Synthesis of 2-Substituted-7-heptyloxy-4,5-dihydro-[1,2,4]-triazolo[4,3-a] quinolin-1(2H)-ones with Anticonvulsant Activity

Article abstract of DOI:10.1002/ardp.200700106

A series of 2-substituted-7-heptyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a] quinolin-1(2H)-ones was synthesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with maximal electroshock (MES) test, subcutaneous pentylenetetrazol (sc-PTZ), and rotarod tests with intraperitoneally injected mice. Among the synthesized compounds, 2-propionyl-7-heptyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one 4b was the most active one and also had the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED₅₀) of 8.2 mg/kg, median toxicity dose (TD₅₀) of 318.3 mg/kg, and the protective index (PI) of 39.0 which is much greater than the PI of the reference drugs phenytoin and carbamazepine.

Full text of DOI:10.1002/ardp.200700106

Arch. Pharm. Chem. Life Sci. 2007, 340, 491–495
C.-X. Wei et al.
491
Full Paper
Synthesis of 2-Substituted-7-heptyloxy-4,5-dihydro-[1,2,4]-
triazolo[4,3-a]quinolin-1(2H)-ones with Anticonvulsant Activity
Cheng-Xi Wei1, 2, Fu-Nan Li2, Long-Xuan Zhao3, Li-Ming Zhao2, Zhe-Shan Quan1, 2
1 Key Laboratory of Organism Functional Factors of the Changbai Mountain, Ministry of Education, Yanbian
University, Yanji, Jilin, P. R. China
2 College of Pharmacy, Yanbian University, Yanji, Jilin, P. R. China
3 Department of Chemistry, Liaoning Normal University, Dalian, Liaoning, P. R. China
A series of 2-substituted-7-heptyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2H)-ones was syn-
thesized. The anticonvulsant effect and neurotoxicity of the compounds were calculated with
maximal electroshock (MES) test, subcutaneous pentylenetetrazole (sc-PTZ), and rotarod tests
with intraperitoneally injected mice. Among the synthesized compounds, 2-propionyl-7-hepty-
loxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one 4b was the most active one and also had
the lowest toxicity. In the anti-MES potency test, it showed median effective dose (ED50) of
8.2 mg/kg, median toxicity dose (TD50) of 318.3 mg/kg, and the protective index (PI) of 39.0 which
is much greater than the PI of the reference drugs phenytoin and carbamazepine.
Keywords: Anticonvulsant / MES / Quinoline / Synthesis / Triazole /
Received: May 17, 2007; accepted: June 1, 2007
DOI 10.1002/ardp.200700106
lione (compound I) showed the strongest activity with an
ED50 value of 29.6 mg/kg in the MES test [6]. Introduction
of a triazole ring to the first and second position of this
compound I caused a remarkable increase in the anticon-
vulsant activity as seen in 7-benzyloxyl-4,5-dihydro-
[1,2,4]triazolo[4,3-a]quinoline (compound II), which
showed an ED50 of 17.3 mg/kg in the MES test [7]. Another
derivative in the group of 7-alkoxy-4,5-dihydro-[1,2,4]tri-
azolo[4,3-a]quinoline, 7-(4-fluorobenzyloxyl)-4,5-dihydro-
[1,2,4]triazolo[4,3-a]quinoline (compound III), showed an
ED50 of 11.1 mg/kg, protective index (PI = TD50/ED50) of 4.6
in the MES test [8]. In our former work, a series of 7-
alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-
one was synthesized and tested for anticonvulsant activ-
ities [9], with the compound 7-heptyloxy-4,5-dihydro-
[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one (compound 3)
showing the most potent anticonvulsant activity with an
ED50 of 9.8 mg/kg in the MES test.
Introduction
Epilepsy, a ubiquitous disease characterized by recurrent
seizures, inflicts, according to epidemiological studies,
more than one million people worldwide [1]. For epilepsy
treatment, nearly 95% of clinically available drugs were
approved before 1985 and they could provide satisfactory
seizure control for 60–70% of patients. These drugs, how-
ever, also cause notable adverse side effects such as
drowsiness, ataxia, gastrointestinal disturbance, hepato-
toxicity, megaloblastic anemia [2–4], and even life
threatening conditions [5]. Research to find more effec-
tive and safer antiepileptic drugs is therefore imperative
and challenging in medicinal chemistry.
