Design and synthesis of 4-benzylpiperidine carboxamides as dual serotonin and norepinephrine reuptake inhibitors

Article abstract of DOI:10.1016/j.bmc.2015.08.022

A series of 4-benzylpiperidine carboxamides were designed and synthesized, and tested for their dual (serotonin and norepinephrine) reuptake inhibition. The synthesis of 4-benzylpiperidine carboxamides involved two main steps: amidation and substitution. Derivatives with 3 carbon linker displayed better activity than with 2 carbon linker. 4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j showed greater dual reuptake inhibition than standard drug venlafaxine HCl.

Full text of DOI:10.1016/j.bmc.2015.08.022

Bioorganic & Medicinal Chemistry 23 (2015) 6418–6426
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Design and synthesis of 4-benzylpiperidine carboxamides as dual
serotonin and norepinephrine reuptake inhibitors
Suresh Paudel a, Yongkai Cao a, Shuohan Guo a, Byeongkwan An b, Kyeong-Man Kim a,
,
⇑
Seung Hoon Cheon a,
⇑
a College of Pharmacy and Research Institute of Drug Development, Chonnam National University, Gwangju 61186, Republic of Korea
b Jeonnam Development Institute for Korean Traditional Medicine, 288, Udeuraendeu-gil, Anyang-myeon, Jangheung-gun, Jeollanam-do 59338, Republic of Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of 4-benzylpiperidine carboxamides were designed and synthesized, and tested for their dual
(serotonin and norepinephrine) reuptake inhibition. The synthesis of 4-benzylpiperidine carboxamides
involved two main steps: amidation and substitution. Derivatives with 3 carbon linker displayed better
activity than with 2 carbon linker. 4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j showed
greater dual reuptake inhibition than standard drug venlafaxine HCl.
Received 10 July 2015
Revised 18 August 2015
Accepted 19 August 2015
Available online 20 August 2015
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
4-Benzylpiperidine carboxamide
Serotonin reuptake inhibitor
Norepinephrine reuptake inhibitor
1. Introduction
and may work as serotonin reuptake inhibitors.20 Furthermore,
arylalkanol-piperidine derivatives 6 with similar structural moi-
Depression is a common and severe illness.1,2 Chronic sadness,
loss of interest, disruption in sleep patterns, fatigue and sometimes
suicidal intension are common features observed in depressed
individuals.3–5 The primary cause of depression is deficiency of
monoamine neurotransmitters, serotonin (5-HT), norepinephrine
(NE) and dopamine (DA) in the brain. Monoamine reuptake inhibi-
tors maintain the concentration of neurotransmitters in the brain
through inhibition of presynaptic monoamine reuptake trans-
porter.6–10 Drugs that inhibit dual (5-HT and NE) neurotransmit-
ters reuptake are prescribed for the treatment of several central
nervous system (CNS) illnesses including depression.11–16
eties also possess serotonin and norepinephrine reuptake inhibi-
tion.21 Thus, considering the structure of trazodone, 5 and 6, we
designed 4-benzylpiperidine carboxamides 7, 8 as possible dual
reuptake inhibitors (Fig. 2). 4-Benzylpiperidine carboxamides 7
and 8 which differ in the length of linker were considered to
explore their impact on inhibition of neurotransmitters reuptake.
The synthesis, biological evaluation and detailed structure–activity
relationship (SAR) of the 4-benzylpiperidine carboxamides are
detailed below.
2. Chemistry
Drawbacks of the selective 5-HT reuptake inhibitors fluoxetine
(1), paroxetine (2) and sertraline (3) include delayed onset of
action and side effects of insomnia and sexual dysfunction
(Fig. 1).17 Trazodone (4), which has a different chemical scaffold
than the other antidepressant drugs, works as a 5-HT reuptake
inhibitor and is devoid of these limitations and side effects.18,19
The drug essentially consists of heterocyclic amine (A), linker (B)
and aromatic region (C) (Fig. 2). Arylpiperazine-containing pyrim-
idine 4-carboxamide derivatives 5 that have three fundamental
components also display good binding affinity for 5-HT transporter
Various aromatic carboxylic acids 9a–9i were refluxed
overnight with excess thionyl chloride and the residue obtained
by evaporating the solvent was further reacted with 3-bromo-
propylamine hydrobromide or 2-chloroethylamine hydrochloride
in the presence of triethylamine (TEA) to give different amides
10a–10i and 11a–11i (Scheme 1). Alternatively, amidation reaction
between aromatic carboxylic acid 9j–9l and 3-bromopropylamine
hydrobromide or 2-chloroethylamine hydrochloride using
1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride
(EDCIꢀHCl) as a coupling reagent gave corresponding amides
10j–10l and 11j–11l. The substitution reaction of 10a–10l and
11a–11l with 4-benzylpiperidine gave carboxamides derivatives
7a–7l and 8a–8l.
⇑
Corresponding authors. Tel.: +82 625302936; fax: +82 625302949 (K.-M.K.);
tel.: +82 625302929; fax: +82 625302911 (S.H.C.).
E-mail addresses: kmkim@jnu.ac.kr (K.-M. Kim), shcheon@jnu.ac.kr (S.H. Cheon).
http://dx.doi.org/10.1016/j.bmc.2015.08.022
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

S. Paudel et al. / Bioorg. Med. Chem. 23 (2015) 6418–6426
6419
H
N
H
N
H
N
O
F
F
F
O
Cl
Cl
1
2
3
F
Figure 1. Some marketed antidepressants (selective 5-HT reuptake inhibitors)—fluoxetine (1), paroxetine (2) and sertraline (3).
A
B
C
A
B
C
O
O
O
N
N
N
N
N
H
Ar
N
N
7
8
4
5
Cl
Cl
N
N
O
H
N
Ar
N
H
N
N
HO
6
N
S
Figure 2. Design of 4-benzylpiperidine carboxamides.
.
HCl H2N(CH2)2Cl
HN
O
or
O
O
O
.
HBr
H2N(CH2)3Br
()
R1
N
()
R1
OH
R1
Cl
R1
N
H
n N
n X
H
iv
i
ii
10a-10l: n = 3
11a 11l
7a-7l: n = 3
8a-8l: n = 2
9a-9i
-
: n = 2
iii
.
O
HCl H2N(CH2)2Cl
or
+
R1
OH
.
HBr
H2N(CH2)3Br
9j-9l
O
R1
R1 =
OH
Cl
*
*
*
*
N
H
S
O
Cl
a
b
c
d
*
*
*
N
*
Cl
Cl
e
f
g
k
h
l
*
*
*
*
Br
MeO
j
i
Scheme 1. Reagents and conditions: (i) SOCl2, benzene/toluene/tetrahydrofuran, reflux; (ii) CH2Cl2, TEA, 0 °C–rt; (iii) EDCIꢀHCl, DMAP, TEA, rt; (iv) DMSO, TEA, 100 °C.

6420
S. Paudel et al. / Bioorg. Med. Chem. 23 (2015) 6418–6426
Table 1
Serotonin and norepinephrine reuptake inhibition by 4-benzylpiperidine carboxamides 7a–l and 8a–l
Compd
R1
RIa
RIb
Compd
R1
RIa
RIb
7a
7b
7c
7d
7e
7f
7g
7h
7i
3,5-Dichlorophenyl
2-Indolyl
Benzo(b)furanyl
Benzo(b)thiophenyl
4-Biphenyl
Diphenylacetyl
Bis(4-chlorophenyl)acetyl
2-Quinolyl
1-Naphthyl
2-Naphthyl
6-Bromo-2-naphthyl
6-Methoxy-2-naphthyl
0.83
0.84
0.84
1.10
1.01
0.26
0.19
0.85
0.6
1.12
1.72c
1.54c
1.80c
1.59c
1.19c
1.37c
0.62c
1.32
1.03
8a
8b
8c
8d
8e
8f
8g
8h
8i
3,5-Dichlorophenyl
2-Indolyl
Benzo(b)furanyl
Benzo(b)thiophenyl
4-Biphenyl
Diphenylacetyl
Bis(4-chlorophenyl)acetyl
2-Quinolyl
1-Naphthyl
2-Naphthyl
6-Bromo-2-naphthyl
6-Methoxy-2-naphthyl
0.64
0.58
0.78
0.77
0.98
0.29
0.40
1.03
0.91
0.8
1.00
1.49c
1.09c
1.92c
1.49c
1.04c
1.54c
0.53
0.10
7j
7k
7l
0.95
1.11
0.98
8j
8k
8l
1.27
0.83
0.94
1.00
0.51
0.63
1.97c
a
b
c
Relative inhibition (serotonin reuptake inhibition at 1 lM by compound under test/venlafaxine HCl).
Relative inhibition (norepinephrine reuptake inhibition at 1
lM by compound under test/GBR-12909).
Relative inhibition (norepinephrine reuptake inhibition at 3
lM by compound under test/venlafaxine HCl).
take inhibitory activity of the selected compounds are presented in
Table 2.
3. Result and discussion
3.1. Biological screening
The fact that serotonin reuptake inhibition by 4-ben-
zylpiperidine carboxamides with a three-carbon linker is better
than the compounds with a two-carbon linker was reinforced by
the IC50 values of 4-biphenyl derivatives 7e and 8e. The activity
of 7e was 17-times better than of 8e. The serotonin reuptake inhi-
bitory activities of compounds containing fused heterocyclic ring
were in the following increasing order: 2-indolyl (7b) < benzo(b)-
furanyl (7c) < benzo(b)thiophenyl (7d). Furthermore, the activity
of unsubstituted naphthyl derivative 7j was greater than
6-bromo-7k and 6-methoxy-substituted 7l naphthyl compounds.
Among 10, 4-benzylpiperidine carboxamides, compounds 7e and
7j showed 3.5- and 2-times better serotonin reuptake inhibitory
activity than the standard drug, venlafaxine HCl.
