Design and synthesis of 6-alkyoxyl[1,2,4]triazolo[1,5-a]quinazoline derivatives with anticonvulsant activity

Article abstract of DOI:10.1007/s00044-011-9875-y

A series of novel 6-alkyoxyl[1,2,4]triazolo[1,5-a]quinazoline derivatives were synthesized in this study. The anticonvulsant activity of all the target compounds 4a-4s, characterized by IR, 1H-NMR and MS, were evaluated using Maximal electroshock test. The pharmacological results showed that some of the compounds displayed positive anticonvulsant activity. Among them, 6-(benzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline (4a) was the most active compound with an ED₅₀ value of 78.9 mg/kg and a PI value of 9.0. Springer Science+Business Media, LLC 2011.

Full text of DOI:10.1007/s00044-011-9875-y

MEDICINAL
CHEMISTRY
RESEARCH
Med Chem Res (2012) 21:3294–3300
DOI 10.1007/s00044-011-9875-y
ORIGINAL RESEARCH
Design and synthesis of 6-alkyoxyl[1,2,4]triazolo[1,5-a]quinazoline
derivatives with anticonvulsant activity
•
Chun-Bo Zhang Chuan-Wen Yang
•
•
Xian-Qing Deng Zhe-Shan Quan
Received: 21 March 2011 / Accepted: 4 November 2011 / Published online: 16 November 2011
Ó Springer Science+Business Media, LLC 2011
Abstract A series of novel 6-alkyoxyl[1,2,4]triazolo[1,5-
a]quinazoline derivatives were synthesized in this study.
The anticonvulsant activity of all the target compounds
2007) several [1,2,4]triazolo[4,3-a]quinoline derivatives
(Fig. 1), which showed considerable anticonvulsant activ-
ities. As a part of our continuous research in this area, we
designed and synthesized several new [1,2,4]triazolo[1,
5-a]quinazoline derivatives, which are the bioisoterisms
of [1,2,4]triazolo[4,3-a]quinolines. From the structure–
activity relationships of [1,2,4]triazolo[4,3-a]quinoline
derivatives, we found that introduction of alkyoxyl groups
into the aryl moiety significantly enhanced the anticon-
vulsant efficacy. Hence, in this study, the [1,2,4]triazol-
o[1,5-a]quinazoline derivatives with alkyoxyl groups in the
6th position were synthesized expecting to have a prom-
ising effect in dealing with the epilepsy.
1
4a–4s, characterized by IR, H-NMR and MS, were eval-
uated using Maximal electroshock test. The pharmacolog-
ical results showed that some of the compounds displayed
positive anticonvulsant activity. Among them, 6-(benzyl-
oxy)-[1,2,4]triazolo[1,5-a]quinazoline (4a) was the most
active compound with an ED50 value of 78.9 mg/kg and a
PI value of 9.0.
Keywords Synthesis Á Triazole Á
Triazolo[1,5-a]quinazoline Á Anticonvulsant Á
Maximal electroshock
1
Their structures were characterized using IR, H-NMR,
MS, and elemental analysis techniques. Their anticonvul-
sant activities were evaluated with maximal electroshock
(MES) test in intraperitoneally injected mice.
Introduction
There is no doubt that epilepsy belongs to the most
encountered neurological conditions since the disease
affects approximately 1% of the population (Strine et al.,
2005). Around 75–80% of epileptic patients may be pro-
vided with adequate seizure control with the help of the
available antiepileptic drugs. The therapeutic failure in 20–
25% of patients and serious side effects in the available
antiepileptic drugs has stimulated intensive research on
novel antiepileptic drugs (Spear, 2001; Bootsma et al.,
2009; Kennedy and Lhatoo, 2008).
Experimental section
Chemistry
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on a
1
FT-IR1730 (Perkin-Elmer, USA). H-NMR spectra were
measured on a BRUKER-300 (Bruker Bioscience, Bille-
rica, MA, USA), and all chemical shifts were given in ppm
relative to tetramethysilane. Mass spectra were measured
on an HP1100LC (Hewlett-Packard, PaloAlto, CA, USA).
