Synthesis and anticonvulsant activity of 1-formamide-triazolo[4,3-a] quinoline derivatives

Article abstract of DOI:10.1007/s12272-010-0502-0

Using 6-hydroxy-3,4-dihydro-2(1H)-quinolone as the starting material, a series of 1-formamide-triazolo[4, 3-a]quinoline derivatives (6a-6n) was synthesized, the anticonvulsant effect and neurotoxicity of the compounds was calculated with maximal electrosh

Full text of DOI:10.1007/s12272-010-0502-0

Arch Pharm Res Vol 33, No 5, 655-662, 2010
DOI 10.1007/s12272-010-0502-0
Synthesis and Anticonvulsant Activity of 1-Formamide-triazolo[4,3-
a]quinoline Derivatives
Cheng-Xi Wei1, 2, Xian-Qing Deng2, Kyu-Yun Chai3, Zhi-Gang Sun1, and Zhe-Shan Quan2
1Institute of Neurosurgery, Inner Mongolia University for Nationalities, Tongliao, Inner Mongolia Autonomous Region
2
3
028007, China, College of Pharmacy, Yanbian University, Yanji, Jilin, 133000, China, and Department of Chemistry,
Wonkwang University, Iksan 570-749, Korea
(Received November 16, 2009/Revised February 2, 2010/Accepted February 2, 2010)
Using 6-hydroxy-3,4-dihydro-2(1
H)-quinolone as the starting material, a series of 1-forma-
mide-triazolo[4, 3- ]quinoline derivatives (6a-6n) was synthesized, the anticonvulsant effect
a
and neurotoxicity of the compounds was calculated with maximal electroshock test and
rotarod tests with intraperitoneally injected in KunMing mice. The results demonstrated that
compound 7-(hexyloxy)-4,5-dihydro-[1,2,4] triazolo[4,3-a]quinoline-1-carboxamide (6d) was the
most active one and also had the lowest toxicity. In the anti-maximal electroshock potency
test, it showed median effective dose (ED50) of 30.1 mg/kg, median toxicity dose (TD50) of 286
mg/kg, and the protective index of 9.5 which is greater than the reference drug carbamazepine
with the protective index value of 6.0.
Key words: Synthesis, Triazole, Quinoline, Formamide, Anticonvulsant, Toxicity
as 30% of medicated patients have inadequate seizure
control, many antiepileptic drugs have serious side
INTRODUCTION
Epilepsy is a syndrome of different cerebral disor- effects and lifelong medication may be required.
ders of central nervous system (CNS), and it is char- In our ongoing search for new compounds with
acterized by paroxysmal, excessive and hypersynchro- anticonvulsant activity, firstly, we found 7-Alkoxy-3,4-
nous discharges of large numbers of neurons (Gasior dihydro-6-methoxyquinolin-2(1 )-one showed anti-
et al , 1997). Anticonvulsant drugs currently on the convulsant activity (Quan et al, 2005), and the com-
H
.
market are of unsatisfactory effectiveness in seizure pounds incorporated triazole at the first and second
control and cause adverse reactions such as drowsi- position have shown marked anticonvulsant activity in
ness, ataxia, gastrointestinal disturbance, hepatotoxi- the maximal electroshock (MES) test (Cui et al., 2005;
city and megaloblastic anemia (Leppik, 1994; Perucca, Xie et al., 2005; Sun et al., 2006; Wei et al., 2007).
1996; Lin and Kadaba, 1997), and even life threaten-
In pursuing our research in the area of anticon-
ing conditions (Al-Soud et al., 2003). In recent years, vulsant activity, compared with the anticonvulsant
the field of antiepileptic drug development is quite drugs, we found that most of them have a carbox-
dynamic, affording many promising research oppor- amide group, for example (Fig. 1), the traditional anti-
tunities. However, current therapy is directed towards convulsant drug Cabamazepine and the new anticon-
reducing seizure frequency. Unfortunately, as many vulsant drug Rufinamide, and so on. It inferred that
carboxamide group was the key group, it may relate to
the acceptor of anticonvulsant function. But there was
Correspondence to: Zhi-Gang Sun, Institute of Neurosurgery,
no report about anticonvulsant activity of the carbox-
amide group linked to the triazolo[4,3-
]quinoline de-
Inner Mongolia University for Nationalities, Tongliao, Inner
Mongolia Autonomous Region 028007, China
E-mail: sunzhigang101@yahoo.cn
Zhe-Shan Quan, College of Pharmacy, Yanbian University,
Yanji, Jilin, 133000, China
a
rivatives, so in this paper, we report the chemical and
anticonvulsant properties of 1-formamide-triazolo[4,3-
a]quinoline derivatives (6a-6n).
Tel & Fax: 86-433-2660606
E-mail: zsquan@ybu.edu.cn
655

656
C.-X. Wei et al.
the solvent under reduced pressure, the residue was
dissolved in dichloromethane (30 mL), washed with
water (3*30 mL) and dried over anhydrous MgSO4.
Evaporation of the solvents gave a crude product,
which was purified by silica gel column chroma-
tography with dichloromethane to a light yellow solid
3a-3n. Yield 70-90%.
6-Alkoxy-3,4-dihydro-2-hydrazine-1H-quinolines
(4a-4n)
A solution of compounds 3a-3n (5 mmol) in 30 mL
THF was added dropwise to a solution of hydrazine
hydrate (25 mmol) in 20 mL THF at room temper-
ature, then the mixture was stirred and heated at
60oC 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 0oC for the next step. Yield 35-
55%.
Fig. 1. The structure of Rufinamide Cabamazepine and 6a-
6n
Ethyl 7-substituted-4,5-dihydro-[1,2,4]triazolo[4,
MATERIALS AND METHODS
3-a]quinoline-1-carboxylate (5a-5n)
Melting points were determined in open capillary
The 6-alkoxy-3,4-dihydro-2-hydrazine-1H-quinoline
1
tubes and were uncorrected. H-NMR spectra were (4 mmol) was added to diethyl oxalate (30 mL), then
measured on a AV-300 (Bruker), and all chemical shifts the mixture was stirred and refluxed for 1h. After the
were given in ppm relative to tetramethysilane. Mass reaction, the solvent was evaporated under reduced
spectra were measured on an HP1100LC (Agilent pressure, the products were recrystallized from petro-
Technologies). Elemental analyses were performed on leum ether with a moderate yield. And then kept for
a 204Q CHN (Perkin Elmer). Microanalyses of C, N the next step.
and H were performed using a Heraeus CHN Rapid
Analyzer. The major chemicals were purchased from Ethyl 7-propoxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]
Alderich Chemical Corporation. All other chemicals quinoline-1-carboxylate (5a)
1
were of analytical grade.