Norepinephrine reuptake inhibition by all 4-benzylpiperidine
carboxamides, except 7d (IC50: 4.75 lM), was greater than the
standard drug, venlafaxine HCl. The norepinephrine reuptake inhi-
bitory activity of 4-biphenyl derivative 7e is additional evidence of
the greater activity achieved with a three-carbon linker than with a
two-carbon linker.
Serotonin and norepinephrine reuptake activities were mea-
sured by a neurotransmitter uptake assay. In the assay, human
embryonic kidney 293 (HEK-293) cells were stably transfected
with human serotonin transporter (hSERT) and human nore-
pinephrine transporter (hNET). The serotonin and norepinephrine
inhibitory activities of the synthesized compounds are presented
in Table 1.
Generally, 4-benzylpiperidine carboxamide derivatives with
three carbon units in the linker showed better serotonin reuptake
inhibitory activities than the compounds with two carbon units.
However, compounds 7h and 7i with longer linkers were less
active than analogs 8h and 8i with shorter linkers. The serotonin
reuptake inhibition of derivatives 7f–7g and 8f–8g with bulky
diphenyl acetyl groups was very low irrespective of the length of
the linker. The remaining derivatives possessed moderate to potent
serotonin reuptake inhibitory activity compared to venlafaxine (RI:
0.5–1.11).
Inhibition of reuptake of norepinephrine by 4-benzylpiperidine
carboxamides also varied mainly on the length of linker. The com-
pounds with a three-carbon linker showed better activity than
compounds with a two-carbon linker. Interestingly, the activity
of 1-naphthyl compound 7i was increased significantly by 13-fold
when the length of linker was extended from two to three carbons.
Majority of 4-benzylpiperidine carboxamides displayed equipotent
or more potent inhibition of norepinephrine reuptake than ven-
lafaxine and GBR-12909.
4-Benzylpiperidine carboxamides 7a, 7b, 7c, 7d, 7e, 7j, 7k, 7l,
8e, and 8h with potent relative serotonin/norepinephrine reuptake
inhibitory activities (RI >0.8) were further analyzed to determine
IC50 values. The IC50 values of serotonin and norepinephrine reup-
4. Conclusion
In summary, we developed 4-benzylpiperidine carboxamide-
based dual reuptake inhibitors. Compounds with various linker
lengths and aromatic rings were synthesized by amidation and
substitution reactions. Primary screening at a single concentration
and IC50 values showed that the compounds having a three-carbon
linker were more active than the ones with a two-carbon linker.
4-Biphenyl- and 2-naphthyl-substituted derivatives 7e and 7j
showed better dual reuptake inhibition than the standard drug,
venlafaxine HCl. Thus, based on the presented results, 4-ben-
zylpiperidine carboxamide can be the basis for the further develop-
ment of promising antidepressant drugs.
Table 2
IC50 value for serotonin and norepinephrine reuptake inhibition of the compounds
5. Experimental section
5.1. Chemistry
Compd
n
R1
hSERT (lM)
hNET (lM)
7a
7b
7c
7d
7e
7j
7k
7l
3
3
3
3
3
3
3
3
2
2
—
3,5-Dichlorophenyl
2-Indolyl
Benzo(b)furanyl
Benzo(b)thiophenyl
4-Biphenyl
0.422
0.546
0.500
0.449
0.056
0.108
1.914
0.323
0.986
0.786
0.204
0.267
0.268
0.621
4.75
0.153
0.342
0.885
0.238
0.472
0.275
2.553
Melting points were determined by the capillary method on
Thomas Hoover melting point apparatus and were uncorrected.
Infrared (IR) spectra were recorded on a JASCO-FT IR spectrometer
using KBr pellets. 1H and 13C NMR data were collected on a Varian
75, 125 and 300 MHz spectrometer and are reported in ppm,
downfield from the peak of the internal standard, tetramethylsi-
lane. Data are reported as chemical shift, number of protons, mul-
tiplicity (s: singlet, d: doublet, t: triplet, q: quartet, quin: quintet,
2-Naphthyl
6-Bromo-2-naphthyl
6-Methoxy-2-naphthyl
4-Biphenyl
2-Quinolyl
—
8e
8h
Venlafaxine HCl

S. Paudel et al. / Bioorg. Med. Chem. 23 (2015) 6418–6426
6421
m: multiplet). Mass spectra were obtained on a Shimadzu UFLC-
MS liquid chromatograph mass spectrometer using the electron
spray ionization (ESI) method. Column chromatography was per-
formed on Merck silica gel 60 (70–230 mesh). Thin-layer chro-
matography was performed using plates coated with silica gel 60
F254 (Merck). Chemical reagents were purchased from Sigma-
Aldrich and Alfa Aesar, and were used without further purification.
(20 mL) in presence of benzene (20 mL), 3-bromopropylamine
hydrobromide (1637 mg, 7.48 mmol and TEA (2 mL, 14.97 mmol)
to obtain 10e (952 mg, 60%) as white solid. Rf = 0.62 (n-hexane/
EtOAc = 1:1). Mp = 135 °C. IR (cmꢂ1): 3324 (NH). 1H NMR
(300 MHz, CDCl3): d 7.87–7.82 (m, 2H, Ar-H), 7.67–7.58 (m, 4H,
Ar-H), 7.50–7.36 (m, 3H, Ar-H), 6.42 (s, 1H, –CONH), 3.69–3.61
(m, 2H), 3.51 (t, J = 6.4 Hz, 2H, –CH2Br), 2.20 (quin, J = 6.5, 2H,
–CH2CH2Br).
5.1.1. N-(3-Bromopropyl)-3,5-dichlorobenzamide (10a)
Compound 9a (191 mg, 1 mmol) was refluxed in excess of thio-
nyl chloride (3 mL) overnight. Excess of thionyl chloride was evap-
orated and the residue was dissolved in CH2Cl2, 3-
bromopropylamine hydrobromide (328 mg, 1.5 mmol was added
followed by triethylamine (TEA; 0.42 mL, 3 mmol). The reaction
mixture was stirred at room temperature. After the reaction was
completed, the reaction mixture was diluted with CH2Cl2 and
sequentially washed with water, 1 N HCl and saturated NaHCO3.
The organic layer was dried over MgSO4, filtered and concentrated.
The obtained product was purified by column chromatography
with n-hexane/ethyl acetate (EtOAc) = 4:1 to obtain 10a, (236 mg,
76%) as white solid. Retention factor Rf = 0.85 (n-hexane/
5.1.6. N-(3-Bromopropyl)-2,2-diphenylacetamide (10f)
The procedure described for the preparation of 10a was used
with compound 9f (600 mg, 2.82 mmol), thionyl chloride (10 mL)
in presence of benzene (10 mL), 3-bromopropylamine hydrobro-
mide (926 mg, 4.23 mmol and TEA (1.17 (10 mL), 8.46 mmol) to
obtain 10f (563 mg, 63%) as light brown liquid. Rf = 0.82 (n-hex-
ane/EtOAc = 1:1). 1H NMR (300 MHz, CDCl3): d 7.43–7.32 (m,
ꢁ11H, Ar-H, overlapped with CHCl3), 7.16 (s, 1H, –CONH), 3.51
(q, J = 6.4 Hz, 2H, –CONH-CH2), 3.38 (t, J = 6.4 Hz, 2H, –CH2Br),
2.17–2.10 (m, 2H, –CH2CH2Br).
5.1.7. N-(3-Bromopropyl)-2,2-bis(4-chlorophenyl)acetamide
(10g)
EtOAc = 1:1). Mp = 98 °C. 1H NMR (300 MHz, CDCl3):
d 7.62
(d, J = 1.8 Hz, 2H, Ar-H), 7.49 (s, J = 1.8 Hz, 1H, Ar-H), 6.38 (s, 1H,
–CONH), 3.62 (q, J = 6.4 Hz, –CONH-CH2), 3.49 (t, J = 6.3 Hz, 2H,
–CH2Br), 2.21 (quin, J = 6.5 Hz, 2H, –CH2CH2Br).
The procedure described for the preparation of 10a was used
with compound 9g (300 mg, 1.06 mmol), thionyl chloride (5 mL),
3-bromopropylamine hydrobromide (348 mg, 1.59 mmol and TEA
(0.44 mL, 3.18 mmol) to obtain 10g (175 mg, 43%) as white solid
Rf = 0.83 (n-hexane/EtOAc = 1:1). Mp = 109 °C. IR (cmꢂ1): 3448
(NH). 1H NMR (300 MHz, CDCl3): d 7.36–7.25 (m, ꢁ11H, over-
lapped with CHCl3 peak), 3.56–3.43 (m, 2H, –CONH-CH2), 3.37 (t,
J = 6.45, 2H, –CH2Br), 2.11 (q, J = 6.5, 2H, –CH2CH2Br).
5.1.2. N-(3-Bromopropyl)-1H-indole-2-carboxamide (10b)
The procedure described for the preparation of 10a was used
with compound 9b (400 mg, 2.48 mmol), thionyl chloride (8 mL)
in presence of THF (10 mL), 3-bromopropylamine hydrobromide
(814 mg, 3.71 mmol) and TEA (1 mL, 7.44 mmol) to obtain 10b
(314 mg, 45%) as light yellow solid. Rf = 0.75 (n-hexane/
EtOAc = 1:1). Mp = 97 °C. 1H NMR (300 MHz, CDCl3): d 9.27 (s,
1H, –NH), 7.65 (dd, J = 8.1, 0.9 Hz, 1H, Ar-H), 7.44 (dd, J = 8.4,
0.9 Hz, 1H, Ar-H), 7.32–7.26 (m, ꢁ3H, Ar-H, overlapped with CHCl3
peak), 7.17–7.12 (m, 1H, Ar-H), 6.84 (dd, J = 2.1, 0.9 Hz, 1H, Ar-H),
6.37 (s, 1H, –CONH), 3.66 (q, J = 6.5 Hz, 2H, –CONH-CH2), 3.51 (t,
J = 6.45 Hz, 2H, –CH2Br), 2.33 (quin, J = 6.45 Hz, 2H, –CH2CH2Br).