Microanalyses of C, N, and H were performed using a
Heraeus CHN Rapid Analyzer (Heraeus GmbH, Hanau,
Germany). The major chemicals were purchased from
Sigma-Aldrich Corporation.
In the efforts to get those agents, we had reported (Xie
et al., 2005; Cui et al., 2005; Guan et al., 2008; Cui et al.,
C.-B. Zhang Á C.-W. Yang Á X.-Q. Deng Á Z.-S. Quan (&)
College of Pharmacy, Yanbian University, Yanji, Jili 133002,
People’s Republic of China
e-mail: zsquan@ybu.edu.cn
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3295
Fig. 1 [1,2,4]triazolo[4,3-
a]quinolines
J = 8.07, H-9), 7.76 (d, 1H, J = 8.22 Hz, H-7), 7.93 (t, 1H,
J = 8.25 Hz, H-8), 8.64 (s, 1H, H-5), 9.52 (s, 1H, H-2),
11.65 (s, 1H, –OH). MS m/z 187 (M ? 1). Anal. Calcd. for
C9H6N4O: C 58.06, H 3.25, N 30.09. Found: C 58.27, H,
3.06, N 30.23.
RO
N
N
N
Synthesis of 8,9-dihydro-[1,2,4]triazolo[1,5-a]quinazolin-
6(7H)-one (1)
The general procedure for the synthesis
of 6-alkyoxyl[1,2,4]triazolo[1,5-a]quinazoline (4a–4s)
Cyclohexane-1,3-dione (2 g, 17.9 mmol) and dimethoxy-
N,N-dimethylmethanemine (DMF-DMA) (2.56 g, 21.4 mmol)
were mixed and heated at 60°C. 2H-1,2,4-triazol-3-amine
was added after the mixture was completely homogenized,
and then the reaction temperature was raised to 105°C. The
mixture was solidified for a few minutes, cooled, and
diluted with propan-2-ol. The precipitate was filtered off
and recrystallized from DMF. Yield: 91.3%; mp
209–211°C. 1H-NMR (CDCl3, 300 MHz): d 2.38–2.45 (m,
2H, H-8), 2.78 (t, 2H, J = 6 Hz, H-7), 3.53 (t, 2H,
J = 6.3 Hz, H-9), 8.59 (s, 1H, H-5), 9.31 (s, 1H, H-2). MS
m/z 189.1 (M ? 1). Anal. Calcd. For C9H8N4O: C 57.44,
H 4.28, N 29.77. Found: C 57.31, H 4.38, N 29.65.
Compound 4 (0.45 g, 2.4 mmol) and K2CO3 (0.40 g,
2.9 mmol) were added to 20 mL DMF. The mixture was
stirred and heated at 80°C for 0.5 h, then various kinds of
substituted benzyl chloride (2.4 mmol) were added, and the
reaction temperature was raised to 100°C. After stirring for
about 3 h, the solvent was removed under reduced pres-
sure. Residue was extracted with dichloromethane and
dried over anhydrous MgSO4. Evaporation of the solvents
got a crude product, which was purified by silica gel col-
umn chromatography with CH2Cl2–CH3OH (50:1) to
obtain compounds, 4a–4s. The yield, melting point, and
spectral data of each compound were given below.
Synthesis of 7-bromo-8,9-dihydro-[1,2,4]triazolo
[1,5-a]quinazolin-6(7H)-one (2)
6-(Benzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline (4a)
Yield: 72.1%; mp 163–165°C. 1H-NMR (CDCl3, 300 MHz):
d 5.35 (s, 2H, –OCH2–), 7.09 (d, 1H, J = 8.07 Hz, H-9),
7.40–7.52 (m, 5H, Ar–H), 7.89 (t, 1H, J = 8.18 Hz, H-8),
7.99 (d, 1H, J = 8.34 Hz, H-7), 8.49 (s, 1H, H-5), 9.71 (s,
1H, H-2); IR (KBr) cm-1: 1620, 1601, 1549 (C=N); MS m/z
277 (M ? 1); Anal. Calcd. for C16H12N4O: C, 69.55; H, 4.38;
N, 20.28. Found: C, 69.33; H, 4.25; N, 20.43.
