N,N-Diethyl-4-[(3-hydroxyphenyl)(piperidin-4-yl)amino] benzamide derivatives: The development of diaryl amino piperidines as potent δ opioid receptor agonists with in vivo anti-nociceptive activity in rodent models

Article abstract of DOI:10.1016/j.bmcl.2009.09.072

We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, establishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered compounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta agonist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed, demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.

Full text of DOI:10.1016/j.bmcl.2009.09.072

Bioorganic & Medicinal Chemistry Letters 19 (2009) 5994–5998
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
N,N-Diethyl-4-[(3-hydroxyphenyl)(piperidin-4-yl)amino] benzamide derivatives:
The development of diaryl amino piperidines as potent d opioid receptor agonists
with in vivo anti-nociceptive activity in rodent models
a
a
a
a
Paul Jones a, Andrew M. Griffin a, , Lars Gawell , Rico Lavoie , Daniel Delorme , Edward Roberts ,
William Brown a, Christopher Walpole a, Wenhau Xiao b, Jamie Boulet b, Maryse Labarre c, Martin Coupal c,
Joanne Butterworth c, Stephane St-Onge c, Lejla Hodzic c, Dominic Salois c
*
a Department of Medicinal Chemistry, AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville St. Laurent, Québec, Canada H4S 1Z9
b Department of Bioscience, AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville St. Laurent, Québec, Canada H4S 1Z9
c Department of InVitro Biology & DMPK, AstraZeneca R&D Montréal, 7171 Frédérick-Banting, Ville St. Laurent, Québec, Canada H4S 1Z9
a r t i c l e i n f o
a b s t r a c t
Article history:
We have investigated a series of phenolic diaryl amino piperidine delta opioid receptor agonists, estab-
lishing the importance of the phenol functional group and substitution on the piperdine nitrogen for delta
agonist activity and selectivity versus the mu and kappa opioid receptors. This study uncovered com-
pounds with improved agonist potency and selectivity compared to the standard, non-peptidic delta ago-
nist SNC-80. In vivo anti-nociceptive activity of analog 8e in two rodent models is discussed,
demonstrating the potential of delta agonists to provide a novel mechanism for pain relief.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 August 2009
Revised 16 September 2009
Accepted 17 September 2009
Available online 22 September 2009
Keywords:
Delta agonism
Antinociception
The discovery of the delta receptor as a member of the opioid
family of receptors and its implication in pain pathways high-
lighted the potential importance of the delta receptor as a novel
treatment for pain.1,2 Early studies demonstrated delta receptor
mediated analgesia using delta selective peptidic agonists,2–4 with
the potential to provide pain relief without the limiting side effects
associated with the commonly used mu opioid receptor agonists
such as morphine and fentanyl (respiratory depression, tolerance
and physical dependence). More recently, Adolor published infor-
mation on their development delta agonist, ADL5859, for pain
management.4b Increasingly, alternative therapeutic areas have
been identified where delta receptor agonists play a beneficial
role.5 They have been shown to possess immunostimulatory activ-
ity,6 involved in modulating anxiety and depression,7 may provide
a means of cardioprotection following ischemia8 and have been re-
ported to be involved in the treatment of irritable bowel
syndrome.9
gen and was first reported by our group,12 followed shortly by Car-
son and Podlogar.13 We herein report on our SAR studies in this
series, focussing on the effects of modifying substitution on the
piperidine nitrogen.
A synthetic scheme was developed to allow access to both the
methyl ether 7 and phenol 8 amino piperidine analogs (Scheme
1). Secondary amine 4 was synthesized under standard reductive
amination conditions using 3-methoxyaniline and 1-benzylpiperi-
din-4-one. Palladium N-arylation of amine 4 was achieved using
xantphos14 as the ligand as it gave a superior yield (85%) of biaryl
amine 5 compared to using BINAP (ꢀ60%) where the reaction could
not be forced to completion, even after prolonged heating. The
N-benzyl group was removed with 1-chloroethyl chloroformate
to yield amine 6 and the southern group installed via reductive
amination or via alkylation using the desired alkyl halide. Final
cleavage of the methyl ether 7 to generate the phenol 8 was
achieved using boron tribromide. All test compounds were purified
by reverse-phase chromatography with a water/acetonitrile gradi-
ent containing 0.05% TFA v/v.15
As part of our earlier contributions in the development of selec-
tive, non-peptidic delta agonists we reported on two distinct series
of compounds of general structure 1, piperizines10 and 2, olefins11
and we now report on a third class of compounds of general struc-
ture 3, aminopiperidines (Fig. 1). Series 3 is related to piperazine
series 1 via inversion of the benzylic carbon and piperazine nitro-
The pharmacological profiles of the compounds were deter-
mined by radioligand binding assays. The binding affinities of all
compounds were determined using cloned human d,
and the agonist potencies (EC50) at the delta receptor were mea-
sured using a GTP [
35S] binding assay.16 In all experiments the
known non-peptic delta agonist SNC-8017 was included as a
control and the efficacy of compounds in the [35S] GTP
S binding
l, j receptors
c-
* Corresponding author. Tel.: +1 514 832 3200; fax: +1 514 832 3232.
E-mail address: andrew.griffin@astrazeneca.com (A.M. Griffin).
c
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.09.072

