Synthesis and dopaminergic activity of some E-3-(piperidin-1-yl)-1-(4-substituted phenyl)prop-2-en-1-one derivatives

Article abstract of DOI:10.1016/j.bmc.2009.08.030

A convenient route for the synthesis of some 2-propen-1-one derivatives with E isomeric configuration is described. The activity of the synthesized compounds was evaluated through behavioral studies of apomorphine-induced licking in animal models. It was demonstrated that most of the synthesized compounds showed moderate activity in inhibition of lickings, among which 6a, was the most active compound at 30 mg/kg.

Full text of DOI:10.1016/j.bmc.2009.08.030

Bioorganic & Medicinal Chemistry 17 (2009) 6908–6913
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Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Synthesis and dopaminergic activity of some
E-3-(piperidin-1-yl)-1-(4-substituted phenyl)prop-2-en-1-one derivatives
Amirhossein Sakhteman a, Alireza Foroumadi a,b, Mohammad Sharifzadeh b,c, Masoud Amanlou a,
Farhoud Rayatnia b, Abbas Shafiee a,b,
*
a Department of Medicinal Chemistry, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14174, Iran
b Pharmaceutical Sciences Research Center, Tehran University of Medical Sciences, Tehran 14174, Iran
c Department of Toxicology, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran 14174, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A convenient route for the synthesis of some 2-propen-1-one derivatives with E isomeric configuration is
described. The activity of the synthesized compounds was evaluated through behavioral studies of apo-
morphine-induced licking in animal models. It was demonstrated that most of the synthesized com-
pounds showed moderate activity in inhibition of lickings, among which 6a, was the most active
compound at 30 mg/kg.
Received 11 May 2009
Revised 8 August 2009
Accepted 13 August 2009
Available online 20 August 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Apomorphine induced licking
Behavioral dopaminergic activity
Prop-2-en-1-one derivatives
1. Introduction
(Fig. 2, structure I).4,5 The result of activity for these compounds re-
vealed lower affinity for cis derivatives to both D1 and D2
The role of dopaminergic system in controlling motor, cognition
and motivational behaviors has been frequently explained. Schizo-
phrenia, a psychiatric illness with the prevalence rate of 1% is iden-
tified by two major types of symptoms: positive (delusion,
hallucination) and negative (abolition, anhedonia and attentional
impairment).1 The biochemical basis of schizophrenia postulates
that dopaminergic activity is increased in the mesolimbic system
of the brain. The activation of D1/D2 receptors in striatum is repre-
sented by an excessive and repetitive behavior called stereotypy.2
Dopamine receptor antagonists are therefore the most important
drugs used to treat the positive symptoms of the disease. Prelimin-
ary treatment of schizophrenia and psychosis has relied on neuro-
leptics including chloropromazine, fluphenazine and haloperidol
(Fig. 1).3 The most occurred problems caused by classic neurolep-
tics mainly involve movement disorders, tardive diskinesia and
extrapyramidal side effects. Clozapine was the protype of new
drugs which were classified as atypical antipsychotics.1,3 The most
observed side effects related to clozapine were agranulocytosis and
seizures.3 For this reasons, research for design and synthesis of
new drugs with more potency and less side effects has been a chal-
lenging aim for medicinal chemists.1,2 As a part of these studies,
synthesis and antidopaminergic activity of some conformationally
restricted cis and trans analogs of haloperidol has been reported
receptors.5 In another study, synthesis and dopaminergic
activity of some 1-cyclohexylmethyl-8-hydroxy-7-methoxy-tetra-
hydroisoquolines, (Fig. 2, II) has been described.6 It was demon-
strated that all 1-cyclohexyl methyl derivatives were able to
displace [H]-raclopride, a selective ligand of D2-dopamine recep-
tor, from its site in rat striatal membrane.6 In addition dopamine
reuptake inhibition activity of propiophenone derivative (structure
III, Fig. 2) has been reported.7 The structure of compound III could
be divided into three fragments: (1) phenyl ring, (2) piperidine
ring, (3) linker attaching phenyl to piperidine.7 In this study by tak-
ing fragments from the structures II and III (phenyl ring from struc-
ture II and linker and piperidine ring from structure III) and
restricting the configuration of linker by a double bond at trans po-
sition, a series of E-3-(piperidin-1-yl)-1-(4-methoxy and hydroxy-
phenyl)-2-propen-1-one derivatives were synthesized and
* Corresponding author. Tel: +98 21 66406757; fax: +98 21 66461178.
E-mail address: ashafiee@ams.ac.ir (A. Shafiee).
Figure 1. Haloperidol.
0968-0896/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2009.08.030

