Synthesis and anti-inflammatory activity evaluation of novel 7-alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolines

Article abstract of DOI:10.1002/ardp.200700182

In this study, a novel series of 7-alkoxy-1-amino-4,5-dihydro[1,2,4] triazole[4,3-a]quinolines were synthesized by using 6-hydroxy-3,4-dihydro-2(1H)- quinolone as the starting material. These compounds were evaluated for anti-inflammatory activity through

Full text of DOI:10.1002/ardp.200700182

288
Arch. Pharm. Chem. Life Sci. 2008, 341, 288–293
Full Paper
Synthesis and Anti-inflammatory Activity Evaluation of Novel
7-Alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolines
Xian-Yu Sun1,2, Cheng-Xi Wei2, Kyu-Yun Chai3, Hu-Ri Piao2, and Zhe-Shan Quan1, 2
1 Key Laboratory of Organism Functional Factors of the Changbai Mountain, Ministry of Education, Yanbian
University, Yanji, Jilin, China
2 College of Pharmacy, Yanbian University, Yanji, Jilin, China
3 Department of Chemistry, Wonkwang University, Iksan, Korea
In this study, a novel series of 7-alkoxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinolines were
synthesized by using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material. These com-
pounds were evaluated for anti-inflammatory activity through monitoring their ability to
inhibit xylene-induced ear edema in mice. Some of the tested compounds exhibited significant
activity, and the compounds 5f (7-(benzyloxy)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-1-amine)
and 5i (7-(p-chlorobenzyloxy)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-1-amine) showed the high-
est anti-inflammatory activity (52% and 58% inhibition, respectively, at 2 h pre-administration)
which were comparable to or even slightly more potent than the reference drug ibuprofen
(55%). Furthermore, the structure-activity relationship of these 1,2,4-triazole quinolines was
demonstrated.
Keywords: Anti-inflammatory / Quinoline / 1,2,4-Triazole /
Received: June 27, 2007; accepted: September 5, 2007
DOI 10.1002/ardp.200700182
vious studies [13, 14], 7-benzyloxy-4,5-dihydro[1,2,4]tria-
Introduction
zole[4,3-a]quinolines (compound 6) and 7-benzyloxy-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline-1-ones (compound
7) were synthesized and tested for anticonvulsant activ-
ity. Since the two compounds have the 1,2,4-triazole
structure, they were assumed to possess anti-inflamma-
tory activity. Then, a third compound 5f (7-benzyloxy-1-
Non-steroidal anti-inflammatory drugs (NSAIDs) are use-
ful tools in the treatment of acute and chronic inflamma-
tion, pain, and fever. However, long-term clinical usage
of NSAIDs is associated with significant side effects of gas-
tro-intestinal lesions, bleeding, and nephrotoxicity.
Therefore, the discovery of new and safer anti-inflamma-
tory drugs represents a challenging goal for such a
research area [1]. As resistance to anti-inflammatory
drugs is widespread, there is an increasing need for iden-
tification of novel structure leads that may be of use in
designing new, potent and less toxic anti-inflammatory
agents.
amino-4,5-dihydro[1,2,4]triazole[4,3-a]quinoline)
was
designed and synthesized to test if an amino group at the
first position of the 1,2,4-triazole ring could give a better
activity. Pharmacological tests on compounds 6, 7, and 5f
demonstrated that only compound 5f showed anti-
inflammatory activity. In view of the observations, we
designed and synthesized a series of 7-alkyoxy-1-amino-
4,5-dihydro[1,2,4]triazole[4,3-a]quinoline derivatives and
investigated the anti-inflammatory activity and struc-
ture-activity relationship of these novel compounds.
Various derivatives of 1,2,4-triazole have been reported
to possess anti-inflammatory activity [2–12]. In our pre-
Correspondence: Zhe-Shan Quan, College of Pharmacy, Yanbian Uni-
versity, No. 121, JuZi Street, Yanji City, Jilin Province 133000, P. R. Chi-
na.