Compound 1 (3.00 g, 16.0 mmol), N-bromosuccinimide
(NBS) (4.26 g, 23.9 mmol), and small amounts of benzoyl
peroxide were placed into a 100-ml round-bottomed flask
containing 50 ml of CCl4 equipped with a reflux condenser
connected with a drying tube. The mixture was stirred at
100°C for 6 h. After cooling, it was filtered and washed
with dichloromethane. The evaporation of the dichloro-
methane gave a crude product, which was purified by silica
gel column chromatography with CH2Cl2–CH3OH (30:1).
Yield: 90.6%; mp 322–324°C. 1H-NMR (CDCl3, 300 MHz):
d 2.78–3.25 (m, 4H, H-8, H-9), 5.98 (s, 1H, H-7), 8.70 (s, 1H,
H-5), 9.38 (s, 1H, H-2). MS m/z 270 (M ? 1). Anal. Calcd.
for C9H9BrN4O: C 40.17; H 3.37; N 20.82. Found: C 40.03;
H 3.24; N 20.96.
6-(2-Fluorobenzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline
(4b)
Yield: 70.2%; mp 166–168°C. 1H-NMR (CDCl3, 300 MHz):
d 5.41 (s, 2H, –OCH2–), 7.13–8.03 (m, 7H, H-7, H-8, H-9,
Ar–H), 8.49 (s, 1H, H-5), 9.68 (s, 1H, H-2); IR (KBr) cm-1
:
1622, 1600, 1549 (C=N); MS m/z 295 (M ? 1); Anal. Calcd.
for C16H11FN4O: C, 65.30; H, 3.77; N, 19.04. Found: C,
65.10; H, 3.92; N, 18.81.
Synthesis of [1,2,4]triazolo[1,5-a]quinazolin-6-ol (3)
Compound 2 (3.50 g, 13.1 mmol) and K2CO3 (2.17 g,
15.7 mmol) were placed into a 100-ml round-bottomed flask
containing 50 ml of ethanol. The mixture was refluxed for
15 min, and then the solvent was removed under reduced
pressure. The residue was dissolved with 50 ml ice–water,
and the solution was neutralized with 10% HCl solution. The
precipitate was filtered off and dried in vacuo to give a crude
product, which was purified by silica gel column chroma-
tography with CH2Cl2–CH3OH (10:1). Yield: 88.4%; mp
6-(3-Fluorobenzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline
(4c)
Yield: 69.4%; mp 159–161°C. 1H-NMR (CDCl3, 300 MHz):
d 5.35 (s, 2H, –OCH2–), 7.05-8.03 (m, 7H, H-7, H-8, H-9,
Ar–H), 8.50 (s, 1H, H-5), 9.71 (s, 1H, H-2); IR (KBr) cm-1
:
1621, 1601, 1548 (C=N); MS m/z 295 (M ? 1); Anal. Calcd.
for C16H11FN4O: C, 65.30; H, 3.77; N, 19.04. Found: C,
65.11; H, 3.89; N, 19.22.
1
348–349°C. H-NMR (DMSO, 300 MHz): d 7.12 (d, 1H,
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Med Chem Res (2012) 21:3294–3300
6-(4-Fluorobenzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline
(4d)
6-(2-Bromobenzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline
(4i)
Yield: 70.2%; mp 189–191°C. 1H-NMR (CDCl3, 300 MHz):
d 5.30 (s, 2H, –OCH2–), 7.06–8.02 (m, 7H, H-7, H-8, H-9,
Yield: 71.3%; mp 199–201°C. 1H-NMR (CDCl3, 300 MHz):
d 5.41(s, 2H, –OCH2–), 7.09–8.03 (m, 7H, H-7, H-8, H-9,
Ar–H), 8.50 (s, 1H, H-5), 9.73 (s, 1H, H-2); IR
(KBr) cm-1: 1622, 1601, 1549 (C=N); MS m/z 356
(M ? 1), 358 (M ? 3); Anal. Calcd. for C16H11BrN4O: C,
54.10; H, 3.12; N, 15.77. Found: C, 54.29; H, 2.94; N,
15.61.
Ar–H), 8.49 (s, 1H, H-5), 9.67(s, 1H, H-2); IR (KBr) cm-1
:
1620, 1601, 1549 (C=N); MS m/z 295 (M ? 1); Anal.