A. Sakhteman et al. / Bioorg. Med. Chem. 17 (2009) 6908–6913
6909
Figure 2. Structures of I, II and III.
evaluated for dopaminergic activity through apomorphine licking
studies in animal model.
(3) was obtained.8 Protection of hydroxyl group in compound 3
with chlorotriisopropyl silane yielded 7-(triisopropylsilyloxy)
chroman-4-one (4a) while methylation of (3) with methyl iodide
afforded 4b.9,10 The two intermediates were then reacted with
CuBr2 to yield the mono brominated intermediates (5a–b). The tar-
get compounds were finally obtained through the addition of 4-
substituted piperidines to the mono brominated intermediates,
5a–b, in the presence of K2CO3. Four of the six substituted
piperidnes in Scheme 1, namely 4-(4-chlorophenyl)piperidin-4-ol,
4-(4-bromophenyl)piperidin-4-ol, 4-phenylpiperidin-4-ol and 4-
benzylpiperidine were commercially available. Meanwhile, the
two 4-phenylpiperidine derivatives having OH at position 4 of phe-
nyl were synthesized through the route depicted in Scheme 2.
2. Results and discussion
2.1. Chemistry
Our convenient strategy for the synthesis of target compounds
with E isomeric configuration is explained in the experimental sec-
tion and depicted in Scheme 1. Reaction of resorcinol (1) with 3-
chloropropionic acid using trifluoromethanesulfonic acid furnished
20,40-dihydroxy-3-chloro propiophenone (2). By intramolecular
cyclization in the next step with NaOH, 7-hydroxy-4-chromanone
Scheme 1. Reagents and conditions: (a) CF3SO3H, rt; (b) NaOH, rt; (c) HCl, rt; (d) CH3I or chlorotrimethylsilane, rt (e) CuBr2, reflux for 5 h; (f) 4-substituted piperidine, K2CO3.
Scheme 2. Reagents and conditions: (a) benzyl chloride, reflux; (b) n-BuLi, ꢀ78 °C, n-benzyl-4-piperidone; (c) HCl, reflux for 15 min; (d) Pd/C(10%), H2 (50 psi), rt, overnight.

