Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent opioid receptor ligands

Article abstract of DOI:10.1016/j.bmc.2015.07.071

A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-(piperidin-4-yl)propionamide derivatives to study

Full text of DOI:10.1016/j.bmc.2015.07.071

Bioorganic & Medicinal Chemistry 23 (2015) 6185–6194
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry
journal homepage: www.elsevier.com/locate/bmc
Discovery of 5-substituted tetrahydronaphthalen-2yl-methyl with
N-phenyl-N-(piperidin-4-yl)propionamide derivatives as potent
opioid receptor ligands
Srinivas Deekonda a, Lauren Wugalter a, Vinod Kulkarni a, David Rankin b, Tally M. Largent-Milnes b,
Peg Davis b, Neemah M. Bassirirad b, Josephine Lai b, Todd W. Vanderah b, Frank Porreca b,
Victor J. Hruby a,
⇑
a Department of Chemistry and Biochemistry, University of Arizona, Tucson, AZ 85721, USA
b Department of Pharmacology, University of Arizona, Tucson, AZ 85721, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A new series of novel opioid ligands have been designed and synthesized based on the 4-anilidopiperidine
Received 28 May 2015
Revised 21 July 2015
Accepted 30 July 2015
Available online 4 August 2015
scaffold containing a 5-substituted tetrahydronaphthalen-2yl)methyl group with different N-phenyl-N-
(piperidin-4-yl)propionamide derivatives to study the biological effects of these substituents on
l and d
opioid receptor interactions. Recently our group reported novel 4-anilidopiperidine analogues, in which
several aromatic ring-contained amino acids were conjugated with N-phenyl-N-(piperidin-4-yl)
propionamide and examined their biological activities at the
l and d opioid receptors. In continuation
Keywords:
Opioids
Pain
Opioid receptors
4-Anilidopiperidines
of our efforts in these novel 4-anilidopiperidine analogues, we took a peptidomimetic approach in the pre-
sent design, in which we substituted aromatic amino acids with tetrahydronaphthalen-2yl methyl moiety
with amino, amide and hydroxyl substitutions at the 5th position. In in vitro assays these ligands, showed
very good binding affinity and highly selective toward the
20 showed excellent binding affinity (2 nM) and 5000 fold selectivity toward the
l
opioid receptor. Among these, the lead ligand
opioid receptor, as well
l
as functional selectivity in GPI assays (55.20 4.30 nM) and weak or no agonist activities in MVD assays.
Based on the in vitro bioassay results the lead compound 20 was chosen for in vivo assessment for efficacy
in naïve rats after intrathecal administration. Compound 20 was not significantly effective in alleviating
acute pain. This discrepancy between high in vitro binding affinity, moderate in vitro activity, and low
in vivo activity may reflect differences in pharmacodynamics (i.e., engaging signaling pathways) or
pharmacokinetics (i.e., metabolic stability). In sum, our data suggest that further optimization of this
compound 20 is required to enhance in vivo activity.
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
Abbreviations: ACN, acetonitrile; Boc, tert-butyloxycarbonyl; BH3-SMe2, Borane
dimethylsulfide; CHO, Chinese hamster ovary; DALEA, [D-Ala2, Leu5] enkephalin
amide; DCM, dichloromethane; DCE, dichloroethane; DOR, delta opioid receptor;
DHP, dihydropyran; DIPEA, N,N-diisopropylethylamine; DAMGO, [D-Ala2,
NMePhe4,Gly5-ol]enkephalin; DPDPE, c[D-Pen2,DPen5]enkephalin; Dmt, 2,6-
Chronic pain is one of the major public health problems in the
world, and more than one hundred million people in the United
States alone are debilitated by chronic pain during their life time.
Unfortunately, current treatments for pain are only partially effec-
tive, and many cause life style altering, debilitating, or dangerous
side effects. Opioid receptors are an important class of GPCRs
which modulate analgesic effects in humans. Among the three opi-
oid receptors, MOR receptors are the most important receptor tar-
get for almost all commercially available opioid agonists.1 The
dimethyltyrosine; GPI, guinea pig isolated ileum; GPCR,
G protein-coupled
receptor; HRMS, high resolution mass spectrometry; HCl, hydrochloric acid;
hDOR, human d opioid receptor; MOR, Mu opioid receptor; MVD, mouse vas
deferens; RP-HPLC, reverse phase high performance liquid chromatography; RT,
room temperature; NaOtBu, sodium tert-butoxide Pd2(dba)3; SAR, structure–
activity relationship; Na(OAc)3BH, sodium triacetoxyborohydride; Pd2dba3, tris
(dibenzylideneacetone)dipalladium; Et3N, triethylamine; Tyr, tyrosine; rMOR, rat
l
opioid receptor; TFA, trifluoroacetic acid; TLC, thin layer chromatography.
other two opioid receptors (d and j) have also a role in analgesia
but have other limitations. Opioids have been used throughout his-
tory for their antinociceptive activities. The presently available
⇑
Corresponding author at present address: Department of Chemistry and
Biochemistry, 1306 E. University Boulevard, Tucson, AZ 85721, USA. Tel.: +1 520
621 6332; fax: +1 520 621 8407.
E-mail address: hruby@email.arizona.edu (V.J. Hruby).
http://dx.doi.org/10.1016/j.bmc.2015.07.071
0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.

6186
S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
opioids have been effective in pain management, but they have
restricted use because of several severe side effects including res-
piratory depression, constipation, analgesic tolerance, physical
dependence, and addiction liabilities. Great efforts have been made
to develop novel opioid analgesics2–13 and this has become a hot
topic in medicinal chemistry. Therefore, there is a current need
for novel opioid ligands that retain analgesic properties and devoid
of side effect profile.
to Scheme 1. The intermediates 1, 3 and 4 were prepared following
synthetic routes described in the literature,21,22 and the intermedi-
ate 2 is commercially available. The treatment of intermediates (1
and 2) with iodo compound 3 in the presence of potassium carbon-
ate in acetone gave the Boc-protected analogues 5 and 7, respec-
tively. The desired compound 6 was prepared by a reductive
amination of intermediate 2 with aldehyde 4. The Boc-protected
analogues 5, 6 and 7 were converted to the corresponding amine
trifluoroacetate derivatives 8, 9 and 10 by treating with 50% triflu-
oroacetic acid in dichloromethane. The amine trifluoroacetate
derivatives 8 and 10 were transformed into the acetamide deriva-
tives 11 and 12 by treating with acetyl chloride in the presence of
triethyl amine in dichloromethane.
Since the discovery of fentanyl6 medicinal chemistry efforts have
yielded thousands of 4-anilidopiperidine analogues. The 4-anili-
dopiperidines have a prominent place due to their high potency,
low cardiovascular toxicity, fast onset, and short duration of action.
The synthesis of new fentanyl analogues with high potency but
reduced side effects is still one of the challenges of opioid research,
and within this context, many 4-anilidopiperidines have been
synthesized.8–14 Bagley et al.14 summarized in great detail the
evolution of the 4-anilidopiperidine class of opioid analgesics and
structure–activity relationships of fentanyl analogues. Here we
describe our approach and SAR of novel 4-anilidopiperidine ana-
2.2. Hydroxyl substituted 4-anilidopiperidine analogues (20–21)
The hydroxy substituted 4-anilidopiperidine analogues 20 and
21 were prepared by a route shown in Scheme 2. The S-alcohol
14 was prepared using the Corey–Bakshi–Shibata oxazaborolidine
reduction23 previously reported in the literature. Treating
S-alcohol 14 with 3, 4-dihydro-2H-pyran in presence of PPTS
(pyridinium p-toluenesulfonate) in dichloromethane gave the
tetrahydropyran protected alcohol 15 in good yield. The protected
alcohol 15 upon reduction with lithium aluminium hydride in
tetrahydrofuran afforded the alcohol 16, and when followed by
treatment with triphenylphosphine, imidazole and I2 gave the iodo
compound 17. The treatment of iodo compound 17 with different
piperidine analogues (1 and 2) in presence of potassium carbonate
in acetone obtained the different 4-anildiopiperidine analogues 18
and 19. Finally the hydroxy substituted analogues 20 and 21 were
achieved by deprotection of tetrahydropyranyl group with PPTS
(pyridinium p-toluenesulfonate) in methanol at reflux temperature
for 3 h.
logues and their biological activities at
l and d opioid receptors.
Portoghese co-workers,15 incorporated enkephalin peptides into
fentanyl, and synthesized 1- and 2-substituted fentanyl analogues.
The resulting analogues showed very weak or no opioid activity. For
the last decade our laboratory has been working on novel opioid
ligands based on the 4-anilidopiperidine and enkephalin conjugate
analogues.16–20 Recently our group reported a structural require-
ment of the 4-anilidopiperidine analogues16 in which the phenethyl
group of fentanyl was replaced by several aromatic ring-containing
amino acids. The biological effects of these analogues showed a
broad range of affinity toward
l and d opioid receptors. In continu-
ation of our efforts in these novel 4-anilidopiperidine analogues in
the present design (Fig. 1), we took a peptidomimetic approach;
where in the phenethyl group is replaced by tetrahydronaph-
thalen-2yl methyl moiety having amino, acetamide and hydroxyl
substitutions at the 5th position. Researchers at Neurosearch21
reported a design, synthesis and pharmacological evolution of
1-phenethylpiperidine derivatives, and their designs are based on
N-phenyl-N-(piperidin-4-ylmethyl)propionamide moiety. Initially
our designs are based on the 5-amino tetrahydronaphthalen-2yl-
methyl group with N-phenyl-N-(piperidin-4-ylmethyl)propi-
onamide derivatives. Further we expanded our design strategy to
(Fig. 1) 5-substituted (amine, amide and hydroxyl) tetrahydron-
apthalene methyl moiety with different 4-anilidopiperidine cores
such as N-phenyl-N-(piperidin-4-ylmethyl)propionamide and
N-phenyl-N-(piperidin-4-yl)propionamide. Our interest here is to
study the effect of the additional hydrophobic cyclohexyl group
with hydroxyl and amine functional group and variation in the
4-anilidopiperidine core on opioid binding and selectivity.