Yield 87.6%, mp 103-105oC; H-NMR (CDCl3, 300
MHz): 7.64 (d, 1H,
2H, 6- and 8-Ar-H), 4.51 (q, 2H,
(10 mmol) and appropriate 3.94 (t, 2H, = 6.5 Hz, OCH2), 3.15 (t, 2H,
= 6.8 Hz, CH2), 1.69-1.73 (m, 2H,
= 7.1 Hz, CH3), 1.04 (t, 3H, = 7.4
J
= 8.6 Hz, 9-Ar-H), 6.83-6.86 (m,
= 7.1 Hz, COOCH2),
= 6.8 Hz,
J
6-Alkoxy-3,4-dihydro-2(1H)-quinolones (2)
The starting compound
1
J
J
alkyl halide (10 mmol) were added to a solution of CH2), 2.96 (t, 2H,
sodium hydroxide in absolute methanol with stirring CH2), 1.47 (t, 3H,
J
J
J
and refluxing for 3 h. The reaction mixture was cooled Hz, CH3). IR (KBr) 1725 cm-1. MS m/z 302 (M+1).
and then poured into ice water. The white precipitate Anal. Calcd. for C16H19N3O3: C, 63.77; H, 6.36; N,
was collected through filtration and dried in a vacuum 13.94. Found: C, 63.71; H, 6.56; N, 13.91.
to produce the crude products 2a-2n with a moderate
yield (65-90%) and sufficient purity for the next stage.
Ethyl 7-butoxy-4,5-dihydro-[1,2,4]triazolo[4,3-
a]
quinoline-1-carboxylate (5b)
Yield 89.5%, mp 97-101oC; 1H-NMR (CDCl3, 300 MHz):
6-Alkoxy-3,4-dihydro-1H-quinoline-2-thiones
7.65 (d, 1H,
J
= 9.2 Hz, 9-Ar-H), 6.82-6.87 (m, 2H, 6-
= 7.1 Hz, COOCH2), 3.99
= 6.4 Hz, OCH2), 3.16 (t, 2H, = 7.0 Hz,
ice bath, P2S5 (1.2 eq), divided into multiple portions, CH2), 2.97 (t, 2H, = 7.0 Hz, CH2), 1.59-1.80 (m, 4H,
was added one portion at a time after the previous (CH2)2), 1.42 (t, 3H, = 7.1 Hz, CH3), 0.99 (t, 3H,
portion had completely dissolved. Then, 6-alkoxy-3,4- 7.3 Hz, CH3). IR (KBr) 1726 cm-1. MS m/z 316 (M+1).
dihydro-2(1 )-quinolone was added and the solution Anal. Calcd. for C17H21N3O3: C, 64.74; H, 6.71; N,
was refluxed for 3 h under nitrogen. After removing 13.32. Found: C, 64.61; H, 6.68; N, 13.50.
(3a-3n)
To a stirring mixture of acetonitrile and triethy- and 8-Ar-H), 4.52 (q, 2H,
lamine in a three-necked round-bottomed flask in an (t, 2H,
J
J
J
J
J
J =
H

Triazolo[4,3-a]quinoline
657
Ethyl 7-(pentyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3- CH2O), 4.51 (q, 2H,
]quinoline-1-carboxylate (5c)
Yield 90.8%, mp 98-100oC; 1H-NMR (CDCl3, 300 3H,
MHz): 7.63 (d, 1H, = 8.7 Hz, 9-Ar-H), 6.81-6.85 (m, (M+1). Anal. Calcd. for C20H19N3O3: C, 68.75; H, 5.48;
2H, 6- and 8-Ar-H), 4.51 (q, 2H, = 7.1 Hz, COOCH2), N, 12.03. Found: C, 68.61; H, 5.51; N, 12.24.
3.97 (t, 2H, = 6.5 Hz, OCH2), 3.15 (t, 2H, = 6.8 Hz,
CH2), 2.96 (t, 2H, = 6.8 Hz, CH2), 1.56-1.79 (m, 6H, Ethyl
(CH2)3), 1.38 (t, 3H, = 7.1 Hz, CH3), 0.93 (t, 3H, triazolo[4,3-
6.8 Hz, CH3). IR (KBr) 1728 cm-1. MS m/z 330 (M+1). Yield 88.7%, mp 122-125oC; H-NMR (CDCl3, 300
Anal. Calcd. for C18H23N3O3: C, 65.63; H, 7.04; N, MHz): 8.05 (d, 1H, = 8.7 Hz, 9-Ar-H), 6.97-7.48 (m,
12.76. Found: C, 65.49; H, 7.14; N, 12.81. 6H, Ar-H), 5.16 (s, 2H, CH2O), 4.51 (q, 2H, = 7.1 Hz,
COOCH2), 3.15 (t, 2H, = 6.8 Hz, CH2), 2.97 (t, 2H,
Ethyl 7-(hexyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3- = 6.8Hz, CH2). 1.46 (t, 3H, = 7.1 Hz, CH3). IR (KBr)
]quinoline-1-carboxylate (5d)
1727 cm-1. MS m/z 368 (M+1). Anal. Calcd. for
Yield 92.3%, mp 58-70oC; H-NMR (CDCl3, 300 MHz): C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C,
7.64 (d, 1H, = 9.1 Hz, 9-Ar-H), 6.81-6.85 (m, 2H, 6- 65.61; H, 5.12; N, 11.41.