Results and discussion
E-mail: zsquan@ybu.edu.cn
Fax: +86 433 266-0568
Synthesis
Compounds were prepared according to Scheme 1. The
starting material 6-hydroxy-3,4-dihydro-2(1H)-quinolone
Abbreviations: Non-steroidal anti-inflammatory drugs (NSAIDs)
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Arch. Pharm. Chem. Life Sci. 2008, 341, 288–293
Triazole-quinolines as Anti-inflammatories
289
Scheme 2. Structure change of compounds 4a–4p.
shown in Scheme 2. But this change could be avoided by
keeping compounds 4a–4p below 08C.
The target compounds 5a–5p were obtained by the
reaction of 4a–4p with cyanogene bromide in dioxane
[18], in which an appropriate volume (about one fifth of
dioxane volume) of aqueous Na2CO3 solution was abso-
lutely necessary [19]. The compounds synthesized were
characterized by IR,1H-NMR, MS, and elemental analysis.
Pharmacological evaluations
Scheme 1. Synthesis of compounds 5a–5p.
Phase-I evaluation (Table 1) indicated that most of the
newly synthesized compounds 5c–5d and 5f–5p showed
reacted with an appropriate amount of alkyl halide in a anti-inflammatory activity at a dose of 200 mg/kg admin-
solution of sodium hydroxide in absolute methanol or n- istered orally and 2 h before the inflammatory agent
butanol (for 2o only) and yielded compounds 2a-2p [15–
17]. Preparing compound 2o (6-(4-methoxybenzyloxy)- loxy)-4,5-dihydro[1,2,4]triazolo[4,3-a]quinolin-1-amine)
quinoline-2-one), n-butanol was used as solvent instead of and 5i (7-(p-chlorobenzyloxy)-4,5-dihydro[1,2,4]tria-
xylene. Among the synthesized compounds, 5f (7-(benzy-
ethanol and KI was added as catalyst, because the strong zolo[4,3-a]quinolin-1-amine) showed the highest ear-
electron-donor activity of the p-methoxy in the phenyl inflammation inhibition rate: 52.36% and 58.29%,
ring would increase the stability of the positive ion of car- respectively.
bon in the benzyl group and, hence, decrease the rate of
nucleophilic substitution; still, only a moderate yield in the light of the compound structure. For alkyloxy-sub-
was gained for this compound. stituted compounds 5a–5e, only hexyloxy-substituted
The results of the pharmacological tests were analyzed
Compounds 3a–3o were prepared by the reaction of compound 5c and octyloxy-substituted compound 5d
compounds 2a–2o with phosphorous pentasulfide in possessed anti-inflammatory activity, suggesting that an
acetonitrile in the presence of triethylamine [15]. Since appropriate length of the alkyl chain at position C-7, or
compound 2p (6-(2,4-dichlorobenzyloxy)quinoline-2-one)
an lipophilic properties were essential to the anti-inflam-
did not dissolve in acetonitrile, dioxane was used as sol- matory activity of these compounds. Among the eleven
vent and compound 2p and phosphorous pentasulfide aryl-substituted derivatives 5f–5p, the electron-donor
reacted in dioxane with stirring and refluxing for 24 h, group on the phenyl ring appeared to contribute more to
which produced 3p (6-(2,4-dichloro-benzyloxy)-quinoline- the anti-inflammatory activity than the electron-acceptor
2-thione) with a moderate yield.
group on the phenyl ring. Comparison of the halogen-
Compounds 3a–3p reacted further with hydrazine substituted derivatives indicated that different halogen
hydrate in THF to afford 4a–4p. Briefly, to a solution of atoms contributed to the anti-inflammatory activity in
hydrazine hydrate in THF, a solution of compounds 3a–
the order of Cl>Br>F; the position of the substituted
3p in THF was added dropwise at room temperature, and group on the phenyl ring greatly influenced the anti-
the mixture was stirred at 608C for 1 h. Then, half of the inflammatory activity with an activity order of p A o A m.