2.3. Phenyl substituted 4-anilidopiperidine analogues (38–40)
Scheme 3 outlines the procedures used to synthesize the phenyl
substituted 4-anilidopiperidine analogues 38, 39 and 40. Reductive
amination of different substituted phenylamine compounds 23, 24
and 25 with 1-benzylpiperidin-4-one using sodium triacetoxy-
borohydride in dichloroethane gave the desired compounds 26–28.
The compounds 29, 30 and 31 were obtained from the respective
amines by the treatment with propionyl chloride under basic con-
ditions. Treatment of 29, 30 and 31 with 1-chloroethylchlorofor-
mate followed by refluxing the resulting carbamate in methanol
afforded the N-debenzylated products 32, 33 and 34.
The piperidine analogues 32, 33 and 34 were treated with iodo
compound 3 in presence of potassium carbonate in acetone which
yielded the Boc-protected analogues 35, 36 and 37. The subsequent
removal of Boc-group provided the final 4-anilidopiperidine
analogues 38, 39 and 40 in good yield. The final compounds were
triturated with diethyl ether to get pure compounds.
2. Chemistry
2.1. Amine and amide substituted 4-anilidopiperidine
analogues (8–12)
3. Results and discussion
Here we described general synthetic method for the
preparation of the title compounds 8–12 (Scheme 1). The
4-anilidopiperidine analogues 8–12 were synthesized according
A series of novel 4-anilidopiperidine derivatives have been
synthesized and tested for biological activities at the
l and d opioid
R
R2
NH2
N
m
O
N
O
N
N
N
O
N
n
O
R1 R2
m=1,0
R=NH2, NHCOCH3, OH
n=1,2
Figure 1. Design principle of 5-substiuted tetrahydronaphthalen-2yl-methyl 4-anilidopiperidine analogues.

S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
6187
NHBoc
NHBoc
O
c
a, b
N
N
m
-Cl+H2N
X
N
m
O
n
2: m=0 1: m=1
3: x=I
5: n=1, m=1, (76% of yield)
6: n=2, m=0, (70%)
7: n=1, m=0, (78%)
4: x=CHO
O
NH3+TFA-
HN
d
N
N
m
m
N
N
O
O
n
8: n=1, m=1, (75%)
9: n=2, m=0, (69%)
10: n=1, m=0, (71%)
11: m=1 (59%)
12: m=0 (69%)
Scheme 1. Preparation of amine and amide substituted 4-anilidopiperidine analogues. Reagents and conditions: (a) K2CO3, acetone, 4 h; (b) Na(OAc)3BH, DCE, few drops of
acetic acid, 12 h; (c) 50% trifluoroacetic acid in DCM, 0 °C to room temperature, 2 h; (d) acetyl chloride, Et3N, 0 °C to room temperature, 3 h.
O
OH
O
O
O
O
b
a
c
d
MeO
MeO
(90%)
MeO
(79%)
HO
(59%)
16
O
14
O
15
13
O
O
O
O
O
NH
N
e
f
m
O
N
N
m
I
O
18: m=0 (69%)
19: m=1 (62%)
2: m=0 1: m=1
17
OH
N
m
N
O
20: m=0 (54%)
21: m=1 (52%)
Scheme 2. Preparation of hydroxyl substituted 4-anilidopiperidine analogues. Reagents and conditions: (a) (R)-2-methyl-CBS-oxazaborolidine, BH3-SMe2, toluene, THF,
À15 °C, 5 h; (b) DHP, PPTS, DCM, 4 h; (c) 1N lithium aluminium hydride in THF, 0 °C to room temperature, 12 h; (d) Ph3P, imidazole, I2, 1:1 diethyl ether/DCM, 1 h; (e) K2CO3,
acetone, 4 h; (f) PPTS, MeOH, reflux temperature, 3 h.
receptors, and the results are summarized below. The opioid bind-
ing affinities at the human d opioid receptor (hDOR) and the rat
opioid receptor (rMOR) were determined by competition analysis
against [3H] DPDPE (d) and [3H] DAMGO (
) respectively using
Compounds 10 and 12 showed good binding affinity of 40 nM
and 50 nM respectively, thus exhibiting 250 fold selective toward
l
the
l
opioid receptor. Compound 20 showed excellent binding
opioid
l
affinity 2 nM with a 5000 fold selectivity toward the
l
membrane preparations from transfected HN9.10 cells that consti-
receptor. The structural difference between compounds 8 and 10,
11 and 12 and 21 and 20 is the methylene group next to the piper-
idine ring. The compounds 10, 12 and 20 without the methylene
group, show very good binding affinity compared to their methy-
lene containing counter parts 8, 11 and 21 (Table 1).
In this study we achieved the lead compound 20 with similar
binding affinity (2 nM) as fentanyl (3.3 nM) at the l opioid recep-
tutively express the respective receptors.24 Functional activities for
d and
mouse vas deferens (MVD, d) and guinea pig isolated ileum (GPI,
) bioassays, respectively, as previously published.25 The binding
affinity results indicate that all these compounds are highly
selective toward the opioid receptor. The compounds 8, 11 and
l opioid receptors were evaluated in stimulated isolated
l
l
21 having amine, acetamide and hydroxyl substitution at the 5th
position of 1,2,3,4 tetrahydronapthalene methyl group with
N-phenyl-N-(piperidin-4-ylmethyl)propionamide core showed
moderate binding affinity of 580 nM, 460 nM and 190 nM toward
tor. The binding affinities and functional activity of fentanyl mole-
cule (Ki 5.9 1.4 and 568 159 nM)10 (3.45 0.45 and
9.45 4.05 nM)15 at
l
and d opioid receptors respectively. In our
structure activity studies the lead compound 20 which has similar
binding affinity of fentanyl at opioid receptor, and highly selec-
tive (5000 fold) in binding affinity as well as in functional selectiv-
ity toward the opioid receptor. Based on the design of 10, we
l
opioid receptor, respectively; poor binding affinity toward d opi-
oid receptor was observed. Replacement of amino group with
hydroxy substitution increased the binding affinity toward the
l
l
l
opioid receptor by three fold. In our further designs, compounds
10, 12, and 20, we replace the N-phenyl-N-(piperidin-4-ylmethyl)
propionamide moiety with N-phenyl-N-(piperidin-4-yl)propi-
onamide with amino, acetamide, and hydroxyl group substituted
at the 5th position of the 1,2,3,4 tetrahydronapthalene moiety.
further designed and synthesized analogues with fluoro, chloro
and 3-methoxy substitutions on the N-phenyl aromatic group.
The resulted ligands 38, 39 and 40 which showed moderate bind-
ing affinity toward the
l opioid receptor and very weak affinity
toward the d opioid receptor. From this SAR we concluded that

6188
S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
R
R
R
R'
R'
a
c, d
b
R'
N
O
N
NH
N
N
O
NH2
26: R, R'=F, (75%)
27: R, R'=Cl, (68%)
29: R, R'=F, (73%)
30: R, R'=Cl, (61%)
22
: R, R'=F
23
:
28 R=Cl, R'=OMe, (75%)
24: R, R'=Cl
R
31:
R=Cl, R'=OMe, (63%)
25:
R=Cl, R'=OMe
R
R'
NHBoc
R'
e
NHBoc
f
+
HN
N
O
N
I
35: R, R'=F, (64%)
36: R, R'=Cl, (67%)
O
N
3
: R=Cl, R'=OMe, (75%)
37
32: R, R'=F, (70%)
33: R, R'=Cl, (78%)
R
N
34:
R=Cl, R'=OMe, (72%)
NH3+TFA-
R'
38: R, R'=F, (78%)
39: R, R'=Cl, (81%)
O
N
40:
R=Cl, R'=OMe, (75%)
Scheme 3. Preparation of phenyl substituted 4-anilidopiperidine analogues. Reagents and conditions: (a) Na(OAc)3BH, Na2SO4, DCM, 12 h; (b) propionyl chloride, Et3N, DCM,
0 °C to room temperature, 4 h; (c) 1-chloroethyl chloroformate, 70 °C, DCE, 2 h; (d) MeOH, reflux temperature; (e) K2CO3, acetone, 4 h; (f) TFA in DCM, 0 °C to room
temperature.
Table 1
Binding affinities and functional activity of the amine, acetamide and hydroxyl substituted 4-anilidopiperidine analogues at DOR and MOR
c
c
Compd
Binding Ki (nM)
MVD (d) IC50 (nM)
GPI (
l
) IC50 (nM)
Ki
l
/d
aLogP
log IC50
MOR (
l)
log IC50
DOR (d)
8d
À5.88 0.16
À5.76 0.39
À7.02 0.11
À5.98 0.16
À6.95 0.12
À8.58 0.05
À6.44 0.13
À6.71 0.05
À5.92 0.04
À5.24 0.22
580
760
40
460
50
À4.71 0.12
6000
12.9% at 1
l
M
M
M
12.2% at 1
l
M
1/10
1/13
1/250
1/21
1/200
1/5000
1/41
1/50
1/7
4.17
4.04
3.53
4.61
4.42
3.93
4.29
3.84
4.63
3.91
9d
nd
>10,000
>10,000
>10,000
>10,000
>10,000
7800
5700
5200
4500
5.3% at 1
7.5% at 1
nd
l
l
8.0% at 1
1020 360
nd
lM
10d
11
12
nd
nd
nd
nd
24.4% at 1
l
M
25.5% at 1
55.20 4.3
600 92
1100 110
nd
nd
lM
20
2
23% at 1
16% at 1
12% at 1
nd
l
l
l
M
M
M
21
190
110
700
2600
À4.59 0.13
À4.91 0.10
À4.71 0.08
À5.00 0.03
38d
39d
40d
nd
1/2
aCompetition assays were carried out using rat brain membranes.
bCompetition against radiolabeled ligand, data collected from at least 2 independent experiments
n.d.: not determined.
c
Concentration at 50% inhibition of muscle contraction at electrically stimulated isolated tissues; these values represent the mean of four tissues within 95% confidence
limit.
d
Trifluoro acetate salts.