In our previous work, a series of derivatives of 6-alkoxy-
3,4-dihydro-2(1H)-quinolione (compounds I–III, and 3)
was first found to have anticonvulsant activities (Figure
1), among which 6-benzyloxy-3,4-dihydro-2(1H)-quino-
In the present study, we report the synthesis and anti-
convulsant activities of 2-substituted-7-heptyloxy-4,5-
dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones (4a–l)
to investigate the contribution of different acyl and alkyl
groups at position 2 of the 7-heptyloxy-4,5-dihydro-
[1,2,4]triazolo[4,3-a]quinoline-1(2H)-one to the anticon-
Correspondence: Zhe-Shan Quan, College of Pharmacy, Yanbian Uni-
versity, No. 121, JuZi Street, Yanji City, Jilin Province 133000, P. R. Chi-
na.
E-mail: e-mail: zsquan@ybu.edu.cn
Fax: +86 433 2660-568
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

492
C.-X. Wei et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 491–495
Figure 1. The compounds of our previous work.
vulsant activity. The chemical structures of the synthe- (4a–l) were conducted at the epilepsy branch of the
sized compounds were confirmed by IR, 1H-NMR, MS, and National Institute of Neurological Disorders and Stroke
elemental analysis. The anticonvulsant activity was eval- (NINDS) following the protocol adopted by the Antiepi-
uated by using the maximal electroshock (MES) test and leptic Drug Development (ADD) program [13–14].
the subcutaneous pentylenetetrazole (sc-PTZ) test. Neuro-
toxicity was evaluated by using the rotarod test.
The results of preliminary (phase I) screening of 4a–l
are summarized in Table 1. All synthesized compounds
exhibited anticonvulsant activities, among which three
compounds, 4a, 4b, and 4f, possessed anticonvulsant
activities against MES-induced seizure at a dose of 30 mg/
kg, one compound 4h was active at a dose of 100 mg/kg,
while others displayed anticonvulsant activity at a dose
Results and discussion
Synthesis
Target compounds were prepared along the reaction of 300 mg/kg. However, none of the 12 compounds exhib-
sequence in Scheme 1. Compound 1 was synthesized ited any potency to the convulsion induced by sc-PTZ at a
using the method described in a former paper of our dose of 300 mg/kg; this was consistent with the leading
group [6]. Then, 6-hydroxy-3,4-dihydro-2(1H)-quinolione compound 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]qui-
and 1-bromoheptane reacted in the solution of potas- nolin-1(2H)-one [9], which, as well, had not exhibited any
sium carbonate methanol and produced the compound potency to the convulsion induced by sc-PTZ at a dose of
1. Compound 1 then reacted with phosphorous pentasul- 300 mg/kg.
fide in acetonitrile in the presence of triethylamine
As a result of preliminary screening, compounds 4a,
under the protection of nitrogen [7] and the resulting 4b, 4f, and 4h were then subjected to phase-II trials for
compound 2 reacted further with methyl hydrazine car- quantification of their anticonvulsant activity and neuro-
boxylate in cyclohexanol to produce compound 3 accord- toxicity in mice. This phase provides an evaluation of the
ing to the method mentioned in references [9–12]. At ED50 and TD50 values. The 95%-confidence interval, slope
last, compounds 4a–l were obtained through an acyla- of the regression line, and SE of the slope were then cal-
tion or alkylation reaction of compound 3 with acyl culated. These data are shown in Table 2, which also
chloride or alkyl halides, respectively.
includes comparisons with marketed antiepileptic drugs
phenytoin and carbamazepine. As shown in Table 2, com-
pounds 4a, 4b, and 4f displayed excellent anticonvulsant
Pharmacological evaluations
Pharmacological tests of the 2-substituted-7-heptyloxy- activity in MES test, with ED50 values of 7.2 mg/kg,
4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones
8.2 mg/kg, and 11.4 mg/kg, respectively. The activities of
Scheme 1. The synthesis route of compounds 4a–l.
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Arch. Pharm. Chem. Life Sci. 2007, 340, 491–495
Triazoloquinolin-1(2H)-ones as Anticonvulsant
493
Table 1. Phase-I anticonvulsant and toxicity data in mice (ip).
Table 2. Phase II quantitative anticonvulsant data in mice (test
drug administered ip).