solvent was removed under reduced pressure, and the Notably, compared with the non-substituted phenyl
product was crystallized in petroleum ether. The precipi- derivative 5f, only one derivative 5i (7-(4-chlorine-benzy-
tate was filtered and washed with petroleum ether, and loxy-)) showed increased activity.
then kept below 08C. The compounds obtained were pure
Based on the results of phase-I screening, two outstand-
enough for the next step. The structures of compounds ing derivatives, 5f and 5i, were chosen to be evaluated in
4a–4p may change gradually at room temperature in the phase-II screening, where the dose was still 200 mg/
about 10 h, and the molecular weight indicated the dis- kg orally administered, but multiple intervals (0.5 h, 1 h,
ubstitution of hydrazine with compounds 3a–3p, as 2 h, 3 h, 4 h, and 24 h) for xylene application were
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Arch. Pharm. Chem. Life Sci. 2008, 341, 288–293
Edema mean l S.D. Inhibiton Rate
Table 1. Anti-inflammatory activity of compounds 5a–5p administrated orally.
Compound
R
Dose
Number of mice
(mg/kg)
(mg)
(%)
CMC-Na
Ibuprofen
6
7
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
–
–
–
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
12.3 l 0.20
5.5 l 0.19*
12.4 l 0.34
12.6 l 0.68
12.4 l 0.15
12.4 l 0.16
9.9 l 0.19*
10.1 l 0.30*
12.9 l 0.24
5.9 l 0.36*
7.6 l 0.24*
11.1 l 0.46*
5.1 l 0.27*
10.7 l 0.35*
11.5 l 0.21*
10 l 0.29*
–
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
200
55.12
–
–
–
–
19.76
17.89
–
52.36
38.37
9.59
58.29
12.68
6.50
18.70
28.70
3.90
13.74
12.68
–CH2C6H5
–CH2C6H5
n-C3H7
n-C4H9
n-C6H13
n-C8H17
n-C12H25
–CH2C6H5
–CH2C6H4(0-Cl)
–CH2C6H4(m-Cl)
–CH2C6H4(p-Cl)
–CH2C6H4(0-F)
–CH2C6H4(m-F)
–CH2C6H4(p-F)
–CH2C6H4(p-Br)
–CH2C6H4(p-CH3)
–CH2C6H4(p-OCH3)
–CH2C6H4(2,4-Cl2)
8.8 l 0.25*
11.2 l 0.29*
10.6 l 0.28*
10.7 l 0.18*
* p a 0.01 compared with theCMC-Na (control) group.
Table 2. Anti-inflammatory activity of compounds 5f and 5i
administered at different times before the xylene application.
Table 3. Anti-inflammatory activity of compounds 5f and 5i at
different doses.
Time
(h)
Dose
(mg/kg)
Inhibition (%)
Time (h)
Dose
(mg/kg)
Inhibition (%)
5f
5i
Ibuprofen
5f
5i
Ibuprofen
0.5
1
2
3
4
200
200
200
200
200
200
42.76b)
46.82
31.30
33.50b)
58.29
34.55
33.25
22.52
33.82
42.60
55.12
35.61
31.30
21.87
2
2
2
200
100
50
52.36a)
33.33
22.03
58.29
49.51b)
24.63
55.12
33.41
25.12
52.36a)
28.46b)
26.91a)
23.09
a)
p a 0.05.
b)
24
p a 0.01 compared with ibuprofen at the corresponding dose.
a)
p a 0.05.
b)
In the phase-III testing, the ear-inflammation inhibi-
p a 0.01 compared with ibuprofen at the corresponding time.
tion rate of compounds 5f, 5i, and the reference drug ibu-
profen (at lower doses 100 mg/kg and 50 mg/kg and
administered 2 h before xylene application) were eval-
uated and compared (Table 3). Compound 5f showed sim-
ilar effects as ibuprofen at the two lower doses, while
compound 5i possessed stronger anti-inflammatory
activity than ibuprofen at 100 mg/kg.