substitution on the N-phenyl group is not well tolerated, and the
fluoro substitution is better compared to other substitutions on
the N-phenyl group.
in vivo antinociceptive activity. Using a rat model of acute nocicep-
tion induced by application of radiant heat to the planar surface of
the hind-paw of naïve animals, we determined the efficacy of 20
Opioid agonist activities of all 4-anilidopiperidine analogues
were evaluated in MVD and GPI assays. In case of amine and acet-
amide substituted 4-anilidopiperidine analogues 8–12 and 38–40
agonist activities in the MVD and the GPI assays were very low
after spinal administration (0.1, 1, 3, 10, and 30 lg; n = 5–11/treat-
ment). Intrathecal administration of ligand 20 did not significantly
raise paw withdrawal latencies (PWLs) at any dose evaluated com-
pared to baseline values (p > 0.05, Fig. 2). Calculation of the area
under the curve (AUC) confirmed a lack of efficacy of compound
20 against acute pain in non-injured rats. These in vivo observations
after spinal administration of compound 20 are discordant with the
high affinity and moderate potency in vitro. Detailed in vivo exper-
imental procedures are given in the experimental section.
and did not correlate with the binding affinities at both
l and d
opioid receptors. Only the hydroxyl substituted 4-anili-
dopiperidine analogues 21 and 20 showed moderate to good ago-
nist activities at GPI assays, and binding affinities very much
correlated with the functional activity. The hydroxyl substituted
analog 21 showed moderate agonist activity(600 90 nM) in GPI
assays, and the ligand 20 showed potent agonist activity
(55 4 nM) in GPI assay. Similarly, both ligands 20 and 21 exhibit
weak agonist activities in MVD assay, that is, correlated with their
binding affinities at DOR.
4. Conclusions
A series of novel opioid ligands designed and synthesized based
on 4-anilidopiperidine analogues containing 5-substituted
tetrahydronaphthalen-2yl-methyl group with different 4-anili-
dopiperidine core moieties. These 4-anilidopiperidine analogues
Based on the in vitro bioassay results showing promising
l
opioid activities, we chose to evaluate the lead compound 20 for

S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
6189
7000
35
25
15
5
5000
30 µg/5 µL
10 µg/5 µL
3 µg/5 µL
1 µg/5 µL
0.1 µg/5 µL
vehicle
3000
1000
1
3
10
30
0.1
Dose (µg in 5µL)
15
30
45
60
90
Vehicle
(a)
(b)
BL
120
240
Time (min)
Figure 2. (a) Compound 20 was evaluated in SD rats using a radiant heat assay. (b) Compound 20 dose-dependency was assessed by constructing a dose response curve.
showed good binding affinity and highly selective toward
l
opioid
the organic extracts were dried over sodium sulfate after work
up. For analytical reversed-phase HPLC a Vydac 218-TP54 column
(5–250 mm) was used with a l gradient of 10–90% acetonitrile in
0.1% TFA/H2O over 40 min at a flow rate of 1 mL/min.
receptor. 5-substituted tetrahydronaphthalen-2yl-methyl group
with N-phenyl-N-(piperidin-4-ylmethyl)propionamide analogues
8, 9, 11 and 21 showed moderate binding affinity and very weak
agonist activities at
l and d receptors, and with similar moiety
the amine, acetamide and hydroxyl substitution at the 5th position
with N-phenyl-N-(piperidin-4-yl)propionamide analogues 10, 12
and 20 showed good binding affinity and high selectivity toward
5.2. In vivo assay
Adult male Sprague–Dawley rats (225–300 g; Harlan,
Indianapolis, IN) were kept in a temperature-controlled environ-
ment with lights on 07:00–19:00 with food and water available
ad libitum. All animal procedures were performed in accordance
with the policies and recommendations of the International
Association for the Study of Pain, The National Institutes of
Health, and with approval from the Animal Care and Use
Committee of the University of Arizona for the handling and use
of laboratory animals.
the
l opioid receptor. In the case of the amine and the acetamide
compounds 10 and 12, agonist activities are very low in the MVD
and the GPI assays which did not correlate with the binding affini-
ties at both
l and d opioid receptors. On the contrary, the hydroxyl
substituted 4-anilidopiperidine analogues 20 and 21 are highly
selective toward the MOR and their agonist activities correlate with
their binding affinities. The lead compound 20 is highly selective
(5000 fold) toward the MOR receptor in binding affinity as well as
selective in functional activity at GPI (l) assays. The ligands 38,
39 and 40 substitutions on the N-phenyl group with fluoro, chloro
and methoxy are not tolerated and these ligands showed very weak
binding affinity. Based on the in vitro bioassay results the lead com-
pound 20 was chosen for in vivo assessment for efficacy in naïve
rats after intrathecal administration. In this assay of acute antinoci-
ception, the direct activation of central opioid receptors at the
spinal level those are often required to block nociceptive transmis-
sion. Compound 20 was not significantly effective in alleviating
acute pain. This discrepancy between high in vitro binding affinity,
moderate in vitro activity, and low in vivo activity may reflect dif-
ferences in pharmacodynamics (i.e., engaging signaling pathways)
or pharmacokinetics (i.e., metabolic stability). In sum, our data sug-
gest that further optimization of this compound 20 is required to
enhance in vivo activity.
5.3. Surgical methods
Rats were anesthetized (ketamine/xylazine anesthesia, 80/
12 mg/kg ip; Sigma–Aldrich) and placed in a stereotaxic head
holder. The cisterna magna was exposed and incised, and an 8-
cm catheter (PE-10; Stoelting) was implanted as previously
reported,26 terminating in the lumbar region of the spinal cord.
Catheters were sutured (3-0 silk suture) into the deep muscle
and externalized at the back of the neck. Seven days after implan-
tation of an indwelling cannula, vehicle (10% DMSO:10% Tween
80:80% saline) and ligand 20 (1, 3, 10, and 30
treatment) were injected in a 5 L volume followed by a 9 lL
saline flush. Catheter placement was verified at completion of
experiments.
lg; n = 6–9/
l
5.4. Behavioral test used
5. Experimental section
Paw-flick latency27was determined as follows. Rats were
allowed to acclimate to the testing room for 30 min prior to testing.
Basal paw withdrawal latencies (PWLs) to an infrared radiant heat
source were measured and ranged between 16.0 and 20.0 sec. A
cutoff time of 33.0 sec was used to prevent tissue damage. After
a single, intrathecal injection of ligand 20 (i.t.) or vehicle, PWLs
were re-assessed 7 times over a duration of to 4 h.
5.1. General considerations
All reactions were performed under N2 unless otherwise noted.
All 1H NMR and 13C NMR were recorded at 500 and 125 MHz,
respectively, on a Bruker DRX 500. Chemical shifts were referred
to TMS as internal standard in the case of CDCl3 solution and to
the residual proton signal of DMSO at 2.5 ppm in the case of
DMSO-d6 solution. The following abbreviations were used in
reporting spectra: s = singlet, d = doublet, t = triplet, m = multiplet.
Mass spectra were recorded on a Thermo Fisher LCQ ion trap mass
spectrometer. High-resolution mass spectra (HRMS) were obtained
using a Bruker Apex ion cyclotran resonance mass spectrometer in
ESI positive mode. Unless otherwise mentioned, all of the solvents
used were of laboratory reagent grade. Usually, the flash chro-
matography was performed using 100–200 mesh silica gel. All of
5.4.1. (R)-tert-Butyl(6-((4-((N-phenylpropionamido)methyl)-
piperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-
yl)carbamate (5 Scheme 1)
To
a solution of N-phenyl-N-(piperidin-4-yl)propionamide
(0.19 g, 0.77, 1.5 equiv) in acetone at room temperature was added
K2CO3 (0.1 g, 0.77 mmol 1.5 equiv) and followed by iodo com-
pound 3 (0.2 g, 0.51 mmol 1.0 equiv). The resultant reaction

6190
S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
mixture was stirred at room temperature for 4 h. The reaction mix-
ture was filtered through Whatman filter paper, and solvent was
removed from the filtrate. The residue obtained upon evaporation
of solvent was chromatographed over silica gel and eluted with
60% ethyl acetate/hexane to give the title compound Boc-protected
4-anilidopiperdiine analog 5 (0.2 g, 76% yield.) as a white colored
solid. MS (ESI) m/z (M+H)+: 506, 1H NMR (499 MHz, chloroform-
d) d 7.42–7.37 (m, 2H), 7.36–7.29 (m, 1H), 7.25 (d, J = 7.4 Hz, 1H),
7.16–7.12 (m, 2H), 7.09–7.06 (m, 1H), 7.00 (s, 1H), 4.82 (d,
J = 7.7 Hz, 1H), 4.74 (d, J = 8.8 Hz, 1H), 3.62 (d, J = 7.1 Hz, 2H),
3.41 (s, 2H), 2.83 (d, J = 11.1 Hz, 2H), 2.78–2.66 (m, 2H), 2.03 (q,
J = 7.2 Hz, 3H), 1.89 (m, 2H), 1.84–1.74 (m, 4H), 1.67–1.58 (m,
2H), 1.48 (s, 9H), 1.35 (t, J = 11.5 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).
13C NMR (126 MHz, CDCl3) d 173.95, 155.40, 143.26, 137.16,
135.82, 129.60, 129.54, 128.41, 128.12, 127.62, 127.05, 79.23,
77.25, 77.20, 77.00, 76.95, 76.75, 62.83, 54.70, 53.17, 48.43,
34.40, 30.54, 29.90, 29.22, 28.43, 27.89, 19.91, 9.66.