P. Jones et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5994–5998
5995
O
O
O
N
N
N
N
X
X
X
N
N
R
N
R
N
R
2, olefin series
1, piperazine series
3, amino piperidine series
O
N
OMe
N
N
SNC-80
Figure 1.
O
N
O
OMe
HN
N
N
OMe
d
c
a, b
N
N
4
5
O
N
O
O
N
N
e
N
OH
N
OMe
f
N
OMe
N
N
N
H
6
R
R
8
7
Scheme 1. Reagents and conditions: (a) 3-methoxyaniline, Ti(OiPr)4; (b) NaBH4, ethanol; (c) 4-bromo-N,N-diethylbenzamide, Pd2(dba)3, xanthphos, NaOtBu, toluene, 110 °C;
(d) (1) CH3CHClOCOCl, Cl(CH2)2Cl; (2) MeOH, reflux; (e) RCH2Br/RCH2Cl, triethylamine, CH2Cl2 or RCHO, MeOH, NaBH3CN, AcOH; (f) 1 N BBr3 in CH2Cl2.
assay calculated in relation to the response from SNC-80 (Emax
100%).
SNC-80 is also a methyl ether, although from the piperazine series
of delta agonists. All analogs demonstrated selective binding to the
delta receptor over mu and kappa receptors.
Turning our attention to phenol derivatives 8, we initially inves-
tigated the effect of introducing alkyl groups onto the southern
piperidine nitrogen as shown in Table 2. Secondary amine 8a,
while selective for the delta receptor, showed reduced agonist
potency compared to the alkyl derivatives 8b, 8c and 8d, demon-
strating the need for substitution on the piperidine nitrogen. Intro-
duction of the allyl group, 8b, and the cyclopropyl group 8c, gave
Representative data for methyl ethers 7 is shown in Table 1,
along with data for the reference delta agonist SNC-80 (see Fig. 1
for structure). All compounds showed reduced binding affinity
and agonist activity at the delta receptor compared to SNC-80
and although compounds evaluated in the GTP [c-
35S] binding as-
say were all full agonists, the most potent analog 2-thiophene 7c
was five times less potent than SNC-80. It is of interest to note
the loss of delta activity when compared to SNC-80 given that