and 8-Ar-H), 4.52 (q, 2H, = 7.1 Hz, COOCH2), 3.98
(t, 2H, = 6.5 Hz, OCH2), 3.16 (t, 2H, = 6.9 Hz, Ethyl
CH2), 2.97 (t, 2H, = 6.9 Hz, CH2), 1.38-1.78 (m, 8H, triazolo[4,3-
(CH2)4), 1.35 (t, 3H, = 7.1 Hz, CH3), 0.92 (t, 3H,
Yield 87.8%, mp 126-128oC; 1H-NMR (CDCl3, 300
6.7 Hz, CH3). IR (KBr) 1730 cm-1. MS m/z 344 (M+1). MHz): 7.68 (d, 1H,
= 9.0 Hz, 9-Ar-H), 7.03-7.42 (m,
Anal. Calcd. for C19H25N3O3: C, 66.45; H, 7.34; N, 6H, Ar-H), 5.10 (s, 2H, CH2O-), 4.52 (q, 2H, = 7.0 Hz,
12.24. Found: C, 66.54; H, 7.46; N, 12.33. COOCH2), 3.17 (t, 2H, = 6.9 Hz, CH2), 2.97 (t, 2H,
= 6.9 Hz, CH2), 1.48 (t, 3H, = 7.0 Hz, CH3). IR (KBr)
Ethyl 7-(heptyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3- 1725 cm-1. MS m/z 368 (M+1). Anal. Calcd. for
]quinoline-1-carboxylate (5e) C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C,
Yield 91%, mp 77-79oC; H-NMR (CDCl3, 300 MHz): 65.59; H, 5.08; N, 11.36.
7.64 (d, 1H, = 9.1 Hz, 9-Ar-H), 6.82-6.87 (m, 2H, 6-
and 8-Ar-H), 4.52 (q, 2H, = 7.1 Hz, COOCH2), 3.98 Ethyl 7-(4-fluorobenzyloxy)-4,5-dihydro-[1,2,4]
(t, 2H, = 6.5 Hz, OCH2), 3.16 (t, 2H, = 6.9 Hz, triazolo[4,3- ]quinoline-1-carboxylate (5j)
CH2), 2.97 (t, 2H,
= 6.9 Hz, CH2), 1.39-1.88 (m, 10H, Yield 87.8%, mp 160-163oC; H-NMR (CDCl3, 300
(CH2)5), 1.32 (t, 3H, = 7.1 Hz, CH3), 0.92 (t, 3H, MHz): 7.68 (d, 1H, = 9.0 Hz, 9-Ar-H), 6.92-7.36 (m,
6.8 Hz, CH3). IR (KBr) 1729 cm-1. MS m/z 344 (M+1). 6H, Ar-H), 5.10 (s, 2H, CH2O), 4.52 (q, 2H,
= 7.0 Hz,
Anal. Calcd. for C19H25N3O3: C, 66.45; H, 7.34; N, COOCH2), 3.17 (t, 2H, = 6.9 Hz, CH2), 2.97 (t, 2H,
12.24. Found: C, 66.54; H, 7.46; N, 12.33. = 6.9 Hz, CH2), 1.48 (t, 3H, = 7.0 Hz, CH3). IR (KBr)
1728 cm-1. MS m/z 368 (M+1). Anal. Calcd. for
Ethyl 7-(octyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3- C20H18FN3O3: C, 65.39; H, 4.94; N, 11.44. Found: C,
]quinoline-1-carboxylate (5f) 65.59; H, 5.08; N, 11.36.
J
= 7.1 Hz, COOCH2), 3.15 (t, 2H,
a
J
= 6.9 Hz, CH2), 2.96 (t, 2H,
J
J = 6.9 Hz, CH2), 1.47 (t,
= 7.1 Hz, CH3). IR (KBr) 1725 cm-1. MS m/z 350
J
J
J
J
J
7-(2-fluorobenzyloxy)-4,5-dihydro-[1,2,4]
]quinoline-1-carboxylate (5h)
J
J
=
a
1
J
J
J
J
J
a
1
J
J
J
J
7-(3-fluorobenzyloxy)-4,5-dihydro-[1,2,4]
]quinoline-1-carboxylate (5i)
J
a
J
J =
J
J
J
J
J
a
1
J
J
J
J
a
1
J
J
J=
J
J
J
J
J
a
Yield 91%, mp 73-75oC; H-NMR (CDCl3, 300 MHz):
7.64 (d, 1H, = 9.1 Hz, 9-Ar-H), 6.82-6.85 (m, 2H, Ar- Ethyl 7-(2-chlorobenzyloxy)-4,5-dihydro-[1,2,4]
H), 4.52 (q, 2H, = 7.1 Hz, COOCH2), 3.98 (t, 2H, triazolo[4,3- ]quinoline-1-carboxylate (5k)
6.5 Hz, OCH2), 3.16 (t, 2H,
= 6.9 Hz, CH2), 2.97 (t, Yield 88%, mp 117-119oC; 1H-NMR (CDCl3, 300 MHz):
2H, = 6.9 Hz, CH2), 1.43-1.78 (m, 12H, (CH2)6), 1.33 8.05 (d, 1H, = 8.7 Hz, 9-Ar-H), 6.97-7.49 (m, 6H, Ar-
(t, 3H, = 7.1 Hz, CH3), 0.92 (d, 3H, = 6.7 Hz, CH3). H), 5.16 (s, 2H, CH2O), 4.52 (q, 2H, = 7.0 Hz,
IR (KBr) 1724 cm-1. MS m/z 344 (M+1). Anal. Calcd. COOCH2), 3.15 (t, 2H,
= 6.9 Hz, CH2), 2.97 (t, 2H,
1
J
J
J
=
a
J
J
J
J
J
J
J
J
for C19H25N3O3: C, 66.45; H, 7.34; N, 12.24. Found: C, = 6.9 Hz, CH2). 1.48 (t, 3H,
66.54; H, 7.46; N, 12.33.
J = 7.0 Hz, CH3). IR (KBr)
1725 cm-1. MS m/z 384 (M+1). Anal. Calcd. for
C20H18ClN3O3: C, 62.58; H, 4.73; N, 10.95. Found: C,
Ethyl 7-(benzyloxy)-4,5-dihydro-[1,2,4]triazolo 62.47; H, 4.89; N, 10.99.
[4,3- ]quinoline-1-carboxylate (5g)
Yield 87.6%, mp 114-118oC; H-NMR (CDCl3, 300 Ethyl 7-(3-chlorobenzyloxy)-4,5-dihydro-[1,2,4]
MHz): 7.66 (d, 1H, = 8.7 Hz, 9-Ar-H), 7.33-7.45 (m, triazolo[4,3- ]quinoline-1-carboxylate (5l)
5H, Ar-H), 6.85-6.94 (m, 2H, Ar-H), 5.09 (s, 2H, Yield 91%, mp 115-117oC; 1H-NMR (CDCl3, 300 MHz):
a
1
J
a

658
C.-X. Wei et al.
