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A. Sakhteman et al. / Bioorg. Med. Chem. 17 (2009) 6908–6913
4.1.8. (E)-1-(2,4-Dihydroxyphenyl)-3-(4-(4-
hydroxyphenyl)piperidin-1-yl)prop-2-en-1-one 6e
(100), 120 (40) Anal. Calcd for C21H23NO4: C, 71.37; H, 6.56; N,
3.96. Found: C, 71.02; H, 6.67; N, 3.72.
Compound 6e (33% yield) mp 138–140 °C, IR cmꢀ1: 3503 (OH),
1615 (C@O), 1H NMR (DMSO-d6, 500 MHz), d: 14.33 (s, 1H, pheno-
lic OH), 9.00 (s, 1H, phenolic OH), 7.92 (d, 1H, Ha, J = 12.5 Hz), 7.53
(d, 1H, H6, J = 8.5 Hz), 7.021- 6.99 (m, 4H, phenyl), 6.36 (d, 1H, H3-
phenyl, J = 2.0 Hz), 6.31 (dd, 1H, H5-phenyl, J = 8.5 Hz, J = 2.5 Hz),
5.80 (d, 1H, Hb, J = 12.5 Hz), 3.80–3.77 (m, 2H, piperidine), 3.52–
3.50 (m, 2H, piperidine), 2.95–2.83 (m, 4H, piperidine) EI-MS m/z
(%) 339 (M+,15), 176 (100) Anal. Calcd for C20H21NO4: C, 70.78;
H, 6.24; N, 4.13. Found: C, 70.55; H, 6.02; N, 4.27.
4.1.14. (E)-3-(4-Benzylpiperidin-1-yl)-1-(2-hydroxy-4-
methoxyphenyl)prop-2-en-1-one 6j
Compound 6j (58% yield), mp 122–124 °C, IR
m
cmꢀ1: 3523
(OH), 1623 (C@O), 1H NMR (DMSO-d6, 80 MHz), d: 14.48 (s, 1H,
phenolic OH), 7.80 (d, 1H, Ha, J = 12.3 Hz), 7.57–6.5 (m, 5H, aro-
matic), 6.5–6.4 (m, 3H, aromatic), 5.77 (d, 1H, Hb J = 12.3 Hz) 3.80
(s, 3H, OCH3), 3.06 (m, 4H, piperidine), 2.57 (d, 2H, CH2-benzylic),
2.10–1.20 (m, 4H, piperidine), EI-MS m/z (%) 351 (M+, 20), 333 (18),
177 (50), 151 (36), 96 (38), 91 (100), 69 (96), 55 (98) Anal. Calcd for
C22H25NO3: C, 75.19; H, 7.17; N, 3.99. Found: C, 74.93; H, 6.94; N,
3.72.
4.1.9. (E)-1-(2,4-Dihydroxyphenyl)-3-(4-hydroxy-4-(4-
hydroxyphenyl)piperidin-1-yl)prop-2-en-1-one 6f
Compound 6f (68% yield), mp 142–144 °C, IR cmꢀ1: 3400 (OH),
1630 (C@O), 1H NMR (DMSO-d6, 500 MHz), d: 14.903 (s, 1H, pheno-
lic OH), 9.24 (s, 1H, phenolic OH), 7.90 (d, 1H, Ha, J = 12.0 Hz), 7.77
(d, 1H, J = 8.5 Hz), 7.30 (d, 2H, phenyl, J = 8.5 Hz), 6.70 (d, 2H, phe-
nyl, J = 8.5 Hz), 6.31 (dd, 1H, H5-phenyl, J = 8.5 Hz, J = 2.5 Hz), 6.12
(d, 1H, H3, J = 2.5 Hz), 6.03 (d, 1H, Hb, J = 12 Hz), 3.80–3.77 (m, 2H,
piperidine), 5.06 (s, 1H, OH), 3.80–3.50 (m, 4H, piperidine), 2.00–
1.65 (m, 2H, piperidine) EI-MS m/z (%) 355 (M+, 20), 192 (100),
Anal. Calcd for C20H21NO5: C, 67.59; H, 5.96; N,3.94. Found: C,
67.14; H, 5.32; N, 3.52.
4.1.15. (E)-1-(2-Hydroxy-4-methoxyphenyl)-3-(4-(4-
hydroxyphenyl)piperidin-1-yl)prop-2-en-1-one 6k
Compound 6k (66% yield) mp 196–198 °C, IR
m
cmꢀ1: 3421
(OH), 1618 (C@O),1H NMR (DMSO-d6, 80 MHz), d: 14.98 (s, 1H,
phenolic OH), 9.14 (s, 1H, OH phenolic), 7.84 (d, 1H, Ha,
J = 12.8 Hz), 7.07 (d, 2H, phenyl, J = 8.0 Hz), 6.7 (d, 2H, phenyl,
J = 8.0 Hz), 6.56–6.43 (m, 3H, phenyl), 6.34–6.17 (d, 1H, Hb,
J = 12.8 Hz), 3.79 (s, 3H, OMe) 2.1–1.6 (m, 8H, piperidine), EI-MS
m/z (%) 353 (M+, 10), 176 (100), 120 (40), Anal. Calcd for
C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C, 71.15; H, 6.78;
N, 3.65.
4.1.10. General procedure for the synthesis of (E)-3-(substituted
piperidin-1-yl)-1-(2-hydroxy-4-methoxyphenyl)prop-2-en-1-
one derivatives (6g–l)
To a solution of 5b (257 mg, 1 mmol) in acetonitrile (10 mL)
was added 4 substituted piperidine derivatives (1 mmol) and
K2CO3 (138 mg, 1 mmol). The reaction mixture was stirred over
night. The solvent was evaporated and the crude mixture was puri-
fied by column chromatography, using petroleum ether–ethyl ace-
tate (70:30) as the mobile phase, to yield the final compounds (6g–
l).
4.1.16. (E)-3-(4-Hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)-1-
(2-hydroxy-4-methoxyphenyl)prop-2-en-1-one 6l
Compound 6l (45% yield) mp 125–127 °C,
m
cmꢀ1: 3435 (OH),
1640 (C@O),1H NMR (DMSO-d6, 80 MHz), d 14.70 (s, 1H, phenolic
OH), 8.96 (s, 1H, phenolic OH), 7.9–7.7 (m, 2H, Ha, H5-phenyl),
7.3 (d, 2H, phenyl, J = 8.0 Hz), 6.8 (d, 2H, phenyl, J = 8.0 Hz), 6.6–
6.3 (m, 2H, H3,4-phenyl), 6.9 (d, 1H, J = 12.0 Hz), 4.91 (s, 1H, OH-
piperidine), 3.60 (s, 3H, OMe), 2.5–1.8 (m, 8H, piperidine), EI-MS
m/z (%) 369 (M+, 16), 192 (100), Anal. Calcd for C21H23NO5: C,
68.28; H, 6.28; N, 3.79. Found: C, 68.49; H, 6.02; N, 3.54.
4.1.11. (E)-3-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-1-
(2-hydroxy-4-methoxyphenyl) prop-2-en-1-one 6g
Compound 6g (56% yield) mp 166–168 °C, IR cmꢀ1: 3421 (OH),
1618 (C@O), 1H NMR (DMSO-d6, 80 MHz), d: 14.59 (s, 1H, phenolic
OH), 7.90 (d, 1H, Ha, J = 12.8 Hz), 7.50–7.42 (m, 7H), 5.8 (d, 1H, Hb,
J = 12.8 Hz), 4.79 (s, 1H, OH-piperidine), 3.81 (s, 3H, OMe), 2.7–1.9
(m, 8H, piperidine): EI-MS m/z (%) 389 (M++2, 7), 387 (M+,18), 369
(M+ꢀH2O, 15), 210 (100), 151 (35), Anal. Calcd for C21H22ClNO4: C,
65.03; H, 5.72; N, 3.61. Found: C, 64.80; H, 5.33; N, 3.27.
4.2. Behavioral studies
Behavioral studies of the synthesized compounds have been
performed based on the protocol, reported by Sharifzadeh et al.12
The subject male Wister rats weighting 170–220 g were kept at
room temperature with 12 h light/12 h dark cycle. The animals
had access to food and water except during experiment. Eight ani-
mals were used for each dose of the target compounds and control
groups.12–14 The whole protocol was approved for by the ethics
committee of the Faculty of Pharmacy at Tehran University of Med-
ical Sciences.
The synthesized structures were dissolved in a vehicle com-
posed of ethanol (5%), tween 80 (5%), propylene glycol(5%) and
water (85%). As a primary screening, all target compounds were in-
jected at 30 mg/kg. Apomorphine (0.5 mg/kg) was injected 15 min
after ip injection of the synthesized compounds. Consequently,
animals were individually placed in a glass cylinder and a mirror
was arranged in an oblique position under the cylinder to make
all observations possible. Ten minutes after administration of apo-
morphine the number of licks was counted by direct observation
during 60 min.12,13
4.1.12. (E)-3-(4-(4-Bromophenyl)-4-hydroxypiperidin-1-yl)-1-
(2-hydroxy-4-methoxyphenyl) prop-2-en-1-one 6h
Compound 6h (49% yield) mp 155–156 °C, IR
m
cmꢀ1: 3395
(OH), 1608 (C@O), 1H NMR (DMSO-d6, 80 MHz), d: 14.56 (s, 1H,
phenolic OH), 7.91 (d, 1H, Ha, J = 12.8 Hz), 7.56–7.40 (m, 7H, aro-
matic), 5.9 (d, 1H, Hb, J = 12.8 Hz), 4.86 (s, 1H, OH-piperidine),
3.81 (s, 3H, OMe), 2.7–1.9 (m, 8H, piperidine), EI-MS m/z (%) 433
(M++2, 14), 431 (M+, 18), 413 (M+ꢀH2O, 12), 254 (100), 149 (80),
Anal. Calcd for C21H22BrNO4: C, 58.34; H, 5.13; N, 3.24. Found: C,
58.64; H, 4.85; N, 2.98.
4.1.13. (E)-1-(2-Hydroxy-4-methoxyphenyl)-3-(4-hydroxy-4-
phenylpiperidin-1-yl)prop-2-en-1-one 6i
Compound 6i (61% yield), mp 186–188 °C, IR
m
cmꢀ1: 3383
(OH), 1618 (C@O), 1H NMR (DMSO-d6, 80 MHz), d: 14.62 (s, 1H,
phenolic OH), 7.85 (d, 1H, Ha, J = 12.1 Hz), 7.61–7.27 (m, 6H, aro-
matic), 6.40–6.32 (m, 2H, aromatic), 6.67 (d, 1H, Hb, J = 12.1 Hz),
4.92 (s, 1H, OH-piperidine), 3.60 (s, 3H, OMe), 2.9–2.0 (m, 8H,
piperidine), EI-MS m/z (%) 353 (M+, 10), 335 (M+ꢀH2O, 10), 175.9
Positive control group received 0.5 mg/kg apomophine (sc),
15 min after administration of haloperidol (0.5 mg/kg, ip), mean-
while for the negative control group a 0.5 mg/kg dose of apomor-
phine was administered 15 min after ip injection of vehicle.