0.039 mol,
5.54 g) was added from a dropping funnel into the stirred
solution of the diazonium salt with subsequent
neutralization by sodium carbonate. After 1-h stirring, a
precipitate was separated and filtered. The solid was
washed with water, air-dried, and then crystallized from
absolute ethanol as yellow crystals, 9.4 g (68%) of 1, Rf:
previous literature data; indomethacin, a standard drug at
dose of 0.9 mg/100 g and after 4 h of carrageen injection
showed anti-inflammatory effect, which is reflected by
the inhibition in edema volume. The obtained results of
test compounds 11a, 11b, and 13 showed strong anti-
inflammatory activity, which resemble the result obtained
by carrageen; also there were nonsignificant changes
between these test compounds and indomethacin. On the
other hand, the results obtained from test compounds 4,
7
, and 9, compared with control group (indomethacin),
0.59 (CHCl : MeOH, 1:1); mp 129–131°C [16]; IR:
3
ꢀ
1
showed anti-inflammatory effect, but they were not as
significant as those of indomethacin.
νmax/cm
3050 (aromatic CH), 2965 (aliphatic CH),
1739 (ester C═O), 1680 (amidic C═O), 1233 (C–O); MS
+
(
EI, 70 eV) m/z (%) = 309 (M , 12.1%). Anal. Calcd. for
C H N O : C, 66.01; H, 4.89; N, 13.58. Found: C,
17 15 3 3
EXPERIMENTAL
65.88; H, 4.75; N, 13.29.
2
-(4-Oxo-6-phenylbenzo[d][1,2,3]triazin-3(4H)-yl)
Melting points were determined using digital
Electrothermal 9100 apparatus (Kleinfeld, Gehrden,
Germany) and were uncorrected. Fourier transform infra-
red spectra (KBr) on Varian PerkinElmer 1430 ratio-
recording infrared spectrophotometer (Nicolet, Madison,
acetohydrazide (2). A mixture of the ester 1 (0.05 mol,
11.65 g) and hydrazine hydrate (98%) (0.05 mol, 2.5 g) in
ethanol (20 mL) was stirred for 2 h at room temperature.
Excess ethanol was evaporated under vacuum, and the
precipitated product was crystallized from ethanol as
1
13
WI, USA). The H and C NMR spectra (400 MHz for
yellowish white crystals, 10.5 g (77%) of 2, Rf: 0.41
1
13
ꢀ1
H NMR, 100 MHz for C NMR) were recorded on a
(CHCl : MeOH, 1:1); mp 246–248°C; IR: νmax/cm
3
Varian Mercury VX-300 NMR spectrometer (Varian Inc.,
Palo Alto, CA, USA), both using tetramethylsilane as in-
ternal standard, and chemical shifts are expressed in δ
values. Mass spectrometry was run on a Hewlett-Packard
3311–3300 (NH and NH ), 3070 (aromatic CH), 2957
2
1
(aliphatic CH), 1680 (C═O), 1662 (amidic C═O);
H
NMR δ: 4.3 (s, 2H, NH ), 4.9 (s, 2H, CH ), 7.9–8.4 (m,
2
2
8H, Ar–H), 9.5 ppm (s, 1H, NH, deuterium oxide
13
5988 spectrometer (CSS Analytical Co Inc., Shawnee,
exchangeable); C NMR δ: 54.5 (aliphatic CH ), 118.7,
2
KS, USA). Progress of the reaction was monitored by
thin-layer chromatography (Merck, Darmstadt, Germany)
121.4, 127.6, 127.9, 128.4, 129.2, 131.4, 138.4, 140.8,
148.4 (Ar–C), 158.4, 170.3 ppm (2 C═O); MS (EI,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. A. Selim, M. H. M. Abd El-Azim, and A. F. El-Farargy
Vol 000
+
7
0 eV) m/z (%) = 295 (M , 0.9%), 232 (36.4%), 208
for C H N O : C, 64, 28; H, 4.58; N, 18, 17. Found:
3
3 28 8 5
(
6
2
100%), 77 (80%). Anal. Calcd. for C H N O : C,
C, 64, 12; H, 4.37; N, 18, 09.
1
5 13 5 2
0
1.01; H, 4.44; N, 23.72. Found: C, 60.90; H, 4.22; N,
3.50.