7.68 (d, 1H,
5.10 (s, 2H, CH2O), 4.52 (q, 2H,
3.17 (t, 2H,
J
= 9.0 Hz, 9-Ar-H), 6.92-7.36 (m, 6H, Ar-H), 7-Butoxy-4,5-dihydro-[1,2,4]triazolo[4,3-
= 7.0 Hz, COOCH2), line-1-carboxamide (6b)
= 6.9 Hz, CH2), 2.97 (t, 2H,
= 6.9 Hz, Yield 88.9%, mp 207-211oC; 1H-NMR (CDCl3, 300
CH2), 1.48 (t, 3H, = 9.7 Hz, 9-Ar-H), 7.73 (s, 1H,
= 7.1 Hz, CH3). IR (KBr) 1729 cm-1. MHz): 7.95 (d, 1H,
MS m/z 384 (M+1). Anal. Calcd. for C20H18ClN3O3: C, NH), 6.81-6.85 (m, 2H, 6- and 8-Ar-H), 6.14 (s, 1H,
a]quino-
J
J
J
J
J
62.58; H, 4.73; N, 10.95. Found: C, 62.49; H, 4.79; N, NH), 3.98 (t, 2H,
11.00. Hz, CH2), 2.96 (t, 2H,
2H, CH2), 1.43-1.56 (m, 2H, CH2), 0.98 (t, 3H,
J
= 6.4 Hz, CH2), 3.13 (t, 2H,
J
= 6.7
J
= 6.7 Hz, CH2), 1.73-1.82 (m,
J
= 7.3
Ethyl 7-(4-chlorobenzyloxy)-4,5-dihydro-[1,2,4] Hz, CH3). IR (KBr) 1688 cm-1. MS m/z 287 (M+1).
triazolo[4,3-
Yield 89.7%, mp 152-154oC; 1H-NMR (CDCl3, 300 19.57. Found: C, 62.73; H, 6.51; N, 19.70.
MHz): 7.67 (d, 1H, = 8.4 Hz, 9-Ar-H), 7.36 (d, 2H,
= 9.0 Hz, 2’, 6’-Ar-H), 7.15 (s, 1H, 6-Ar-H), 7.08 (d, 2H, 7-(Pentyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-
= 9.0 Hz, 3’, 5’-Ar-H), 6.99 (d, 1H, = 8.4 Hz, 8-Ar- noline-1-carboxamide (6c)
H), 5.06 (s, 2H, CH2O), 4.52 (q, 2H,
= 7.1 Hz, Yield 91.4%, mp 160-162oC; 1H-NMR (CDCl3, 300
COOCH2),3.16 (t, 2H, = 6.8 Hz, CH2), 2.97 (t, 2H, MHz): 7.99 (d, 1H, = 8.6 Hz, 9-Ar-H), 7.64 (s, 1H,
= 6.8 Hz, CH2), 1.47 (t, 3H, = 7.1 Hz, CH3). IR (KBr) NH), 6.84-6.89 (m, 2H, 6- and 8-Ar-H), 6.11 (s, 1H,
1727 cm-1. MS m/z 384 (M+1). Anal. Calcd. for NH), 3.96 (t, 2H,
= 6.4 Hz, CH2), 3.13 (t, 2H, = 6.7
C20H18ClN3O3: C, 62.58; H, 4.73; N, 10.95. Found: C, Hz, CH2), 2.96 (t, 2H, = 6.7 Hz, CH2), 1.29-1.88 (m,
62.50; H, 4.87; N, 10.91. 6H, (CH2)3), 0.93 (t, 3H, = 6.6 Hz, CH3). IR (KBr) 1692
cm-1. MS m/z 301 (M+1). Anal. Calcd. for C16H20N4O2:
Ethyl 7-(4-methylbenzyloxy)-4,5-dihydro-[1,2,4] C, 63.98; H, 6.71; N, 18.65. Found: C, 63.75; H, 6.76;
a]quinoline-1-carboxylate (5m)
Anal. Calcd. for C15H18N4O2: C, 62.92; H, 6.34; N,
J
J
a]qui-
J
J
J
J
J
J
J
J
J
J
J
triazolo[4,3-
Yield 89.8%, mp 144-146oC; 1H-NMR (CDCl3, 300
MHz): 7.65 (d, 1H, = 8.6 Hz, 9-Ar-H), 7.31 (d, 2H,
a
]quinoline-1-carboxylate (5n)
N, 18.49.
J
J
7-(Hexyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-a]qui-
= 7.9 Hz, 2’, 6’-Ar-H), 7.26 (s, 1H, 6-Ar-H), 7.20 (d, 2H, noline-1-carboxamide (6d)
= 7.9 Hz, 3’, 5’-Ar-H), 6.92 (d, 1H,
= 8.6 Hz, 8-Ar- Yield 87.2%, mp 169-173oC; 1H-NMR (CDCl3, 300
H), 5.05 (s, 2H, CH2O), 4.52 (q, 2H, = 7.2 Hz, MHz): 7.99 (d, 1H, = 8.6 Hz, 9-Ar-H), 7.65 (s, 1H,
COOCH2), 3.16 (t, 2H, = 6.8 Hz, CH2), 2.96 (t, 2H, NH), 6.82-6.86 (m, 2H, 6- and 8-Ar-H), 6.14 (s, 1H,
= 6.8 Hz, CH2), 2.37 (s, 3H, Ph-CH3), 1.47 (t, 3H, NH), 3.96 (t, 2H, = 6.5 Hz, CH2), 3.12 (t, 2H, = 6.8
= 6.8 Hz, CH2), 1.25-1.80 (m,
J
J
J
J
J
J
J
=
J
J
7.2 Hz, CH3). IR (KBr) 1728 cm-1. MS m/z 364 (M+1). Hz, CH2), 2.95 (t, 2H,
J
Anal. Calcd. for C21H21N3O3: C, 69.41; H, 5.82; N, 8H, (CH2)4), 0.92 (t, 3H,
11.56. Found: C, 69.35; H, 5.94; N, 11.49.
J = 7.8 Hz, CH3). IR (KBr) 1675
cm-1. MS m/z 315 (M+1). Anal. Calcd. for C17H22N4O2:
C, 64.95; H, 7.05; N, 17.82. Found: C, 64.76; H, 7.15;
7-Substituted-4,5-dihydro-[1,2,4]triazolo[4,3-a]qui- N, 17.91.