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A. Sakhteman et al. / Bioorg. Med. Chem. 17 (2009) 6908–6913
Table 1
Licking count average SE of the target compounds (6a–l) and controls
Code
6a–f 6a
R
X
Y
n
Licking count SE
H
H
H
H
H
H
Me
Me
Me
Me
Me
Me
Cl
Br
H
OH
OH
OH
H
0
0
0
1
0
0
0
0
0
1
0
0
115 24.6**
6b
6c
6d
6e
1860 318.7*
1317 135.2**
618 71.72**
664 51.92**
1450 207.4**
1575 85.39**
1140 92.74**
1800 83.67**
520 80**
H
OH
OH
Cl
Br
H
H
OH
OH
H
6f
OH
OH
OH
OH
H
6g–l 6g
Figure 3. Preferred conformation of the target compounds (6a–l).
6h
6i
6j
6k
6l
Reaction of 4-bromophenol (7), with benzylbromide provided 1-
(benzyloxy)-4-bromobenzene (8). The compound 8 was then
reacted with n-butyl lithium at -78°C followed by n-benzyl-4-pip-
eridone, to yield 9. Dehydration of 9 in acidic medium followed by
hydrogenation at 49 psi in the presence of Pd/C(10%) as catalyst,
yielded 4-(piperidin-4-yl)phenol (11). In addition, by direct hydro-
genation of 9 at 49 psi 4-(4-hydroxyphenyl)piperidin-4-ol (12) was
obtained.
H
OH
1325 154.8**
2675 77.73
3.667 1.52**
(+) Apomorphine (0.5 mg/kg) + Haloperidol
(0.5 mg/kg)
(ꢀ) Apomorphine (0.5 mg/kg) + Vehicle
2850 183.9
*
Tukey Post ANOVA test, P <0.01 with respect to negative control.
Tukey Post ANOVA test, P <0.001 with respect to negative control.
**
Final purification of the target compounds (6a–l) was per-
formed with column chromatography using ethyl acetate–petro-
leum ether as the mobile phase and the purity of the synthesized
compounds was rechecked by thin layer chromatography using
various solvents with different polarities.
compounds having p <0.01 and p <0.001 in respect to negative con-
trol were considered to be active and assigned with ꢁ and ꢁꢁ,
respectively. Based on the statistical values, the order of activity
for the group of compounds having OH at position 4 of phenyl ring
was 6a > 6d, 6e > 6f, 6c > 6b. Therefore, compound 6a with 4-chlo-
rophenyl substituent was the most active compound. On the other
hand, the order of activity for the group of compounds with meth-
oxy at the same position was 6j > 6h, 6k > 6g P 6i > 6l. The most
dopaminergic activity in this group was pertained to 6j with benzyl
substituent. Compound 6a was the most active compound in both
series and its activity was comparable to the positive control (hal-
operidol, p >0.05). The most dopaminergic activity after 6a was ob-
served for 6j, 6d and 6e. A common feature observed in these three
compounds was the absence of OH group at the 4 position of piper-
idine ring. In addition, the two compounds 6j and 6d had a benzyl
substituent at position 4 of piperidine, while 6e contained an
unsubstituted phenyl at this position. Finally, it is noteworthy to
mention that in most compounds when R = H, they were more ac-
tive than the compounds having R = Me (8a > 6g, 6c > 6i, 6e > 6k
and 6f > 6l).
In order to obtain further information about the most active
compound, 6a, response activity calculations were repeated at
10, 30 and 50 mg/kg for this compound. The plot of activity for
6a at three doses is shown in Figure 5. Result of this study revealed
that, increasing the administered dose of 6a from 10 to 30 mg/kg
increased the activity. However, increasing the dose from 30 to
50 mg/kg did not change the dopaminergic activity significantly.
Therefore, the highest activity of compound 6a could be observed
at 30 mg/kg in animal models.
Based on 1H NMR data, the coupling constant (J) of AB quartet
system, relating two hydrogens at the site of double bond was
12–13 Hz, it could be therefore concluded that the configuration
of double bond in final compounds (6a–l) is (E) rather than (Z)
(Fig. 3). In addition, phenolic hydrogens adjacent to carbonyl moi-
eties in all target compounds (6a–l) were observed at 14–15 ppm.
The reason for deshield phenolic protons are explained by intramo-
lecular hydrogen bond interactions between corresponding OH
and adjacent carbonyl moieties (Fig. 3). A possible mechanism for
reaction of piperidines with 5b is depicted in Figure 4. It is reason-
able to assume that the E2 elimination of 5b in basic solution af-
fords intermediate I. In the next step, by Michael addition of
substituted piperidines, followed by ring cleavage of the resulted
intermediate II, the target compound 6 was formed. It should be
mentioned that the N-substituted 2- and 3-alkyl-3-aminoacryl-
ophenones has been synthesized by other routes.11
2.2. Biological activity
The results of behavioral dopaminergic activity for the target
compounds (6a–l), in terms of licking count inhibition are listed
in Table1. One way analysis of variances (ANOVA) followed by a
post Tukey test was performed on the raw data to compare the
compounds with each other and their related control groups. The
Figure 4. A possible mechanism for the reaction of substituted piperidines with monobrominated intermediate (5b).