5996
P. Jones et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5994–5998
Table 1
Binding affinity and d agonist activity of selected methyl ethers 7
Compound
R
Binding affinities (Ki nM)
d Agonist activity
EC50 (nM) EMax (%)
d
l
j
SNC-80
1.29 0.13
352 43
4169 829
2.99 0.06
101
1
7a
7b
7c
7d
7e
49.6 30.0
18.2 0.9
11.1 1.2
50.2 8.1
14.0 0.8
2106 315
1596 22
1963 582
2533 214
1299 62
3606 876
2549 635
6405 1071
7081 1790
4985 998
141 18
101
5
S
S
17.4 4.0
173 62
O
O
86.5 22.9
125 44
115 11
193 82
H
N
7f
22.8 1.5
4445 287
>10,000
N
similar profiles while the cyclohexyl derivative showed a drop in
delta binding and activation. None of these derivatives showed
improvements in activity at the delta receptor in comparison to
SNC-80.
of a small group on the ring can decrease mu binding while main-
taining activity at the delta receptor.
Heterocyclic derivatives were more extensively studied and
they generally had improved selectivity for delta/mu as well as
gave having improved physical chemical properties (data not
shown). For thiophene and furan substitution the 3-isomer is pre-
ferred over the 2-isomer and the 2-imidazole 8n 12 times more po-
tent that regiomeric imidazole 8p. Methylation of 2-imidazole 8n
to give 8r proved to be detrimental, causing a 12-fold drop in ago-
nist potency. Overall most of the heterocyclic analogs had im-
proved delta agonist potency compared to SNC-80 (see Table 1).
Of all the heterocyclic derivatives investigated, only the 3-furyl
8j, 3-thiophenyl 8k and 2-pyridinyl 8o were more potent delta
agonists than benzyl substituted 8e.
Within our program, phenol 8e was identified as a candidate of
interest and was assessed in two rodent models of nociception.
Compound 8e demonstrated excellent binding affinity, agonist po-
tency and good selectivity for the delta receptor, as well as having a
moderate pharmacokinetic profile the in rat (half-life 0.8 h; bio-
availability, 25%).
In our previous work in the piperazine series 110 and olefin ser-
ies 211 we did not investigate the effects of a southern aromatic or
heteroaromatic group on delta activation and selectivity. Such
modifications were introduced in the current series and data re-
ported in Table 3. Benzyl derivative 8e shows enhanced agonist po-
tency versus the corresponding methyl ether 7a (0.56 nM vs
141 nM), highlighting the importance of the phenol functionality
for good agonist activity at the delta receptor. Furthermore, when
comparing the potency of southern benzyl substituted 8e to the al-
kyl derivatives in Table 2, a positive effect of the southern aromatic
group on delta binding and activation is seen. Compound 8e also
showed improved delta agonist potency compared to SNC-80,
although selectivity over mu and kappa opioid receptors was de-
creased. SAR around 8e was expanded to investigate effects of sub-
stituents on the southern aromatic ring (agonist activity and
selectivity over mu and kappa) and also to determine if heterocy-
cles were tolerated in this position (see Table 3). The incorporation
of heterocycles would enable us to modulate the physical chemical
properties of the molecules (aqueous solubility, lipophilicity).
Substitution at the benzylic position with a methyl group, 8f,
was not tolerated and showed a sevenfold drop in agonist potency
compared to 8e. Analogs 8g to 8i demonstrated that substitution
on the aromatic ring effected binding at the mu receptor: p-Me
8g showed enhanced mu binding (62 nM) whereas o-F 8h had de-
creased binding at mu (162 nM) as well as m-F 8i (472 nM). Both
8h and 8i had improved delta/mu selectivity compared to unsub-
stituted phenyl derivative 8e, demonstrating that the introduction
Phenol 8e was evaluated in vivo in both the mouse abdominal
constriction antinociception model for acute pain and the rat car-
rageenan model for acute inflammatory hyperalgesia. In the mouse
acetic acid induced abdominal constriction model, 8e produced a
dose dependent response with an ED50 of 21.5 1.5
l
mol/kg iv
mol/kg
and a maximum inhibition of writhing of 57 9% at 25
l
iv.18 The pre-administration of the delta selective antagonist nal-
trindole blocked the observed anti-nociceptive response confirm-
ing the analgesic effect is mediated through activation of the
delta receptor. In the rat carrageenan model, 8e produced a dose
dependent response with an ED50 of 17.5
lmol/kg iv and a maxi-
Table 2
Binding affinity and d agonist activity of phenols 8 with N-alkyl substitution
Compound
R
Binding affinities (Ki nM)
Selectivity ratios
d Agonist activity
d
l
j
l/d
k/d
EC50 (nM)
EMax (%)
8a
8b
8c
8d
H
Allyl
CH2-cyclohexyl
CH2-cyclopropyl
0.99 0.05
1.03 0.07
2.30 0.23
0.97 0.05
87
9
901 67
88
127
125
129
910
96
315
522
25.6 3.2
4.13 0.92
18.9 2.9
3.40 0.19
105
77
106
5
2
8
130 23
289 60
126 24
98
9
726 26
508 91
80 10