noline-1-carboxamide (6a-6n)
Compounds 5a-5n (3 mmol) were added into ammonia 7-(Heptyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-
(30 mL) respectively, then the mixture was stirred for noline-1-carboxamide (6e)
1h at room temperature. After the reaction, the white Yield 91.4%, mp 169-172oC; 1H-NMR (CDCl3, 300
precipitate was collected through filtration and dried MHz): 7.99 (d, 1H, = 8.6 Hz, 9-Ar-H), 7.64 (s, 1H,
NH), 6.82-6.85 (m, 2H, 6- and 8-Ar- H), 6.11 (s, 1H,
NH), 3.96 (t, 2H, = 6.4 Hz, CH2), 3.13 (t, 2H, = 6.7
Hz, CH2), 2.96 (t, 2H, = 6.7 Hz, CH2), 1.31-1.91 (m,
10H, (CH2)5), 0.93 (t, 3H, J = 6.6 Hz, CH3). IR (KBr)
a]qui-
J
in a vacuum.
J
J
7-Propoxy-4,5-dihydro-[1,2,4]triazolo[4,3-
a]quino-
J
line-1-carboxamide (6a)
Yield 90.5%, mp 207-210oC; 1H-NMR (CDCl3, 300 1685 cm-1. MS m/z 329 (M+1). Anal. Calcd. for
MHz): 7.96 (d, 1H,
NH), 6.93 (s, 1H, NH), 6.81-6.87 (m, 2H, 6- and 8-Ar- 65.81; H, 7.35; N, 17.26.
H), 3.95 (t, 2H, = 6.2 Hz, CH2), 3.12 (t, 2H, = 6.6
= 6.6 Hz, CH2), 1.76-1.82 (m, 7-(Octyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-
= 7.2 Hz, CH3). IR (KBr) 1691 noline-1-carboxamide (6f)
J = 9.3 Hz, 9-Ar-H), 7.75 (s, 1H, C18H24N4O2: C, 65.83; H, 7.37; N, 17.06. Found: C,
J
J
Hz, CH2), 2.98 (t, 2H,
2H, CH2), 1.05 (t, 3H,
J
J
a]qui-
cm-1. MS m/z 273 (M+1). Anal. Calcd. for C14H16N4O2: Yield 86.9%, mp 161-163oC; 1H-NMR (CDCl3, 300
C, 61.75; H, 5.92; N, 20.58. Found: C, 61.52; H, 5.98; MHz): 8.19 (d, 1H,
J = 8.6 Hz, 9-Ar-H), 7.80 (s, 1H,
N, 20.48. NH), 7.01-7.04 (m, 2H, 6- and 8-Ar-H), 6.15 (s, 1H,

Triazolo[4,3-a]quinoline
659
NH), 4.14 (t, 2H,
Hz, CH2), 3.13 (t, 2H,
12H, (CH2)6), 1.05 (d, 3H,
J
= 6.5 Hz, CH2), 3.31 (t, 2H,
J
= 6.9 NH2), 6.85-7.49 (m, 6H, Ar-H), 5.69 (s, 1H, NH2), 5.16
J
= 6.9 Hz, CH2), 1.47-1.98 (m, (s, 2H, CH2O), 3.16 (t, 2H,
J
= 6.9 Hz, CH2), 2.97 (t,
J
= 7.8 Hz, CH3). IR (KBr) 2H, J
= 6.9 Hz, CH2). IR (KBr) 1685 cm-1. MS m/z 355
1683 cm-1. MS m/z 343 (M+1). Anal. Calcd. for (M+1). Anal. Calcd. for C18H15ClN4O2: C, 60.94; H,
C19H26N4O2: C, 66.64; H, 7.65; N, 16.36. Found: C, 4.26; N, 15.79. Found: C, 60.69; H, 4.38; N, 15.88.
66.54; H, 7.75; N, 16.31.
7-(3-Chlorobenzyloxy)-4,5-dihydro-[1,2,4]triazolo
7-Benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]qui- [4,3-
noline-1-carboxamide (6g)
Yield 93.8%, mp 172-174oC; 1H-NMR (CDCl3, 300
Yield 90.9%, mp 217-219oC; 1H-NMR (CDCl3, 300 MHz): 8.06 (d, 1H,
= 9.6 Hz, 9-Ar-H), 7.46 (s, 1H,
MHz): 8.05 (d, 1H, = 8.7 Hz, 9-Ar-H), 7.42 (s, 1H, NH2), 6.92-7.38 (m, 6H, Ar-H), 5.77 (s, 1H, NH2), 5.09
NH), 7.31-7.38 (m, 5H, Ar-H), 6.94 (m, 2H, 6- and 8- (s, 2H, CH2O), 3.15 (t, 2H, = 6.9 Hz, CH2), 2.97 (t,
Ar-H), 5.79 (s, 1H, NH), 5.09 (s, 2H, CH2O), 3.14 (t, 2H,
= 6.9 Hz, CH2). IR (KBr) 1695 cm-1. MS m/z 355
a]quinoline-1-carboxamide (6l)
J
J
J
J
2H,
J = 6.9 Hz, CH2), 2.96 (t, 2H, J = 6.9 Hz, CH2). IR (M+1). Anal. Calcd. for C18H15ClN4O2: C, 60.94; H,
(KBr) 1666 cm-1. MS m/z 321 (M+1). Anal. Calcd. for 4.26; N, 15.79. Found: C, 60.78; H, 4.49; N, 15.89.
C18H16N4O2: C, 67.49; H, 5.03; N, 17.49. Found: C,
67.51; H, 5.23; N, 17.61.