5.1.8. N-(3-Bromopropyl)quinoline-2-carboxamide (10h)
The procedure described for the preparation of 10a was used
with compound 9h (550 mg, 3.17 mmol), thionyl chloride (8 mL),
3-bromopropylamine hydrobromide (1040 mg, 4.75 mmol) and
TEA (1.32 mL, 9.51 mmol) to obtain 10 h (697 mg, 75%) as white
solid Rf = 0.87 (n-hexane/EtOAc = 1:1). Mp = 94 °C. IR (cmꢂ1):
3526 (NH). 1H NMR (300 MHz, CDCl3): d 8.42 (s, 1H, –CONH),
8.30 (s, 2H, Ar-H), 7.88 (ddd, J = 8.1, 1.5, 0.6 Hz, 1H, Ar-H), 7.77
(ddd, J = 8.4, 6.9, 1.5 Hz, 1H, Ar-H), 7.62 (ddd, J = 8.1, 6.9, 1.2 Hz,
1H, Ar-H), 7.59 (d, J = 6.9 Hz, 1H, Ar-H), 3.74–3.66 (m, 2H,
–CONH-CH2), 3.53 (t, J = 6.6 Hz, 2H, –CH2Br), 2.27 (quin, J = 6.6,
2H, –CH2CH2Br).
5.1.3. N-(3-Bromopropyl)benzo(b)furan-2-carboxamide (10c)
The procedure described for the preparation of 10a was used
with compound 9c (300 mg, 1.85 mmol), thionyl chloride (5 mL)
in presence of benzene (10 mL), 3-bromopropylamine hydrobro-
mide (607 mg, 2.77 mmol), TEA (0.77 mL, 5.55 mmol) to obtain
10c (480 mg, 92%) as white solid. Rf = 0.72 (n-hexane/EtOAc = 1:1).
Mp = 88 °C. 1H NMR (300 MHz, CDCl3): d 7.63 (ddd, J = 7.8, 1.2,
0.6 Hz, 1H, Ar-H), 7.48–7.45 (m, 2H, Ar-H), 7.39 (ddd, J = 8.4, 7.2,
1.2 Hz, 1H, Ar-H), 7.29–7.24 (m, 1H, Ar-H), 7.04 (s, 1H, –CONH),
3.64 (q, J = 6.5 Hz, 2H, –CONH-CH2), 3.49 (t, J = 6.6 Hz, 2H, –CH2Br),
2.21 (quin, J = 6.5 Hz, 2H, –CH2CH2Br).
5.1.9. N-(3-Bromopropyl)-1-naphthamide (10i)
The procedure described for the preparation of 10a was used
with compound 9i (500 mg, 2.90 mmol), thionyl chloride (10 mL)
in presence of toluene (10 mL), 3-bromopropylamine hydrobro-
mide (952 mg, 4.35) and TEA (1.21 mL, 8.7 mmol) to obtain 10i
(626 mg 74%) as white solid. Rf = 0.74 (n-hexane/EtOAc = 1:1).
Mp = 104 °C. 1H NMR (300 MHz, CDCl3): d 8.24–8.21 (m, 1H, Ar-
H), 7.88–7.82 (m, 2H, Ar-H), 7.52–7.49 (m, 3H, Ar-H), 7.40–7.35
(m, 1H, Ar-H), 6.41 (s, 1H, –CONH), 3.59 (q, J = 6.4 Hz, 2H, –
CONHCH2), 3.46 (t, J = 6.4 Hz, 2H, –CH2Br), 2.18 (quin, J = 6.4 Hz,
2H, –CH2CH2Br).
5.1.4. N-(3-Bromopropyl)benzo[b]thiophene-2-carboxamide
(10d)
The procedure described for the preparation of 10a was used
with compound 9d (220 mg, 1.23 mmol), thionyl chloride (3 mL)
in presence of toluene (5 mL), 3-bromopropylamine hydrobromide
(402 mg, 1.84 mmol) and TEA (0.51 mL, 3.69 mmol to obtain 10d
(325 mg, 89%) as white solid. Rf = 0.74 (n-hexane/EtOAc = 1:1).
Mp = 122 °C. 1H NMR (300 MHz, CDCl3): d 7.86–7.79 (m, 3H, Ar-
H), 7.43–7.38 (m, 2H, Ar-H), 6.47 (s, 1H, –CONH), 3.64 (q,
J = 6.4 Hz, 2H, –CONH-CH2), 3.51 (t, J = 6.3 Hz, 2H, –CH2Br), 2.23
(quin, J = 6.4 Hz, 2H, –CH2CH2Br).
5.1.10. N-(3-Bromopropyl)-2-naphthamide (10j)
The 9j (250 mg, 1.45 mmol) was dissolved in CH2Cl2 (5 mL).
EDCIꢀHCl (333 mg, 1.74 mmol) was added to reaction mixture fol-
lowed by DMAP (8.9 mg, 0.07 mmol). To the reaction solution 3-
bromopropylamine hydrobromide (317 mg, 1.45 mmol) was added
and stirred for 30 min. TEA (0.66 mL, 4.78 mmol) was poured
slowly drop wise and stirred reaction at room temperature. After
the reaction was completed, the reaction mixture was diluted with
CH2Cl2 and washed with water. The organic layer was dried over
MgSO4, filtered and concentrated. The obtained product was
5.1.5. N-(3-Bromopropyl)-1,2-dihydro-[1,10-biphenyl]-4-
carboxamide (10e)
The procedure described for the preparation of 10a was used
with compound 9e (1000 mg, 4.99 mmol), thionyl chloride

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S. Paudel et al. / Bioorg. Med. Chem. 23 (2015) 6418–6426
purified by column chromatography with hexane/EtOAc (4:1) to
obtain 10j (266 mg, 63%) as white solid. Rf = 0.79 (n-hexane/
EtOAc = 1:1). Mp = 124 °C. 1H NMR (300 MHz, CDCl3): d 8.28 (s,
1H, 1-H), 7.92–7.80 (m, 4H, Ar-H), 7.60–7.51 (m, 2H, Ar-H), 6.54
(s, 1H, –CONH), 3.68 (q, J = 6.4 Hz, 2 Hz, –CONH-CH2), 3.53 (t,
J = 6.3, 2H, –CH2Br), 2.25 (quin, J = 6.6 Hz, 2H, –CH2CH2Br).
5.1.16. N-(2-Chloroethyl)benzo[b]thiophene-2-carboxamide
(11d)
The procedure described for the preparation of 10a was used
with compound 9d (200 mg, 1.12 mmol), thionyl chloride (3 mL)
in presence of toluene (5 mL), 2-chloroethylamine hydrochloride
(195 mg, 1.68 mmol) and TEA (0.46 mL, 3.36 mmol) to obtain 11d
(228 mg, 85%) as white solid. Rf = 0.73 (n-hexane/EtOAc = 1:1).
Mp = 144 °C. IR (cmꢂ1): 3316 (NH). 1H NMR (300 MHz, CDCl3): d
7.87–7.80 (m, 3H, Ar-H), 7.46–7.37 (m, 2H, Ar-H), 6.62 (s, 1H,
–CONH), 3.86–3.80 (m, 2H), 3.77–3.73 (m, 2H).
5.1.11. 6-Bromo-N-(3-chloropropyl)-2-naphthamide (10k)
The procedure described for the preparation of 10j was used
with compound 9k (300 mg, 1.19 mmol), EDCIꢀHCl (272 mg,
1.42 mmol), DMAP (11.31 mg, 0.06 mmol), 3-bromopropylamine
hydrobromide (260 mg, 1.19 mmol) and TEA (0.54 mL, 3.92 mmol)
to obtain 10k (242 mg, 55%) as white solid. Rf = 0.71 (n-hexane/
EtOAc = 1:1). Mp = 98 °C. 1H NMR (300 MHz, CDCl3): d 8.25 (s,
1H, Ar-H), 8.04 (d, J = 1.8 Hz, 1H, Ar-H), 7.86–7.77 (m, 3H, Ar-H),
7.61 (dd, J = 8.7, 1.8 Hz, 1H, 7-H), 6.5 (s, 1H, –CONH), 3.68 (q,
J = 6.4, 2H, –CONH-CH2), 3.53 (t, J = 6.45, 2H, –CH2Br), 2.26 (quin,
J = 6.45, 2H, –CH2CH2Br).
5.1.17. N-(2-Chloroethyl)-1,2-dihydro-[1,10-biphenyl]-4-
carboxamide (11e)
The procedure described for the preparation of 10a was used
with compound 9e (1000 mg, 4.99 mmol), thionyl chloride
(20 mL) in presence of benzene (20 mL), 2-chloroethylamine
hydrochloride (867 mg, 7.48 mmol and TEA (2 mL, 14.97 mmol)
to obtain 11e (718 mg, 55%) as white solid. Rf = 0.61 (n-hexane/
EtOAc = 1:1). Mp = 172 °C. 1H NMR (300 MHz, CDCl3): d 7.89–7.84
(m, 2H, Ar-H), 7.70–7.60 (m, 4H, Ar-H), 7.50–7.36 (m, 3H, Ar-H),
6.58 (s, 1H, –CONH), 3.87–3.75 (m, 4H).