Calcd. for C16H11FN4O: C, 65.30; H, 3.77; N, 19.04.
Found: C, 65.11; H, 3.64; N, 18.83.
6-(2-Chlorobenzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline
(4e)
6-(4-Methbenzyloxy)-[1,2,4]triazolo
[1,5-a]quinazoline (4j)
1
Yield: 71.4%; mp 202–203°C. H-NMR (CDCl3 300 MHz):
d 5.45 (s, 2H, –OCH2–), 7.10–8.04 (m, 7H, H-7, H-8, H-9,
Ar–H), 8.50 (s, 1H, H-5), 9.73 (s, 1H, H-2); IR
(KBr) cm-1: 1622, 1600, 1551 (C=N); MS m/z 312
(M ? 1) 314 (M ? 3); Anal. Calcd. for C16H11ClN4O: C,
61.84; H, 3.57; N, 18.03. Found: C, 61.62; H, 3.69; N,
18.21.
Yield: 72.5%; mp 158–159°C. 1H-NMR (CDCl3, 300 MHz):
d 2.40 (s, 3H, –CH3), 5.30 (s, 2H, –OCH2–), 7.07–7.99 (m,
7H, H-7, H-8, H-9, Ar–H), 8.48 (s, 1H, H-5), 9.64 (s, 1H,
H-2); IR (KBr) cm-1: 1620, 1601, 1549 (C=N); MS m/z
291 (M ? 1); Anal. Calcd. for C17H14N4O: C, 70.33; H,
4.86; N, 19.30. Found: C, 70.49; H, 4.99; N, 19.48.
6-(3-Chlorobenzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline
(4f)
6-(4-Methoxybenzyloxy)-[1,2,4]triazolo
[1,5-a]quinazoline (4k)
Yield: 68.3%; mp 196–198°C. 1H-NMR (CDCl3, 300 MHz):
d 5.32 (s, 2H, –OCH2–), 7.04–8.03 (m, 7H, H-7, H-8, H-9,
Ar–H), 8.50 (s, 1H, H-5), 9.70 (s, 1H, H-2); IR
(KBr) cm-1: 1622, 1601, 1550 (C=N); MS m/z 312
(M ? 1) 314 (M ? 3); Anal. Calcd. for C16H11ClN4O: C,
61.84; H, 3.57; N, 18.03. Found: C, 61.71; H, 3.45; N,
18.25.
Yield: 69.8%; mp 179–181°C. 1H-NMR (CDCl3, 300 MHz):
d 3.83 (s, 3H, –OCH3), 5.26 (s, 2H, –OCH2–), 6.87-7.97
(m, 7H, H-7, H-8, H-9, Ar–H), 8.48 (s, 1H, H-5), 9.64 (s,
1H, H-2); IR (KBr) cm-1: 1620, 1601, 1549 (C=N); MS m/
z 307 (M ? 1); Anal. Calcd. for C17H14N4O2: C, 66.66; H,
4.61; N, 18.29. Found: C, 66.50; H, 4.76; N, 18.15.
6-(4-Chlorobenzyloxy)-[1,2,4]triazolo[1,5-a]quinazoline
(4g)
4-(([1,2,4]Triazolo[1,5-a]quinazolin-6-
yloxy)methyl)benzonitrile (4l)
Yield: 70.6%; mp 190–192°C. 1H-NMR (CDCl3, 300 MHz):
d 5.31 (s, 2H, –OCH2–), 7.04–8.01 (m, 7H, H-7, H-8, H-9,
Ar–H), 8.49 (s, 1H, H-5), 9.66 (s, 1H, H-2); IR
(KBr) cm-1: 1620, 1601, 1549 (C=N); MS m/z 312
(M ? 1), 314 (M ? 3); Anal. Calcd. for C16H11ClN4O: C,
61.84; H, 3.57; N, 18.03. Found: C, 61.62; H, 3.38; N,
18.27.
Yield: 66.7%; mp 248–250°C. 1H-NMR (CDCl3, 300 MHz):
d 5.42 (s, 2H, –OCH2–), 7.03–8.06 (m, 7H, H-7, H-8, H-9,
Ar–H), 8.50 (s, 1H, H-5), 9.70 (s, 1H, H-2); IR (KBr) cm-1
:
1620, 1601, 1549 (C=N); MS m/z 302 (M ? 1); Anal.