(E)-N -(4-Nitrobenzylidene)-2-(4-oxo-6-phenylbenzo[d]
[1,2,3]triazin-3(4H)-yl)acetohydrazide (5). To a solution of
the hydrazide 2 (0.002 mol, 0.438 g) in absolute ethanol
(10 mL), p-nitrobenzaldehyde (0.002 mol) was added.
The reaction mixture was refluxed for 3 h, and the
precipitated product was filtered, washed with water, and
crystallized from ethanol as deep yellow crystals, 0.29 g
0
N -(5,5-Dimethyl-3-oxocyclox-1-enyl)-2-(4-oxo-6-
phenylbenzo[d][1,2,3]triazin-3(4H)-yl)acetohydrazide (3).
A mixture of equimolar amounts of 5,5-dimethyl-1,3-
cyclohexanedione (dimedone) and hydrazide 2 (0.05 mol)
was heated under reflux in toluene (15 mL) for 4 h using
Dean–Stark water separator. The reaction mixture was
allowed to cool at room temperature. The obtained
crystalline product was filtered, dried, and recrystallized
from toluene as greenish yellow crystals, 7.5 g (70%) of
(55%) of 5, Rf: 0.32 (CHCl : MeOH, 1:1); mp 292–
3
ꢀ
1
294°C; IR: νmax/cm 3388–3216 (NH), 3072 (aromatic
CH), 2958 (aliphatic CH), 1670 (C═O), 1639 (amidic
1
C═O), 1614 (C═N); H NMR δ: 5.3 (s, 2H, CH
), 5.7 (s,
2
3
, Rf: 0.33 (CHCl : MeOH, 1:1); mp 267–269°C; IR:
1H, ═CH), 7.9–8.3 (m, 12H, Ar–H), 12.1 ppm (s, 1H,
NH); C NMR δ: 119.2, 124.0, 124.4, 125.3, 127.6,
3
ꢀ
1
13
νmax/cm 3197 (2 NH), 2957 (aliphatic CH), 1710 (br, 2
C═O), 1690 (amidic C═O), 1583 (NH bending
127.8, 127.9, 128.1, 128.7, 129.1, 131.1, 138.6, 140.8,
1
scissoring); H NMR δ: 0.97 (s, 3 H, CH ), 1.02 (s, 3H,
144.1, 148.4, 151.2 (Ar–C), 146.2 (C═N), 159.5,
3
+
CH ), 2.1 (s, 2H, CH ), 2.2 (s, 2H, CH ), 5.1 (s, 1H,
171.3 ppm (2 C═O); MS (EI, 70 eV) m/z (%) = 428 (M ,
3
2
2
═
CH), 5.2 (s, 2H, N–CH ), 8.8 (s, 1H, ═C–NH), 7.9–8.3
m, 8H, Ar–H), 10.3 ppm (s, 1H, NH–CO); C NMR δ:
3.2%). Anal. Calcd. for C22H N O : C, 61.68; H, 3.76;
16 6 4
N, 19.62. Found: C, 61.55; H, 3.62; N, 19.50.
2
1
3
(
2
2
1
7.5 (2 CH ), 40.3, 49.5, 55.32, 101, 163 (3 CH , CMe ,
═C), 116.6, 121.9, 127.3, 127.6, 128.7, 129.2, 131.6,
38.4, 140.9, 148.6 (Ar–C), 155.5, 168.4, and 196.1 ppm
2-(2-(4-Oxo-6-phenylbenzo[d][1,2,3]triazin-3(4H)-yl)aceto
3
2
2
phenylhydrazine carbothioamide (6).
A mixture of
compound
2 (0.012 mol, 2.634 g) and phenyl
isothiocyanate (0.012 mol, 1.62 g) in ethanol (15 mL)
was refluxed for 1 h, and the precipitated product was
filtered and crystallized from ethanol as yellow crystals,
(
(
3 C═O); MS (EI, 70 eV) m/z (%) = 417 (2.1%), 416
3%), 331 (4.1%), 203 (88.8%), 77 (100%). Anal. Calcd.
for C H N O : C, 66.17; H, 5.55; N, 16.78. Found: C,
6
23 23 5 3
3
2
3
.29 g (76%) of 5, Rf: 0.27 (CHCl : MeOH, 1:1); mp
6.05; H, 5.42; N, 16.59.