5.1.12. N-(3-Bromopropyl)-6-methoxy-2-naphthamide (10l)
The procedure described for the preparation of 10j was used
with compound 9l (500 mg, 2.47 mmol), EDCIꢀHCl (567 mg,
2.96 mmol), DMAP (14.6 mg, 0.12 mmol), 3-bromopropylamine
hydrobromide (540 mg, 2.47 mmol) and TEA (1.1 mL, 8.15 mmol)
to obtain 10l (493 mg, 62%) as white solid. Rf = 0.54 (n-hexane/
EtOAc = 1:1). Mp = 118 °C. 1H NMR (300 MHz, CDCl3): d 8.20 (s,
1H, Ar-H), 7.81–7.74 (m, 3H, Ar-H), 7.20–7.13 (m, 2H, Ar-H), 6.54
(s, 1H, –CONH), 3.93 (s, 1H, –OCH3), 3.66 (q, J = 6.4 Hz, 2H,
–CONHCH2), 3.52 (t, J = 6.4 Hz, 2H, –CH2Br), 2.24 (quin, J = 6.4 Hz,
2H, –CH2CH2Br).
5.1.18. N-(2-Chloroethyl)-2,2-diphenylacetamide (11f)
The procedure described for the preparation of 10a was used
with compound 9f (530 mg, 2.49 mmol), thionyl chloride (10 mL)
in presence of benzene, 2-chloroethylamine hydrochloride
(432 mg, 3.73 mmol and TEA (1 mL, 7.47 mmol) to obtain 11f
(386 mg, 60%) as light yellow liquid. Rf = 0.82 (n-hexane/
EtOAc = 1:1). 1H NMR (300 MHz, CDCl3): d 7.43–7.33 (m, 11H),
3.73–3.65 (m, 4H).
5.1.19. N-(2-Chloroethyl)-2,2-bis(4-chlorophenyl)acetamide
(11g)
5.1.13. 3,5-Dichloro-N-(2-chloroethyl)benzamide (11a)
The procedure described for the preparation of 10a was used
with compound 9a (400 mg, 2.09 mmol), thionyl chloride (5 mL),
2-chloroethylamine hydrochloride (365 mg, 3.14 mmol) and tri-
ethylamine (TEA; 0.87 mL, 6.27 mmol) to obtain 11a (422 mg,
80%) as white solid. Rf = 0.85 (n-hexane/EtOAc = 1:1). Mp = 135 °
C. IR (cmꢂ1): 1634 (C@O). 1H NMR (300 MHz, CDCl3): d 8.90 (s,
1H, –CONH), 7.87 (d, J = 1.8 Hz, 2H, Ar-H), 7.83 (t, J = 1.95 Hz, 1H,
Ar-H), 3.73 (t, J = 11.7 Hz, –CONH-CH2).
The procedure described for the preparation of 10a was used
with compound 9g (300 mg, 1.06 mmol), thionyl chloride (5 mL),
2-chloroethylamine hydrochloride (184 mg, 1.59 mmol and TEA
(0.44 mL), 3.18 mmol) to obtain 11g (138 mg, 40%) as white solid.
Rf = 0.85 (n-hexane/EtOAc = 1:1). Mp = 129 °C. 1H NMR (300 MHz,
CDCl3): d 7.48–7.42 (m, 1H, –CONH), 7.37–7.30 (m, ꢁ9H, Ar-H,
overlapped with CHCl3 peak), 3.73–3.64 (m, 4H).
5.1.20. N-(2-Chloroethyl)quinoline-2-carboxamide (11h)
The procedure described for the preparation of 10a was used
with compound 9h (200 mg, 1.15 mmol), thionyl chloride (3 mL),
2-chloroethylamine hydrochloride (200 mg, 1.72 mmol and TEA
(0.48 mL, 3.45 mmol) to obtain 11h (200 mg, 74%) as white solid.
Rf = 0.68 (n-hexane/EtOAc = 1:1). Mp = 85 °C. 1H NMR (300 MHz,
CDCl3): d 8.65 (s, 1H, –CONH), 8.30 (d, J = 2.1 Hz, 2H, Ar-H), 8.14–
8.11 (m, 1H, Ar-H), 7.8 (dd, J = 8.1, 0.9 Hz, 1H, Ar-H), 7.75 (ddd,
J = 8.4, 6.9, 1.5 Hz, 1H, Ar-H), 7.62 (ddd, J = 8.1, 6.9, 1.5 Hz, 1H,
Ar-H), 3.93–3.86 (m, 2H), 3.80–3.76 (m, 2H).
5.1.14. N-(2-Chloroethyl)-1H-indole-2-carboxamide (11b)
The procedure described for the preparation of 10a was used
with compound 9b (500 mg, 3.10 mmol), thionyl chloride
(10 mL) in presence of THF (10 mL), 2-chloroethylamine
hydrochloride (835 mg, 4.65 mmol) and TEA (1.3 mL, 9.3 mmol)
to obtain 11b (345 mg, 50%) as light yellow solid. Rf = 0.74 (n-hex-
ane/EtOAc = 1:1). Mp = 158 °C. IR (cmꢂ1): 3444 (NH). 1H NMR
(300 MHz, CDCl3): d 10.43 (s, 1H, –NH), 7.65 (dd, J = 8.1, 0.9 Hz,
1H, Ar-H), 7.57 (t, J = 5.4 Hz, 1H, –CONH), 7.41 (m, 1H, Ar-H),
7.31 (m, 1H, Ar-H), 7.24 s, 1H, Ar-H), 7.20 (ddd, J = 8.1, 6.9,
1.2 Hz, 1H, Ar-H), 3.94 (q, J = 5.7 Hz, 2H, –CONH-CH2), 3.78 (t,
J = 5.8 Hz, 2H, –CH2Cl).
5.1.21. N-(2-Chloroethyl)-1-naphthamide (11i)
The procedure described for the preparation of 10a was used
with compound 9i (600 mg, 3.48 mmol), thionyl chloride (10 mL)
in presence of toluene (10 mL), 2-chloroethylamine hydrochloride
(605 mg, 5.22 mmol) and TEA (1.45 ml, 8.7 mmol) to obtain 11i
(528 mg (65%) as white solid. Rf = 0.60 (n-hexane/EtOAc = 1:1).
Mp = 104 °C. IR (cmꢂ1): 3310 (NH). 1H NMR (300 MHz, CDCl3): d
8.21–8.18 (m, 1H, 1-H), 7.82–7.77 (m, 2H, Ar-H), 7.48–7.44 (m,
3H, Ar-H), 7.32–7.27 (m, 1H, Ar-H), 6.80 (s, 1H, –CONH), 3.68–
3.58 (m, 4H).
5.1.15. N-(2-Chloroethyl)benzo(b)furan-2-carboxamide (11c)
The procedure described for the preparation of 10a was used
with compound 9c (324 mg, 2 mmol), thionyl chloride (5 mL) in
presence of benzene (10 mL), 2-chloroethylamine hydrochloride
(348 mg, 3 mmol) and TEA (0.83 mL, 6 mmol) to obtain 11c
(402 mg, 90%) as white solid. Rf = 0.72 (n-hexane/EtOAc = 1:1).
Mp = 115 °C. IR (cmꢂ1): 3691 (NH). 1H NMR (300 MHz, CDCl3): d
7.69–7.66 (m, 1H, Ar-H), 7.54–7.49 (m, 2H, Ar-H), 7.46–7.4 (m,
1H, Ar-H), 7.33–7.27 (m, 1H, Ar-H), 7.04 (s, 1H, –CONH),
3.88–3.82 (m, 2H), 3.78–3.73 (m, 2H).
5.1.22. N-(2-Chloroethyl)-2-naphthamide (11j)
The procedure described for the preparation of 10j was used
with compound 9j (320 mg, 1.85 mmol), EDCIꢀHCl (425 mg,

S. Paudel et al. / Bioorg. Med. Chem. 23 (2015) 6418–6426
6423
2.22 mmol), DMAP (11 mg, 0.01 mmol), 2-chloroethylamine
5.1.27. N-(3-(4-Benzylpiperidin-1-yl)propyl)benzo(b)furan-2-
carboxamide (7c)
hydrochloride (214 mg, 1.85 mmol) and TEA (0.85 mL, 6.10 mmol)
to obtain 11j (259 mg, 60%) as white solid. Rf = 0.60 (n-hexane/
EtOAc = 1:1). Mp = 138 °C. IR (cmꢂ1): 3058 (NH). 1H NMR
(300 MHz, CDCl3): d 8.31 (s, 1H, Ar-H), 7.95–7.82 (m, 4H, Ar-H),
7.61–7.52 (m, 2H, Ar-H), 6.71 (s, 1H, –CONH), 3.91–3.77 (m, 4H).
The procedure described for the preparation of 7a was used
with compound 10c (300 mg, 1.06 mmol), 4-benzylpiperidine
(0.37 mL, 2.12 mmol), TEA (0.59 mL, 4.24 mmol) and DMSO
(2.5 mL) to obtain 7c (183 mg, 46%) as white solid. Rf = 0.40 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 104 °C. IR (cmꢂ1): 3203 (NH).
1H NMR (300 MHz, CDCl3): d 8.71 (s, 1H, –CONH), 7.68–7.65 (m,
1H, Ar-H), 7.55 (dd, J = 8.4, 0.9 Hz, 1H, Ar-H), 7.45–7.38 (m, 2H,
Ar-H), 7.31–7.11 (m, ꢁ7H, Ar-H, overlapped with CHCl3), 3.58 (q,
J = 5.6 Hz, 2H, –CONH-CH2), 2.98 (d, J = 11.7 Hz, 2H, –CH2Ph), 2.60
(d, J = 6.6 Hz, 2H), 2.49 (t, J = 5.8 Hz, 2H, –CH2N), 1.92–1.38 (m,
9H); 13C NMR (125 MHz, CDCl3): d 158.8, 154.8, 149.6, 140.6,
129.0, 128.3, 127.8, 126.5, 125.9, 123.6, 122.7, 111.5, 109.9, 58.6,
54.2, 43.3, 40.2, 38.2, 32.3, 24.7. HRMS (ESI): m/z 377.2162 (M
+H)+ (calcd for C24H29N2O2, 377.2229).