Com-
R
MESa)
4h
Sc-PTZb)
Toxicity
PIc)
a)
b)
pound
Compound
MES, ED50
Tox, TD50
0.5h
0.5h 4h
0.5h
4h
3
4a
4b
4f
9.8 (8.5–11.4)
7.2 (5.2–11)
8.2 (5.8–12)
11.4 (9.0–14.4)
37.8 (24.0–60.2) 122.8 (117–129)
9.5 (8.0–10.5) 65.5 (52.5–72.9)
204.6 (170.5–245.4) 20.8
c)
4a
4b
4c
4d
4e
4f
4g
4h
4i
-COCH3
-COC2H5
30
30
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
100
–
–
–
–
–
–
–
–
–
–
–
–
–
88.0 (58–120)
318.3 (217–450)
289.2 (200–414)
12.2
39.0
25.4
3.25
6.9
n-COC4H9 300
n-COC5H11 300
n-COC6H13 300
-COPh
-C2H5
n-C3H7
n-C4H9
n-C6H13
n-C7H15
-CH2Ph
300
300
100
300
300
300
300
300
300
100
4h
Phenytoin
Carbamazepine 8.8 (5.5–14.1)
30
71.6 (45.9–135.0) 8.1
300
100
300
300
300
300
a)
Dose measured in mg/kg.
b)
PI = TD50/ED50.
4j
4k
4l
c)
Minimal neurotoxicity was determined by the rotarod test
30 min after the tested compounds were administrated.
All of tested compounds were dissolved in polyethylene glycol-
400.
a)
The maximal electroshock test was induced after 30 min past
administration of the tested compounds.
Subcutaneous pentylenetetrazole (85 mg/kg) 30 min after the
tested compounds were administrated.
4d, and 4e showed weak activities at the dose of 300 mg/
kg. The 2-benzoyl derivative 4f showed lower anticonvul-
sant activity than compound 3 with an ED50 value of
11.4 mg/kg, but it possessed lower neurotoxicity with a
PI value of 25.4.
b)
c)
– = No activity at 300 mg/kg.
Compound 3 was alkylated at the 2 position, no matter
how big or small the alkyl group was; the compounds all
showed markedly reduced activities. In fact, all 5 com-
pounds 4g to 4l, except one 4h, showed weak activities at
the dose of 300 mg/kg. The 2-propyl derivative 4h showed
lower anticonvulsant activity with an ED50 value of
37.8 mg/kg and high neurotoxicity with PI value of 3.3.
compound 4a and 4b increased obviously compared with
the leading compound 3, and they were better than the
activities of the reference drugs phenytoin and carbama-
zepine. Furthermore, the two compounds exhibited
weak neurotoxicity. The PI value of compound 4b is 39,
which is higher than that of the reference drugs pheny-
toin and carbamazepine (6.9 and 8.1, respectively).
Analyzing the activities of the synthesized compounds
4a–l, the following SAR was gained. The length of the
acyl chain appeared to have direct impact on anticonvul-
sant activity of the 2-acyl derivatives. From 4a to 4e, as
the acyl chain length increased, ED50 gradually increased
with the compound 4a (with the 2-acetyl-substituted
group) being the most active compound. 4a exhibited
more potent anticonvulsant activity than compound 3
and the reference drugs phenytoin and carbamazepine
with ED50 values of 7.2 mg/kg in anti-MES activity. But 4a
had high neurotoxicity with TD50 = 88.0 mg/kg and PI =
12.2. So, among the five compounds, 4b (with the 2-pro-
pionyl-substituted group) could be considered the poten-
tially most useful and safe therapeutic compound with
ED50 = 8.2 mg/kg, TD50 = 318.3 mg/kg and PI = 39.0. Its neu-
rotoxicity was the lowest in all the synthesized com-
pounds and was also markedly lower than that of the
reference drugs phenytoin and carbamazepine.
Conclusions
A new series of anticonvulsant compounds, 2-substi-
tuted-7-heptyloxy-4,5-dihydro- [1,2,4]triazolo[4,3-a]quino-
lin-1(2H)-ones was synthesized and the pharmacological
properties were evaluated. The result showed that with
acylation of 7-heptyloxy-4,5-dihydro- [1,2,4]triazolo[4,3-
a]quinoline-1(2H)-one 3 at position 2 – and the acyl group
was small – the anticonvulsant activities became stron-
ger. When compound 3 was acylated at the 2-position
and the acyl group was big, the anticonvulsant activities
were markedly reduced. Compound 4a was the most
active one among the series 4a to 4l. But it exhibits high
neurotoxicity. Compound 4b could be considered the
potentially most useful and safe therapeutic, as its neuro-
toxicity was the lowest in all the synthesized compounds
and was also markedly lower than reference drugs pheny-
toin and carbamazepine. Compound 3 was alkylated at
position 2, no matter how big or how small the alkyl
group was, the compounds all showed markedly reduced
activities.
When compound 3 was acylated at the 2 position with
a big acyl group, such as valeryl, hexanoyl, and hepta-
noyl, the compounds exhibited markedly reduced activ-
ities. In the phase-I pharmacology test, compounds of 4c,
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494
C.-X. Wei et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 491–495
8.15 (m, 3H, Ar-H), 4.01 (t, 2H, J = 6.4 Hz, –OCH2), 3.34 (t, 2H, J =
6.4 Hz, –COCH2), 3.00 (t, 2H, J = 6.08 Hz, 5-CH2), 2.94 (t, 2H, J =
5.79 Hz, 4-CH2), 1.34–1.80 (m, 16H, 86–CH2), 0.91–0.97 (m, 6H,
26–CH3). MS: m/z 400 [M+1]. Anal. Calcd. for C23H33N3O3: C 69.14,
H 8.33, N 10.52. Found: C 69.02, H 8.49, N 10.36.
Experimental
Chemistry
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on a FT-
IR1730 (Perkin-Elmer) 1H-NMR spectra were measured on a
BRUKER-300 (Bruker Bioscience, Billerica, MA, USA), and all
chemical shifts were given in ppm relative to tetramethylsilane.
Mass spectra were measured on an HP1100LC (Hewlett-Packard,
Palo Alto, CA, USA). Microanalyses of C, N, and H were performed
using a Heraeus CHN Rapid Analyzer (Heraeus GmbH, Hanau,
Germany).
2-Heptanoyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4e
Mp. 110–1138C. Yield: 68%. IR (m cm– 1 KBr): 1726 (C=O), 1631
(C=O), 1505 (C=N), 1255 (C–O). 1H-NMR (acetone-d6 ppm): 6.92–
8.16 (m, 3H, Ar-H), 4.01 (t, 2H, J = 6.4 Hz, –OCH2), 3.47 (t, 2H, J =
6.4 Hz, –COCH2), 2.95 (t, 2H, J = 5.96 Hz, 5-CH2), 2.88 (t, 2H, J =
6.34 Hz, 4-CH2), 1.05–2.30 (m, 20H, 106–CH2), 0.86–0.98 (m, 6H,
26–CH3). MS: m/z 414 [M+1]. Anal. Calcd. for C24H35N3O3: C 69.70,
H 8.53, N 10.16. Found: C 69.97, H 8.38, N 10.47.
General procedure for the preparation of 2-Acyl-7-
heptyloxy-4, 5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-
1(2H)–ones 4a–f
A mixture of 3 (1 g, 0.003 mol) and acyl chloride (0.006 mol) was
added to toluene (50 mL) with TEA as antacid. The mixture was
refluxed for 6 h in a nitrogen atmosphere. Solvents were
removed under reduced pressure and the residue was dissolved
in 30 mL of dichloromethane, washed with water (30 mL63),
and dried over with anhydrous MgSO4. Dichloromethane was
evaporated by spin evaporation in vacuo, solids were obtained
and purified by crystallization with methanol.
2-Benzoyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4f
Mp. 140–1468C. Yield: 68%. IR (m cm– 1 KBr): 1753 (C=O), 1635
1
(C=O), 1504 (C=N), 1251 (C–O). H-NMR (acetone-d6 ppm): 6.93–
8.17 (m, 8H, Ar-H), 4.02 (t, 2H, J = 6.4 Hz, –OCH2), 3.08 (t, 2H, 5-
CH2), 2.94 (t, 2H, J = 5.64 Hz, 4-CH2), 0.98–2.06 (m, 10H, 56–CH2),
0.90 (t, 3H, J = 7.5 Hz, –CH3) MS: m/z 406 [M+1]. Anal. Calcd. for
C24H27N3O3: C 71.09, H 6.71, N 10.36. Found: C 70.88, H 6.97, N
10.46.