assessed. The results are shown in Table 2. As the interval
lengthened, the anti-inflammatory activity of com-
pounds 5f and 5i first increased and then declined; the
peak activity was observed at the 2 h interval. Comparing
5f and 5i, compound 5f showed stronger activity than
compound 5i at all time points except the 2 h-point. Com-
pared with the reference drug ibuprofen, compound 5f
showed a significantly higher activity at 0.5 h after
administration but comparable (1 h, 24 h) or lower (2–
4 h) activity at other time points, indicating its quick
absorption and potential for acute anti-inflammatory
action. Compound 5i showed similar activity level as the
reference drug at all time points except at 1 h time point,
when it had lower activity than ibuprofen.
Conclusions
A new series of anti-inflammatory compounds, 7-alkoxy-
1-amino-4,5-dihydro[1,2,4]-triazole[4,3-a]quinolines, were
synthesized and their anti-inflammatory activity was
evaluated by an in-vivo test. Two of the compounds, 5f
and 5i, exhibited anti-inflammatory activity comparable
with the reference drug ibuprofen.
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Arch. Pharm. Chem. Life Sci. 2008, 341, 288–293
Triazole-quinolines as Anti-inflammatories
291
This study is supported by a grant from National Natural Sci- General procedure for the synthesis of 7-alkoxy-1-amino-
ence Foundation of China (No. 30460151) and a grant from the 4,5-dihydro[1,2,4]triazole[4,3-a]quinolines 5a–5p
In a three-neck round-bottomed flask with thermometer, com-
pounds 4a–4p (3 mmol) were dissolved in 60 mL dioxane, and
the solution was treated with Na2CO3 (3 mmol) in 12 mL H2O.
Then, cyanogene bromide (3 mmol) in 20 mL dioxane was added
Key Projects Fund of Ministry of Education of China (No.
20070422029).
The authors have declared no conflict of interest
dropwise to the mixture kept in an ice-bath and then the reac-
tion temperature was kept below 108C; after stirring for 2 h, the
solvent was removed under reduced pressure. The residue was
purified by silica gel chromatography (dichloromethane-metha-
nol 10 : 1).
Experimental
Chemistry
Melting points were determined in open capillary tubes and
7-Propyloxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-
were uncorrected. IR spectra were recorded (in KBr) on a FT-
a]quinoline 5a
IR1730. 1H-NMR spectra were measured on a Bruker-300 (Bruker
1
Mp. 161–1638C; yield 32%; H-NMR (CDCl3, 300 MHz) d 1.04 (t,
Bioscience, Billerica, MA, USA) and all chemical shifts were given
in ppm relative to tetramethylsilane. Mass spectra were meas-
ured on an HP1100LC (Hewlett-Packard, Palo Alto, CA, USA).
Microanalyses of C, N and H were performed using a Heraeus
CHN Rapid Analyzer (Heraeus, Germany).
3H, J = 7.4 Hz, -CH3), 1.76–1.85 (m, 2H, -CH2-), 3.92 (t, 2H, J =
6.5 Hz, -OCH2-), 2.93–3.03 (m, 4H, -CH2-CH2-), 4.78 (s, 2H, -NH2),
6.84–6.87 (m, 2H, H-6, H-9), 7.64–7.68 (m, 1H, H-8). IR (KBr) cm– 1
:
3410 and 3093 (-NH2), 1502 (-OCH2-); MS m/z 245 [M + 1]; Anal.
Calcd. for C13H16N4O: C, 63.91; H, 6.60; N, 22.93. Found: C, 63.95;
H, 6.67; N, 22.85.