5.1.23. 6-Bromo-N-(2-chloroethyl)-2-naphthamide (11k)
The procedure described for the preparation of 10j was used
with compound 9k (251 mg, 0.99 mmol), EDCIꢀHCl (226 mg,
1.18 mmol), DMAP (6 mg, 0.05 mmol), 2-chloroethylamine
hydrochloride (115 mg, 0.99 mmol) and TEA (0.45 mL, 3.26 mmol)
to obtain 11k (161 mg, 52%) as white solid. Rf = 0.77 (n-hexane/
EtOAc = 1:1). Mp = 150 °C. IR (cmꢂ1): 307 (NH). 1H NMR
(300 MHz, CDCl3): d 8.27 (s, 1H, Ar-H), 8.04 (s, 1H, Ar-H), 7.88–
7.77 (m, 3H, Ar-H), 7.63–7.59 (m, 1H, Ar-H), 6.75 (s, 1H, –CONH),
3.90–3.76 (m, 4H).
5.1.28. N-(3-(4-Benzylpiperidin-1-yl)propyl)benzo[b]thiophene-
2-carboxamide (7d)
5.1.24. N-(2-Chloroethyl)-6-methoxy-2-naphthamide (11l)
The procedure described for the preparation of 10j was used
with compound 9l (500 mg, 2.47 mmol), EDCIꢀHCl (567 mg,
2.96 mmol), DMAP (14.6 mg, 0.12 mmol), 2-chloroethylamine
hydrochloride (286 mg, 2.47 mmol) and TEA (1.1 mL, 8.15 mmol)
to obtain 11l (390 mg, 60%) as white solid. Rf = 0.57 (n-hexane/
EtOAc = 1:1). Mp = 133 °C. IR (cmꢂ1): 3657 (NH). 1H NMR
(300 MHz, CDCl3): d 8.23 (s, 1H, Ar-H), 7.83–7.76 (m, 3H, Ar-H),
7.22–7.15 (m, 2H, Ar-H), 6.69 (s, 1H, –CONH), 3.94 (s, 1H,
–OCH3), 3.89–3.83 (m, 2H), 3.80–3.76 (m, 2H).
The procedure described for the preparation of 7a was used
with compound 10d (310 mg, 1.04 mmol), 4-benzylpiperidine
(0.37 mL, 2.08 mmol), TEA (0.58 mL, 4.16 mmol) and DMSO
(2.5 mL) to obtain 7d (221 mg, 54%) as white solid. Rf = 0.31 (n-
hexane/EtOAc/MeOH = 2.5:1.5:1). Mp = 111 °C. IR (cmꢂ1): 3225
(NH). 1H NMR (300 MHz, CDCl3): d 8.75 (s,1H, –CONH), 7.90–7.81
(m, 3H, Ar-H), 7.46–7.38 (m, 2H, Ar-H), 7.29–7.07 (m, ꢁ6H, Ar-H,
overlapped with CHCl3), 3.57 (q, J = 5.4 Hz, 2H, –CONH-CH2), 3.00
(d, J = 12 Hz, 2H, –CH2Ph), 2.52–2.50 (m, 4H), 1.91–1.83 (m, 2H),
1.79–1.72 (m, 2H), 1.69–1.51 (m, 3H), 1.43–1.30 (m, 2H); 13C
NMR (125 MHz, CDCl3): d 162.3, 140.8, 140.4, 139.6, 139.2, 129.0,
128.3, 126.1, 125.9, 124.9, 124.8, 122.7, 58.8, 54.2, 43.5, 41.3,
37.8, 32.4, 24.4. HRMS (ESI): m/z 393.1943 (M+H)+ (calcd for
5.1.25. N-(3-(4-Benzylpiperidin-1-yl)propyl)-3, 5-dichlorobenza
mide (7a)
The mixture of compound 10a (130 mg, 0.41 mmol), 4-ben-
zylpiperidine (0.15 mL, 0.83 mmol), TEA (0.23 mL, 1.67 mmol)
and DMSO (1 mL) was stirred at 100 °C. After the reaction was
completed, the water was added to the reaction mixture and
extracted with ethyl acetate. The organic layer was dried over
MgSO4, filtered and concentrated. The obtained product was puri-
fied by column chromatography on silica gel with n-hexane/EtOAc/
MeOH (10:1.5:0.5) to obtain 7a (101 mg, 60%) as white solid.
Rf = 0.51 (n-hexane/EtOAc/MeOH = 2.5:1.5:1). Mp = 105 °C. IR
(cmꢂ1): 3311 (NH). 1H NMR (300 MHz, CDCl3): d 9.12 (s, 1H,
–CONH), 7.73 (d, J = 2.1 Hz, 2-H), 7.51 (t, J = 1.8 Hz, 1H, 4-H),
7.30–7.17 (m, ꢁ6H, Ar-H, overlapped with CHCl3), 3.55 (q,
J = 5.2 Hz, 2H, –CONH-CH2), 3.00 (d, J = 11.7 Hz, 2H, –CH2Ph),
2.58–2.52 (m, 4H), 1.85 (t, J = 10.95, 2H, –CH2N), 1.78–1.49 (m,
5H), 1.31–1.18 (m, 2H); 13C NMR (125 MHz, CDCl3): d 164.5,
140.6, 138.0, 135.2, 131.0, 129.0, 128.2, 125.9, 125.8, 59.5, 54.3,
42.8, 42.0, 38.1, 32.5, 23.5. HRMS (ESI): m/z 405.1443 (M+H)+
(calcd for C22H27Cl2N2O, 405.1500).
C24H29N2OS, 393.2000).
5.1.29. N-(3-(4-Benzylpiperidin-1-yl)propyl)-[1,10-biphenyl]-4-
carboxamide (7e)
The procedure described for the preparation of 7a was used
with compound 10e (300 mg, 0.94 mmol), 4-benzylpiperidine
(0.33 mL, 1.88 mmol), TEA (0.52 mL, 3.76 mmol) and DMSO
(3 mL) to obtain 7e (213 mg, 55%) as white solid. Rf = 0.28 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 108 °C. IR (cmꢂ1): 3103 (NH).
1H NMR (300 MHz, CDCl3): d 8.62 (s, 1H, –CONH), 7.92–7.88 (m,
2H, Ar-H), 7.67–7.61 (m, 4H, Ar-H), 7.50–7.30 (m, 3H, Ar-H),
7.27–7.08 (m, ꢁ7H, Ar-H, overlapped with CHCl3), 3.58 (q,
J = 5.4 Hz, 2H, –CONH-CH2), 2.99 (d, J = 11.7 Hz, 2H, –CH2Ph),
2.55–2.52 (m, 4H), 1.92–1.73 (m, 4H), 1.66–1.52 (m, 3H), 1.31–
1.25 (m, 2H); 13C NMR (125 MHz, CDCl3): d 167.1, 143.9, 140.4,
140.2, 133.9, 129.1, 129.0, 128.3, 128.0, 127.8, 127.2, 127.0,
125.9, 58.7, 54.1, 43.5, 41.0, 37.8, 32.4, 24.6. HRMS (ESI): m/z
413.2527 (M+H)+ (calcd for C28H33N2O, 413.2593).
5.1.26. N-(3-(4-Benzylpiperidin-1-yl)propyl)-1H-indole-2-
carboxamide (7b)
5.1.30. N-(3-(4-Benzylpiperidin-1-yl)propyl)-2,2-diphenyl
acetamide (7f)
The procedure described for the preparation of 7a was used
with compound 10b (400 mg, 1.42 mmol), 4-benzylpiperidine
(0.50 mL, 2.84 mmol), TEA (0.79 mL, 5.68 mmol) and DMSO
(3 mL) to obtain 7b (239 mg, 45%) as light yellow solid. Rf = 0.42
(n-hexane/EtOAc/MeOH = 2.5:1.5:1). Mp = 113 °C. IR (cmꢂ1): 3344
(NH). 1H NMR (300 MHz, CDCl3): d 7.65 (d, J = 8.1 Hz, 1H, Ar-H),
7.57 (t, J = 5.6 Hz, 1H, –CONH), 7.46 (d, J = 8.4 Hz, 1H, Ar-H),
7.35–7.08 (m, 9H), 3.65 (q, J = 6.3 Hz, 2H, –CONH-CH2), 2.91 (d,
J = 11.7 Hz, 2H, –CH2Ph), 2.51–2.43 (m, 4H), 1.89–1.81 (m, 4H),
1.62–1.45 (m, 3H), 1.36–1.25 (m, 2H); 13C NMR (125 MHz, CDCl3):
160.9, 140.6, 134.6, 129.1, 128.2, 125.8, 125.7, 125.3, 125.9, 121.0,
119.2, 112.7, 105.1, 56.6, 54.1, 43.2, 38.2, 37.9, 31.9, 29.8, 26.3.
The procedure described for the preparation of 7a was used
with compound 10f (350 mg, 1.05 mmol), 4-benzylpiperidine
(0.37 mL, 2.1 mmol), TEA (0.58 mL, 4.2 mmol) and DMSO (3 mL)
to obtain 7f (237 mg, 53%) as white solid. Rf = 0.40 (n-hexane/
EtOAc = 1:1). Mp = 115 °C. 1H NMR (300 MHz, CDCl3): d 7.54–7.01
(m, ꢁ17H, overlapped with CHCl3), 4.79 (s, 1H, –CH), 3.29
(q, J = 5.7 Hz, 2H, –CONH-CH2), 2.75 (d, J = 10.8 Hz, 2H, –CH2Ph),
2.49 (d, J = 6.6 Hz, 2H), 2.29 (t, J = 6.3 Hz, 2H, –CH2N), 1.74 (t,
J = 11.1, Hz),1.59–1.43 (m, 5H), 1.14–1.03 (m, 2H); 13C NMR
(125 MHz, CDCl3): d 171.8, 140.9, 139.6, 128.9, 128.7, 128.4,
128.0, 126.9, 125.7, 59.0, 57.2, 53.7, 42.9, 39.4, 37.6, 31.9, 25.1.

