584
J. Karolak-Wojciechowska et al. / Il Farmaco 53 (1998) 579±585
100.0 (8-C), 104.0, 114.2, 122.5 (6-C), 126.5 (5-C), 142.8
144.7 (2-C), 167.6, 168.1, 172.3; chemical shift data without
assignments refer to quaternary aromatic carbon atoms.
was ®ltered, thoroughly washed with ether, and dissolved in
15 ml of 2 N NaOH. The solution was stirred for 1 h with
ethyl ether, the ether solution was separated and discarded,
whereas the aqueous solution was neutralized to pH 8±9 by
adding solid NH4Cl to precipitate the crude product. The
®nal puri®cation was done by recrystallization from ethanol.
Anal.: 4a. Calc. for C18H15N3O2: C, 70.81; H, 4.95; N,
13.76. Found: C, 70.62; H, 4.89; N, 13.80%. 4b. Calc. for
C17H13N3O2: C, 70.09; H, 4.50; N, 14.42. Found: C, 70.23;
H, 4.37; N, 14.38%. 4c. Calc. for C16H10ClN3O: C, 64.98; H,
3.41; N, 14.21. Found: C, 65.11; H, 3.28; N, 14.12%. 4f.
Calc. for C17H10F3N3O: C, 62.01; H, 3.06; N, 12.76. Found:
C, 61.87; H, 2.96; N, 12.70%. 4g. Calc. for C17H13N3O: C,
74.17; H, 4.76; N, 15.26. Found: C, 74.05; H, 4.84; N,
15.19%. 4h. C17H13N3O: C, 74.17; H, 4.76; N, 15.26.
Found: C, 74.27; H, 4.70; N, 15.24%.
4.1.4. 7-(6)-Substituted ethyl 4-chloroquinoline-3-
carboxylates (3)
The general procedure was as follows. The appropriately
6- or 7-substituted ethyl 4-hydroxyquinoline-3-carboxylate
(2) (0.025 mol) was cautiously added to ice-cooled phos-
phorus oxychloride (17.5 ml) and the mixture was re¯uxed
under argon for 5 h. Upon cooling, the mixture was poured
onto crushed ice, neutralized with ammonia, and extracted
with methylene chloride as rapidly as possible. The organic
layer was washed with saline, dried with MgSO4, and
evaporated to yield the crude product which was puri®ed
by recrystallization from petroleum ether or hexane.
Ethyl 4-chloro-7-ethoxyquinoline-3-carboxylate (3a),
m.p. 120±1228C (petroleum ether, 45±608C fraction),
yield 60%. Anal.: Calc. for C14H14ClNO3: C, 60.11; H,
5.04; N, 5.01. Found: C, 60.17; H, 4.92; N, 4.98%.
Ethyl 4-chloro-7-methoxyquinoline-3-carboxylate (3b),
m.p. 130±1328C (hexane), yield 67%. Anal.: Calc. for
(Cl3H12ClNO3): C, 58.77; H, 4.55; N, 5.27. Found: C,
58.85; H, 4.48; N, 5.20%.
Ethyl 4-chloro-6-methoxyquinoline-3-carboxylate (3e),
m.p. 96±988C (petroleum ether), yield 54%. Anal.: Calc.
for (C13H12ClNO3): C, 58.77; H, 4.55; N, 5.27. Found: C,
58.88; H, 4.39; N, 5.18%.
Ethyl 4-chloro-6-methylquinoline-3-carboxylate (3g),
m.p. 64±668C (petroleum ether), yield 71%. Anal.: Calc.
for (C13H12ClNO2): C, 62.53; H, 4.84; N, 5.61. Found: C,
62.44; H, 4.78; N, 5.58%.
4.1.6. 7-(6)-Substituted 2-arylpyrazolo[3,2-c]quinolin-3-
ones (5±7)
The general procedure was as follows. 4-Chlorophenyl-
hydrazine hydrochloride (0.005 mol) was suspended in 60
ml of xylene and the mixture was stirred for 2 h with 5 ml of
aqueous ammonia. The xylene layer was separated and
distilled until moisture stopped passing with the distillate.