A. Sakhteman et al. / Bioorg. Med. Chem. 17 (2009) 6908–6913
6911
one (4b, 281.5 mg, 1.25 mmol) with CuBr2 (900 mg, 4 mmol). The
resulted mixture was purified by column chromatography with
ethyl acetate–petroleum ether (40:60) as the mobile phase to af-
ford 5b (310 mg 1.2 mmol, 76% yield), mp 166–168 °C, 1H NMR
(DMSO-d6, 80 MHz) d: 7.83 (d, 1H, H5, J = 8 Hz), 6.50 (dd, 1H, H6,
J = 2.5 Hz, J = 8 Hz), 6.46 (d, H8, J = 2.5 Hz), 4.62–4.57 (m, 3H,
H2,H3), 3.86 (s, 3H, OCH3), EI-MS m/z (%) 258 (M++2, 20), 256
(M+, 21), 148 (100), 121 (58), 79 (40), 61 (60), Anal. Calcd for
C10H9BrO3: C, 46.72; H. Found: C, 46.32; H, 3.41.
3500
3000
2500
2000
1500
1000
500
4.1.3. General procedure for synthesis of (E)-3-(4-hydroxy-4-
phenyl and benzyl piperidin-1-yl)-1-(4-methoxyphenyl)-prop-
2-en-1-one derivatives (6a–f)
To a solution of 5a (398 mg, 1 mmol) in acetonitrile (10 mL),
was added 4 substituted piperidine derivatives (1 mmol) and
K2CO3 (138 mg, 1 mmol). After refluxing the mixture for 1 h, the
solvent was evaporated and the crude mixture was purified by col-
umn chromatography, using petroleum ether–ethyl acetate
(60:40) as the mobile phase to afford the final compounds (6a–f).
0
(-) Control
10
30
50
Dose (mg/Kg) of 6a
Figure 5. Dose dependent activity of 6a.
3. Conclusion
4.1.4. (E)-3-(4-(4-Chlorophenyl)-4-hydroxypiperidin-1-yl)-1-
A simple method for the synthesis of some 2-propen-1-one
derivatives with E configuration is described. The activity of the
synthesized compounds was evaluated through behavioral studies.
It was shown that most synthesized compounds had moderate
activity. Compound 6a having chlorine in para position of the ben-
zyl ring was the most active compound.
(2,4-dihydroxyphenyl)prop-2-en-1-one 6a
Compound 6a (75% yield), mp 118–120 °C, IR
m
cmꢀ1: 3405
(OH), 1613 (C@O),1H NMR (DMSO-d6, 80 MHz), d: 14.50 (s, 1H,
phenolic OH), 7.90 (d, 1H, Ha, J = 12.0 Hz), 7.75–7.2 (m, 5 H, aro-
matic), 6.4–6.2 (m, 2H, aromatic), 6.1 (d, 1H, Hb, J = 12.0 Hz),
3.06–1.20 (m, 8H, piperidine), EI-MS m/z (%) 375 (M++2, 8), 373
(M+, 25), 355 (M+ꢀH2O, 33), 210 (100), Anal. Calcd for
C20H20ClNO4: C, 64.26; H, 5.39; N, 3.75. Found: C, 64.11; H, 5.22;
N, 3.42.
4. Experimental
4.1. Synthesis procedure
4.1.5. (E)-3-(4-(4-Bromophenyl)-4-hydroxypiperidin-1-yl)-1-
Chemical reagents and solvents used in this study were pur-
chased from Merck AG or Aldrich Chemical. Column chromatogra-
phy purifications were performed on Merck Silica Gel (70–
230 mesh). All melting points were determined with a Kofler hot
stage apparatus and are uncorrected. IR spectra were recorded on
a Nicolet FT-IR Magna 550 spectrophotometer. 1H NMR spectra
were measured using a Bruker FT-80 or FT-500 MHz, and chemical
shifts are expressed as d (ppm) with respect to tetramethylsilane as
internal standard. The mass spectra were run on a Finigan TSQ-70
spectrometer at 70 eV. Elemental microanalyses were carried out
with a Perkin–Elmer 240-C apparatus and were within 0.4% of
the theoretical values for C, H, and N.
(2,4-dihydroxyphenyl)prop-2-en-1-one 6b
Compound 6b (73% yield), mp 210–212 °C, IR
m
cmꢀ1: 3373
(OH), 1615 (C@O), 1H NMR (DMSO-d6, 500 MHz) d: 15.00 (s, 1H,