Calcd. for C17H11N5O: C, 67.77; H, 3.68; N, 23.24. Found:
C, 67.96; H, 3.79; N, 23.08.
6-(2,4-Dichlorobenzyloxy)-[1,2,4]triazolo[1,5-
a]quinazoline (4h)
2-(([1,2,4]Triazolo[1,5-a]quinazolin-6-
yloxy)methyl)benzonitrile (4m)
Yield: 65.4%; mp 237–239°C. 1H-NMR (CDCl3, 300 MHz):
d 5.41(s, 2H, –OCH2–), 7.08–8.06 (m, 6H, H-7, H-8, H-9,
Ar–H), 8.50 (s, 1H, H-5), 9.70 (s, 1H, H-2); IR
(KBr) cm-1: 1624, 1601, 1551 (C=N); MS m/z 346
(M ? 1), 348 (M ? 3); Anal. Calcd. for C16H10Cl2N4O: C,
55.67; H, 2.92; N, 16.23. Found: C, 55.84; H, 2.78; N,
16.11.
Yield: 61.8%; mp 230–232°C. 1H-NMR (CDCl3, 300 MHz):
d 5.54 (s, 2H, –OCH2–), 7.14–8.05 (m, 7H, Ar–H), 8.50 (s,
1H, H-5), 9.70 (s, 1H, H-2); IR (KBr) cm-1: 1620, 1601,
1549 (C=N); MS m/z 302 (M ? 1); Anal. Calcd. for
C17H11N5O: C, 67.77; H, 3.68; N, 23.24. Found: C, 67.61;
H, 3.50; N, 23.39.
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6-Butoxy-[1,2,4]triazolo[1,5-a]quinazoline (4n)
1549 (C=N); MS m/z 299 (M ? 1); Anal. Calcd. for
C17H22N4O: C, 68.43; H, 7.43; N, 18.78. Found: C, 68.68;
H, 7.26; N, 18.94.
Yield: 71.8%; mp 140–142°C. 1H-NMR (CDCl3, 300 MHz):
d 0.93 (t, 3H, J = 7.29 Hz, –CH3), 1.55–1.70 (m, 2H,
–CH2–), 1.91–2.00 (m, 2H, –CH2–), 4.24 (t, 2H, J =
6.33 Hz, –OCH2–), 7.01 (d, 1H, J = 7.74 Hz, H-9), 7.86–
7.97 (m, 2H, H-7, H-8), 8.49 (s, 1H, H-5), 9.65 (s, 1H,
H-2); IR (KBr) cm-1: 1618, 1599, 1549 (C=N); MS m/z
243(M ? 1); Anal. Calcd. for C13H14N4O: C, 64.45; H,
5.82; N, 23.13.Found: C, 64.64; H, 5.98; N, 23.29 .
6-(Decyloxy)-[1,2,4]triazolo[1,5-a]quinazoline (4s)
Yield: 67.9%; mp 128–130°C. 1H-NMR (CDCl3, 300 MHz):
d 0.87 (t, 3H, J = 6.57 Hz, –CH3), 1.27–1.42 (m, 12H,
–CH2–CH2–CH2–CH2–CH2–CH2–), 1.52–1.55 (m, 2H,
–CH2–), 1.92–2.03 (m, 2H, –CH2–), 4.21 (t, 2H,
J = 6.30 Hz, –OCH2–), 6.96 (d, 1H, J = 7.68 Hz, H-9),
7.82–7.92 (m, 2H, H-7, H-8), 8.46 (s, 1H, H-5), 9.62 (s, 1H,
H-2); IR (KBr) cm-1: 1620, 1601, 1549 (C=N); MS m/z
327 (M ? 1); Anal. Calcd. for C19H26N4O: C, 69.91; H,
8.03; N, 17.16. Found: C, 70.14; H, 7.92; N, 17.30.