3
ꢀ
1
61–262°C; IR: νmax/cm 3050 (aromatic CH), 3331,
3
-Amino-2-(5,5-dimethyl-3-oxocyclohex-1-enyl)-5-(4-
nitrophenyl)-7-oxo-6-(4-oxo-6-phenylbenzo[d][1,2,3]triazin-
(4H)-yl)-2,5,6,7-tetrahydro-1H-1,2-diazepine-4-carbonitrile
4). A mixture of equimolar amounts of enaminone 3 and
-(4-nitrobenzylidene)malononitrile (0.001 mol) in ethanol
15 mL) containing four drops of trimethylamine was
227, 3219 (3 NH), 2931 (aliphatic CH), 1688 (C═O),
1
3
(
2
(
1630 (amidic C═O), 1300 (C═S); H NMR δ: 5.2 (s, 2H,
CH ), 7.2–8.3 (m, 13H, Ar–H), 10 (s, 2H, 2NH),
2
1
3
10.5 ppm (s, 1H, NH). C NMR δ: 55.1 (aliphatic CH2),
119.6, 124.3, 124.4, 125.1, 127.6, 127.8, 127.9, 128.5,
128.9, 129.3, 131.4, 138.4, 138.6, 140.5, 148.4, 151.2
(Ar–C), 159.5, 170.3 (2 C═O), 186.2 ppm (C═S). MS
heated under reflux for 12 h. The reaction mixture was
cooled, and the precipitated product was filtered, washed
with water, and crystallized from ethanol as yellow
+
(EI, 70 eV) m/z (%) = 430 (M , 9.1%). Anal. Calcd. for
crystals, 5.5 g (44%) of 4, Rf: 0.37 (CHCl : MeOH,
C H N O S: C, 61.38; H, 4.21; N, 19.72. Found: C,
61.15; H, 4.02; N, 19.58.
3
22 18 6 2
ꢀ
1
1
:1); mp 298–299°C; IR: νmax/cm 3446 (NH ), 3341
2
(
(
(
NH), 3020 (aromatic CH), 2958 (aliphatic CH), 2184
6
-Phenyl-3-((4-phenyl-5-thioxo-4,5-dihydro-1H-pyrrol-3-
CN), 1690 (br, 2 C═O), 1680 (amidic C═O), 1650
yl)methyl)benzo[d][1,2,3]triazin-4(3H)-one (7).
The
1
conj, C═C); H NMR δ: 0.8 (s, 6H, CH ), 2.1 (s, 2H,
thiosemicarbazide 6 (0.001 mol, 0.354 g) was dissolved
in concentrated sulfuric acid (5 mL) while being cooled
and was allowed to stand for 15 min. The reaction
mixture was then quenched with ice and treated with
concentrated ammonia solution till neutral to litmus
paper. The precipitate product was crystallized from
ethanol as yellow crystals, 0.29 g (76%) of 7, Rf: 0.41
(CHCl : MeOH, 1:1); mp 271–273°C; IR: νmax/cm
3258 (NH), 2937 (aliphatic CH), 3051 (aromatic CH),
1688 (C═O); H NMR δ: 3.88 (s, 2H, aliphatic CH ), 5.8
3
dimedone CH ), 2.2 (s, 2H, dimedone CH ), 4.45 (s, 1H,
dimedone CH), 4.93 (d, J = 2.4, Hz, 1H, diazepinone
CH), 4.33 (d, J = 1.7, Hz, 1H, diazepinone CH), 6.63 (s,
2
2
2
H, NH ), 7.5–8.3 (m, 12H, Ar–H), 11.2 ppm (s, 1H,
2
1
3
NH, deuterium oxide exchangeable); C NMR δ: 27.7 (2
CH ), 28.5 (diazepinone CH ), 31.9 (CMe ), 36.5
3
2
2
ꢀ
1
(dimedone CH2), 52.5 (dimedone CH2), 63.2
(diazepinone CH), 68.3 (diazepinone CH2), 100.1
(dimedone CH), 117.3 (CN), 119.6, 121.4, 125.3, 127.6,
3
1
2
1
1
1
27.7, 127.9, 128.6, 128.9, 129.2, 131.4, 138.6, 140.8,
44.1, and 148.5 (Ar–C), 155.1 (dimedone C), 157.5,
(s, 1H, pyrrole thion ═CH,), 6.9–8.3 (m, 14H, Ar–H and
olefinic CH═C), 10 ppm (s, NH); C NMR δ: 57.2
13
71.4, 191.3 (3 C═O), 160.5 ppm (diazepinone CHNH );
(aliphatic CH ), 63.5 (pyrrole thion CH), 115.7 (pyrrole
2
2
+
MS (EI, 70 eV) m/z (%) = 616 (M , 10.2%). Anal. Calcd.