7-(4-Chlorobenzyloxy)-4,5-dihydro-[1,2,4]triazolo
[4,3- ]quinoline-1-carboxamide (6m)
a
7-(2-Fluorobenzyloxy)-4,5-dihydro-[1,2,4]triazolo Yield 92.4%, mp 212-214oC; 1H-NMR (CDCl3, 300
[4,3- ]quinoline-1-carboxamide (6h) MHz): 8.05 (d, 1H, = 8.7 Hz, 9-Ar-H), 7.47 (s, 1H,
Yield 92.4%, mp 190-193oC; 1H-NMR (CDCl3, 300 NH2), 7.28 (d, 2H,
= 7.2 Hz, 2’, 6’-Ar-H), 7.36 (d, 2H,
MHz): 7.67 (d, 1H, = 8.9 Hz, 9-Ar-H), 7.52 (s, 1H, = 7.2 Hz, 3’, 5’-Ar-H), 6.90-6.94 (m, 2H, 6- and 8- Ar-
NH), 7.35-7.47 (m, 4H, Ar-H), 6.93 (m, 2H, 6- and 8- H), 5.80 (s, 1H, NH2), 5.05 (s, 2H, CH2O), 3.14 (t, 2H,
Ar-H), 5.81 (s, 1H, NH), 5.16 (s, 2H, CH2O), 3.16 (t, = 6.9 Hz, CH2), 2.96 (t, 2H, = 6.9Hz, CH2). IR
2H, = 6.9 Hz, CH2), 2.97 (t, 2H, J
= 6.9 Hz, CH2). IR (KBr) 1687 cm-1. MS m/z 355 (M+1). Anal. Calcd. for
a
J
J
J
J
J
J
J
(KBr) 1675 cm-1. MS m/z 339 (M+1). Anal. Calcd. for C18H15ClN4O2: C, 60.94; H, 4.26; N, 15.79. Found: C,
C18H15FN4O2: C, 63.90; H, 4.47; N, 16.56. Found: C, 60.88; H, 4.51; N, 15.87.
63.79; H, 4.56; N, 16.48.
7-(4-Methylbenzyloxy)-4,5-dihydro-[1,2,4]triazolo
7-(3-Fluorobenzyloxy)-4,5-dihydro-[1,2,4]triazolo
[4,3- ]quinoline-1-carboxamide (6i)
Yield 93.8%, mp 206oC; H-NMR (CDCl3, 300 MHz): MHz): 8.02 (d, 1H,
8.06 (d, 1H, = 9.6 Hz, 9-Ar-H), 7.46 (s, 1H, NH2), NH), 7.31 (d, 2H,
6.92-7.36 (m, 6H, Ar-H), 5.77 (s, 1H, NH2), 5.09 (s, 2H, = 7.8 Hz, 3’, 5’-Ar-H), 6.90-6.93 (m, 2H, 6- and 8- Ar-
CH2O), 3.15 (t, 2H, = 6.9 Hz, CH2), 2.97 (t, 2H, H), 6.10 (s, 1H, NH), 5.04 (s, 2H, CH2O), 3.13 (t, 2H,
6.9 Hz, CH2). IR (KBr) 1676 cm-1. MS m/z 339 (M+1). = 6.9 Hz, CH2), 2.95 (t, 2H,
= 6.9 Hz, CH2), 2.57 (s,
Anal. Calcd. for C18H15FN4O2: C, 63.90; H, 4.47; N, 3H, Ph-CH3). MS m/z 335 (M+1). Anal. Calcd. for
[4,3-
Yield 92.3%, mp 184-186oC; 1H-NMR (CDCl3, 300
= 8.4 Hz, 9-Ar-H), 7.63 (s, 1H,
= 7.8 Hz, 2’, 6’-Ar-H), 7.19 (d, 2H,
a]quinoline-1-carboxamide (6n)
a
1
J
J
J
J
J
J
=
J
J
16.56. Found: C, 63.79; H, 4.55; N, 16.63.
C19H18N4O2: C, 68.25; H, 5.43; N, 16.76. Found: C,
68.01; H, 5.55; N, 16.61.
7-(4-Fluorobenzyloxy)-4,5-dihydro-[1,2,4]triazolo
[4,3-a]quinoline-1-carboxamide (6j)
Pharmacology
The evaluation of the anticonvulsant activity follow-
Yield 92.4%, mp 222-224oC; 1H-NMR (CDCl3, 300
MHz): 7.67 (d, 1H,
NH2), 6.85-7.44 (m, 6H, Ar-H), 5.77 (s, 1H, NH2), 5.16 (ADD) of the National Institute of Health following
(s, 2H, CH2O), 3.16 (t, 2H, = 6.9 Hz, CH2), 2.97 (t, previously described testing procedures (USA). Adult
2H,
= 6.9 Hz, CH2). IR (KBr) 1675 cm-1. MS m/z 339 male and female KunMing mice (18-25g) were used as
(M+1). Anal. Calcd. for C18H15FN4O2: C, 63.90; H, experimental animals. Animals of the same age and
J = 8.9 Hz, 9-Ar-H), 7.52 (s, 1H, ed the Anticonvulsant Drug Development Program
J
J
4.47; N, 16.56. Found: C, 63.78; H, 4.56; N, 16.61.
weight were selected, in order to minimize biological
variability. The animals were maintained on a 12 h
light/dark cycle and allowed free access to food and
water, except during the time they were removed from
7-(2-Chlorobenzyloxy)-4,5-dihydro-[1,2,4]triazolo
[4,3-a]quinoline-1-carboxamide (6k)
Yield 92.4%, mp 196-198oC; 1H-NMR (CDCl3, 300 their cages for testing. The test substance was admini-
MHz): 7.67 (d, 1H,
J = 8.9 Hz, 9-Ar-H), 7.49 (s, 1H, stered in 30% polyethylene glycol 400 (PEG) and 10%

660
C.-X. Wei et al.
a: RX/NaOH, CH3CH2OH, ref; b: P2S5, CH3CN/TEA; c: NH2NH2
d: diethyl oxalate, ref; e: NH3 H2O/CH3OH, rt.
·H2O/THF;
·
Scheme 1. The synthesis route
Table I. Phase I: Quantitative anticonvulsant data in
mice (i.p.)
water. The drugs were administered intraperitoneally
(i.p.) in mice in a volume of 0.05 mL/20 g body weight.
MES
MES
Toxicity
Com-
pound
R
MES screening
(50mg/kg) (100mg/kg) (300mg/kg)
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 sec. Protection
against the spread of MES-induced seizures was
defined as the abolition of the hind leg and tonic
maximal extension component of the seizure. At 30
min after the administration of the compounds, the
activities were evaluated in MES test.