6-(Pentyloxy)-[1,2,4]triazolo[1,5-a]quinazoline (4o)
Yield: 70.5%; mp 133–135°C. 1H-NMR (CDCl3, 300 MHz):
d 0.98 (t, 3H, J = 7.16 Hz, –CH3), 1.42–1.61 (m, 4H,
–CH2–CH2–), 1.93–2.02 (m, 2H, –CH2–), 4.23 (t, 2H,
J = 6.37 Hz, –OCH2–), 6.98 (d, 1H, J = 7.72 Hz, H-9),
7.84–7.94 (m, 2H, H-7, H-8), 8.48 (s, 1H, H-5), 9.64 (s, 1H,
H-2); IR (KBr) cm-1: 1618, 1599, 1549 (C=N); MS m/z
257 (M ? 1); Anal. Calcd. for C14H16N4O: C, 65.61; H,
6.29; N, 21.86. Found: C, 65.84; H, 6.11; N, 22.04.
Pharmacology
All the titled compounds (4a–4s) were screened for their
anticonvulsant activities by means of the most-adopted
seizure models—the Maximal electroshock seizure (MES)
test. The MES test was carried out according to the stan-
dard described in the Antiepileptic Drug Development
Program (ADD) of the National Institutes of Health (USA).
All the compounds, dissolved in DMSO, were tested with
KunMing mice in the 18–22 g weight range purchased
from the Laboratory of Animal Research, College of
Pharmacy, Yanbian University.
6-(Hexyloxy)-[1,2,4]triazolo[1,5-a]quinazoline (4p)
Yield: 68.7%; mp 128–129°C. 1H-NMR (CDCl3, 300 MHz):
d 0.96 (t, 3H, J = 6.67 Hz,–CH3), 1.38–1.40 (m, 6H,
–CH2–CH2–), 1.56–1.59 (m, 2H, –CH2–), 4.22 (t, 2H,
J = 6.35 Hz, –OCH2–), 6.98 (d, 1H, J = 7.67 Hz, H-9),
7.84–7.94 (m, 2H, H-7, H-8), 8.48 (s, 1H, H-5), 9.63 (s, 1H,
H-2); IR (KBr) cm-1: 1619, 1600, 1549 (C=N); MS m/z
271 (M ? 1); Anal. Calcd. for C15H18N4O: C, 66.64; H,
6.71; N, 20.73. Found: C, 66.83; H, 6.60; N, 20.88.
Maximal electroshock seizure (MES) test
The MES test was carried out by the methods described in
the ADD of the National Institutes of Health (USA) (Krall
et al., 1978; Porter et al., 1984). Seizures were elicited with
a 60-Hz alternating current of 50 mA intensity in mice.
The current was applied via corneal electrodes for 0.2 s.
Protection against the spread of MES-induced seizures was
defined as the abolition of tonic maximal extension of the
hind leg. At 30 min after the administration of the com-
pounds, the activities were evaluated in MES test. In phase-
I screening, each compound was administered at the dose
levels of 100 mg/kg for evaluating the preliminary anti-
convulsant activity. For determination of the median
effective dose (ED50) and the median toxic dose (TD50),
the phase-II screening was prepared. Groups of ten mice
were given a range of intraperitoneal (i.p.) doses of the
tested compound until at least three points were established
in the range of 10–90% seizure protection or minimal
observed neurotoxicity. From the plot of these data, the
respective ED50 and TD50 values, 95% confidence inter-
vals, slope of the regression line, and the standard error of
the slope were calculated by means of a computer program
6-(Heptyloxy)-[1,2,4]triazolo[1,5-a]quinazoline (4q)
Yield: 69.3%; mp 130–132°C. 1H-NMR (CDCl3, 300 MHz):
d 0.89 (t, 3H, J = 6.14 Hz, –CH3), 1.25–1.45 (m, 6H,
–CH2–CH2–CH2–), 1.52–1.59 (m, 2H, –CH2–), 1.94–1.99
(m, 2H, –CH2–), 4.23 (t, 2H, J = 6.41 Hz, –OCH2–), 7.00
(d, 1H, J = 7.86 Hz, H-9), 7.86–7.96 (m, 2H, H-7, H-8),
8.48 (s, 1H, H-5), 9.65 (s, 1H, H-2); IR (KBr) cm-1: 1619,
1601,1549 (C=N); MS m/z 285 (M ? 1); Anal. Calcd. for
C16H20N4O: C, 67.58; H, 7.09; N, 19.70. Found: C, 67.79;
H, 6.92; N, 19.91.