The appropriately substituted ethyl 4-chloroquinoline-3-
carboxylate (0.003 mol) was then added; the reaction
continued as above to yield the corresponding 5.
An analogous procedure starting with 4-methoxyphenyl-
hydrazine and 4-¯uorophenylhydrazine was used to prepare
6 and 7, respectively.
Data for compounds 5±7 are given in Table 1.
1
The representative H NMR spectrum is reported for 5a
Compounds 3c, 3d, 3f, and 3h were prepared analo-
gously. Their melting points were consistent with the litera-
ture data.
(400 MHz, DMSO-d6): 1.50 (t, 3H, CH3), 4.17 (q, 2H, CH2),
7.41 (dd, 1H, J8;6 2:1 Hz, J8;9 9:4 Hz, 8-CH), 7.5±7.8
(m, 6H), 8.17 (d, 1H, J 9:4 Hz, 9-CH), 8.97 (s, 1H, 4-
CH).
Representative NMR spectra are reported for 3a: 1H
NMR (400 MHz, CDCl3): 1.46 (t, 3H, J 7:0, ether
CH3), 1.52 (t, 3H, J 7:1, ester CH3), 4.22 (q, 2H,
J 7:0, ether CH2), 4.48 (q, 2H, J 7:1, ester CH2), 7.32
(dd, 1H, J6;8 2:3 Hz, J6;5 9:3 Hz, 6-CH), 7.41 (d, 1H,
J 2:3 Hz, 8-CH), 8.29 (d, 1H, J 9:3 Hz, 5-CH), 9.16 (s,
1H, 2-CH).
Anal.: 5b Calc. for C17H12ClN3O2: C, 62.68; H, 3.71; N,
12.90. Found: C, 62.49; H, 3.67; N, 12.85%. 5c. Calc. for
C16H9Cl2N3O: C, 58.20; H, 2.75; N, 12.73. Found: C, 58.02;
H, 2.81; N, 21.37%. 5f. Calc. for C17H9ClF3N3O: C, 56.14;
H, 2.49; N, 11.55. Found: C, 55.97; H, 2.38; N, 11.60%. 5h.
Calc. for C17H12ClN3O: C, 65.92; H, 3.90; N, 13.57. Found:
C, 66.09; H, 3.78; N, 13.48%. 6f. Calc. for C18H12F3N3O2: C,
60.17; H, 3.37; N, 11.69. Found: C, 59.94; H, 3.28; N,
11.65%. 7f. Calc. for C17H9F4N3O: C, 58.80; H, 2.61; N,
12.10. Found: C, 58.64; H, 2.53; N, 12.19%.
13C NMR (400 MHz, CDCl3): 14.6 and 14.3 (2 £ CH3),
64.2 and 61.8 (2 £ CH2), 108.1 (8-C), 121.1, 120.5, 121.8
(6-C), 126.7 (5-C), 143.5, 150.9 (2-C), 151.7, 162.0, 164.6
(CyO); chemical shift data without assignments refer to
quaternary aromatic carbon atoms.
4.2. Receptor tests
4.1.5. 7-(6)-Substituted 2-phenylpyrazolo[3,2-c]quinolin-3-
ones (4)
Rat brains were homogenized at 08C in 20 vols. of 50 mM
Tris±HCl (pH 7.4) and the homogenates were incubated for
1 h at 378C and centrifuged at 20 000 £ g. Samples of the
homogenate (800 ml corresponding to 13.3 mg of the brain
tissue) were mixed with 1000 ml of [3H]¯unitrazepam
(speci®c activity 81 Ci/mM) and 100 ml of the tested
compound (1027 M). The mixture was incubated for 2 h
The general procedure was as follows. The appropriately
6- or 7-substituted 4-chloroquinoline-3-carboxylate (3)
(0.0036 mol) and 0.45 g (0.0045 mol) of phenylhydrazine
was re¯uxed in 20 ml of xylene for 4 h. A bright yellow
product quickly began to precipitate. Ethyl ether was added
to the cooled mixture to complete precipitation and the solid