(5 mL). The resulting reaction mixture was stirred for 2 h, and the
solvent was stripped of under reduced pressure. The resultant resi-
due was washed with diethyl ether a couple of times and dried
afforded the amine trifluoroacetate derivative as a white solid
(0.2 g, 74.9% of yield) ESI MS m/z 406 (MH)+. HRMS [M+H]+
406.2855 (theoretical 406.2852); 1H NMR (499 MHz, DMSO-d6) d
11.10 (d, J = 10.0 Hz, 1H), 8.79–8.51 (m, 3H), 7.67 (dd, J = 8.3,
4.6 Hz, 1H), 7.54–7.43 (m, 3H), 7.43–7.39 (m, 1H), 7.35 (m,
J = 7.1 Hz, 3H), 4.42 (q, J = 5.6 Hz, 1H), 4.22–4.10 (m, 2H),
3.79–3.63 (m, 1H), 3.55 (d, J = 4.9 Hz, 1H), 3.52–3.45 (m, 1H),
3.44–3.33 (m, 2H), 3.23 (d, J = 11.8 Hz, 2H), 2.85–2.68 (m, 3H),
2.09 (m, 1H), 1.95 (m, 4H), 1.83–1.69 (m, 2H), 1.68–1.51 (m, 3H),
0.95–0.82 (t, 3H). 13C NMR (126 MHz, DMSO-d6)
d 173.05,
143.00, 138.41, 134.20, 132.78, 130.17, 130.13, 129.43, 128.73,
128.16, 72.62, 70.98, 66.81, 60.64, 58.85, 53.23, 51.47, 47.98,
44.08, 40.50, 40.43, 40.33, 40.26, 40.17, 40.09, 40.00, 39.83,
39.67, 39.55, 39.50, 32.83, 28.84, 27.77, 27.53, 26.75, 18.61, 10.03.
5.4.2. (R)-tert-Butyl(6-(2-(4-(N-phenylpropionamido)piperidin-
1-yl)ethyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (6
Scheme 1)
5.4.5. (R)-N-(1-(2-(5-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)-
ethyl)piperidin-4-yl)-N-phenylpropionamide (9 Scheme 1)
Prepared as described for 8 from 6 (R)-tert-butyl(6-((4-((N-
phenylpropionamido)methyl)piperidin-1-yl)methyl)-1,2,3,4-te-
trahydronaphthalen-1-yl)carbamate (0.12 g, 0.23) afforded the
title compound 9 as a white solid (0.085 g, 69% of yield). ESI MS
m/z 406 (MH)+. HRMS [M+H]+ 406.2851 (theoretical 406.2852);
1H NMR (499 MHz, DMSO-d6) d 9.63–9.46 (m, 1H), 8.32 (d,
J = 5.7 Hz, 3H), 7.53–7.43 (m, 3H), 7.41 (d, J = 8.0 Hz, 1H),
7.28–7.23 (m, 2H), 7.11 (dd, J = 8.1, 1.8 Hz, 1H), 7.05 (s, 1H), 4.75
(m, 1H), 4.40 (q, J = 5.4 Hz, 1H), 3.61–3.51 (m, 2H), 3.22–3.07 (m,
4H), 2.93–2.83 (m, 2H), 2.80–2.63 (m, 2H), 2.08–1.94 (m, 3H),
1.90–1.80 (m, 4H), 1.73 (m, 1H), 1.60–1.49 (m, 2H), 0.89 (t,
J = 7.4 Hz, 3H). 13C NMR (126 MHz, DMSO-d6) d 172.69, 138.61,
138.39, 137.65, 131.71, 130.85, 130.02, 129.94, 129.76, 129.07,
126.93, 72.67, 71.04, 66.89, 60.66, 56.77, 51.31, 49.64, 47.99,
44.22, 40.50, 40.33, 40.24, 40.17, 40.00, 39.83, 39.67, 39.50,
29.52, 28.95, 28.28, 27.89, 27.81, 18.66, 9.97.
To a solution of (R)-tert-butyl 6-(2-oxoethyl)-1,2,3,4-tetrahy-
dronaphthalen-1-yl carabamate 4 (0.18 g, 0.62 mmol, 1 equiv)
and 4-(N-phenylpropionamido)piperidin-1-ium chloride 2 (0.36 g,
1.55 mmol, 2.5 equiv) in dichloroethane (10 mL) was added
sodium triacetoxyborohydride (0.26 g, 1.24 mmol, 2 equiv). After
stirring overnight at room temperature, the reaction solution was
diluted with ethyl acetate and washed with saturated sodium
bicarbonate and brine. The organic phase was dried over sodium
sulfate and evaporated to dryness in vacuo. The crude product
was purified by flash chromatography 70% ethyl acetate/hexane
to give the title compound 6 as a white powder (0.22 g, 70% yield)
MS (ESI) m/z (M+H)+: 506, 1H NMR (499 MHz, chloroform-d) d
7.42–7.31 (m, 3H), 7.22 (d, J = 7.9 Hz, 1H), 7.10–7.04 (m, 2H),
6.95 (d, J = 8.0 Hz, 1H), 6.87–6.82 (m, 1H), 4.79 (m, 1H), 4.76–
4.63 (m, 2H), 3.01–2.93 (m, 2H), 2.77–2.60 (m, 4H), 2.54–2.45
(m, 2H), 2.20–2.10 (m, 2H), 2.02–1.96 (m, 1H), 1.92 (q, J = 7.4 Hz,
2H), 1.79 (m, 4H), 1.46 (s, 9H), 1.41 (m, 2H), 1.01 (t, J = 7.4 Hz,
3H). 13C NMR (126 MHz, CDCl3) d 173.46, 155.38, 139.07, 138.80,
137.35, 134.99, 130.40, 129.23, 129.08, 128.72, 128.20, 126.51,
79.20, 77.26, 77.21, 77.00, 76.75, 60.41, 53.05, 52.10, 48.36,
33.33, 30.59, 30.54, 29.19, 28.49, 28.42, 19.90, 9.59.
5.4.6. (R)-N-(1-((5-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)-
methyl)piperidin-4-yl)-N-phenylpropionamide (10 Scheme 1)
Prepared as described for 8 from 7 (R)-tert-butyl(6-((4-(N-
phenylpropionamido)piperidin-1-yl)methyl)-1,2,3,4-tetrahydron-
aphthalen-1-yl)carbamate (0.15 g, 0.30) afforded the title compound
10 as a white solid (0.11 g, 71% of yield). ESI MS m/z 392 (MH)+.
HRMS [M+H]+ 392.2696 (theoretical 392.2696); 1H NMR
(499 MHz, DMSO-d6) d 9.76–9.45 (m, 1H), 8.38 (d, J = 5.5 Hz, 3H),
7.51 (d, J = 8.0 Hz, 1H), 7.49–7.41 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H),
7.24 (s, 1H), 7.21 (d, J = 6.8 Hz, 2H), 4.70 (m, 1H), 4.45 (q,
J = 5.5 Hz, 1H), 4.17 (s, 2H), 3.30 (d, J = 10.8 Hz, 2H), 3.11 (q,
J = 11.6 Hz, 2H), 2.84–2.63 (m, 2H), 2.05 (m, 1H), 1.98–1.77 (m,
6H), 1.77–1.69 (m, 1H), 1.56–1.42 (m, 2H), 0.87 (t, J = 7.4 Hz, 3H).
13C NMR (125 MHz, DMSO-d6) d172.6, 159.3, 159.1.8, 158.8,
158.5, 138.6, 138.5, 134.3, 132.3, 130.7, 130.1, 129.8, 129.2,
129.0, 128.9, 120.4, 118.1, 115.7, 113.4, 51.3, 51.2, 49.2, 48.0,
28.7, 28.1, 27.7, 27.4, 18.5, 9.8.
5.4.3. (R)-tert-Butyl(6-((4-(N-phenylpropionamido)piperidin-1-
yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate (7
Scheme 1)
Prepared as described for 5 from (R)-tert-butyl(6-(iodomethyl)-
1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 3 (0.25 g, 0.64 mmol,
1 equiv) and 4-(N-phenylpropionamido)piperidin-1-ium chloride 2
(0.22 g, 0.96 mmol, 1 equiv) in 10 mL of acetone and 0.26 g of K2CO3
afforded the title compound 7 (0.25 g, 78% of yield) as a light brown
colored solid. MS (ESI) m/z (M+H)+: 492. 1H NMR (499 MHz, chloro-
form-d) d 7.42–7.33 (m, 3H), 7.23 (d, J = 7.9 Hz, 1H), 7.04 (m, 3H),
6.93 (s, 1H), 4.79 (t, J = 6.5 Hz, 1H), 4.72 (d, J = 8.8 Hz, 1H), 4.65 (m,
1H), 3.37 (s, 2H), 2.86 (d, J = 11.8 Hz, 2H), 2.78–2.61 (m, 2H), 2.08
(m, 2H), 2.00 (m, 1H), 1.90 (q, J = 7.5 Hz, 2H), 1.83–1.69 (m, 4H),
1.46 (s, 9H), 1.43–1.32 (m, 2H), 1.00 (t, J = 7.5 Hz, 3H). 13C NMR
(125 MHz, CDCl3) d 173.4, 155.3, 138.9, 137.1, 136.9, 135.9, 130.3,
129.5, 129.1, 128.4, 128.1, 127.0, 79.1, 62.6, 53.0, 52.4, 48.4, 30.5,
29.1, 28.4, 28.4, 19.8, 9.5.