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S. Paudel et al. / Bioorg. Med. Chem. 23 (2015) 6418–6426
5.1.31. N-(3-(4-Benzylpiperidin-1-yl)propyl)-2,2-bis(4-chloro
phenyl)acetamide (7g)
5.1.35. N-(3-(4-Benzylpiperidin-1-yl)propyl)-6-bromo-2-
naphthamide (7k)
The procedure described for the preparation of 7a was used
with compound 10g (200 mg, 0.49 mmol), 4-benzylpiperidine
(0.17 mL, 0.98 mmol), TEA (0.27 mL, 2.96 mmol) and DMSO
(2 mL) to obtain 7g (84 mg, 35%) as light brown liquid. Rf = 0.30,
(n-hexane/EtOAc = 1:1). 1H NMR (300 MHz, CDCl3): d 7.64 (t,
J = 4.0 Hz, 1H, –CONH), 7.36–7.25 (m, ꢁ7H, Ar-H, overlapped with
CHCl3), 7.20–7.16 (m, 2H, Ar-H), 3.35 (q, J = 5.7 Hz, 2H, –CONH-
CH2), 2.80 (d, J = 11.7 Hz, 2H, –CH2Ph), 2.51 (d, J = 6.9 Hz, 2H),
2.36 (t, J = 6.1, 2H, –CH2N), 1.83–1.75 (m, 2H), 1.66–1.45 (m, 5H),
1.11–1.02 (m, 2H); 13C NMR (75 MHz, CDCl3): d 170.7, 140.2,
137.9, 133.2, 130.0, 129.1, 128.8, 128.2, 125.9, 57.70, 57.66, 53.8,
43.0, 40.0, 37.7, 32.0, 24.6.
The procedure described for the preparation of 7a was used
with compound 10k (120 mg, 0.32 mmol), 4-benzylpiperidine
(0.11 mL, 0.64 mmol), TEA (0.18 mL, 1.28 mmol) and DMSO
(1 mL) to obtain 7k (65 mg, 44%) as white solid. Rf = 0.38 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 100 °C. IR (cmꢂ1): 3286 (NH).
1H NMR (300 MHz, CDCl3): d 8.85 (t, J = 4.3 Hz, 1H, –CONH), 8.08
(d, J = 1.8 Hz, 1H, Ar-H), 7.94 (d, J = 1.5 Hz, 1H, Ar-H), 7.85–7.77
(m, 2H, Ar-H), 7.63 (dd, J = 8.7 Hz, 1.8 Hz, 1H, Ar-H), 7.29–7.14
(m, ꢁ4H, Ar-H, overlapped with CHCl3), 7.05–7.02 (m, 2H, Ar-H),
3.61 (q, J = 5.4 Hz, 2H, –CONH-CH2), 2.30 (d, J = 11.7 Hz, 2H, –CH2-
Ph), 2.55 (t, J = 5.5 Hz, 2H), 2.45 (d, J = 6.9, 2H), 1.91–1.70 (m, 4H),
1.66–1.50 (m, 3H), 1.25–1.17 (m, 2H); 13C NMR (125 MHz, CDCl3):
d 167.1, 140.1, 135.6, 132.7, 131.0, 130.4, 130.0, 129.9, 128.9,
128.2, 127.3, 127.2, 125.9, 125.1, 121.6, 58.5, 53.9, 43.0, 40.9,
5.1.32. N-(3-(4-Benzylpiperidin-1-yl)propyl)quinoline-2-carbo
xamide (7h)
37.6, 32.0, 24.1. HRMS (ESI): m/z 465.1505 (M+H)+ (calcd for C26
-
The procedure described for the preparation of 7a was used
with compound 10h (100 mg, 0.34 mmol), 4-benzylpiperidine
(0.12 mL, 0.68 mmol), TEA (0.19 mL, 1.36 mmol) and DMSO
(2 mL) to obtain 7h (70 mg, 53%) as white solid. Rf = 0.34 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 130 °C. IR (cmꢂ1): 3280 (NH).
H3079BrN2O, 465.1542), 467.1478 (M+H)+ (calcd for C26H3081BrN2O,
467.1521).
5.1.36. N-(3-(4-Benzylpiperidin-1-yl)propyl)-6-methoxy-2-
naphthamide (7l)
1H NMR (300 MHz, CDCl3):
d
8.87 (s, 1H, –CONH), 8.30
The procedure described for the preparation of 7a was used
with compound 10l (200 mg, 0.62 mmol), 4-benzylpiperidine
(0.22 mL, 1.24 mmol), TEA (0.34 mL, 2.48 mmol) and DMSO
(2 mL) to obtain 7l (129 mg, 50%) as brown solid. Rf = 0.29 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 118 °C. IR (cmꢂ1): 3277 (NH).
(t, J = 9 Hz, 1H, Ar-H), 8.18 (d, J = 8.4 Hz, 2H, Ar-H), 7.88
(d, J = 8.4 Hz, 1H, Ar-H), 7.80–7.75 (m, 1H, Ar-H), 7.61 (t,
J = 7.5 Hz, 1H, Ar-H), 7.27–7.08 (m, 5H, Ar-H), 3.62 (q, J = 9.3 Hz,
2H, –CONH-CH2), 2.97 (d, J = 11.4 Hz, 2H, –CH2Ph), 2.53–2.47 (m,
4H), 1.91–1.64 (M, 4H), 1.60–1.35 (m, 5H); 13C NMR (125 MHz,
CDCl3): d 164.8, 150.0, 146.5, 140.2, 137.2, 130.0, 129.8, 129.3,
129.0, 128.2, 127.85, 127.75, 125.9, 118.9, 56.8, 53.8, 42.7, 41.0,
38.5, 37.6, 31.1, 29.7, 25.8.
1H NMR (300 MHz, CDCl3):
d 8.84 (s, 1H, CONH), 8.38 (d,
J = 1.2 Hz, 1H, Ar-H), 8.28 (d, J = 8.7 Hz, 1H, Ar-H),7.98 (dd, J = 9.1,
8.1 Hz, 1H, Ar-H), 7.91 (d, J = 9.3 Hz, 1H, Ar-H), 7.38 (d, J = 9 Hz,
1H, Ar-H), 7.28–7.15 (m, ꢁ5H, Ar-H, overlapped with CHCl3),
7.07–7.04 (m, 2H, Ar-H), 4.06 (s, 3H, –OCH3), 3.62 (q, J = 5.3 Hz,
2H, –CONH-CH2), 3.01 (d, J = 11.1 Hz, 2H, –CH2Ph), 2.56
(t, J = 5.5 Hz, 2H), 2.47 (d, J = 6.9 Hz, 2H), 1.92–1.75 (m, 4H),
1.66–1.48 (m, 3H), 1.30–1.25 (m, 2H); 13C NMR (125 MHz, CDCl3):
d 167.5, 158.9, 140.4, 136.1, 130.33, 130.28, 129.0, 128.2, 128.0,
127.2, 126.8, 125.9, 124.8, 119.5, 105.7, 58.7, 55.3, 54.0, 43.2,
41.0, 37.8, 32.3, 24.6. HRMS (ESI): m/z 417.2480 (M+H)+ (calcd
for C27H33N2O2, 417.2542).
5.1.33. N-[3-(4-Benzylpiperidin-1-yl)propyl]-1-naphthamide
(7i)
The procedure described for the preparation of 7a was used
with compound 10i (100 mg, 0.34 mmol), 4-benzylpiperidine
(0.12 mL, 0.68 mmol), TEA (0.19 mL, 1.36 mmol) and DMSO
(1 mL) to obtain 7i (59 mg, 45%) as white solid. Rf = 0.66 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 125 °C. 1H NMR (300 MHz,
CDCl3): d 8.59 (s, 1H, –CONH), 8.38–8.35 (m, 1H, Ar-H), 7.94–
7.86 (m, 2H, Ar-H), 7.64–7.49 (m, 4H, Ar-H), 7.25–7.12 (m, 3H,
Ar-H), 6.97–6.95 (m, 2H, Ar-H), 3.63 (q, J = 5.5 Hz, 2H, –CONH-
CH2), 2.81 (d, J = 11.4 Hz, 2H, –CH2Ph), 2.47 (t, J = 5.8, 2H), 2.15
(d, J = 5.8 Hz, 2H), 1.79–1.69 (m, 4H), 1.36–1.25 (m, 3H), 0.66–
0.53 (m, 2H); 13C NMR (125 MHz, CDCl3): d 169.4, 140.5, 135.4,
133.7, 130.3, 130.2, 129.0, 128.3, 128.1, 126.9, 126.3, 125.8,
125.7, 125.0, 124.7, 58.3, 53.7, 43.0, 40.8, 37.5,32.0, 29.7, 24.6.
5.1.37. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-3,5-dichloroben
zamide (8a)
The procedure described for the preparation of 7a was used
with compound 11a (100 mg, 0.40 mmol), 4-benzylpiperidine
(0.14 mL, 0.80 mmol) and TEA (0.22 mL, 1.6 mmol) in DMSO
(1 mL) to obtain 8a (101 mg, 60%) as white solid. Rf = 0.61 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 109 °C. 1H NMR (300 MHz,
CDCl3): d 7.63 (d, J = 1.8 Hz, 2H, Ar-H), 7.48 (t, J = 1.8 Hz, 1H, Ar-
H), 7.30–7.25 (m, ꢁ6H, Ar-H, overlapped with CHCl3), 6.84 (s, 1H,
–CONH), 3.49 (q, J = 5.6 Hz, 2H, –CONH-CH2), 2.88 (d, J = 11.7 Hz,
2H, –CH2Ph), 2.56–2.52 (m, 4H), 1.97 (ddd, J = 11.7, 2.1 Hz, 2H, –
CH2N), 1.69–1.48 (m, 3H), 1.35–1.21 (m, 2H); 13C NMR
(125 MHz, CDCl3): d 164.9, 140.5, 137.7, 135.3, 131.1, 129.1,
128.2, 125.9, 125.7, 56.6, 53.7, 43.1, 37.9, 36.9, 32.2.