5a
5b
5c
5d
5e
5f
5g
5h
5i
n-C3H7
n-C4H9
n-C5H11
n-C6H13
n-C7H15
n-C8H17
-CH2Ph
1/3
3/3
3/3
1/3
1/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
0/3
1/3
2/3
3/3
3/3
3/3
2/3
1/3
1/3
2/3
0/3
0/3
0/3
0/3
0/3
2/3
3/3
3/3
3/3
2/3
1/3
0/3
0/3
2/3
1/3
1/3
0/3
0/3
1/3
3/3
3/3
3/3
3/3
3/3
3/3
2/3
3/3
3/3
2/3
2/3
1/3
0/3
1/3
1/3
2/3
2/3
3/3
2/3
3/3
2/3
1/3
2/3
2/3
2/3
2/3
1/3
3/3
2/3
2/3
1/3
1/3
2/3
3/3
2/3
2/3
2/3
3/3
2/3
2/3
2/3
3/3
-CH2Ph (
-CH2Ph (3-F)
-CH2Ph ( -F)
-CH2Ph ( -Cl)
2-F)
Rotarod test
5j
5k
5l
4
At 30 min after the administration of the com-
pounds, the animals were placed and tested on a 1-in.
diameter; knurled plastic rod rotating at 6 rpm for 1
min. The abilities of animals to maintain balance were
tested. Neurotoxicity was indicated by the inability of
the animal to maintain the equilibrium in each of
three trials. The results are tabulated in Table I and
Table II.
2
-CH2Ph (3-Cl)
-CH2Ph (4-Cl)
5m
5n -CH2Ph (4-CH3)
6a
6b
6c
6d
6e
6f
6g
6h
6i
n-C3H7
n-C4H9
n-C5H11
n-C6H13
n-C7H15
n-C8H17
-CH2Ph
RESULTS
A series of Triazolo[4,3-a]quinoline derivatives (5a-
5n and 6a-6n) were synthesized and tested as anti-
convulsant agents in KunMing mice against the
maximal electroshock (MES) test, the results showed
that the series of derivatives exhibit different anticon-
vulsant activities. No compound exhibited better anti-
convulsant activity than reference drugs carbamaze-
pine. The results demonstrated that compound 7-
(hexyloxy)-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoline-
-CH2Ph (
-CH2Ph (3-F)
-CH2Ph ( -F)
-CH2Ph ( -Cl)
2-F)
6j
6k
6l
4
2
-CH2Ph (3-Cl)
-CH2Ph (4-Cl)
6m
6n -CH2Ph (4-CH3)
1-carboxamide (6d) was the most active one and also it showed median effective dose (ED50) of 30.1 mg/kg,
had the lowest toxicity. In the anti-MES potency test, median toxicity dose (TD50) of 286 mg/kg, and the

Triazolo[4,3-a]quinoline
661
Table 2. Phase II: Quantitative anticonvulsant data in mice (test drug administered i.p.)a
b
c
Compound
ED50
TD50
PI (TD50/ED50)
5b
5c
6b
6c
6d
6e
6f
6i
d33.9 (21.3-49.8)d
36.8 (11.9-56.9)
43.0 (22.5-79.6)
35.5 (18.6-57.3)
30.1 (19.0-48.2)
29.8 (18.2-41.0)
43.2 (26.4-67.5)
39.6 (25.6-51.6)
10.1 (6.01-22.1)
213 (108.2-486.6)
224 (132.6-368.0)
216 (116.8-356.8)
256 (153.2-452.3)
286 (188.6-406.2)
224 (142.6-422.2)
182 (101.2-296.7)
191 (106.1-360.0)
69.1 0(39.2-110.0)
6.3
6.1
5.0
7.2
9.5
7.5
4.2
4.8
6.0
Carbamazepine
aAll the tested compounds were dissolved in polyethylene glycol-400.
bThe dose measured in mg/kg.
cMinimal neurotoxicity was determined by the rotarod test 30 min after the tested compounds were administrated.
d95% confidence limits given in parentheses.
protective index (PI) of 9.5 which is greater than the 100% protection. Compounds 5b
,
5c and 6c-6e exhi-
reference drug carbamazepine with PI value of 6.0.
bited 100% protection after drug administration at 50
mg/kg dose. All the compounds showed different
neurotoxicity at the maximum dose administered (300
mg/kg).
DISCUSSION
And compounds 6b, 6f and 6i were showed more
Chemistry
Target compounds 6a-6n were synthesized accord- than half anti-MES activity. All the compounds
ing to Scheme 1. Compounds 4a-4n were prepared showed different neurotoxicity at the maximum dose
according to the reference method (Sun et al., 2009). administered (300 mg/kg).
Compound 5a-5n were prepared according to the
As a result of preliminary screening, compounds 5b
,
reference method (Zimmer et al , 1975). 4a-4n were 5c
.
,
6b-6f and 6i were then subjected to Phase II trials
added to superfluous diethyl oxalate respectively, for quantification of their anticonvulsant activity and
then the mixture was stirred and refluxed. Com- neurotoxicity in mice. This phase provides an evalua-
pounds 6a-6n were obtained by compounds 5a-5n tion of the ED50 and TD50 values. The 95%-confidence
reacting with concentrated ammonia spirit spreaded interval, slope of the regression line, and SE of the
around CH3OH at room temperature.
slope were then calculated. These data are shown in
Table II which also includes comparisons with market-
ed antiepileptic drugs carbamazepine. No compound
Pharmacology
Initial anticonvulsant evaluation of the 1-form- exhibited better anticonvulsant activity than refer-
amide-triazolo[4,3- ]quinolines were undertaken by ence drugs carbamazepine. Among the synthesized
a
following the anticonvulsant drug development (ADD) compounds, compound 6d was the most active one and
program protocol (Krall et al., 1978; Poter et al., also had the lowest toxicity. In the anti-MES potency
1984). The profile of anticonvulsant activity was esta- test, it showed median effective dose (ED50) of 30.1
blished after i.p. injections by electrical and chemical mg/kg, median toxicity dose (TD50) of 286 mg/kg, and
tests. The electrical test employed was the Maximal the protective index (PI) of 9.5 which is greater than
Electroshock Seizure (MES) patern test. The acute the reference drug carbamazepine with PI value of
neurological toxicity was determined in the rotarod 6.0.
test (Sun et al., 2006). The activity and toxicity profile
The structure-activity relationship of the compounds
for the tested compounds is summarized in Phase I, 5a-5n was analyzed using their activity in the MES
Table I along with the literature data for standard test. For the 6 alkyl chain-substituted derivatives 5a-
drug. All the compounds were active in the MES test, 5f, the length of the alkyl chain appeared to have a
indicative of their ability to prevent seizure spread.