P. Jones et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5994–5998
5997
Table 3
Binding affinity and d agonist activity of phenols 8 with N-benzyl and N-CH2heterocycle substitution
Compound
R
Binding affinities (Ki nM)
Selectivity ratios
/d /d
d Agonist activity
EC50 (nM) EMax (%)
d
l
K
l
j
8e
8f
0.42 0.03
88 11
744 127
210
463
97
1771
1564
1133
1266
0.56 0.07
3.79 0.26
1.14 0.10
1.13 0.38
100
2
1.40 0.28
0.64 0.02
0.76 0.05
648 122
2191 506
726 63
967 55
101 14
8g
8h
62
9
105
111
5
2
162 41
472 33
342
F
8i
0.70 0.05
1358 90
670
1929
2.63 0.48
92
2
F
O
S
8j
0.22 0.01
0.27 0.01
0.42 0.02
0.65 0.10
177 21
127 15
115 17
181 28
121 15
495 165
263 23
453 71
802
470
276
278
550
1825
632
0.22 0.02
0.22 0.02
1.29 0.28
1.41 0.43
105 13
8k
8l
97
101
104
3
5
5
O
S
8m
696
H
N
8n
8o
8p
8q
8r
0.30 0.02
0.24 0.02
1.61 0.08
1.02 0.03
1.70 0.11
1251 110
205 26
1189 204
2043 220
1451 124
4568 460
4595 405
4168
854
3959
8523
901
1.17 0.59
0.25 0.03
14.1 1.6
5.87 2.05
14.5 3.7
118 14
N
98
4
8
N
N
309 55
192
105
N
H
1549 210
772 197
1514
452
4465
2691
111 17
N
N
92
6
N
mum anti-hyperalgesic effect at 30
l
mol/kg iv with 60 12%
for potent agonist activity and that the agonist activity is also
modulated by substitution on the piperidine nitrogen. The incor-
poration of pendent aromatic and heteroaromatic groups has
been found to give analogs that have improved potency at the
delta receptor and improved selectivity over the mu and kappa
receptors compared to the known standard delta agonist, SNC-
80. We also describe in vivo data showing the anti-nociceptive ef-
fect of 8e in two rodent models, the mouse abdominal constric-
tion model and in the rat carrageenan, demonstrating the
potential of delta agonists to provide a novel mechanism for pain
relief.
reversal.19 It is of interest to note that no convulsant activity was
observed with 8e at doses administered in the abdominal constric-
tion model and carrageenan model. This is contrary to reports for
SNC-80 and BW373U86, where convulsant activity was seen at
similar doses producing an anti-nociceptive effect.20 Phenol 8e
did however produce hyperactivity at doses above 30 lmol/kg iv.
In summary, we have continued our earlier work in the devel-
opment of non-peptic delta receptor agonists and now report on
SAR studies in the amino piperidine series 3 (Fig. 1). This work
has shown that within this series of agonists, the phenol is crucial

5998
P. Jones et al. / Bioorg. Med. Chem. Lett. 19 (2009) 5994–5998
compound 8e: 1H NMR (CD3OD) dH 1.16 (br s, 6H), 1.69–1.73 (m, 2H), 2.22
Further studies from our group within this series of delta ago-
(d, J = 14 Hz, 2H), 3.27 (t, J = 8 Hz, 2H), 3.35–3.51 (m, 6H), 4.27 (s, 2H), 4.28–
4.35 (m, 1H), 6.69 (d, J = 9 Hz, 3H), 7.20–7.23 (m, 4H), 7.46 (s, 6H). MS (ESI) m/z
458.23 (MH+); compound 8o: 1H NMR (400 MHz, DMSO-d6) dY 1.07 (t, 6H),
1.66–1.75 (m, 2H), 2.01–2.05 (m, 2H), 3.21–3.46 (m, 8H), 4.20–4.23 (m, 1H),
4.39 (s, 2H), 6.37–39 (m, 1H), 6.45–6.48 (m, 1H), 6.64 (d, J = 8.4 Hz, 2H), 6.66–
6.68 (m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.21–7.24 (m, 1H), 7.43–7.51 (m, 2H),
7.88–7.92 (s, 1H), 8.62–8.63 (m, 1H), 9.53 (br s, 1H), 9.69 (br s, 1H). MS. (ESI) m/
z 459.23 (MH+).
nists, focussing on modifications of the phenol group are reported
in the following paper.
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3 mM MgCl2, 1 mg/ml BSA, pH 7.4. The amounts of bound radioactivity were
determined at equilibrium by filtration. The nonspecific (NS) binding was
defined in the presence of 10
were determined from 2-parameter logistic curve fits of percent specific
binding versus log (molar ligand), solving for IC50 and hill slope.GTP[
35S
binding assays. Membranes expressing 10 pmol of hDOR per mg protein were
combined with test compounds and approximately 0.2 nM GTP[
35S in 50 mM
Hepes, 20 mM NaOH, pH 7.4, 5 mM MgCl2, 100 mM NaCl, 1 mM EDTA, 1 mM
DTT, 0.1% BSA, 15 M GDP. The bound radioactivity was determined after 1 h
by filtration. Control and stimulated binding were determined in the absence
and presence of 3 M SNC-80 respectively. Values of EC50 and Emax for ligands
were obtained from 3-parameter logistic curve fits of percent stimulated
GTP[
35S binding versus log (molar ligand), solving for EC50 and hill slope, and
% Emax
lM naloxone. The IC50 values of test compounds
c
]
c
]
l
l
c
]
.
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1.5
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lmol/kg.
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l
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