thion ═C), 118.1, 123.3, 124.5, 125.1, 127.3, 127.6, 127.9,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2018
New 1, 2, 3-Benzotriazine Derivatives
13
128.3, 128.7, 129.1, 131.3, 138.4, 140.1, 142.8, 144.1,
8.3 (m, 8H, Ar–H), 11.14 ppm (s, 1H, NH); C NMR δ:
148.4, 151.2 (Ar–C), 128.5 (pyrrole thion ═CH), 171.3
19.1 (2 CH ), 56.9 (aliphatic CH ), 105.5, 106.8, 116.3,
3
2
(
C═O), 192.2 ppm (C═S); MS (EI, 70 eV) m/z (%) = 410
126.2 (pyrrole C), 119.9, 121.2, 127.6, 127.9, 128.8,
129.6, 131.4, 138.9, 140.5, 148.3, 158.4, 171.2 (Ar–C),
+
(M , 3.1%). Anal. Calcd. for C H N OS: C, 70.22; H,
2
4 18 4
4
.42; N, 13.65. Found: C, 70.05; H, 4.21; N, 13.44.
158.4, 171.2 ppm (2 C═O); MS (EI, 70 eV) m/z = 373
+
(
E)-N-(3,4-Diphenylthiazol-2(3H)-ylidene)-2-(4-oxo-6-
(M , 2.3%). Anal. Calcd. for C21
H
N
19
5
O
2
: C, 67.55; H,
phenylbenzo[d][1,2,3]triazin-3(4H)-yl)acetohydrazide (8).
A mixture of 6 (0.001 mol, 0.354 g), phenacylbromide
5.13; N, 18.76. Found: C, 67.33; H, 4.95; N, 18.59.
General procedures of compounds (11a, b). A solution
of hydrazide 2 (0.002 mol, 0.438 g) was treated with the
respective active methylene compounds (acetyl acetone
and benzoyl acetone) (0.002 mol) in ethanol (10 mL).
The mixture was refluxed for 6 h and then poured into
water to give a precipitate. The precipitate was collected,
washed with water several times, and recrystallized from
ethanol to afford 11a, b.
(0.001 mol, 0.233 g), and fused sodium acetate (0.328 g,
0.004 mol) was heated in absolute ethanol (10 mL) under
reflux for 10 h while being stirred. The mixture was
cooled and diluted with water, and the separated product
was crystallized from ethanol as yellowish green crystals,
0
2
.59 g (72%) of 8, Rf: 0.53 (CHCl : MeOH, 1:1); mp
83–285°C; IR: νmax/cm 3242 (NH), 3050 (aromatic
3
ꢀ
1
CH), 2951 (aliphatic CH), 1680 (C═O), 1623 (amidic
3
-(2-(3,5-Dimethyl-1H-pyrazol-1-yl)-2-oxoethyl)-6-
1
C═O); H NMR δ: 4.9 (s, 1H, ═CH), 5.6 (s, 2H, CH ),
phenylbenzo[d][1,2,3]triazin-4(3H)-one (11a).
