L. Santana et al. / European Journal of Medicinal Chemistry 37 (2001) 503–510
509
53.13, 50.55, 39.23, 26.50. MS: m/z=488 [M]+, 410,
205, 162, 135. Anal.: C24H30Cl2N2O7S (C, H, N).
CH3O), 3.15 (m, 4H, N4(CH2)2), 2.73 (m, 6H,
CH2N1(CH2)2), 2.04 (m, 2H, CH2CH2CH2). 13C-NMR
(CDCl3) l 163.22, 162.10, 160.55, 154.18, 150.72,
148.60, 146.20, 136.36, 130.10, 129.32, 120.60, 119.46,
118.43, 114.77, 113.03, 108.90, 100.45, 67.02, 55.95,
53.70, 53.45, 51.12, 29.12. MS: m/z=550 [M]+, 410,
205, 162, 135. Anal.: C29H32Cl2N2O7S (C, H, N).
6.1.4.3. 4-Methanesulphonyl-7-{3-[4-(p-nitrophenyl)-1-
piperazinyl]propyloxy}coumarin (9a). Yield 60% (from
5a); m.p. (2·HCl) 194–98 °C. 1H-NMR (CDCl3) l (free
base) 8.12 (d, J=9.40, 2H, o-NO2), 7.62 (d, J=8.80,
H, H-5), 6.91 (d, J=2.40, 1H, H-8), 6.86 (dd, J=8.80,
2.40, 1H, H-6), 6.81 (d, J=9.40, 2H, o-NO2), 6.35 (s,
1H, H-3), 4.14 (t, J=6.24, 2H, CH2O), 3.44 (m, 4H,
N4(CH2)2), 3.37 (s, 3H, SCH3), 2.62 (m, 6H,
CH2N1(CH2)2), 2.05 (m, 2H, CH2CH2CH2). 13C-NMR
(CDCl3) l 162.71, 160.24, 157.97, 155.69, 153.55,
141.36, 126.36, 124.92, 113.29, 113.23, 112.08, 102.17,
101.08, 65.39, 55.59, 52.43, 45.58, 39.51, 25.12. MS:
m/z=503 [M]+, 220, 165, 120. Anal.: C23H25N3O8S (C,
H, N).
6.1.4.7. 4-Benzenesulphonyl-7-{3-[4-(p-nitrophenyl)-1-
piperazinyl]propyloxy}coumarin (11a). Yield 53% (from
5a); m.p. (2·HCl) 222–224 °C. 1H-NMR (CDCl3) l
(free base) 8.13 (d, J=9.38, 2H, o-NO2), 8.02 (d,
J=7.85, 2H, o-SO2), 7.83 (m, 1H, p-SO2), 7.75 (m, 2H,
m-SO2), 7.44 (d, J=8.68, 1H, H-5), 7.18 (d, J=9.38,
2H, m-NO2), 7.05 (s, 1H, H-8), 6.90 (d, J=8.68, 1H,
H-6), 6.10 (s, 1H, H-3), 4.15 (t, 2H, CH2O, J=6.20),
3.45 (m, 4H, N4(CH2)2), 2.63 (m, 6H, CH2N1(CH2)2),
2.10 (m, 2H, CH2CH2CH2). 13C-NMR (CDCl3) l
163.02, 162.71, 161.30, 160.43, 155.50, 150.70, 140.04,
136.24, 130.48, 129.33, 127.30, 124.67, 113.82, 112.83,
107.63, 105.48, 101.28, 66.49, 54.12, 53.90, 48.36 26.92.
MS: m/z=565 [M]+, 425, 220, 165, 120. Anal.:
C28H29Cl2N3O8S (C, H, N).
6.1.4.4.
4-Methanesulphonyl-7-{3-[4-(p-methoxy-
phenyl)-1-piperazinyl]propyloxy}coumarin (9b). Yield
63% (from 5b); m.p. (2·HCl) 177–179 °C. 1H-NMR
(DMSO-d6) l (free base) 7.70 (d, J=9.38, 1H, H-5),
6.88 (d, J=9.60, 4H), 6.82 (m, 6H, H-6, H-8, o,
m-OCH3), 5.31 (s, 1H, H-3), 4.12 (t, J=9.60, 2H,
CH2O), 3.67 (s, 3H, CH3O), 3.15 (s, 3H, CH3S), 3.07
(m, 4H, N4(CH2)2), 2.72 (m, 6H, CH2N1(CH2)2), 1.98
(m, 2H, CH2CH2CH2). 13C-NMR (DMSO-d6) l 163.50,
161.83, 157.45, 154.22, 154.14, 145.23, 126.49, 120.38,
114.83, 114.02, 112.22, 102.28, 101.72, 67.10, 55.43,
55.54, 53.13, 49.84, 38.43, 26.83. MS: m/z=488 [M]+,
205, 162, 135. Anal.: C24H30Cl2N2O7S (C, H, N).