phenolic OH), 7.80 (d, 1H, Ha, J = 12.0 Hz), 7.76 (d, 1H, H6-phenyl,
J = 9.0 Hz), 7.5–7.4 (m, 4H, aromatic), 6.22 (dd, 1H, H5-phenyl,
J = 2.0 Hz, J = 9.0 Hz), 6.12 (d, 1H, H3-phenyl, J = 2.0 Hz), 6.05 (d,
1H, Hb, J = 12.0 Hz), 2.77–2.76 (m, 4H, piperidine), 2.00 (s, 1H,
OH-piperidine), 1.80–1.65 (m, 2H, piperidine), 1.5–1.48 (m, 2H,
piperidine) EI-MS m/z (%): 419 (M++2, 17), 417 (M+, 18), 254
(100), Anal. Calcd for C20H20BrNO4: C, 57.43; H, 4.82; N, 3.35.
Found: C, 57.14; H, 4.61; N, 3.10.
Synthesis of intermediates 2–4 and 8–12 was performed
according to the procedure depicted in Schemes 1 and 2, respec-
tively.8–10
4.1.6. (E)-1-(2,4-Dihydroxyphenyl)-3-(4-hydroxy-4-
phenylpiperidin-1-yl)prop-2-en-1-one 6c
Compound 6c (34% yield) mp 115–117 °C, IR
m
cmꢀ1: 3370
(OH), 1627 (C@O), 1H NMR (DMSO-d6, 80 MHz), d: 14.00 (s, 1H,
phenolic OH), 7.90 (d, 1H, Ha, J = 12.1 Hz), 7.8–7.3 (m, 6H, aro-
matic), 6.50–6.30 (m, 2H, H3, H5), 6.9 (d, 1H, Hb, J = 12.1 Hz), 4.76
(s, 1H, OH piperidine), 2.0–1.3 (m, 8H, piperidine), EI-MS m/z (%)
339 (M+, 18), 176 (100), Anal. Calcd for C20H21NO4 C, 70.78; H,
6.24; N, 4.13. Found: C, 70.95; H, 6.02; N, 3.85.
4.1.1. Synthesis of 3-bromo-7-(triisopropylsilyloxy)chroman-4-
one (5a)
7-(triisopropylsilyloxy)-4-chromanone (400 mg, 1.25 mmol)
was treated with a heterogeneous mixture of CuBr2 (900 mg,
4 mmol) in CHCl3–ethyl acetate (30 mL, 1:1) and the resulted mix-
ture was refluxed for 5 h. The mixture was filtered, washed with
ethyl acetate and the solvent was evaporated. The resulted oil
was purified by column chromatography using petroleum ether–
ethyl acetate (90:10) as the mobile phase to afford compound 5a
(300 mg, 60% yield). 1H NMR (DMSO-d6, 80 MHz) d: 7.79 (d, 1H,
H5, J = 8.0 Hz), 6.48 (dd, 1H, H6, J = 2.5 Hz, J = 8.0 Hz), 6.40 (d, 1H,
H8, J = 2.5 Hz), 4.58–4.40 (m, 3H, H2,H3), 1.3–1 (m, 21 H, isopropyl),
Anal. Calcd for C18H27BrO3Si: C, 54.13; H, 6.81. Found: C, 54.35; H,
6.62.
4.1.7. (E)-3-(4-Benzylpiperidin-1-yl)-1-(2,4-
dihydroxyphenyl)prop-2-en-1-one 6d
Compound 6d (70% yield) mp 82–84 °C, IR cmꢀ1: 3544 (OH),
1618 (C@O), 1H NMR (DMSO-d6, 500 MHz), d: 14.4 (s, 1H, phenolic
OH), 7.89 (d, 1H, Ha, J = 12.0 Hz), 7.57 (d, 1H, H6, J = 8.0 Hz), 7.3–7.1
(m, 5H, phenyl), 6.46 (dd, 1H, H5-phenyl, J = 2.0 Hz, J = 8.0 Hz), 6.12
(d, 1H, H3-phenyl, J = 2.0 Hz), 5.98 (d, 1H, Hb, J = 12.0 Hz), 2.87–
2.76 (m, 2H, piperidine), 2.42 (s, 2H, CH2, benzylic), 2.10 (s, 1H,
OH-piperidine), 1.70–1.50 (m, 6H, piperidine), EI-MS m/z (%) 337
(M+, 18), 174 (100) Anal. Calcd for C21H23NO3: C, 74.75; H, 6.87;
N, 4.15. Found: C, 74.96; H, 6.53; N, 3.98.
4.1.2. Synthesis of 3-bromo-7-methoxy-4-chromanone (5b)
This compound was prepared according to the method de-
scribed for 5a, through the reaction of 7-methoxy-chroman-4-

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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.

A. Sakhteman et al. / Bioorg. Med. Chem. 17 (2009) 6908–6913
6913
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Acknowledgement
This work was financially supported by grants from Research
Council of Tehran University of Medical Sciences and INSF (Iran Na-
tional Science Foundation).
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