5.1.34. N-(3-(4-Benzylpiperidin-1-yl)propyl)-2-naphthamide
(7j)
The procedure described for the preparation of 7a was used
with compound 10j (100 mg, 0.52 mmol), 4-benzylpiperidine
(0.19 mL, 1.04 mmol), TEA (0.29 mL, 2.08 mmol) and DMSO
(1 mL) to obtain 7j (100 mg, 50%) as white solid. Rf = 0.36 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 118 °C. IR (cmꢂ1): 3226 (NH).
1H NMR (300 MHz, CDCl3): d 8.84 (s, 1H, –CONH), 8.34 (s, 1H, 1-
H), 7.99–7.87 (m, 4H, Ar-H), 7.59–7.53 (m, 2H, Ar-H), 7.26–7.11
(m, 2H, Ar-H, overlapped with CHCl3), 7.03–7.01(m, 2H, Ar-H),
3.62 (q, J = 5.3 Hz, 2H, –CONHCH2), 3.00 (d, J = 11.7 Hz, 2H, –CH2-
Ph), 2.55 (t, J = 5.7 Hz, 2H, –CH2N), 2.43 (d, J = 6.9 Hz, 2H), 1.91–
1.75 (m, 4H), 1.64–1.49 (m, 3H), 1.29–1.17 (m, 2H); 13C NMR
(300 MHz, CDCl3): d 167.5, 140.4, 134.7, 132.7, 132.6, 129.0,
128.9, 128.23, 128.15, 127.8, 127.4, 127.3, 126.6, 125.9, 124.2,
58.9, 54.1, 43.2, 41.3, 37.8, 32.4, 24.4. HRMS (ESI): m/z 387.2329
(M+H)+ (calcd for C26H31N2O, 387.2436).
5.1.38. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-1H-indole-2-carbox
amide (8b)
The procedure described for the preparation of 7a was used
with compound 11b (300 mg, 1.34 mmol), 4-benzylpiperidine
(0.47 mL, 2.68 mmol), TEA (0.74 mL, 5.36 mmol) and DMSO
(2 mL) to obtain 8b (208 mg, 43%) as light yellow solid. Rf = 0.45
(n-hexane/EtOAc/MeOH = 2.5:1.5:1).
Mp = 169 °C.
1H
NMR
(300 MHz, CDCl3): d 7.66 (d, J = 7.2, 1H, Ar-H), 7.46–7.43 (m, 1H,
Ar-H). 7.30–7.10 (m, ꢁ10H, Ar-H, overlapped with CHCl3), 7.03
(s, J = 4.5 Hz, 1H, –CONH), 6.84 (d, J = 1.2 Hz, 1H, Ar-H), 3.5 (q,
J = 5.7 Hz, 2H, –CONH-CH2), 2.92 (d, J = 11.7, 2H, –CH2Ph), 2.62–

S. Paudel et al. / Bioorg. Med. Chem. 23 (2015) 6418–6426
6425
2.48 (m, 4H), 2.02–1.94 (m, 2H), 1.69–1.51 (m, 3H), 1.38–1.30 (m,
5.1.43. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-2,2-bis(4-chloro
phenyl)acetamide (8g)
2H); 13C NMR (75 MHz, CDCl3): d 161.8, 140.4, 136.3, 130.9, 129.0,
128.2, 127.6, 125.9, 124.2, 121.8, 120.4, 112.0, 102.3, 56.8, 53.6,
43.0, 37.8, 36.1, 31.9.
The procedure described for the preparation of 7a was used with
compound 11g (180 mg, 0.52 mmol), 4-benzylpiperidine (0.18 mL,
1.04 mmol), TEA (0.29 mL, 2.08 mmol) and DMSO (2 mL) to obtain
8g (82 mg, 33%) as white solid. Rf = 0.35 (n-hexane/EtOAc = 1:1).
Mp = 107 °C. 1H NMR (300 MHz, CDCl3): d 7.29–7.24 (m, 6H, Ar-H),
7.18–7.12 (m, 7H, Ar-H), 6.50 (s, 1H, –CONH), 4.83 (s, 1H, –CH),
3.28 (q, J = 5.5 Hz, 2H, CONH-CH2), 2.64 (d, J = 11.4 Hz, 2H, –CH2Ph),
2.50 (d, J = 6.9 Hz, 2H), 2.33 (t, J = 5.8 Hz, 2H, –CH2N), 1.81 (t,
J = 10.8 Hz, 2H), 1.55–1.37 (m, 3H), 1.04–0.95 (m, 2H); 13C NMR
(125 MHz, CDCl3): d 171.0, 160.8, 140.6, 137.9, 133.3, 130.3, 129.1,
128.9, 128.2, 125.9, 57.1, 56.1, 53.4, 43.2, 37.8, 36.4, 32.2.
5.1.39. N-(2-(4-Benzylpiperidin-1-yl)ethyl)benzo(b)furan-2-
carboxamide (8c)
The procedure described for the preparation of 7a was used
with compound 11c (400 mg, 1.78 mmol), 4-benzylpiperidine
(0.63 mL, 3.56 mmol), TEA (1.0 mL, 7.12 mmol) and DMSO (3 mL)
to obtain 8c (342 mg, 53%) as white solid. Rf = 0.45 (n-hexane/
EtOAc/MeOH = 2.5:1.5:1). Mp = 125 °C. 1H NMR (300 MHz, CDCl3):
d 7.67 (ddd, 7.8, 1.2, 0.6 Hz, 1H), 7.54–7.51 (m, 1H), 7.44–7.38 (m,
2H), 7.31–7.14 (m, ꢁ8H, overlapped with CHCl3), 3.55 (q, J = 5.8 Hz,
2H, –CONH-CH2), 2.91 (d, J = 11.7 Hz, 2H, –CH2Ph), 2.58–2.55 (m,
4H), 2.02–1.93 (m, 2H), 1.68–1.48 (m, 3H), 1.39–1.30 (m, 2H);
13C NMR (125 MHz, CDCl3): d 158.9, 154.8, 149.1, 140.6, 129.1,
128.2, 127.7, 126.7, 125.8, 123.6, 122.6, 111.8, 110.1, 56.8, 53.8,
43.2, 37.9, 36.3, 32.3.
5.1.44. N-(2-(4-Benzylpiperidin-1-yl)ethyl)quinoline-2-carbo
xamide (8h)
The procedure described for the preparation of 7a was used
with compound 11h (100 mg, 0.43 mmol), 4-benzylpiperidine
(0.15 mL, 0.86 mmol), TEA (0.24 mL, 1.72 mmol) and DMSO
(2 mL) to obtain 8h (112 mg, 55%) as white solid. Rf = 0.78 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 86 °C. 1H NMR (300 MHz,
CDCl3): d 8.58 (t, J = 4.8 Hz, 1H, –CONH), 8.23–8.26 (m, 2H, Ar-H),
8.10 (d, J = 8.7 Hz, 1H, 5-H), 7.85 (d, J = 8.1 Hz, 1H, 3-H), 7.79–
7.73 (m, 1H, Ar-H), 7.63–7.57 (m, 1H, Ar-H), 7.30–7.14 (m, ꢁ6H,
Ar-H, overlapped with CHCl3), 3.62 (q, J = 6.20 Hz, 2H, CONH-
CH2), 2.96 (d, J = 11.4 Hz, 2H, –CH2Ph), 2.62 (t, J = 6.4 Hz, 2H),
2.56 (d, J = 6.9 Hz, 2H), 2.04–1.96 (m, 2H), 1.68–1.49 (m, 3H),
1.41–1.30 (m, 2H); 13C NMR (125 MHz, CDCl3): d 164.4, 149.9,
146.4, 140.6, 137.3, 129.9, 129.7, 129.2, 129.0, 128.1, 127.7,
127.6, 125.7, 118.8, 57.1, 53.8, 43.1, 37.9, 36.6, 32.2. HRMS (ESI):
m/z 374.2221 (M+H)+ (calcd for C24H28N3O, 374.2232).
5.1.40. N-(2-(4-Benzylpiperidin-1-yl)ethyl)benzo[b]thiophene-
2-carboxamide (8d)
The procedure described for the preparation of 7a was used
with compound 11d (250 mg, 1.04 mmol), 4-benzylpiperidine
(0.37 mL, 2.08 mmol), TEA (0.58 mL, 4.16 mmol) and DMSO
(2 mL) to obtain 8d (204 mg, 52%) as white solid. Rf = 0.45 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 117 °C. 1H NMR (300 MHz,
CDCl3): d 7.84–7.77 (m, 3H, Ar-H), 7.42–7.11 (m, ꢁ8H, Ar-H, over-
lapped with CHCl3), 7.08 (s, 1H, –CONH), 3.51 (q, J = 5.7 Hz, 2H,
–CONH-CH2), 2.88 (d, J = 11.7 Hz, 2H, –CH2Ph), 2.52–2.51 (m, 4H),
1.99–1.91 (m, 2H), 1.67–1.48 (m, 3H), 1.35–1.26 (m, 2H); 13C
NMR (125 MHz, CDCl3): d 162.3, 140.8, 140.5, 139.2, 138.8, 129.1,
128.2, 126.2, 125.9, 125.1, 125.0, 124.8, 122.7, 56.8, 53.6, 43.1,
37.9, 36.7, 32.3.
5.1.45. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-1-naphthamide (8i)
The procedure described for the preparation of 7a was used
with compound 11i (100 mg, 0.43 mmol), 4-benzylpiperidine
(0.15 mL, 0.86 mmol), TEA (0.24 mL, 1.72 mmol) and DMSO
(1 mL) to obtain 8i (69 mg, 43%) as brown solid. Rf = 0.29 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 80 °C. 1H NMR (300 MHz,
CDCl3): d 8.37–8.32 (m, 1H, Ar-H), 7.93–7.85 (m, 2H, Ar-H), 7.61
(dd, J = 7.2, 1.2 Hz, 1H, Ar-H), 7.56–7.4 (m, 3H, Ar-H), 7.29–7.10
(m, ꢁ6H, Ar-H, overlapped with CHCl3), 6.60 (s, 1H, –CONH), 3.61
(q, J = 5.7 Hz, 2H, –CONH-CH2), 2.89 (d, J = 11.4 Hz, 2H, –CH2Ph),
2.57 (t, J = 6 Hz, 2H), 2.50 (d, J = 6.9 Hz, 2H), 2.00–1.91 (m, 2H),
1.65–1.49 (m, 3H), 1.29–1.20 (m, 2H); 13C NMR (125 MHz, CDCl3):
d 169.5, 140.5, 134.7, 133.7, 130.4, 130.2, 129.1, 128.3, 128.2,
127.0, 126.3, 125.9, 125.5, 125.1, 124.8, 56.8, 53.7, 43.1, 37.9,
36.8, 32.1, 29.7.
5.1.41. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-[1,10-biphenyl]-4-
carboxamide (8e)
The procedure described for the preparation of 7a was used
with compound 11e (250 mg, 0.96 mmol), 4-benzylpiperidine
(0.34 mL, 1.92 mmol), TEA (0.53 mL, 3.84 mmol) and DMSO
(2 mL) to obtain 8e (191 mg, 50%) as white solid. Rf = 0.29 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 148 °C. IR (cmꢂ1): 3027 (NH).
1H NMR (300 MHz, CDCl3): d 7.87–7.84 (m, 2H, Ar-H), 7.68–7.39
(m, 4H, Ar-H), 7.49–7.35(m, 3H, Ar-H), 7.31–7.16 (m, ꢁ6H, Ar-H,
overlapped with CHCl3), 7.02 (s, 1H, –CONH), 3.54 (q, J = 5.6 Hz,
2H, –CONH-CH2), 2.90 (d, J = 11.7, 2H, –CH2Ph), 2.59–2.51 (m,
6H), 2.10–1.93 (m, 2H), 1.68–1.51 (m, 3H), 1.35–1.24 (m, 2H);
13C NMR (125 MHz, CDCl3): d 167.2, 144.0, 140.6, 140.1, 133.5,
129.2, 129.0, 128.3, 128.0, 127.7, 127.20, 127.15, 125.9, 56.9,
53.7, 43.2, 37.9, 36.9, 32.4. HRMS (ESI): m/z 399.2386 (M+H)+
(calcd for C27H31N2O, 399.2436).
5.1.46. N-(2-(4-Benzylpiperidin-1-yl) ethyl)-2-naphthamide (8j)
The procedure described for the preparation of 7a was used with
compound 11j (100 mg, 0.43 mmol), 4-benzylpiperidine (0.15 mL,
0.86 mmol), TEA (0.24 mL, 1.72 mmol) and DMSO (1 mL) to obtain
8j (77 mg, 48%) as white solid. Rf = 0.72 (n-hexane/EtOAc/
MeOH = 2.5:1.5:1). Mp = 110 °C. 1H NMR (300 MHz, CDCl3): d 8.30
(s, 1H, Ar-H), 7.95–7.81 (m, 4H, Ar-H), 7.59–7.52 (m, 2H, Ar-H),
7.30–7.25 (m, ꢁ3H, Ar-H, overlapped with CHCl3), 7.21–7.13 (m,
3H, Ar-H), 3.58 (q, J = 5.6 Hz, 2H, –CONH-CH2), 2.93 (d, J = 11.7, 2H,
–CH2Ph), 2.62–2.54 (m, 4H), 2.04–1.96 (m, 2H, –CH2N), 1.70–1.50
((m, 3H), 1.37–1.28 (m, 2H); 13C NMR (125 MHz, CDCl3): d 167.5,
140.6, 134.7, 132.7, 132.0, 129.1, 129.0, 128.4, 128.2, 127.7, 127.5,
126.7, 125.9, 123.7, 56.8, 53.7, 43.2, 37.9, 36.9, 32.3.
5.1.42. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-2,2-diphenylaceta
mide (8f)
The procedure described for the preparation of 7a was used
with compound 11f (150 mg, 0.54 mmol), 4-benzylpiperidine
(0.19 mL, 1.08 mmol), TEA (0.30 mL, 2.16 mmol) and DMSO
(2 mL) to obtain 8f (111 mg, 50%) as light brown liquid. Rf = 0.31
(n-hexane/EtOAc = 1:1). 1H NMR (300 MHz, CDCl3): d 7.45–7.42
(m, 1H, Ar-H), 7.29–7.20 (m, 12H, Ar-H overlapped with CHCl3),
7.10–7.08 (m, 3H, Ar-H), 6.51 (s, 1H, –CONH), 3.30–3.23 (m, 2H),
2.62 (d, J = 11.1 Hz, 2H, –CH2Ph), 2.46 (d, J = 6.9 Hz, 2H), 2.29 (t,
J = 6.15, 2H), 1.78 (t, J = 10.8 Hz, 2H), 1.51–1.38 (m, 3H), 1.10–
0.95 (m, 2H); 13C NMR (125 MHz, CDCl3): d 171.8, 140.5, 139.7,
129.1, 129.0, 128.7, 128.4, 128.2, 127.9, 127.6, 127.1, 125.9, 59.2,
56.2, 53.4, 43.2, 37.7, 36.4, 32.0.
5.1.47. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-6-bromo-2-naphtha
mide (8k)
The procedure described for the preparation of 7a was used
with compound 11k (100 mg, 0.32 mmol), 4-benzylpiperidine

6426
S. Paudel et al. / Bioorg. Med. Chem. 23 (2015) 6418–6426
(0.11 mL, 0.64 mmol), TEA (0.18 mL, 1.28 mmol) and DMSO (1 mL)
to obtain 8k (60 mg, 42%) as white solid. Rf = 0.29 (n-hexane/
EtOAc/MeOH = 2.5:1.5:1). Mp = 151 °C. 1H NMR (300 MHz, CDCl3):
d 8.28 (s, 1H, Ar-H), 8.04 (d, J = 1.8 Hz, 1H, Ar-H), 7.87–7.78 (m, 3H,
Ar-H), 7.30–7.13 (m, ꢁ7H, overlapped with CHCl3), 3.58 (q,
J = 5.5 Hz, 2H, –CONH-CH2), 2.94 (d, J = 11.7 Hz, 2H, –CH2Ph),
2.62–2.54 (m, 4H), 2.05–1.96 (m, 2H), 1.70–1.51 (m, 3H), 1.38–
1.28 (m, 2H); 13C NMR (125 MHz, CDCl3): d 167.3, 139.9, 135.6,
131.8, 131.0, 130.7, 130.0, 129.7, 129.0, 128.3, 127.8, 127.3,
126.1, 124.9, 121.8, 57.0, 53.6, 42.7, 37.2, 36.2, 31.0.
PA, USA). Prepared cells were washed three times with ice cold
uptake buffer (200 L/well). Cell lysis was done by 0.3 mL of 1%
l
sodium dodecyl sulfate per well with shaking in a KMC-1205S sha-
ker (Vision Scientific, Daejeon, South Korea) for about 2 h. Radioac-
tivity was measured using a Wallac 1450 MicroBetaÒ TriLux liquid
scintillation counter (PerkinElmer). Venlafaxine hydrochloride was
used as a standard dual (5-HT and NA) reuptake inhibitor and GBR
12909 was used as the standard NA reuptake inhibitor.
Acknowledgments
5.1.48. N-(2-(4-Benzylpiperidin-1-yl)ethyl)-6-methoxy-2-naph
thamide (8l)
This research was supported by Basic Science Research Program
through the National Research Foundation of Korea (NRF) funded
by the Ministry of Education (Grant No. 2012R1A1A2006613)
and K.M. Kim was funded by KRF-2014R1A2A2A01002547. The
authors would like to thank the Korea basic science institute
Gwangju center for performing the 1H NMR and 13C NMR.
The procedure described for the preparation of 7a was used
with compound 11l (350 mg, 1.33 mmol), 4-benzylpiperidine
(0.47 mL, 2.66 mmol), TEA (0.74 mL, 5.32 mmol) and DMSO
(3 mL) to obtain 8l (256 mg, 48%) as white solid. Rf = 0.29 (n-hex-
ane/EtOAc/MeOH = 2.5:1.5:1). Mp = 155 °C. 1H NMR (300 MHz,
CDCl3): d 8.23 (s, 1H, 1-H), 7.83–7.74 (m, 3H, Ar-H), 7.30–7.12
(m, ꢁ8H, Ar-H, overlapped with CHCl3), 7.06 (t, J = 4.2 Hz, 1H, –
CONH), 3.92 (s, 1H, –OCH3), 3.56 (q, J = 5.6 Hz, 2H, –CONH-CH2),
2.91 (d, J = 11.4 Hz, 2H, –CH2Ph), 2.59–2.53 (m, 4H), 2.01–1.92
(m, 2H), 1.68–1.48 (m, 3H), 1.36–1.27 (m, 2H); 13C NMR
(125 MHz, CDCl3): d 167.5, 159.0, 140.5, 136.2, 130.5, 129.7,
129.1, 128.2, 128.1, 127.3, 127.0, 125.9, 124.2, 119.6, 105.6, 56.8,
55.4, 53.7, 43.1, 37.9, 36.6, 32.2.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2015.08.022.
References and notes
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l
L
l
l
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After 15 min, 100 l
L of the radiolabeled 60 nM 3H-SERT (Perk-
inElmer, Waltham, MA, USA) or 60 nM 3H-NET (PerkinElmer) per
well was added (final concentration/well, 20 nM) and incubated
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