6-Alkoxy-3,4-dihydro-2(1H)-quinolones 2a–2p
The starting compound 1 (10 mmol) and appropriate alkyl hal-
ide (10 mmol) were added to a solution of sodium hydroxide in
absolute methanol with stirring and refluxing for 3 h. The reac-
tion mixture was cooled and then poured into ice water. The
white precipitate was collected through filtration and dried in a
vacuum to produce the crude products 2a–2n and 2p with a
moderate yield and sufficient purity for the next stage. The start-
7-Butyloxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-
a]quinoline 5b
Mp. 121–1238C; yield 34%; 1H-NMR (CDCl3, 300 MHz) d 0.98 (t,
3H, J = 7.1 Hz, -CH3), 1.43–1.55 (m, 2H, -CH2-), 1.72–1.81 (m, 2H, -
CH2-), 3.94 (t, 2H, J = 6.4 Hz, -OCH2-), 2.95–3.01 (m, 4H, -CH2-CH2-),
5.30 (s, 2H, -NH2), 6.85–6.88 (m, 2H, H-6, H-9), 7.69–7.71 (m, 1H,
H-8). IR (KBr) cm– 1: 3340 and 3122 (-NH2), 1512 (-OCH2-); MS m/z
259 [M + 1]; Anal. Calcd. for C14H18N4O: C, 65.09; H, 7.02; N, 21.69.
Found: C, 65.12; H, 7.08; N, 21.59.
ing compound
1
(10 mmol), p-methoxybenzyl chloride
(10 mmol) and KI (5 mmol) were added to a solution of sodium
hydroxide in absolute n-butanol with stirring and refluxing for
6 h. Next, the solvent was evaporated under reduced pressure;
the residue was washed with water to produce a white solid 2o
with a moderate yield.
7-Hexyloxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-
a]quinoline 5c
Mp. 86–888C; yield 33%; 1H-NMR (CDCl3, 300 MHz) d 0.92 (t, 3H, J
= 7.1 Hz, -CH3), 1.26–1.82 (m, 8H, (-CH2-)4), 3.96 (t, 2H, J = 6.4 Hz, -
OCH2-), 2.94-3.03 (m, 4H, -CH2-CH2-), 4.45 (s, 2H, -NH2), 6.85–6.89
(m, 2H, H-6, H-9), 7.64–7.67 (m, 1H, H-8). IR (KBr) cm– 1: 3336 and
3119 (-NH2), 1508 (-OCH2-); MS m/z 287 [M + 1]; Anal. Calcd. for
C16H22N4O: C, 67.11; H, 7.74; N, 19.56. Found: C, 67.15; H, 7.78; N,
19.50.
6-Alkoxy-3,4-dihydro-1H-quinoline-2-thiones 3a–3p
To a stirring mixture of acetonitrile and triethylamine in a
three-necked round-bottomed flask in an ice bath, P2S5 (1.2 eq),
divided into multiple portions, was added one portion at a time
after the previous portion had completely dissolved. Then, 6-
alkoxy-3,4-dihydro-2(1H)-quinolone was added and the solution
was refluxed for 3 h under nitrogen. After removing the solvent
under reduced pressure, the residue was dissolved in dichloro-
methane (30 mL), washed with water (3630 mL) and dried over
anhydrous MgSO4. Evaporation of the solvents gave a crude prod-
uct, which was purified by silica gel column chromatography
with dichloromethane to a light yellow solid 3a–3o. Compound
2p and phosphorous pentasulfide reacted in dioxane with stir-
ring and refluxing for 24 h. The solvent was evaporated under
reduced pressure; the residue was washed with water to produce
a light yellow solid 3p.
7-Octyloxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-
a]quinoline 5d
1
Mp. 109–1118C; yield 37%; H-NMR (CDCl3, 300 MHz) d 0.90 (t,
3H, J = 7.2 Hz, -CH3), 1.26–1.84 (m, 12H, (-CH2-)6), 3.96 (t, 2H, J =
6.4 Hz, -OCH2-), 2.94–3.02 (m, 4H, -CH2-CH2-), 4.67 (s, 2H, -NH2),
6.85–6.88 (m, 2H, H-6, H-9), 7.64–7.67 (m, 1H, H-8). IR (KBr) cm– 1
:
3345 and 3105 (-NH2), 1515 (-OCH2-); MS m/z 315 [M + 1]; Anal.