Yellow
2
1
3
7
.5–8.2 (m, 18H, Ar–H), 10.5 ppm (s, 1H, NH); C NMR
crystals, 0.29 g (72%) of 11a, Rf: 0.48 (CHCl : MeOH,
3
ꢀ
1
δ: 54.5 (aliphatic CH ), 106.3, 147.7, 149.13 (thiazole C),
1:1); mp 280–282°C; IR: νmax/cm 3080 (aromatic CH),
2991 (aliphatic CH), 1680 (C═O), 1632 (amidic C═O);
2
1
1
1
2
19.8, 121.2, 124.2, 127.6, 127.9, 128.2, 128.8, 129.5,
30.4, 131.4, 138.5, 140.6, 141.5, 141.9 (Ar–C), 158.5,
72.4 ppm (2 C═O); MS (EI, 70 eV) m/z (%) = 530 (M ,
1
H NMR δ: 2.3 (s, 3H, CH ), 2.5 (s, 3H, CH ), 5.3 (s,
3
3
+
2H, CH ), 6.3 (s, 1H, ═CH), 7.4–8.5 ppm (m, 8H, Ar–
2
13
.4%). Anal. Calcd. for C H N O S: C, 67.91; H, 4.18;
H); C NMR δ: 13.3, 13.62 (2 CH ), 49.9 (aliphatic
3
0
22
6
2
3
N, 15.84. Found: C, 67.77; H, 4.14; N, 15.69.
CH), 110.2 (pyrazole CH), 120.2, 122.3, 127.7, 127.9,
6
-Phenyl-3-(5-(phenylamino)-1,3,4-oxadiazol-2yl)
128.3, 123.6, 130.7, 137.8, 141.2, 148.3, 159.4, 170.3
methylbenzo[d][1,2,3]triazin-4(3H)-one (9). A mixture of 6
0.001 mol, 0.354 g) and dicyclohexylcarbodiimide
0.001 mol, 0.2 g) in toluene (10 mL) was refluxed for
2 h. The reaction mixture was cooled, and the separated
(
Ar–C), 143.8, 153.3 (pyrazole C), 159.5, 170.1 ppm (2
+
(
(
1
C═O); MS (EI, 70 eV) m/z (%) = 359 (M , 11.1%).
Anal. Calcd. for C H N O : C, 66.84; H, 4.77; N,
20 17 5 2
1
9.49. Found: C, 66.77; H, 4.72; N, 19.33.
solid was filtered. The clear filtrate was concentrated, and
the separated product was filtered off and crystallized
from ethanol as faint yellow crystals, 0.32 g (62%) of 9,
3-(2-(3-Methyl-5-phenyl-1H-pyrazol-1-yl)-2-oxoethyl)-6-
phenylbenzo[d][1,2,3]triazin-4(3H)-on (11b).
Yellowish
white crystals, 0.25
(CHCl : MeOH, 1:1); mp 289–292°C; IR: νmax/cm
g (65%) of 11b, Rf: 0.43
ꢀ
1
Rf: 0.47 (CHCl : MeOH, 1:1); mp 295–297°C; IR:
3
3
ꢀ
1
νmax/cm
(
3313 (NH), 3083 (aromatic CH), 2948
aliphatic CH ), 1673 (C═O); H NMR δ: 5.8 (s, 2H,
3086 (aromatic CH), 2998 (aliphatic CH), 1690 (C═O),
1
1
1672 (amidic C═O); H NMR δ: 2.3 (s, 3H, CH ), 5.6 (s,
2
3
CH ), 6.9–8.3 (m, 13H, Ar–H), 10.5 ppm (s, 1H, NH);
1H, ═CH), 5.9 (s, 2H, CH ), 7.3–8.3 ppm (m, 13H, Ar–
2
2
1
3
13
C NMR δ: 49.5 (CH ), 117.8, 118.6, 122.4, 124.1,
H); C NMR δ: 13.3 (CH ), 55.4 (aliphatic CH ), 106.3
2
3
2
1
1
27.1, 127.9, 128.4, 129.2, 131.7, 138.5, 139.9, 140.3,
(pyrazole CH), 118.1, 123.2, 124.1, 125.3, 127.3, 127.5,
127.9, 128.5, 128.3, 129.3, 131.1, 138.4, 138.7, 140.5,
148.4, 151.2 (Ar–C), 133.6, 146.3 (pyrazole C), 160.5,
48.4 (Ar–C), 157.6 (C═O), 162.9, 169.3 ppm
+
(oxadiazole C); MS (EI, 70 eV) m/z (%) = 396 (M ,
+
3.2%). Anal. Calcd. for C H N O : C, 66.66; H, 4.07;
172.3 ppm (2 C═O); MS (EI, 70 eV) m/z (%) = 421 (M ,
2
2 16 6 2
N, 21.20. Found: C, 66.51; H, 3.97; N, 21.11.