2-Acetyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-a]-
quinolin-1(2H)-one 4a
Mp. 93–968C. Yield: 75%. IR (m cm– 1 KBr): 1724 (C=O), 1630 (C=O),
1502 (C=N), 1258 (C–O). 1H-NMR (acetone-d6 ppm): 6.91–8.14 (m,
3H, Ar-H), 4.01 (t, 2H, J = 6.0 Hz, –OCH2), 3.01 (t, 2H, J = 6.20 Hz, 5-
CH2), 2.90 (t, 2H, J = 5.96 Hz, 4-CH2), 2.52 (S, 3H, -COCH3), 1.34–
1.98 (m, 10H, 8 6 CH2), 0.90 (t, 3H, J = 6.1 Hz, -CH3). MS: m/z 344
[M+1]. Anal. Calcd. for C19H25N3O3: C 66.45, H 7.34, N 12.24.
Found: C 66.23, H 7.61, N 12.18.
General procedure for preparation of 2-Alkyl-7-heptyloxy-
4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones
4g–l
A mixture of 3 (1 g, 0.003 mol) and alkyl halides (0.005 mol) was
added to toluene (50 mL) with TEBA as activator. The mixture
was refluxed for 6 h in a nitrogen atmosphere. Solvents were
removed under reduced pressure and the residue was dissolved
in 30 mL of dichloromethane, washed with water (30 mL63),
and dried over with anhydrous MgSO4. Dichloromethane was
evaporated by spin evaporation in vacuo; solids were obtained
and purified by crystallization with methanol.
2-Propionyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4b
Mp. 116–1208C. Yield: 74%. IR (m cm– 1 KBr): 1726 (C=O),
1
1631(C=O), 1504 (C=N), 1256 (C–O). H-NMR (acetone-d6 ppm):
6.92–8.15 (m, 3H, Ar-H), 4.02 (t, 2H, J = 6.0 Hz, –OCH2), 3.06 (t, 2H,
J = 6.7 Hz, –COCH2), 2.95 (t, 2H, J = 5.98 Hz, 5-CH2), 2.86 (t, 2H, J =
6.00 Hz, 4-CH2), 1.30–1.49 (m, 10H, 56CH2), 0.88–1.20 (m, 6H,
26CH3). MS: m/z 358 [M+1]. Anal. Calcd. for C20H27N3O3: C 67.20,
H 7.61, N 11.76. Found: C 66.95, H 7.95, N 11.61.
2-Ethyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4g
Mp. 52–558C. Yield: 54%. IR (m cm– 1 KBr): 1710 (C=O), 1506 (C=N),
1
1255 (C–O). H-NMR (acetone-d6 ppm): 6.89–8.24 (m, 3H, Ar-H),
4.01 (t, 2H, J = 6.43 Hz, –OCH2), 3.78 (t, 2H, J = 7.17 Hz, –NCH2),
3.01 (t, 2H, J = 6.45 Hz, 5-CH2), 2.87 (t, 2H, J = 6.36 Hz, 4-CH2),
1.27–2.06 (m, 10H, 56–CH2), 0.88–0.96 (m, 6H, 26–CH3). MS:
m/z 330 [M+1]. Anal. Calcd. for C19H27N3O2: C 69.27, H 8.26, N
12.76. Found: C 69.45, H 8.01, N 12.41.
2-Pentanoyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4c
Mp. 115–1208C. Yield: 65%. IR (m cm– 1 KBr): 1725 (C=O),
1
1630(C=O), 1504 (C=N), 1256 (C–O). H-NMR (acetone-d6 ppm):
6.93–8.24 (m, 3H, Ar-H), 4.03 (t, 2H, J = 6.4 Hz, –OCH2), 3.04 (t, 2H,
J = 6.7 Hz, –COCH2), 2.97 (t, 2H, J = 6.18 Hz, 5-CH2), 2.86 (t, 2H, J =
6.04 Hz, 4-CH2), 1.34–1.81 (m, 14H, 76–CH2), 0.95–1.06 (m, 6H,
26–CH3). MS: m/z 386 [M+1]. Anal. Calcd. for C22H31N3O3: C 68.54,
H 8.11, N 10.90. Found: C 68.68, H 7.94, N 10.79.
2-Propyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4h
Mp. 47–498C. Yield: 58%. IR (m cm– 1 KBr): 1710 (C=O), 1504 (C=N),
1
1253 (C–O). H-NMR (acetone-d6 ppm): 6.81–8.24 (m, 3H, Ar-H),
4.03 (t, 2H, J = 6.3 Hz, –OCH2), 3.68 (t, 2H, J = 7.1 Hz, –NCH2), 3.00
(t, 2H, J = 6.84 Hz, 5-CH2), 2.88 (t, 2H, J = 8.67 Hz, 4-CH2), 1.33–
2.53 (m, 12H, 66CH2), 0.90–0.96 (m, 6H, 26CH3). MS: m/z 344
[M+1]. Anal. Calcd. for C20H29N3O2: C 69.94, H 8.51, N 12.23.
Found: C 70.16, H 8.45, N 12.06.
2-Hexanoyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4d
Mp. 130–1348C. Yield: 65%. IR (m cm– 1 KBr): 1726 (C=O), 1631
(C=O), 1504 (C=N), 1256 (C–O). 1H-NMR (acetone-d6 ppm): 6.91–
i 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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Arch. Pharm. Chem. Life Sci. 2007, 340, 491–495
Triazoloquinolin-1(2H)-ones as Anticonvulsant
495
ponent of the seizure indicated protection against the spread of
MES-induced seizures. The sc-PTZ test involved subcutaneous
injection of a convulsant dose (CD97) of pentylenetetrazole
(85 mg/kg in mice). Elevation of the pentylenetetrazole-induced
seizure threshold was indicated by the absence of clonic spasms
for at least 5 s duration over a 30 min period following adminis-
tration of the tested compound. Anticonvulsant drug-induced
neurologic deficit was detected in mice using the rotarod ataxia
test.
2-Butyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4i
Mp. 65–698C. Yield: 57%. IR (m cm– 1 KBr): 1711 (C=O), 1504 (C=N),
1
1254 (C–O). H-NMR (acetone-d6 ppm): 6.78–8.25 (m, 3H, Ar-H),
3.96 (t, 2H, J = 6.4 Hz, –OCH2), 3.73 (t, 2H, J = 6.8 Hz, –NCH2), 2.95
(t, 2H, J = 6.93 Hz, 5-CH2), 2.84 (t, 2H, J = 5.07 Hz, 4-CH2), 1.33–
1.76 (m, 14H, 76CH2), 0.90–0.98 (m, 6H, 26CH3). MS: m/z 358
[M+1]. Anal. Calcd. for C21H31N3O2: C 70.55, H 8.74, N 11.75.
Found: C 70.65, H 8.47, N 11.51.
The pharmacological parameters estimated in phase-I screen-
ing were quantified for compounds 4a–l in phase-II screening
(Table 2). Anticonvulsant activity was expressed in terms of the
median effective dose (ED50), and neurotoxicity was expressed as
the median toxic dose (TD50). For determination of the ED50 and
TD50 values, groups of 10 mice were given a range of intraperito-
neal doses of the tested drug until at least three points were
established in the range of 10–90% seizure protection or mini-
mal observed neurotoxicity. From the plot of this data, the
respective ED50 and TD50 values, 95% confidence intervals, slope
of the regression line, and the standard error of the slope were
calculated by means of a computer program written at National
Institute of Neurological Disorders and Stroke, Bethesda, MD,
USA.
2-Hexyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4j
Mp. 51–548C. Yield: 58%. IR (m cm– 1 KBr): 1710 (C=O), 1506 (C=N),
1
1256 (C–O). H-NMR (acetone-d6 ppm): 6.92–8.16 (m, 3H, Ar-H),
4.01 (t, 2H, J = 6.4 Hz, –OCH2), 3.47 (t, 2H, J = 2.6 Hz, –NCH2), 2.95
(t, 2H, J = 5.88 Hz, 5-CH2), 2.88 (t, 2H, J = 6.06 Hz, 4-CH2), 1.05–
2.30 (m, 18H, 96CH2), 0.84–0.96 (m, 6H, 26CH3). MS: m/z 386
[M+1]. Anal. Calcd. for C23H35N3O2: C 71.65, H 9.15, N 10.90.
Found: C 71.45, H 9.41, N 10.98.
2-Heptyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4k
Mp. 54–588C. Yield: 58%. IR (m cm– 1 KBr): 1711 (C=O), 1506 (C=N),
This work was supported by the National Science Foundation
of China (No. 30460151).