Calcd. for C18H26N4O: C, 68.76; H, 8.33; N, 17.82. Found: C, 68.82;
H,8.37; N, 17.76.
6-Alkoxy-3,4-dihydro-2-hydrazine-1H-quinolines 4a–4p
A solution of compounds 3a–3p (5 mmol) in 30 mL THF was
added dropwise to a solution of hydrazine hydrate (25 mmol) in
20 mL THF at room temperature, then the mixture was stirred
and heated at 608C for 1 h. After the reaction, half of the solvent
was evaporated under reduced pressure; the products were
recrystallized from petroleum ether with a moderate yield, and
then kept at 08C for the next step.
7-Dodecyloxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-
a]quinoline 5e
1
Mp. 114–1168C; yield 35%; H-NMR (CDCl3, 300 MHz) d 0.89 (t,
3H, J = 7.4 Hz, -CH3), 1.27–1.82 (m, 20H, (-CH2-)10), 3.97 (t, 2H, J =
6.4 Hz, -OCH2-), 2.94–3.03 (m, 4H, -CH2-CH2-), 4.48 (s, 2H, -NH2),
6.85–6.88 (m, 2H, H-6, H-9), 7.64–7.67 (m, 1H, H-8). IR (KBr) cm– 1
:
3350 and 3086 (-NH2), 1523 (-OCH2-); MS m/z 371 [M + 1]; Anal.
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Calcd. for C22H34N4O: C, 71.31; H, 9.25; N, 15.12. Found: C, 71.35;
H,9.28; N, 15.04.
7-(4-Fluorobenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5l
1
Mp. 160–1628C; yield 38%; H-NMR (CDCl3, 300 MHz) d 2.95–
3.03 (m, 4H, -CH2-CH2-), 4.72 (s, 2H, -NH2), 5.04 (s, 2H, -OCH2-),
6.91–6.96 (m, 2H, H-6, H-9), 7.06–7.43 (m, 4H, Ar-H), 7.67–7.70
(m, 1H, H-8). IR (KBr) cm– 1: 3335 and 3098(-NH2), 1518 (-OCH2-);
MS m/z 312 [M + 1]; Anal. Calcd. for C17H15FN4O: C, 65.80; H, 4.87;
N, 18.05. Found: C, 65.86; H, 4.92; N, 17.99.
7-Benzyloxy-1-amino-4,5-dihydro[1,2,4]triazole[4,3-
a]quinoline 5f
1
Mp. 156–1588C; yield 34%; H-NMR (CDCl3, 300 MHz) d 3.00–
3.06 (m, 4H, -CH2-CH2-), 4.42 (s, 2H, -NH2), 5.10 (s, 2H, -OCH2-),
6.93–6.99 (m, 2H, H-6, H-9), 7.36–7.44 (m, 5H, Ar-H), 7.66–7.69
(m, 1H, H-8). IR (KBr) cm– 1: 3340 and 3126 (-NH2), 1511 (-OCH2-);
MS m/z 293 [M + 1]; Anal. Calcd. for C17H16N4O: C, 69.85; H, 5.52;
N, 19.17. Found: C, 69.90; H, 5.56; N, 19.10.
7-(4-Brominebenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5m
1
Mp. 160–1628C; yield 31%; H-NMR (CDCl3, 300 MHz) d 2.94–
3.04 (m, 4H, -CH2-CH2-), 4.65 (s, 2H, -NH2), 5.04 (s, 2H, -OCH2-),
6.89–6.95 (m, 2H, H-6, H-9), 7.29–7.54 (m, 4H, Ar-H), 7.65–7.68
(m, 1H, H-8). IR (KBr) cm– 1: 3340 and 3105 (-NH2), 1524 (-OCH2-);
MS m/z 371 [M + 1]; Anal. Calcd. for C17H15BrN4O: C, 55.00; H,
4.07; N, 15.09. Found: C, 55.03; H, 4.11; N, 15.03.