12.3%). Anal. Calcd. for C H N O : C, 71.25; H, 4.54;
2
5 19 5 2
N, 16.62. Found: C, 71.09; H, 4.38; N, 16.53.
N-(2,5-Dimethyl-1H-pyrrol-1-yl)-2-(4-oxo-6-phenylbenzo
[
d][1,2,3]triazin-3(4H)-yl)acetamide (10).
A mixture of
hydrazide 2 (0.002 mol, 0.438 g) and 2,5-hexanedione
0.002 mol, 0.25 mL) in glacial acetic acid (5 mL) was
N-(1,3-Dioxoisoindolin-2-yl)-2-(4-oxo-6-phenylbenzo[d]
[1,2,3]triazin-3(4H)-yl)acetamide (12).
A mixture of
(
hydrazide 2 (0.002 mol, 0.438 g), phthalic anhydride
(0.002 mol, 0.296 g) in absolute ethanol (10 mL) with a
few drops of glacial acetic acid was refluxed for 6 h. The
reaction mixture was concentrated to obtain compound
12, which was crystallized from ethanol as yellowish
stirred at room temperature overnight. On diluting the
mixture with water, the precipitate product was filtered
off and crystallized from ethanol as yellowish white
crystals, 0.49 g (72%) of 10, Rf: 0.53 (CHCl : MeOH,
1
3
ꢀ
1
:1); mp 269–270°C; IR: νmax/cm 3284 (NH), 3067
white crystals, 0.51
g
(78%) of 12, Rf: 0.33
ꢀ
1
(
(
aromatic CH), 2978 (aliphatic CH ), 1681 (C═O), 1620
(CHCl : MeOH, 1:1); mp 282–284°C; IR: νmax/cm
2
3
1
amidic C═O); H NMR δ: 2.1 (s, 6H, 2CH ), 5.3 (s, 2H,
3197 (NH), 3093 (aromatic CH), 2991 (aliphatic CH),
3
1
CH ), 5.6 and 5.9 (dd, J = 1.7, 4.8 Hz, 2H, 2 ═CH), 7.9–
broad band 1672–1694 (4 C═O); H NMR δ: 5.3 (s, 2H,
2
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Y. A. Selim, M. H. M. Abd El-Azim, and A. F. El-Farargy
Vol 000
Table 1
The anti-inflammatory activity of the new compounds (mean + SE).
Initial
Thickness of rat paw (mm) after
thickness
Groups
(zero time)
1 h
2 h
3 h
4 h
Control
Indomethacin
Celecoxib
4
7
9
2.0 ± 0.0
2.1 ± 0.22
2.0 ± 0.0
2.1 ± 0.25
2.0 ± 0.0
2.0 ± 0.0
2.0 ± 0.0
2.1 ± 0.2
2.0 ± 0.0
5.75 ± 0.25
2.12 ± 0.12
6.75 ± 0.25
2.25 ± 0.25
3.75 ± 0.31
4.75 ± 0.14
4.2 ± 0.12
7.37 ± 0.24
3.25 ± 0.25
7.37 ± 0.24
3.75 ± 0.14
3.87 ± 0.31 NS
5.12 ± 0.125
5.25 ± 0.14
4.25 ± 0.14
3.75 ± 0.32 NS
3.75 ± 0.32 NS
3.25 ± 0.14 NS
a
a
a
a
a
a
a,b
a,b
a,b
a,b
a,b
3.22 ± 0.25
3.75 ± 0.25 NS
a,b
a,b
a,b
4.0 ± 0.2
3.75 ± 0.25
3.75 ± 0.25
5.0 ± 2.0
a,b
a,b
a
a,b
a,b
4.62 ± 0.24
a,c
a,d
4.75 ± 0.14
4.75 ± 014
a
a
a
11a
11b
13
2.12 ± 0.125 NS
3.25 ± 0.25
2.75 ± 0.14
2.75 ± 0.14 NS
3.5 ± 0.2 NS
a,b
a,b
a,b
a
4.37 ± 0.24
4.5 ± 0.24
a,c
a,c
a
a
3.12 ± 0.125
3.25 ± 0.25 NS
NS, nonsignificant.
a
Compared with control (carrageenan only), p < 0.001.
b
Compared with indomethacin, p < 0.001.