6-(Octyloxy)-[1,2,4]triazolo[1,5-a]quinazoline (4r)
Yield: 70.6%; mp 118–119°C. 1H-NMR (CDCl3, 300 MHz):
d 0.90 (t, 3H, J = 6.77 Hz, –CH3),1.31–1.38 (m, 8H,
–CH2–CH2–CH2–CH2–), 1.52–1.64 (m, 2H, –CH2–), 1.92–
2.01 (m, 2H, –CH2–), 4.24 (t, J = 6.42 Hz, 2H, –OCH2–),
7.01 (d, 1H, H-9), 7.87–7.97 (m, 2H, H-7, H-8), 8.49 (s,
1H, H-5), 9.66 (s, 1H, H-2); IR (KBr) cm-1: 1620, 1601,
123

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Med Chem Res (2012) 21:3294–3300
written by the National Institute of Neurological Disorders
and Stroke.
Table 1 Preliminary evaluation of compounds 4a–4s in the MES in
mice (i.p.)
Compounds
R
MES (100 mg/kg)
Neurotoxicity screening (NT)
4a
4b
4c
4d
4e
4f
–CH2C6H5
4/5a
2/5
0/5
0/5
0/5
0/5
0/5
0/5
2/5
1/5
0/5
1/5
1/5
0/5
3/5
2/5
2/5
1/5
0/5
–CH2C6H4(o-F)
–CH2C6H4(m-F)
–CH2C6H4(p-F)
–CH2C6H4(o-Cl)
–CH2C6H4(m-Cl)
–CH2C6H4(p-Cl)
–CH2C6H3(2,4-Cl2)
–CH2C6H4(o-Br)
–CH2C6H4(p-CH3)
–CH2C6H4(p-OCH3)
–CH2C6H4(p-CN)
–CH2C6H4(o-CN)
n-C4H9
The neurotoxicity of the compounds were measured in
mice by the rotarod test (Krall et al., 1978; Porter et al.,
1984). The mice were trained to stay on an accelerating
rotarod of diameter 3.2 cm that rotates at 10 rpm. Trained
animals were given i.p. injection of the test compounds.
Neurotoxicity was indicated by the inability of the animal
to maintain equilibrium on the rod for at least 1 min in
each of the trials.
4g
4h
4i
4j
4k
4l
Results and discussion
4m
4n
4o
4p
4q
4r
4s
a
Chemistry
n-C5H11
To obtain compounds with anticonvulsant activities, we
designed and synthesized several new 6-alkyoxyl[1,2,4]-
triazolo[1,5-a]quinazoline derivatives. The synthesis of 6-al-
kyoxyl[1,2,4]triazolo[1,5-a]quinazolines has not been repor-
ted before this study. As shown in Scheme 1, The starting
material cyclohexane-1,3-dione reacted with dimethoxy-N,
N-dimethylmethanemine (DMF–DMA) and aminotriazole to
form 8,9-dihydro-[1,2,4]triazolo[1,5-a]quinazolin-6(7H)-one
(1) in a good yield of 91.3% (Shikhaliev et al., 2005). In the
next step, several methods were tested to achieve the dehy-
drogenation product of the intermediate 1 (such as treating
n-C6H13
n-C7H15
n-C8H17
n-C10H21
Number of animals protected/number of animals tested
the intermediate with 2,3-dichloro-5,6-dicyanobenzoquinone
(DDQ), or sulphur powder coupled with nitrobenzene, or
SOCl2, and so on); however, no expected product was
obtained. Finally, the dehydrogenation product (3) was
Scheme 1 Synthesis route of
target compounds (4a–4S)
O
O
N
N
O
O
NH
NH2
NBS
CCl4
N
+
+
N
O
N
N
N
1
O
OH
OR
Br
CO
/K
OH
H
1.C2
RX/DMF
K2CO3
N
3
2
5
N
N
2.HCl
N
N
N
N
N
N
N
N
N
4a-4s
2
3
4e: -CH2Ph(o-Cl)
4f: -CH2Ph(m-Cl)
4g: -CH2Ph(p-Cl)
4h:-CH2Ph(2,4-Cl2) 4m: -CH2Ph(o-CN)
4i: -CH2Ph(o-Br) 4n: n-C4H9
4j: -CH2Ph(p-CH3)
4k: -CH2Ph(p-OCH3)
4l: -CH2Ph(p-CN)
4o: n-C5H11
4p: n-C6H13
4q: n-C7H15
4r: n-C8H17
R:
4a: -CH2Ph
4b: -CH2Ph(o-F)
4c: -CH2Ph(m-F)
4d: -CH2Ph(p-F)
4s: n-C10H21
123

Med Chem Res (2012) 21:3294–3300
3299
Table 2 Quantitative
anticonvulsant data of 4a in
mice (i.p.)
Compound
R
ED50 (mg/kg)
TD50 (mg/kg)
PI (TD50/
ED50)
4a
–CH2C6H5
78.9 (66.9–91.0)
11.8 (9.7–14.1)
272 (247–338)
710.1 (615.5–819.1)
76.1 (69.1–83.7)
426 (369–450)
9.0
6.4
1.6
Carbamazepine
Valproate
–
–
obtained by bromination and dehydrobromination with the
total yield of 80%. 7-bromo-8,9-dihydro-[1,2,4]triazol-
o[1,5-a]quinazolin-6(7H)-one (2) was obtained by bro-
mination of compound 1 with N-bromosuccinimide (NBS)
in the CCl4, which then, under the condition of dehydro-
bromination, using K2CO3 in this case, became [1,2,4]-
triazolo[1,5-a]quinazolin-6-ol (3). Compounds 4a–4s were
finally achieved by reacting compound 3 with halogenated
hydrocarbon in N,N-dimethylformamide (DMF) in the
presence of K2CO3. The structures of new compounds were
characterized by spectral methods and elementary analysis.
All spectral data corroborated the assumed structures.
weaker anticonvulsant activity compared with carbamaze-
pine (ED50 = 11.8 mg/kg), but a higher activity compared
with valproate (ED50 = 272 mg/kg). Moreover, compound
4a showed a better PI compared with carbamazepine and
valproate (9.0 vs. 6.4 and 1.6) because of its low neuro-
toxicity (TD50 = 710 mg/kg).
Conclusion
Nineteen novel 6-alkyoxyl[1,2,4]triazolo[1,5-a]quinazoline
derivatives were synthesized in this study. Their anticon-
vulsant activities were evaluated using maximal electro-
shock (MES) test. The results of pharmacology showed
that some of the compounds displayed anticonvulsant
activities in varying degrees at the dose of 100 mg/kg.
Among them, 6-(benzyloxy)-[1,2,4]triazolo[1,5-a]quinaz-
oline (4a) was the most active compound with the ED50
value of 78.9 mg/kg, and PI value of 9.0, which were
higher than those of carbamazepine and valproate.
Pharmacology
The MES seizure model was used for preliminary (phase I)
screening of compounds 4a–4s, and the results are presented
in Table 1. As shown in Table 1, some of the compounds
were active in the MES test at the dose of 100 mg/kg,
indicative of their ability to prevent seizure spread. Among
the benzyl group-substituted derivatives (4a–4m), six com-
pounds 4a, 4b, 4i, 4j, 4l, and 4m showed protection against
MES-induced seizure in varying degrees at the dose of
100 mg/kg. It seemed that introduction of electron-donor
group (4b–4i and 4l–4m) or electron-withdrawing group
(4j–4k) on the benzyl ring both decreased the anticonvulsant
activity (compared with 4a, non-substituted in the ring of
benzyl group). Six alkoxy-substituted derivatives (4n–4s)
were also designed and prepared, all of them expressed
anticonvulsant activity except 4n and 4s. The length of the
alkoxyl chain appeared to have impact on anticonvulsant
activity of the alkoxy-substituted derivatives (4n-4s). From
4o to 4s, as the alkoxyl chain length increased, anticonvul-
sant activity gradually decreased, with the compound
4o (with the 6-pentyloxy group) being the most active
compound.
Acknowledgment This study was supported by the National Nat-
ural Science Foundation of China (No. 30860340).
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