7-(2-Chlorobenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5g
1
Mp. 168–1708C; yield 29%; H-NMR (CDCl3, 300 MHz) d 2.96–
3.04 (m, 4H, -CH2-CH2-), 4.51 (s, 2H, -NH2), 5.19 (s, 2H, -OCH2-),
6.95–7.00 (m, 2H, H-6, H-9), 7.30–7.54 (m, 4H, Ar-H), 7.68–7.71
(m, 1H, H-8). IR (KBr) cm– 1: 3349 and 3108 (-NH2), 1521 (-OCH2-);
MS m/z 327 [M + 1], 329 [M + 3]; Anal. Calcd. for C17H15ClN4O: C,
62.48; H, 4.63; N, 17.15. Found: C, 62.50; H, 4.68; N, 17.11.
7-(4-Methylbenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5n
1
Mp. 118–1208C; yield 35%; H-NMR (CDCl3, 300 MHz) d 2.93–
3.03 (m, 4H, -CH2-CH2-), 3.75 (s, 3H, -CH3), 4.80 (s, 2H, -NH2), 5.04 (s,
2H, -OCH2-), 6.91–6.96 (m, 2H, H-6, H-9), 7.20–7.33 (m, 4H, Ar-H),
7.64–7.66 (m, 1H, H-8). IR (KBr) cm– 1: 3313 and 3136 (-NH2), 1502
(-OCH2-); MS m/z 307 [M + 1]; Anal. Calcd. for C18H18N4O: C, 70.57;
H, 5.92; N, 18.29. Found: C, 70.63; H, 5.98; N, 18.23.
7-(3-Chlorobenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5h
1
Mp. 162–1648C; yield 33%; H-NMR (CDCl3, 300 MHz) d 2.94–
3.02 (m, 4H, -CH2-CH2-), 4.71 (s, 2H, -NH2), 5.05 (s, 2H, -OCH2-),
6.90–6.95 (m, 2H, H-6, H-9), 7.27–7.44 (m, 4H, Ar-H), 7.67–7.70
(m, 1H, H-8). IR (KBr) cm– 1: 3280 and 3103 (-NH2), 1662 (-OCH2-);
MS m/z 327 [M + 1], 329 [M + 3]; Anal. Calcd. for C17H15ClN4O: C,
62.48; H, 4.63; N, 17.15. Found: C, 62.49; H, 4.70; N, 17.10.
7-(4-Methoxybenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5o
1
Mp. 115–1178C; yield 40%; H-NMR (CDCl3, 300 MHz) d 2.95–
3.02 (m, 4H, -CH2-CH2-), 3.83 (s, 3H, -OCH3), 4.82 (s, 2H, -NH2), 5.01
(s, 2H, -OCH2-), 6.92–6.96 (m, 2H, H-6, H-9), 7.34–7.66 (m, 4H, Ar-
H), 7.90–7.94 (m, 1H, H-8). IR (KBr) cm-1: 3329 and 3118 (-NH2),
1508 (-OCH2-); MS m/z 323 [M + 1]; Anal. Calcd. for C18H18N4O2: C,
67.07; H, 5.63; N, 17.38. Found: C, 67.11; H, 5.69; N, 17.30.
7-(4-Chlorobenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5i
1
Mp. 166–1688C; yield 35%; H-NMR (CDCl3, 300 MHz) d 2.94–
3.04 (m, 4H, -CH2-CH2-), 4.60 (s, 2H, -NH2), 5.06 (s, 2H, -OCH2-),
6.90–6.96 (m, 2H, H-6, H-9), 7.35–7.38 (m, 4H, Ar-H), 7.66–7.69
(m, 1H, H-8). IR (KBr) cm– 1: 3339 and 3124 (-NH2), 1516 (-OCH2-);
MS m/z 327 [M + 1], 329 [M + 3]; Anal. Calcd. for C17H15ClN4O: C,
62.48; H, 4.63; N, 17.15. Found: C, 62.52; H, 4.72; N, 17.13.