Compared with indomethacin, p < 0.01.
c
d
Compared with indomethacin, p < 0.05.
1
3
CH ), 7.9–8.3 (m, 12H, Ar–H), 11.2 ppm (s, 1H, NH);
C
dose of 0.9 mg/100 g. The test compounds were injected
(IP) to six groups at the same dose level, whereas the last
group was injected (IP) with celecoxib at the dose of
0.9 mg/100 g. One hour later, edema in the right hind paw
was induced by injection of 0.1 mL of 10% carrageen. The
thickness of the paw was measured 1, 2, 3, and 4 h after
carrageen injection to determine the anti-inflammatory
activity of the test compounds (Table 1).
2
NMR δ: 56.6 (aliphatic CH ), 121.6, 124.3, 123.4, 124.1,
27.3, 127.8, 127.9, 128.6, 128.9, 129.2, 131.4, 138.4,
38.6, 140.5, 149.4, 151.2 (Ar–C), 160.5, 166.2, 168.3,
71.3 ppm (4 C═O); MS (EI, 70 eV) m/z (%) = 425 (M ,
2
1
1
1
1
+
5.2%). Anal. Calcd. for C H N O : C, 64.94; H, 3.55;
2
3 15 5 4
N, 16.46. Found: C, 64.78; H, 3.42; N, 16.20.
N-(2-Methoxyphenyl)-2-(4-oxo-6-phenylbenzo[d][1,2,3]
triazin-3(4H)-yl)acetamide (13).
phenylbenzo[d][1,2,3]triazin-4(3H)-one
0
(
A
mixture of 6-
(0.002 mol,
.294 g) and 2-chloro-N-(2-methoxyphenyl)acetamide
0.002 mol) was refluxed for 4 h in DMF in the presence
CONCLUSION
of anhydrous potassium carbonate. The mixture was
cooled, diluted with water, and then filtered. The
separated solid was washed with ethanol, dried, and
crystallized from DMF/ethanol mixture as reddish yellow
A series of new heterocyclic compounds of some 1,2,3-
benzotriazine derivatives were synthesized in this study
with the hope of discovering a new structure that leads to
serving as potent anti-inflammatory agents. On the basis
of these screening results, compounds 11a, 11b, and 13
showed significant activity in induced carrageen paw
edema and have been targeted for further studies, with
nonsignificant changes between these test compounds and
standard drug (indomethacin). New compounds were
elucidated by chemical and spectroscopic data.
crystals, 0.21 g (65%) of 13, Rf: 0.53 (CHCl : MeOH,
3
ꢀ
1
1
:1); mp 273–275°C; IR: νmax/cm 3233 (NH), 3023
(
(
aromatic CH), 2976 (aliphatic CH), 1687 (C═O), 1633
1
amidic C═O); H NMR δ: 3.8 (s, 3H, CH ), 5.3 (s, 2H,
3
CH ), 6.9–8.3 (s, 12H, Ar–H), 9.8 amidic (br, 1H, NH);
2
1
3
C NMR δ: 53.1 (aliphatic CH ), 55.2, (OCH ), 113.5,
2
3
1
1
14.5, 119.6, 119.9, 121.2, 121.8, 127.6, 127.8, 129.7,
30.8, 131.4, 138.5, 148.3 (Ar–C), 158.4, 170.2 ppm (2
+
C═O); MS (EI, 70 eV) m/z (%) = 386 (M , 9.1%). Anal.
Calcd. for C H N O : C, 68.38; H, 4.70; N, 14.50.
Found: C, 68.22; H, 4.53; N, 14.32.
Anti-inflammatory activity evaluation. The rat hind paw
edema method [20] was applied to determine the anti-
inflammatory activity of the test compounds (4, 7, 9, 11a,
Acknowledgments. A.F.E. thanks Prof. Dr. N. Krausa, Lehrstuhl
für Organische Chemie, TU Dortmund, Germany, for his contin-
uous help and repeated invitation. The authors also thank Dr. A.
Attia, Pharmacology Department, Faculty of Pharmacy, Zagazig
University, Egypt, for pharmacological screening.
22 18 4 3
11b, and 13) using indomethacin as a standard. Mature
REFERENCES AND NOTES
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They were divided into 10 equal groups (each with five).
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[
[
[
[
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet