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Synthesis of 2-Substituted-7-heptyloxy-45-dihydro-[124]-triazolo[43-a]quinolin-12H-ones with Anticonvulsant Activity.

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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 synthesized. 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-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.
Keywords: Anticonvulsant / MES / Quinoline / Synthesis / Triazole /
Received: May 17, 2007; accepted: June 1, 2007
DOI 10.1002/ardp.200700106
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, however, also cause notable adverse side effects such as
drowsiness, ataxia, gastrointestinal disturbance, hepatotoxicity, megaloblastic anemia [2 – 4], and even life
threatening conditions [5]. Research to find more effective and safer antiepileptic drugs is therefore imperative
and challenging in medicinal chemistry.
In our previous work, a series of derivatives of 6-alkoxy3,4-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-
Correspondence: Zhe-Shan Quan, College of Pharmacy, Yanbian University, No. 121, JuZi Street, Yanji City, Jilin Province 133000, P. R. China.
E-mail: e-mail: zsquan@ybu.edu.cn
Fax: +86 433 2660-568
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2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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 anticonvulsant 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]triazolo[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 7alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)one was synthesized and tested for anticonvulsant activities [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.
In the present study, we report the synthesis and anticonvulsant activities of 2-substituted-7-heptyloxy-4,5dihydro-[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-
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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 synthesized compounds were confirmed by IR, 1H-NMR, MS, and
elemental analysis. The anticonvulsant activity was evaluated by using the maximal electroshock (MES) test and
the subcutaneous pentylenetetrazole (sc-PTZ) test. Neurotoxicity was evaluated by using the rotarod test.
Results and discussion
Synthesis
Target compounds were prepared along the reaction
sequence in Scheme 1. Compound 1 was synthesized
using the method described in a former paper of our
group [6]. Then, 6-hydroxy-3,4-dihydro-2(1H)-quinolione
and 1-bromoheptane reacted in the solution of potassium carbonate methanol and produced the compound
1. Compound 1 then reacted with phosphorous pentasulfide in acetonitrile in the presence of triethylamine
under the protection of nitrogen [7] and the resulting
compound 2 reacted further with methyl hydrazine carboxylate in cyclohexanol to produce compound 3 according to the method mentioned in references [9 – 12]. At
last, compounds 4a – l were obtained through an acylation or alkylation reaction of compound 3 with acyl
chloride or alkyl halides, respectively.
Pharmacological evaluations
Pharmacological tests of the 2-substituted-7-heptyloxy4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-1(2H)-ones
(4a – l) were conducted at the epilepsy branch of the
National Institute of Neurological Disorders and Stroke
(NINDS) following the protocol adopted by the Antiepileptic Drug Development (ADD) program [13 – 14].
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
of 300 mg/kg. However, none of the 12 compounds exhibited any potency to the convulsion induced by sc-PTZ at a
dose of 300 mg/kg; this was consistent with the leading
compound 7-alkoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2H)-one [9], which, as well, had not exhibited any
potency to the convulsion induced by sc-PTZ at a dose of
300 mg/kg.
As a result of preliminary screening, compounds 4a,
4b, 4f, and 4h were then subjected to phase-II trials for
quantification of their anticonvulsant activity and neurotoxicity in mice. This phase provides an evaluation of the
ED50 and TD50 values. The 95%-confidence interval, slope
of the regression line, and SE of the slope were then calculated. These data are shown in Table 2, which also
includes comparisons with marketed antiepileptic drugs
phenytoin and carbamazepine. As shown in Table 2, compounds 4a, 4b, and 4f displayed excellent anticonvulsant
activity in MES test, with ED50 values of 7.2 mg/kg,
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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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
Table 1. Phase-I anticonvulsant and toxicity data in mice (ip).
MESa)
Com- R
pound
4a
4b
4c
4d
4e
4f
4g
4h
4i
4j
4k
4l
-COCH3
-COC2H5
n-COC4H9
n-COC5H11
n-COC6H13
-COPh
-C2H5
n-C3H7
n-C4H9
n-C6H13
n-C7H15
-CH2Ph
Sc-PTZb)
Table 2. Phase II quantitative anticonvulsant data in mice (test
drug administered ip).
Toxicity
Compound
0.5h
4h
0.5h
4h
0.5h
4h
30
30
300
300
300
30
300
100
300
300
300
300
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
– c)
–
–
–
–
–
–
–
–
–
–
–
100
–
300
300
100
300
300
300
300
300
300
100
–
–
–
–
–
–
–
–
–
–
–
–
All of tested compounds were dissolved in polyethylene glycol400.
a)
The maximal electroshock test was induced after 30 min past
administration of the tested compounds.
b)
Subcutaneous pentylenetetrazole (85 mg/kg) 30 min after the
tested compounds were administrated.
c)
– = No activity at 300 mg/kg.
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 carbamazepine. Furthermore, the two compounds exhibited
weak neurotoxicity. The PI value of compound 4b is 39,
which is higher than that of the reference drugs phenytoin 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 anticonvulsant 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-propionyl-substituted group) could be considered the potentially most useful and safe therapeutic compound with
ED50 = 8.2 mg/kg, TD50 = 318.3 mg/kg and PI = 39.0. Its neurotoxicity was the lowest in all the synthesized compounds and was also markedly lower than that of the
reference drugs phenytoin and carbamazepine.
When compound 3 was acylated at the 2 position with
a big acyl group, such as valeryl, hexanoyl, and heptanoyl, the compounds exhibited markedly reduced activities. In the phase-I pharmacology test, compounds of 4c,
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2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
MES, ED50a)
3
9.8 (8.5 – 11.4)
4a
7.2 (5.2 – 11)
4b
8.2 (5.8 – 12)
4f
11.4 (9.0 – 14.4)
4h
37.8 (24.0 – 60.2)
Phenytoin
9.5 (8.0 – 10.5)
Carbamazepine 8.8 (5.5 – 14.1)
a)
b)
c)
Tox, TD50b)
PIc)
204.6 (170.5 – 245.4)
88.0 (58 – 120)
318.3 (217 – 450)
289.2 (200 – 414)
122.8 (117 – 129)
65.5 (52.5 – 72.9)
71.6 (45.9 – 135.0)
20.8
12.2
39.0
25.4
3.25
6.9
8.1
Dose measured in mg/kg.
PI = TD50/ED50.
Minimal neurotoxicity was determined by the rotarod test
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 anticonvulsant 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.
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 compounds 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.
Conclusions
A new series of anticonvulsant compounds, 2-substituted-7-heptyloxy-4,5-dihydro- [1,2,4]triazolo[4,3-a]quinolin-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[4,3a]quinoline-1(2H)-one 3 at position 2 – and the acyl group
was small – the anticonvulsant activities became stronger. 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 neurotoxicity was the lowest in all the synthesized compounds
and was also markedly lower than reference drugs phenytoin 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.
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C.-X. Wei et al.
Experimental
Chemistry
Melting points were determined in open capillary tubes and
were uncorrected. IR spectra were recorded (in KBr) on a FTIR1730 (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).
General procedure for the preparation of 2-Acyl-7heptyloxy-4, 5-dihydro-[1,2,4]triazolo[4,3-a]quinoline1(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-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, 5CH2), 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.
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),
1631(C=O), 1504 (C=N), 1256 (C–O). 1H-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-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),
1630(C=O), 1504 (C=N), 1256 (C–O). 1H-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-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 –
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2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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.
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.
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
(C=O), 1504 (C=N), 1251 (C–O). 1H-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, 5CH2), 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.
General procedure for preparation of 2-Alkyl-7-heptyloxy4,5-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-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),
1255 (C–O). 1H-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-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),
1253 (C–O). 1H-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.
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Arch. Pharm. Chem. Life Sci. 2007, 340, 491 – 495
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),
1254 (C–O). 1H-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.
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),
1256 (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 = 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),
1255 (C–O). 1H-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.
2-Benzyl-7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinolin-1(2H)-one 4l
Mp. 100 – 1058C. Yield: 42%. IR (m cm – 1 KBr): 1712 (C=O), 1506
(C=N), 1254 (C–O). 1H-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.
Triazoloquinolin-1(2H)-ones as Anticonvulsant
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 administration of the tested compound. Anticonvulsant drug-induced
neurologic deficit was detected in mice using the rotarod ataxia
test.
The pharmacological parameters estimated in phase-I screening 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 intraperitoneal doses of the tested drug until at least three points were
established in the range of 10 – 90% seizure protection or minimal 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.
This work was supported by the National Science Foundation
of China (No. 30460151).
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The MES test, sc-PTZ test, and rotarod test were carried out by
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