direct impact on the anticonvulsant activity of the 7-
The results of preliminary (Phase I) screening of 5a- alkyloxyl derivatives. As the alkyl chain length in-
5n and 6a-6n are summarized in Table I. In the anti- creased from 3 to 8, the value of anticonvulsant
MES test, after drug administration at 100 mg/kg activity gradually increased and the compound 5b
dose, compounds 5b-5d, 6a-6f, 6h and 6i showed (with the 7-butoxy substituted group) had the

662
C.-X. Wei et al.
quinoline. Biol. Pharm. Bull., 28, 1216-1220 (2005).
smallest ED50. However, the trend reversed when the
alkyl chain increased from 4 to 8. For the 8 phenyl-
substituted derivatives 5g-5n, no compound had MES
activity under 50 mg/kg-1. And the structure-activity
relationship of the compounds 6a-6n was analyzed
using their activity in the MES test too. For the 6
alkyl chain-substituted derivatives 6a-6f, the length
of the alkyl chain appeared to have a direct impact on
the anticonvulsant activity of the 6-alkyloxyl deriva-
tives. As the alkyl chain length increased from 3 to 6,
the value of ED50 gradually decreased and the com-
Gasior, M., Carter, R. B., Goldberg, S. R., and Witkin, J. M.,
Anticonvulsant and behavioral effects of neuroactive
steroids alone and in conjunction with diazepam. J.
Pharmacol. Exp. Ther., 282, 543-553 (1997).
Krall, R. J., Penry, J. K., White, B. G., Kupferberg, H. J., and
Swinyard, E. A., Antiepileptic drug development: II.
Anticonvulsant drug screening. Epilepsia, 19, 409-428
(1978).
Leppik, I. E., Antiepileptic drugs in development: prospects
for the near future. Epilepsia, 35, 29-40 (1994).
Lin, Z. and Kadaba, P. K., Molecular targets for the rational
design of antiepileptic drugs and related neuroprotective
agents. Med. Res. Rev., 17, 537-572 (1997).
Perucca, E., The new generation of antiepileptic drugs:
advantages and disadvantages. Br. J. Clin. Pharmacol.
42, 531-543 (1996).
Porter, R. J., Cereghino, J. J., Gladding, G. D., Hessie, B. J.,
Kupferberg, H. J., Scoville, B., and White, B. G., Anti-
epileptic Drug Development Program. Cleve. Clin. Q., 51,
293-305 (1984).
pound 6e (with the
n-heptyl substituted group) had
the smallest ED50. However, the trend reversed when
the alkyl chain increased from 7 to 8. For the 8
phenyl-substituted derivatives 6g-6n, 3 compounds
had MES activity under 50 mg/kg-1. And among the
substituted benzyloxyl, the position of the substituted
group on the phenyl ring appeared to greatly influence
the anticonvulsant activity; among the three fluoro-
benzyloxy substituted compounds 6h, 6i and 6j, the
,
Quan, Z. S., Wang, J. M., Rae, J. R., Kwak, K. C., Kang, H.
C., Jun, C. S., and Chai, K. Y., Synthesis of 6-Alkyloxyl-
3,4-dihydro-2(1H)-quinoliones and Their Anticonvulsant
Activities. Bull. Kor. Chem. Soc., 26, 1757-1760(2005).
Sun, X. Y., Jin, Y. Z., Li, F. N., Li, G., Chai, K. Y., and Quan,
Z. S., Synthesis of 8-alkoxy-4,5-dihydro-[1,2,4]triazole
[4,3-a]quinoline-1-ones and evaluation of their anticon-
vulsant properties. Arch. Pharm. Res., 29, 1080-1085
(2006).
Sun, X. Y., Zhang, L., Wei, C. X., Piao, H. R., and Quan, Z. S.,
Design, synthesis of 8-alkoxy-5,6-dihydro-[1,2,4]triazino
[4,3-a]quinolin-1-ones with anticonvulsant activity. Eur.
J. Med. Chem., 44, 1265-1270 (2009).
potency order was
sub- stituted phenyl derivatives, the potency order
m-F > o-F > p-F. Among the four p-
was H > F > CH3 > Cl. And generally speaking, the F
substitut- ed compounds showed much more activity
than the Cl substituted compounds. This structure-
activity relationship might be explained by the lipid-
water partition coefficients of the compounds, which
affect the crossing of the blood-brain barrier by the
compounds. The compound 6d (with the n-hexyl sub-
stituted group) had an ED50 value of 30.1 mg/kg-1, the
ED50 was little biger than 6e, but the TD50 of compound
6d was much biger than 6e, it possessed weaker
neurotoxicity and had a PI value of 9.5. Therefore,
compound 6d could be considered a potentially useful
and safe antiepileptic therapeutic.
Wei, C. X., Li, F. N., Zhao, L. X., Zhao, L. M., and Quan, Z.
S., Synthesis of 2-substituted-7-heptyloxy-4,5-dihydro-
[1,2,4]-triazolo[4,3-a]quinolin-1(2H)-ones with anticonvul-
sant activity. Arch. Pharm. (Weinheim), 340, 491-495
(2007).
REFERENCES
Xie, Z. F., Chai, K. Y., Piao, H. R., Kwak, K. C., and Quan, Z.
S., Synthesis and anticonvulsant activity of 7-alkoxyl-4,5-
dihydro-[1,2,4]triazolo[4,3-a]quinolines. Bioorg. Med. Chem.
Lett., 15, 4803-4805 (2005).
Al-Soud, Y. A., Al-Masoudi, N. A., and Ferwanah, Ael-R., Syn-
thesis and properties of new substituted 1,2,4-triazoles:
potential antitumor agents. Bioorg. Med. Chem., 11, 1701-
1708 (2003).
Cui, L. J., Xie, Z. F., Piao, H. R., Li, G., Chai, K. Y., and
Quan, Z. S., Synthesis and anticonvulsant activity of 1-
substituted-7-benzyloxy-4,5-dihydro-[1,2,4]triazolo[4,3-a]
Zimmer, H., Kokosa, J. M., and Shah, K. J., Synthsis of Con-
1a
densed heterocyclic systems. VI.
Some ring closure
reaxtions involving 1-hydrazinophthalazine. J. Org. Chem.,
40, 2901-2906 (1975).