5.4.7. (R)-N-((1-((5-Acetamido-5,6,7,8-tetrahydronaphthalen-
2-yl)methyl)piperidin-4-yl)methyl)-N-phenylpropionamide (11
Scheme 1)
To
a solution of the amine 8 (R)-N-((1-((5-amino-5,6,7,
8-tetrahydronaphthalen-2-yl)methyl)piperidin-4-yl)methyl)-
N-phenylpropionamide (0.1 g, 0.24 mmol 1 equiv) in dry dichloro-
methane (6 mL) at 0 °C under argon atmosphere was added
triethylamine (0.085 mL, 0.72 mmol) followed by acetyl chloride
(0.019 mL, 0.265 mmol) drop wise. The reaction mixture was stir-
red at room temperature for 1 h and was worked up by adding
water followed by extraction with dichloromethane. The combined
5.4.4. (R)-N-((1-((5-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)-
methyl)piperidin-4-yl)methyl)-N-phenylpropionamide (8
Scheme 1)
To an ice-cold stirred solution of the 5 (0.26 g, 0.51 mmol,
1 equiv) in dichloromethane (5 mL) was added trifluoroacetic acid

S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
6191
organic extracts were washed with water, brine and dried. The
residue obtained upon evaporation of solvent was chro-
matographed over silica gel and eluted with 60% ethyl acetate/hex-
ane to give the acetamide derivative 11 as a light yellow color solid
(0.065 g, 59% yield). ESI MS m/z 448 (MH)+. HRMS [M+H]+
448.2956 (theoretical 448.2958); 1H NMR (499 MHz, chloroform-
d) d 7.40 (t, J = 7.7 Hz, 2H), 7.32 (t, J = 7.4 Hz, 1H), 7.18–7.10 (m,
2H), 7.03 (d, J = 6.9 Hz, 2H), 6.90 (d, J = 8.1 Hz, 1H), 5.77 (dd,
J = 11.3, 6.7 Hz, 1H), 3.62 (d, J = 7.1 Hz, 2H), 3.39 (s, 2H), 2.92–
2.69 (m, 4H), 2.34–2.19 (bs, 4H), 2.19–2.10 (m, 1H), 2.10–1.98
(m, 4H), 1.87 (m, 2H), 1.78 (m, 1H), 1.62 (d, J = 14.3 Hz, 2H), 1.33
(m, J = 2H), 1.01 (t, J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) d
174.11, 173.91, 143.28, 137.08, 129.87, 129.58, 128.10, 127.60,
127.39, 124.72, 77.25, 77.20, 77.00, 76.75, 62.78, 54.73, 54.14,
53.25, 34.47, 29.95, 29.41, 28.92, 27.87, 27.02, 22.96, 9.65.
tetrahydronaphthalene-2-carboxylate 15 (2.1 g, 7.37 mmol) in
THF (15 mL) was added over ca 30 min. The reaction mixture was
warmed to room temperature overnight, and then cooled in an
ice-salt bath the next morning. Water (1.4 mL) in THF (1.5 mL)
was added to the reaction mixture over 3 h. Vigorous gas evolution
was occurred, 5 N sodium hydroxide (1.4 mL) was added over
20 min followed by water (4.2 mL). After stirring for an additional
1 h, the reaction mixture was filtered, and the filtrate was concen-
trated in vacuo. The residue was reconstituted in methanol and ace-
tonitrile, and concentrated in vacuo again to provide the title
compound 16 as a color less liquid (1.7 g, 79% yield), the title com-
pound used without further purification in the subsequent step.
5.4.11. 2-(((S)-6-(Iodomethyl)-1,2,3,4-tetrahydronaphthalen-1-
yl)oxy)tetrahydro-2H-pyran (17 Scheme 2)
To
a solution of ((5S)-5-((tetrahydro-2H-pyran-2-yl)oxy)-
5.4.8. (R)-N-(1-((5-Acetamido-5,6,7,8-tetrahydronaphthalen-2-
yl)methyl)piperidin-4-yl)-N-phenylpropionamide (12
Scheme 1)
5,6,7,8-tetrahydronaphthalen-2-yl)methanol 16 (1.3 g, 4.96 mmol)
in dichloromethane/ether (1:1, 30 mL) at room temperature were
added triphenylphosphine (1.9 g, 7.35 mmol) and imidazole
(0.5 g, 7.35 mmol). To this stirred solution was then added iodine
(1.86 g, 14.7 mmol). After stirring for 20 min, the reaction was
quenched with 10% Na2S2O3 (20 mL) until it became a clear two-
phase solution. The aqueous phase was extracted with ether, and
combined organic phase was dried over sodium sulfate, filtered,
and evaporated to dryness. Flash chromatography silica gel 10%
ethyl acetate/hexane afforded the desired product 17 as a light yel-
low color liquid (1.1 g, 59% yield). ESI MS m/z 395 (MNa)+. 1H NMR
(499 MHz, chloroform-d; 1:1 diastereomeric ratio) d 7.43 (d,
J = 8.0 Hz, 0.5 H), 7.24–7.19 (m, 1.0 H), 7.18–7.15 (dd, J = 7.9,
2.0 Hz, 0.5 H), 7.13–7.09 (m, 1H), 4.89–4.83 (m, 1H), 4.80–4.65
(m, 1H), 4.42 (s, 2H), 4.05–3.95(m, 1H), 3.64–3.52 (m, 1H), 2.85–
2.75 (m, 1H), 2.72–2.63 (m, 1H), 2.08–1.81 (m, 4H), 1.80–1.69
(m, 2H), 1.67–1.50 (m, 4H). 13C NMR (126 MHz, CDCl3) d 138.23,
138.16, 137.97, 137.95, 137.01, 136.75, 129.95, 129.41, 129.19,
128.90, 126.40, 125.99, 99.04, 95.56, 77.25, 77.00, 76.74, 73.63,
70.51, 62.72, 62.64, 31.10, 31.04, 30.49, 30.30, 29.11, 28.78,
27.56, 25.52, 19.77, 19.70, 18.89, 18.75, 5.95, 5.82.
Prepared as described for 11 from 10 (R)-N-(1-((5-amino-5,6,
7,8-tetrahydronaphthalen-2-yl)methyl)piperidin-4-yl)-N-phenyl-
propionamide (0.17 g, 0.39 mmol) afforded the title compound 12
as a light yellow color solid (0.12 g, 69% of yield). ESI MS m/z 434
(MH)+. HRMS [M+H]+ 434.2801 (theoretical 434.2802); 1H NMR
(499 MHz, chloroform-d) d 7.42–7.34 (m, 3H), 7.16 (d, J = 7.9 Hz,
1H), 7.08–7.04 (m, 2H), 7.03 (dd, J = 7.9 Hz, 1H), 6.96 (s, 1H), 5.65
(d, J = 8.4 Hz, 1H), 5.19–5.07 (m, 1H), 4.64 (m, 1H), 3.37 (s, 2H),
2.85 (d, J = 11.9 Hz, 2H), 2.80–2.64 (m, 2H), 2.08 (t, J = 12.3 Hz,
2H), 2.00 (s, 3H), 1.90 (q, J = 7.4 Hz, 2H), 1.81–1.76 (m, 3H), 1.76–
1.69 (m, 3H), 1.44–1.32 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H). 13C NMR
(126 MHz, CDCl3)
d 173.44, 169.07, 138.93, 137.36, 137.24,
135.33, 130.38, 129.70, 129.22, 128.54, 128.20, 127.16, 77.25,
77.20, 77.00, 76.75, 62.65, 53.07, 53.04, 52.28, 47.28, 30.55,
30.13, 29.20, 28.51, 23.58, 19.87, 9.61.
5.4.9. (5S)-Methyl 5-((tetrahydro-2H-pyran-2-yl)oxy)-5,6,7,8-
tetrahydronaphthalene-2-carboxylate (15 Scheme 2)
To a solution of (S)-methyl 5-hydroxy-5,6,7,8-tetrahydronaph-
thalene-2-carboxylate 14 (1.65 g, 8.0 mmol, 1 equiv) in dry
dichloromethane (20 mL) was added 3,4-Dihydro-2H-pyran
(1.0 mL, 12 mmol) followed by pyridinium p-toluenesulfonate
(0.2 g, 0.8 mmol, 0.1 equiv) under argon atmosphere. The reaction
mixture was stirred at room temperature for 4 h, and the reaction
mixture was diluted with dichloromethane and washed with water
twice and brine and dried. The residue obtained upon evaporation
of solvent was chromatographed over silica gel and eluted with
15% ethyl acetate/hexane to afford the protected alcohol 15 as a
viscous oil (2.1 g, 90% yield) ESI MS m/z 313 (MNa)+. 1H NMR
(499 MHz, chloroform-d; 1:1 diastereomeric ratio) d 7.85–7.76
(m, 2H), 7.58 (d, J = 8.1 Hz, 0.5 H), 7.36 (d, J = 8.0 Hz, 0.5 H), 5.01–
4.68 (m, 2H), 4.00 (m, 1H), 3.90 (s, 3H), 3.65–3.48 (m, 1H), 2.88
(m, 1H), 2.81–2.69 (m, 1H), 2.13–1.93 (m, 3H), 1.92–1.69 (m,
4H), 1.69–1.47 (m, 3H). 13C NMR (126 MHz, CDCl3) d 167.11,
167.05, 142.16, 141.93, 137.71, 137.54, 130.25, 130.04, 129.21,
128.88, 128.64, 128.61, 126.78, 126.49, 99.29, 95.63, 94.52, 77.25,
77.20, 77.00, 76.74, 73.79, 70.52, 62.90, 62.83, 62.67, 51.99,
51.96, 30.99, 30.91, 30.58, 30.28, 29.03, 28.70, 27.36, 25.39,
25.33, 19.69, 19.67, 18.94, 18.77.
5.4.12. N-Phenyl-N-(1-(((5S)-5-((tetrahydro-2H-pyran-2-yl)oxy)-
5,6,7,8-tetrahydronaphthalen-2-yl)methyl)piperidin-4-yl)propi-
onamide (18 Scheme 2)
Prepared as described for 5 from 2-(((S)-6-(iodomethyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)oxy)tetrahydro-2H-pyran 17 (0.12 g,
0.33 mmol, 1 equiv) and 4-(N-phenylpropionamido)piperidin-1-
ium chloride 2 (0.15 g, 0.67 mmol, 2 equiv) in 10 mL of acetone
and 0.18 g of K2CO3 afforded the title compound 18 (0.11 g, 69%
of yield) as a light yellow color viscous liquid. MS (ESI) m/z (M
+H)+: 477. 1H NMR (499 MHz, chloroform-d; 1:1 diastereomeric
ratio) d 7.42–7.32 (m, J = 7.0, 6.5, 3.4 Hz, 3.5 H), 7.18 (d, J = 7.8 Hz,
0.5H), 7.08–7.03 (m, 2.5 H), 7.01 (dd, J = 7.8, 1.8 Hz, 0.5H), 6.97–
6.93 (m, 1H), 4.90–4.85 (m, 0.5H), 4.85–4.75 (m, 1H), 4.70–4.61
(m, 1.5H), 4.00 (m, 1H), 3.62–3.50 (m, 1H), 3.38 (s, 2H), 2.94–2.83
(m, 2H), 2.82–2.72 (m, 1H), 2.72–2.61 (m, 1H), 2.13–1.79 (m, 8H),
1.79–1.65 (m, 4H), 1.65–1.44 (m, 4H), 1.45–1.31 (m, 2H), 1.00 (t,
J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 173.42, 138.96,
137.45, 137.35, 137.30, 137.08, 135.81, 135.55, 130.41, 129.66,
129.36, 129.25, 129.20, 128.78, 128.16, 126.83, 126.40, 98.95,
95.36, 77.25, 77.20, 77.00, 76.94, 76.75, 73.68, 70.56, 62.85, 62.67,
62.55, 53.12, 53.10, 52.33, 52.31, 31.10, 31.06, 30.62, 30.52, 29.23,
28.88, 28.50, 27.64, 25.56, 19.84, 19.61, 18.99, 18.87, 9.60.
5.4.10. ((5S)-5-((Tetrahydro-2H-pyran-2-yl)oxy)-5,6,7,8-
tetrahydronaphthalen-2-yl)methanol (16 Scheme 2)
To an oven dried 3-neck, 100 mL round-bottomed flask
equipped with argon inlet/outlet, addition funnel, thermometer,
was added THF (20 mL) and LAH (14.74 mL of a 1 M solution in
THF, 14.74 mmol). The reaction mixture was cooled in an ice-salt
bath, and (5S)-methyl 5-((tetrahydro-2H-pyran-2-yl)oxy)-5,6,7,8-
5.4.13. N-Phenyl-N-((1-(((5S)-5-((tetrahydro-2H-pyran-2-yl)oxy)-
5,6,7,8-tetrahydronaphthalen-2-yl)methyl)piperidin-4-yl)methyl)-
propionamide (19 Scheme 2)
Prepared as described for 5 from 2-(((S)-6-(iodomethyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)oxy)tetrahydro-2H-pyran 17 (0.15 g,

6192
S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
0.40 mmol, 1 equiv) and 4-((N-phenylpropionamido)methyl)piper-
idin-1-ium chloride 2 (0.22 g, 0.80 mmol, 2 equiv) in 10 mL of ace-
tone and 0.22 g of K2CO3 afforded the title compound 19 (0.10 g,
62% of yield) as a light brown color viscous liquid. MS (ESI) m/z
(M+H)+: 491. 1H NMR (499 MHz, chloroform-d; 1:1 diastereomeric
ratio) d 7.43–7.38 (m, 2.5H), 7.36–7.31 (m, 1H), 7.20 (d, J = 7.8 Hz,
0.5H), 7.16–7.12 (m, 2H), 7.11–7.05 (m, 1H), 7.03–6.99 (m, 1H),
4.90 (t, J = 3.7 Hz, 0.5H), 4.84 (dd, J = 4.9, 2.9 Hz, 0.5H), 4.81 (t,
J = 4.8 Hz, 0.5H), 4.70 (t, J = 4.7 Hz, 0.5H), 4.05 (m, 0.5H), 3.98 (m,
0.5H), 3.66–3.52 (m, 3H), 3.47–3.37 (m, 2H), 2.90–2.75 (m, 3H),
2.68 (m, 1H), 2.03 (q, J = 7.4 Hz, 2H), 1.96–1.68 (m, 8H),
1.67–1.45 (m, 7H), 1.41–1.27 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13C
NMR (126 MHz, CDCl3) d 173.83, 173.82, 143.01, 137.40, 137.23,
137.13, 137.06, 135.42, 135.19, 129.54, 129.50, 129.26, 129.11,
128.63, 128.01, 127.53, 126.74, 126.29, 98.96, 95.14, 77.23, 77.18,
76.98, 76.72, 73.63, 70.33, 62.88, 62.64, 62.45, 54.54, 53.10,
53.06, 53.01, 34.28, 30.94, 30.55, 29.81, 29.14, 28.80, 27.78,
27.43, 25.40, 19.78, 19.49, 18.90, 18.72, 9.56.
and the reaction mixture was stirred at room temperature over-
night. Aqueous sodium hydrogen carbonate was added followed
by stirring for 30 min. The reaction mixture was extracted with
dichloromethane and the combined organic phases were washed
with brine, dried over sodium sulfate, filtrated and concentrated
in vacuo. The residue obtained upon evaporation of solvent was
chromatographed over silica gel and eluted with 35% ethyl acet-
ate/hexane to give the 26 as a light yellow colored solid (1.2 g,
75% yield).
5.4.17. 1-Benzyl-N-(3,4-dichlorophenyl)piperidin-4-amine (27
Scheme 3)
Prepared as described for 26 from N-benzylpiperidone (1 g,
5.2 mmol, 1 equiv) and 3,4 dichloroaniline (0.85 g, 5.2 mmol,
1 equiv) afforded the title compound 27 as a yellow color solid
(1.2 g, 68% of yield).
5.4.18. 1-Benzyl-N-(4-chloro-3-methoxyphenyl)piperidin-4-
amine (28 Scheme 3)
5.4.14. (S)-N-(1-((5-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-yl)-
methyl)piperidin-4-yl)-N-phenylpropionamide (20 Scheme 2)
To a solution of 18 (N-phenyl-N-(1-(((5S)-5-((tetrahydro-2H-
pyran-2-yl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl)piperi-
din-4-yl)propionamide) (0.13 g, 0.27 mmol) in dry methanol
(10 mL) under argon atmosphere was added pyridinium p-toluene-
sulfonate (0.020 g, 0.08 mmol), and the resulting mixture was stir-
red at reflux temperature of methanol for 3 h. The reaction mixture
was allowed to cool to room temperature and the solvent was
evaporated under reduced pressure. The residue obtained upon
evaporation of solvent was chromatographed over silica gel and
eluted with 5% methanol: dichloromethane to give the title pro-
duct 20 as a white color sticky solid (0.054 g, 54% yield.) ESI MS
m/z 393 (MH)+. HRMS [M+H]+ 393.2534 (theoretical 393.2536);
1H NMR (499 MHz, chloroform-d) d 7.42–7.35 (m, 3H), 7.33 (d,
J = 7.8 Hz, 1H), 7.07–7.05 (m, 3H), 6.97 (s, 1H), 4.75 (s, 1H), 4.65
(m, 1H), 3.38 (s, 2H), 2.92–2.82 (m, 2H), 2.80–2.75 (m, 1H), 2.72–
2.61 (m, 1H), 2.14–2.03 (m, 2H), 1.99–1.83 (m, 4H), 1.79–1.69
(m, 2H), 1.67–1.57 (m, 3H) 1.39 (m, 2H), 1.00 (t, J = 7.4 Hz, 3H).
13C NMR (125 MHz, CDCl3) d173.4, 138.7, 137.5, 136.9, 130.3,
129.6, 129.2, 128.4, 128.1, 127.1, 67.8, 62.7, 53.4, 53.0, 52.0, 32.2,
30.3, 29.1, 28.4, 18.7, 9.5.
Prepared as described for 26 from N-benzylpiperidone (1 g,
5.3 mmol, 1 equiv) and 4-chloro-3-methoxyaniline (0.81 g,
5.3 mmol, 1 equiv) afforded the title compound 28 as a white color
solid (1.32 g, 75% of yield).
5.4.19. N-(1-Benzylpiperidin-4-yl)-N-(3,4-difluorophenyl)-
propionamide (29 Scheme 3)
1-Benzyl-N-(3,4-difluorophenyl)piperidin-4-amine 26 (1.2 g,
3.64 mmol 1 equiv) was dissolved in toluene (15 mL). Propionic
anhydride (0.93 mL, 7.28 mmol, 2 equiv) was added and the
reaction mixture was heated to reflux temperature overnight.
The reaction mixture was poured in to sodium hydroxide (1 M,
25 mL) solution and stirred for 30 min. The organic layer was
washed with water until pH 7, washed with brine and dried over
sodium sulfate, filtrated and concentrated in vacuo to give product
(0.95 g, 73% of yield) as a light yellow colored solid.
5.4.20. N-(1-Benzylpiperidin-4-yl)-N-(3,4-dichlorophenyl)-
propionamide (30 Scheme 3)
Prepared as described for 29 from 27 1-benzyl-N-(3,4-
dichlorophenyl)piperidin-4-amine (1.2 g, 3.58 mmol, 1 equiv)
afforded the title compound 30 as a yellow colored solid (0.85 g,
61% of yield).
5.4.15. (S)-N-((1-((5-Hydroxy-5,6,7,8-tetrahydronaphthalen-2-
yl)methyl)piperidin-4-yl)methyl)-N-phenylpropionamide (21
Scheme 2)
5.4.21. N-(1-Benzylpiperidin-4-yl)-N-(4-chloro-3-methoxyphenyl)-
propionamide (31 Scheme 3)
Prepared as described for 20 from 19 N-phenyl-N-((1-(((5S)-5-
((tetrahydro-2H-pyran-2-yl)oxy)-5,6,7,8-tetrahydronaphthalen-2-yl)
methyl)piperidin-4-yl)methyl)propionamide (0.070 g, 0.14 mmol)
afforded the title compound 21 as a light yellow colored solid
(0.030 g, 52% of yield). ESI MS m/z 407(MH)+. HRMS [M+H]+
407.2692 (theoretical 407.2693); 1H NMR (499 MHz, chloroform-
d) d 7.43–7.38 (m, 2H), 7.34 (dd, J = 9.1, 7.5 Hz, 2H), 7.17–7.10 (m,
3H), 7.04 (s, 1H), 4.77 (t, J = 4.6 Hz, 1H), 3.62 (d, J = 7.1 Hz, 2H),
3.44 (s, 2H), 2.84 (dd, J = 12.2, 8.1 Hz, 2H), 2.80–2.76 (m, 1H),
2.74–2.65 (m, 1H), 2.08–1.85 (m, 6H), 1.83–1.73 (m, 1H),
1.68–1.59 (m, 4H), 1.35 (d, J = 12.8 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H).
13C NMR (125 MHz, CDCl3) d 173.9, 143.2, 136.8, 129.5, 128.3,
128.0, 127.5, 127.0, 67.9, 62.8, 54.5, 53.3, 53.1, 34.4, 34.2, 32.3,
29.9, 29.2, 27.8, 18.7, 9.6.
Prepared as described for 29 from 28 1-benzyl-N-(4-chloro-
3-methoxyphenyl)piperidin-4-amine (0.98 g, 3.0 mmol, 1 equiv)
afforded the title compound 31 as a white colored solid (0.70 g,
63% of yield).
5.4.22. N-(3,4-Difluorophenyl)-N-(piperidin-4-yl)propionamide
(32 Scheme 3)
N-(3,4-Difluorophenyl)-N-(piperidin-4-yl)propionamide
29
(0.95 g, 2.65 mmol, 1 equiv) was dissolved in dichloromethane
(10 mL). 1-Chloroethyl chloroformate (1.43 mL, 13.25 mmol,
5 equiv) was added and the reaction mixture was heated to reflux
temperature for 3 h and then concentrated in vacuo. The resulting
residue was dissolved in methanol (10 mL) and heated to reflux
temperature for 2 h, followed by concentration in vacuo. Diethyl
ether was added and the resulting solid was filtrated and dried.
The solid material was dissolved in water, washed with diethyl
ether a couple of times, basified with sodium hydroxide (3 M).
Extraction with diethyl ether, washing with brine, drying
over sodium sulfate and concentration in vacuo gave N-(3,4-
difluorophenyl)-N-(piperidin-4-yl)propionamide (0.5 g, 70% of
yield) as a light yellow colored solid.
5.4.16. 1-Benzyl-N-(3,4-difluorophenyl)piperidin-4-amine (26
Scheme 3)
N-Benzylpiperidone (1 g, 5.2 mmol, 1 equiv), 3, 4 difluoroaniline
(0.52 mL, 5.2 mmol, 1 equiv) and sodium sulfate (3.7 g, 26.4 mmol,
5 equiv) were suspended in dichloromethane (20 mL). Sodium
triacetoxyborohydride (1.3 g, 6.33 mmol, 1.2 equiv) was added

S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
6193
5.4.23. N-(3,4-Dichlorophenyl)-N-(piperidin-4-yl)propionamide
(33 Scheme 3)
Prepared as described for 32 from N-(1-benzylpiperidin-4-yl)-
N-(3,4-dichlorophenyl)propionamide (0.67 g, 0.23) afforded the
title compound 33 as a light brown colored solid (0.4 g, 78% of
yield).
2.2 Hz, 1H), 6.56 (d, J = 2.2 Hz, 1H), 4.77 (s, 1H), 4.69 (d, J = 8.8 Hz,
1H), 4.63–4.56 (m, 1H), 3.85 (s, 3H), 3.34 (s, 2H), 2.84 (d,
J = 11.4 Hz, 2H), 2.73–2.61 (m, 2H), 2.10–2.00 (m, 2H), 2.00–1.87
(m, 3H), 1.82–1.62 (m, 5H), 1.44 (s, 9H), 1.40–1.27 (m, 2H), 0.99 (t,
J = 7.4 Hz, 3H). 13C NMR (126 MHz, CDCl3) d 173.22, 155.41,
138.58, 137.21, 137.05, 136.01, 130.39, 129.55, 128.46, 127.03,
123.19, 122.69, 114.20, 79.27, 77.25, 77.20, 77.00, 76.94, 76.75,
62.65, 56.29, 53.00, 52.37, 48.47, 30.67, 30.57, 29.23, 28.45, 19.95,
9.64.
5.4.24. N-(4-Chloro-3-methoxyphenyl)-N-(piperidin-4-yl)-
propionamide (34 Scheme 3)
Prepared as described for 32 from N-(1-benzylpiperidin-4-yl)-
N-(4-chloro-3-methoxyphenyl)propionamide (0.63 g, 1.63 mmol,
1 equiv) afforded the title compound 34 as a light brown colored
(0.35 g, 72% of yield).
5.4.28. (R)-N-(1-((5-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)-
methyl)piperidin-4-yl)-N-(3,4-difluorophenyl)propionamide
(38 Scheme 3)
Prepared as described for 8 from 35 (R)-tert-butyl(6-((4-(N-(3,4-
difluorophenyl)propionamido)piperidin-1-yl)methyl)-1,2,3,4-te-
trahydronaphthalen-1-yl)carbamate (0.12 g, 0.23) afforded the title
compound 38 as a white solid (0.1 g, 78% of yield). ESI MS m/z 428
(MH)+. HRMS [M+H]+ 428.2509 (theoretical 428.2508); 1H NMR
(499 MHz, DMSO-d6) d 9.97–9.71 (m, 1H), 8.37 (d, J = 5.5 Hz, 3H),
7.59–7.44 (m, 3H), 7.29 (d, J = 8.0 Hz, 1H), 7.25 (s, 1H), 7.12 (d,
J = 9.0 Hz, 1H), 4.74–4.61 (m, 1H), 4.45 (m, 1H), 4.18 (s, 2H), 3.37–
3.24 (m, 2H), 3.17–3.04 (m, 2H), 2.80–2.67 (m, 2H), 2.12–2.00 (m,
1H), 2.00–1.79 (m, 6H), 1.74 (m, 1H), 1.50 (m, 2H), 0.89 (t,
J = 7.4 Hz, 3H). 13C NMR (125 MHz, DMSO-d6) d 172.5, 159.3,
159.0, 158.7, 158.5, 150.8, 150.5, 148.9, 148.5 138.6, 135.2, 134.2,
130.2, 129.2, 129.0, 128.37, 128.31, 120.5, 120.4, 118.3, 118.1,
115.9, 58.9, 51.2, 51.1, 49.2, 48.0, 28.7, 28.1, 27.7, 27.2, 18.5, 9.6.
5.4.25. (R)-tert-Butyl(6-((4-(N-(3,4-difluorophenyl)propionam-
ido)piperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)-
carbamate (35 Scheme 3)
Prepared as described for 5 from (R)-tert-butyl(6-(iodomethyl)-
1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 3 (0.15 g, 0.38 mmol,
1 equiv)
and
N-(3,4-difluorophenyl)-N-(piperidin-4-yl)propi-
onamide 32 (0.15 g, 0.58 mmol, 1.5 equiv) in 10 mL of acetone
and 0.1 g of K2CO3 afforded the title compound 35 as a light brown
colored solid (0.13 g, 64% of yield). MS (ESI) m/z (M+H)+: 528. 1H
NMR (499 MHz, chloroform-d) d 7.24 (d, J = 7.9 Hz, 1H), 7.21–
7.15 (m, 1H), 7.03 (d, J = 8.0 Hz, 1H), 6.96–6.90 (m, 2H), 6.83 (m,
1H), 4.80 (t, J = 6.2 Hz, 1H), 4.72 (d, J = 8.9 Hz, 1H), 4.67–4.56 (m,
1H), 3.37 (s, 2H), 2.87 (d, J = 11.1 Hz, 2H), 2.76–2.65 (m, 2H), 2.07
(m, 2H), 2.03–1.96 (m, 1H), 1.92 (q, J = 7.3 Hz, 2H), 1.84–1.59 (m,
5H), 1.47 (s, 9H), 1.36 (m, 2H), 1.02 (t, J = 7.4 Hz, 3H). 13C NMR
(125 MHz, CDCl3) d 173.0, 155.3, 151.1, 149.0, 148.9, 137.1,
136.9, 135.9, 135.2, 129.5, 128.4, 126.9, 126.8, 126.7, 126.3,
126.2, 119.7, 119.5, 117.6, 117.4, 79.2, 62.6, 53.0, 52.4, 48.4, 30.5,
29.2, 28.5, 28.4, 19.9, 9.5.
5.4.29. (R)-N-(1-((5-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)
methyl)piperidin-4-yl)-N-(3,4-dichlorophenyl)propionamide
(39 Scheme 3)
Prepared as described for 8 from 36 (R)-tert-butyl(6-((4-(N-
(3,4-dichlorophenyl)propionamido)piperidin-1-yl)methyl)-1,2,3,4-
tetrahydronaphthalen-1-yl)carbamate (0.15 g, 0.26) afforded the
title compound 39 as a white solid (0.1 g, 81% of yield). ESI MS
m/z 460 (MH)+. HRMS [M+H]+ 460.1917 (theoretical 460.1916);
1H NMR (499 MHz, DMSO-d6) d 9.69 (d, J = 11.1 Hz, 1H), 8.58–
8.16 (m, 3H), 7.73 (d, J = 8.5 Hz, 1H), 7.66–7.61 (m, 1H), 7.51 (d,
J = 8.0 Hz, 1H), 7.27 (m, 3H), 4.70 (d, J = 12.7 Hz, 1H), 4.50–4.39
(m, 1H), 3.30 (d, J = 12.0 Hz, 2H), 3.11 (m, 2H), 2.74 (m, 2H),
2.13–1.98 (m, 1H), 2.01–1.81 (m, 6H), 4.25–4.10 (m, 2H), 1.74
(m, 1H), 1.47 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H). 13C NMR (125 MHz,
DMSO-d6) d 172.2, 159.2, 159.0, 158.7, 158.5, 138.6, 138.5, 134.2,
132.9, 132.3, 132.1, 131.56, 131.51, 130.2, 129.2, 129.0, 121.1,
118.7, 116.3, 113.9, 58.9, 51.2, 49.2, 48.0, 28.7, 28.3, 27.7, 27.2,
18.5, 9.6.
5.4.26. (R)-tert-Butyl(6-((4-(N-(3,4-dichlorophenyl)propionamido)-
piperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carba-
mate (36 Scheme 3)
Prepared as described for 5 from (R)-tert-butyl(6-(iodomethyl)-
1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 3 (0.12 g, 0.32 mmol,
1 equiv) and N-(3,4-dichlorophenyl)-N-(piperidin-4-yl)propionamide
33 (0.14 g, 0.48 mmol, 1.5 equiv) in 10 mL of acetone and 0.08 g of
K2CO3 afforded the title compound 36 (0.12 g, 67% of yield) as a
light brown colored solid. MS (ESI) m/z (M+H)+: 560. 1H NMR
(499 MHz, chloroform-d)
d 7.48 (d, J = 8.4 Hz, 1H), 7.24 (d,
J = 7.9 Hz, 1H), 7.19 (d, J = 2.4 Hz, 1H), 7.07–7.01 (m, 1H), 6.96–
6.91 (m, 2H), 4.86–4.76 (m, 1H), 4.72 (d, J = 8.9 Hz, 1H), 4.68–
4.57 (m, 1H), 3.37 (s, 2H), 2.93–2.82 (m, 2H), 2.79–2.63 (m, 2H),
2.08 (d, J = 11.8 Hz, 2H), 1.99 (m, 1H), 1.96–1.87 (m, 2H), 1.84–
1.67 (m, 5H), 1.47 (s, 9H), 1.41–1.29 (m, 2H), 1.02 (t, J = 7.4 Hz,
3H). 13C NMR (125 MHz, CDCl3) d 172.9, 155.4, 138.5, 137.2,
137.0, 136.0, 133.1, 132.9, 132.2, 130.9, 129.9, 129.5, 128.5,
127.0, 79.3, 62.6, 53.0, 52.9, 52.5, 48.5, 30.6, 29.2, 28.7, 28.5,
19.9, 9.5.
5.4.30. (R)-N-(1-((5-Amino-5,6,7,8-tetrahydronaphthalen-2-yl)-
methyl)piperidin-4-yl)-N-(4-chloro-3-methoxyphenyl)propi-
onamide (40 Scheme 3)
Prepared as described for 8 from 37 (R)-tert-butyl(6-((4-(N-(4-
chloro-3-methoxyphenyl)propionamido)piperidin-1-yl)methyl)-1,
2,3,4-tetrahydronaphthalen-1-yl)carbamate (0.13 g, 0.23) afforded
the title compound 40 as a white solid (0.1 g, 75% of yield). ESI MS
m/z 456 (MH)+. HRMS [M+H]+ 456.2416 (theoretical 456.2412); 1H
NMR (499 MHz, DMSO-d6) d 9.77 (d, J = 10.1 Hz, 1H), 8.40 (s, 3H),
7.50 (dd, J = 13.2, 8.1 Hz, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H),
7.01 (s, 1H), 6.86–6.74 (m, 1H), 4.66 (d, J = 12.5 Hz, 1H), 4.52–
4.39 (m, 1H), 4.25–4.12 (m, 2H), 3.84 (s, 3H), 3.34–3.24 (m, 2H),
3.19–3.06 (m, 2H), 2.73 (m, 2H), 2.06 (m, 1H), 2.01–1.81 (m, 6H),
1.80–1.67 (m, 1H), 1.53 (m, 2H), 0.89 (t, J = 7.3 Hz, 3H), 13C NMR
(125 MHz, DMSO-d6) d 172.5, 159.3, 159.0, 158.7, 158.5, 155.4,
138.6, 138.5, 134.3, 132.3, 130.5, 130.2, 129.2, 129.0, 123.6,
121.7, 121.0, 118.7, 116.3, 115.6, 113.9, 65.3, 58.9, 56.8, 51.3,
49.3, 48.0, 28.7, 28.1, 27.7, 27.4, 18.5, 15.6, 9.7.
5.4.27. (R)-tert-Butyl(6-((4-(N-(4-chloro-3-methoxyphenyl)pro-
pionamido)piperidin-1-yl)methyl)-1,2,3,4-tetrahydronaphtha-
len-1-yl)carbamate (37 Scheme 3)
Prepared as described for 5 from (R)-tert-butyl(6-(iodomethyl)-
1,2,3,4-tetrahydronaphthalen-1-yl)carbamate 3 (0.12 g, 0.32 mmol,
1 equiv) and N-(3-chloro-4-methoxyphenyl)-N-(piperidin-4-yl)
propionamide 34 (0.14 g, 0.48 mmol, 1.5 equiv) in 10 mL of acetone
and 0.09 g of K2CO3 afforded the title compound 37 (0.13 g, 75% of
yield) as a light yellow colored solid. MS (ESI) m/z (M+H)+: 556. 1H
NMR (499 MHz, chloroform-d) d 7.34 (d, J = 8.2 Hz, 1H), 7.21 (d,
J = 7.8 Hz, 1H), 7.03–6.98 (m, 1H), 6.91 (s, 1H), 6.60 (dd, J = 8.2,

6194
S. Deekonda et al. / Bioorg. Med. Chem. 23 (2015) 6185–6194
10. Jagerovic, N.; Cano, C.; Elguero, J.; Goya, P.; Callado, L. F.; Meana, J. J.; Gir_on, R.;
Acknowledgments
Abalo, R.; Ruiz, D.; Goicoechea, C.; Martin, M. A. Bioorg. Med. Chem. 2002, 10,
817.
The work was supported by grants from the U.S. Public Health
Service NIDA (Grants 314450 NIDA 2P01 DA006284). We thank
Christine Kasten for assistance with the manuscript.
11. Vardanyan, R. S.; Hruby, V. J. Future Med. Chem. 2014, 6, 385.
12. Podolsky, A. T.; Sandweiss, A.; Hua, J.; Bilskyc, E. J.; Cain, J. P.; Kumirov, V. K.;
Lee, Y. S.; Hruby, V. J.; Vardanyan, R. S.; Vanderaha, T. W. Life Sci. 2013, 93,
1010.
13. Subramanian, G.; Paterlini, M. G.; Portoghese, P. S.; Ferguson, D. M. J. Med.
Chem. 2000, 43, 381.
Supplementary data
14. Bagley, J. R.; Kudzma, L. V.; Lalinde, N. L.; Colapret, J. A.; Huang, B.-S.; Lin, B. S.;
Jerussi, T. P.; Benvenga, M. J.; Doorley, B. M. Med. Res. Rev. 1991, 11, 403.
15. Essawi, M. Y. H.; Portoghese, P. S. J. Med. Chem. 1983, 26, 348.
16. Lee, Y. S.; Nyberg, J.; Moye, S.; Agnes, R. S.; Davis, P.; Ma, S.-W.; Lai, J.; Porreca,
F.; Vardanyan, R.; Hruby, V. J. Bioorg. Med. Chem. Lett. 2007, 17, 2161.
17. Petrov, R. R.; Vardanyan, R. S.; Lee, Y. S.; Ma, S.-W.; Davis, P.; Begay, L. J.; Lai, J.;
Porreca, F.; Hruby, V. J. Bioorg. Med. Chem. Lett. 2006, 16, 4946.
18. Lee, Y. S.; Petrov, R. R.; Park, C.; Ma, S.-W.; Davis, P.; Lai, J.; Porreca, F.; Hruby, V.
J. J. Med. Chem. 2007, 50, 5528.
19. Lee, Y. S.; Kulkarani, V.; Cowell, S. M.; Ma, S.-W.; Davis, P.; Lai, J.; Porreca, F.;
Vardanyan, R.; Hruby, V. J. J. Med. Chem. 2011, 54, 382.
20. Petrov, R. R.; Lee, Y. S.; Vardanyan, R. S.; Liu, L.; Ma, S.-W.; Davis, P.; Lai, J.;
Porreca, F.; Vanderah, T. W.; Hruby, V. J. Bioorg. Med. Chem. Lett. 2013, 23, 3434.
21. Dan, P.; Birgitte, E. L.; Gordon, M.; Ostergaard, N. E.; Paul, R. J. WO 2007093603
2007.
22. Ben, A.C.; Toshihiro, A.; Kaustav, B.; Jian, C. J.; Brooks, H. J.; Wenyuan, Q. WO
2006041888 2006.
23. Corey, E. J.; Bakshi, R. K.; Shibata, S. J. Am. Chem. Soc. 1987, 109, 5551.
24. Misicka, A.; Lipkowski, A. W.; Horvath, R.; Davis, P.; Kramer, T. H.; Yamamura,
H. I.; Hruby, V. J. Life Sci. 1992, 51, 1025.
25. Kramer, T. H.; Davis, P.; Hruby, V. J.; Burks, T. F.; Porreca, F. J. Pharmacol. Exp.
Ther. 1993, 266, 577.
26. Yaksh, T. L.; Rudy, T. A. Physiol. Behav. 1976, 17, 1031.
27. Hargreaves, K.; Dubner, R.; Brown, F.; Flores, C.; Joris, J. Pain 1988, 3277.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmc.2015.07.071.
References and notes
1. Kieffer, B. L. Trends Pharmacol. Sci. 1999, 20, 19.
2. Eguchi, M. Med. Res. Rev. 2004, 24, 182.
3. Mosberg, H. I.; Yeomans, L.; Harland, A. A.; Bender, A. M.; Sobczyk-Kojiro, K.;
Anand, J. P.; Clark, J. M.; Jutkiewicz, E. M.; Traynor, J. R. J. Med. Chem. 2013, 56,
2139.
4. Anand, J. P.; Purington, L. C.; Pogozheva, I. D.; Traynor, J. R.; Mosberg, H. I. Chem.
Biol. Drug Des. 2012, 80, 763.
5. Wang, C.; McFadyen, I. J.; Traynor, J. R.; Mosberg, H. I. Bioorg. Med. Chem. Lett.
1998, 8, 2685.
6. Janssen, P. A. J. Br. J. Anaesthesia 1962, 34, 260.
7. Gentilucci, L.; Tolomelli, A.; De Marco, R.; Artali, R. Curr. Med. Chem. 2012, 19,
1587; Kaczor, A.; Matosiuk, D. Curr. Med. Chem. 2002, 9, 1567.
8. Weltrowska, G.; Chung, N. N.; Lemieux, C.; Guo, J.; Lu, Y.; Wilkes, B. C.; Schiller,
P. W. J. Med. Chem. 2010, 53, 2875.
9. Vucꢀkovic´, S.; Prostran, M.; Ivanovic´, M.; Dosꢀen-Mic´ovic´, L.; Todorovic´, Z.; Nesꢀic´,
´
´
Z.; Stojanovic, R.; Divac, N.; Mikovic, Z. Curr. Med. Chem. 2009, 16, 2468.