1
1255 (C–O). H-NMR (acetone-d6 ppm): 6.89–8.25 (m, 3H, Ar-H),
4.00 (t, 2H, J = 6.0 Hz, –OCH2), 3.73 (t, 2H, J = 6.5 Hz, –NCH2), 3.00
(t, 2H, J = 6.48 Hz, 5-CH2), 2.87 (t, 2H, J = 6.12 Hz, 4-CH2), 1.11–
2.06 (m, 20H, 106CH2), 0.86–0.92 (m, 6H, 26CH3). MS: m/z 400
[M+1]. Anal. Calcd. for C24H37N3O2: C 72.14, H 9.33, N 10.52.
Found: C 72.41, H 9.20, N 10.32.
References
[1] W. Loscher, Eur. J. Pharmacol. 1998, 342, 1–13.
[2] I. E. Leppik, Epilepsia 1994, 35, S4, 29–40.
2-Benzyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo-
[4,3-a]quinolin-1(2H)-one 4l
[3] E. Perucca, Br. J. Clin. Pharmacol. 1996, 42, 531–543.
[4] Z. Lin, P. K. Kadaba, Med. Res. Rev. 1997, 17, 537–572.
Mp. 100–1058C. Yield: 42%. IR (m cm– 1 KBr): 1712 (C=O), 1506
1
(C=N), 1254 (C–O). H-NMR (acetone-d6 ppm): 6.90–8.26 (m, 8H,
Ar-H), 4.05 (t, 2H, J = 6.4 Hz, –OCH2), 3.40 (t, 2H, J = 7.2 Hz, –NCH2),
2.98 (t, 2H, J = 6.0 Hz, 5-CH2), 2.84 (t, 2H, J = 6.3 Hz, 4-CH2), 1.16–
2.01 (m, 10H, 56CH2), 0.86–0.94 (m, 6H, 26CH3). MS: m/z 392
[M+1]. Anal. Calcd. for C24H29N3O2: C 73.63, H 7.47, N 10.73.
Found: C 73.33, H 7.70, N 10.59.
[5] Y. A. Al-Soud, N. A. Al-Masoudi, Ael-R. Ferwanah, Bioorg.
Med. Chem. 2003, 1, 1701–1708.
[6] Z. S. Quan, J. M. Wang, J. R. Rho, K. C. Kwak, et al., Bull.
Kor. Chem. Soc. 2005, 26, 1757–1760.
[7] L. J. Cui, Z. F. Xie, H. R. Piao, G. Li, et al., Biol. Pharm. Bull.
2005, 28, 1216–1220.
Pharmacology
[8] Z. F. Xie, K. Y. Chai, H. R. Piao, K. C. Kwak, Z. S. Quan,
The MES test, sc-PTZ test, and rotarod test were carried out by
the Antiepileptic Drug Development Program (ADD), Epilepsy
Branch, National Institutes of Health, Bethesda, MD, USA
[13, 14]. All compounds were tested for anticonvulsant activities
with C57B/6 mice in the 18–25 g-weight range purchased from
the Laboratory of Animal Research, College of Pharmacy, Yan-
bian University. The tested compounds were dissolved in poly-
ethylene glycol-400. In phase-I screening (Table 1) each com-
pound was administered at three dose levels (30, 100, and
300 mg/kg ip, to a total of six mice, using two for each dose) with
anticonvulsant activity and neurotoxicity assessed at intervals
of 30 min and 4 h after administration. Anticonvulsant efficacy
was measured in the MES test and the sc-PTZ test. In the MES
test, 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. Abolition of the hind-leg tonic-extensor com-
Bioorg. Med. Chem. Lett. 2005, 15, 4803–4805.
[9] H. G. Jin, X.Y. Sun, K. Y. Chai, H. R. Piao, Z. S. Quan, Bio-
org. Med. Chem. 2006, 14, 6868–6873.
[10] R. Gitto, V. Orlando, S. Quartarone, G. De Sarro, et al., J.
Med. Chem. 2003, 46, 3758–3761.
[11] M. Zappala, R. Gitto, F. Bevacqua, S. Quartarone, et al., J.
Med. Chem. 2000, 43, 4834–4839.
[12] A. Chimirri, F. Bevacqua, R. Gitto, S. Quartarone, et al.,
Med. Chem. Res. 1999, 9, 203–212.
[13] R. J. Krall, J. K. Penry, B. G. White, H. J. Kupferberg, E. A.
Swinyard, Epilepsia 1978, 19, 409–428.
[14] R. J. Poter, J. J. Cereghino, G. D. Gladding, B. J. Hessie, et
al., Cleveland Clin. Q. 1984, 51, 293–305.
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