6.1.4.8. 4-Benzenesulphonyl-7-{3-[4-(p-methoxyphenyl)-
1-piperazinyl]propyloxy}coumarin (11b). Yield 55%
(from 5b); m.p. (2·HCl) 221–223 °C. 1H-NMR
(DMSO-d6) l (free base) 8.11 (d, J=7.88, 2H, o-SO2),
7.86 (m, 1H, p-SO2), 7.71 (m, 2H, m-SO2), 7.46 (d,
J=8.77, 1H, H-5), 7.07 (s, 1H, H-8), 6.91 (m, 5H, H-6,
o-and m-OCH3), 6.11 (s, 1H, H-3), 4.18 (s 2H, CH2O),
3.68 (s, 3H, CH3O), 3.38 (m, 4H, N4(CH2)2), 2.77 (m,
6H, CH2N1(CH2)2), 1.97 (m, 2H, CH2CH2CH2). 13C-
NMR (DMSO-d6) l 163.38, 162.89, 161.49, 159.48,
154.23, 151.03, 146.12, 136.40, 130.02, 128.31, 125.80,
119.12, 114.64, 113.02, 108.64, 103.21, 101.44, 67.02,
56.03, 54.80, 53.67, 51.03, 28.09. MS: m/z=550 [M]+,
205, 162, 135. Anal.: C29H32Cl2N2O7S (C, H, N).
6.1.4.5. 4-Benzenesulphonyl-6-{3-[4-(p-nitrophenyl)-1-
piperazinyl]propyloxy}coumarin (10a). Yield 46% (from
4a); m.p. (2·HCl) 236–238 °C. 1H-NMR (CDCl3) l
(free base) 8.13 (d, J=9.40, 2H, o-NO2), 8.02 (d,
J=7.25, 2H, o-SO2), 7.75 (m, 1H, p-SO2), 7.64 (m, 2H,
o-SO2), 7.24 (d, J=9.01, 1H, H-8), 7.15 (dd, J=9.01,
2.86, 1H, H-7), 7.07 (d, J=2.86, 1H, H-5), 6.88 (d,
J=9.40, 2H, m-NO2), 6.21 (s, 1H, H-3), 4.05 (t, J=
6.20, 2H, CH2O), 3.45 (m, 4H, N4(CH2)2), 2.63 (m, 6H,
CH2N1(CH2)2), 2.05 (m, 2H, CH2CH2CH2). 13C-NMR
(CDCl3) l 163.33, 163.09, 160.85, 155.60, 150.81,
149.07, 138.72, 134.73, 129.12, 126.90, 126.48, 119.48,
118.64, 117.50, 112.92, 112.80, 101.03, 67.20, 54.60,
53.72, 49.60, 29.38. MS: m/z=565 [M]+, 318, 220, 141.
Anal.: C28H29Cl2N3O8S (C, H, N).
6.2. Pharmacology
6.2.1. 5-HT1A receptor binding assay
Male Sprague–Dawley rats weighing about 200 g
were decapitated and the cortex and hippocampus were
dissected out and immediately homogenised (ultraTur-
rax homogeniser, 10 s) in 15 mL of ice-cold 50 mM
Tris–HCl buffer containing 2.0 mM CaCl2, 1.0 mM
MgCl2 and 1.0 mM MnCl2 (pH 7.4). After centrifuga-
tion for 12.5 min at 17 000 rpm, the pellets were resus-
pended in the same buffer and homogenisation and
centrifugation were repeated. The tissue homogenate
was diluted to 5 mg mL−1 with the buffer, incubated
for 10 min at 37 °C, treated with 10 nM pargyline, and
reincubated for 10 min. Incubation mixtures (2 mL)
contained various concentrations of test compound (di-
luted in 50 mM Tris–HCl buffer, pH 7.4), 1nM [3H]-8-
6.1.4.6. 4-Benzenesulphonyl-6-{3-[4-(p-methoxyphenyl)-
1-piperazinyl]propyloxy}coumarin (10b). Yield 50%
(from 4b); m.p. (2·HCl) 177–178 °C. 1H-NMR
(CDCl3) l (free base) 8.02 (d, J=7.64, 2H, o-SO2), 7.75
(m, 1H, p-SO2), 7.63 (m, 2H, m-SO2), 7.24 (d, J=9.06,
1H, H-8), 7.14 (dd, J=9.06, 2.85, 1H, H-7), 7.01 (d,
J=2.85, 1H, H-5), 6.78 (m, 4H, o, m-OCH3), 6.27 (s,
1H, H-3), 4.02 (t, J=6.15, 2H, CH2O), 3.77 (m, 3H,