7-(2,4-Dichlorobenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5p
Mp. 154–156 C; yield 35%;1H-NMR (CDCl3, 300 MHz) d 2.96–3.04
(m, 4H, -CH2-CH2-), 4.59 (s, 2H, -NH2), 5.14 (s, 2H, -OCH2-), 6.93–
6.98 (m, 2H, H-6, H-9), 7.28–7.50 (m, 4H, Ar-H), 7.68–7.71 (m, 1H,
H-8). IR (KBr) cm– 1: 3309 and 3107 (-NH2), 1500 (-OCH2-); MS m/z
361 [M + 1], 363 [M + 3], 365 [M + 5]; Anal. Calcd. for C17H14Cl2N4O:
C, 56.52; H, 3.91; N, 15.51. Found: C, 56.56; H, 3,94; N, 15.41.
7-(2-Fluorobenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5j
1
Mp. 148–1508C; yield 37%; H-NMR (CDCl3, 300 MHz) d 2.89–
3.03 (m, 4H, -CH2-CH2-), 4.79 (s, 2H, -NH2), 5.14 (s, 2H, -OCH2-),
6.93–6.97 (m, 2H, H-6, H-9), 7.07–7.51 (m, 4H, Ar-H), 7.67–7.70
(m, 1H, H-8). IR (KBr) cm– 1: 3336 and 3089 (-NH2), 1512 (-OCH2-);
MS m/z 312 [M + 1]; Anal. Calcd. for C17H15FN4O: C, 65.80; H, 4.87;
N, 18.05. Found: C, 65.88; H, 4.90; N, 17.99.
Pharmacology
The anti-inflammatory activity was evaluated by an in-vivo inhib-
ition assay monitoring xylene-induced ear edema [19]. All tested
compounds were homogenized with 0.5% sodium carboxyme-
thylcellulose (CMC-Na) and administered orally to Kunming
mice (20-25 g body weight, 10 animals per group). Control mice
received the vehicle only (0.5% sodium carboxymethylcellulose,
0.2 mL/10 g). At a specified later time, 20 lL xylene was applied
to the surface of the right ear of each mouse by a micropipette.
Mice were sacrificed 30 min later and a cylindrical plug (7 mm
diameter) was excised from each of the treated and untreated
ears. Edema was quantified by the difference in weight between
the two plugs. The anti-inflammatory activity was expressed as
percent edema reduction as compared to the CMC-Na adminis-
7-(3-Fluorobenzyloxy)-1-amino-4,5-
dihydro[1,2,4]triazole[4,3-a]quinoline 5k
1
Mp. 158–1608C; yield 34%; H-NMR (CDCl3, 300 MHz) d 2.87–
3.01 (m, 4H, -CH2-CH2-), 4.87 (s, 2H, -NH2), 5.18 (s, 2H, -OCH2-),
6.76–6.79 (m, 2H, H-6, H-9), 7.04–7.37 (m, 4H, Ar-H), 7.72–7.75
(m, 1H, H-8). IR (KBr) cm– 1: 3305 and 3120 (-NH2), 1504 (-OCH2-);
MS m/z 312 [M + 1]; Anal. Calcd. for C17H15FN4O: C, 65.80; H, 4.87;
N, 18.05. Found: C, 65.89; H, 4.92; N, 17.96.
i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2008, 341, 288–293
Triazole-quinolines as Anti-inflammatories
293
tered control group. The NSAID drug ibuprofen was tested in
parallel as an activity reference. Edema values, expressed as
mean l standard deviation, were compared statistically using
Student's t-test. A level of p a 0.05 was adopted as the test of sig-
nificance.
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i 2008 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com