4-Phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives as non-peptidic selective δ-opioid agonists with potential anxiolytic/antidepressant properties. Part 2

Article abstract of DOI:10.1016/j.bmcl.2007.05.012

Novel 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives have been prepared and their synthesis described herein. In vitro affinities for δ-, μ-, and κ-opioid receptors are reported. Evaluation of some representative compounds from this series in the mo

Full text of DOI:10.1016/j.bmcl.2007.05.012

Bioorganic & Medicinal Chemistry Letters 17 (2007) 3860–3863
4-Phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives as
non-peptidic selective d-opioid agonists with potential
anxiolytic/antidepressant properties. Part 2
a,b,
a,c
a,b
*
´
´ ´
Andres A. Trabanco,
Nancy Aerts, Rosa M. Alvarez,a,b Jose I. Andres,
Inge Boeckx,a,c Javier Fernandez, Antonio Gomez, Frans E. Janssens,a,c
Joseph E. Leenaerts,a,c Ana I. De Lucas,a,b Encarna Matesanz,a,b
Thomas Stecklera,c and Shirley Pullana,c
a,b
a,b
´
´
aJohnson & Johnson Pharmaceutical Research & Development, Research & Early Development Europe, CNS-Psychiatry, Spain
bDivision of Janssen-Cilag, Medicinal Chemistry Department, Jarama 75, 45007 Toledo, Spain
cDivision of Janssen Pharmaceutica N.V., Turnhoutseweg 30, B2340 Beerse, Belgium
Received 18 April 2007; revised 2 May 2007; accepted 3 May 2007
Available online 10 May 2007
Abstract—Novel 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives have been prepared and their synthesis described herein. In
vitro affinities for d-, l-, and j-opioid receptors are reported. Evaluation of some representative compounds from this series in
the mouse neonatal ultrasonic vocalization test and the mouse tail suspension test revealed anxiolytic- and antidepressant-like
effects, respectively, upon subcutaneous administration.
Ó 2007 Elsevier Ltd. All rights reserved.
The presence of at least three populations of opioid
receptors, l, d, and j, is well established and docu-
mented. All three populations appear to be present in
the central and peripheral nervous system of many spe-
cies, including human beings.1 There is an increasing
rationale suggesting that endogenous opioids are involved
in the response to antidepressant treatment and stress-
related disorders such as depression and anxiety.2
Endogenous enkephalins have been hypothesized to
diminish the impact of stress, which could be mediated,
at least to some extent, via activation of d-opioid recep-
tors.3 For example, the psychological stress of housing
conditions and rank status has been demonstrated to
alter the functional activity of d-opioid receptors in rats.4
Moreover, prenatal stress, which functions as an animal
model of depression, has been shown to induce a down-
regulation of d-opioid receptors in different hypotha-
lamic regions in rats.5 In addition, the monoamine
oxidase A inhibitor moclobemide, a clinically active
antidepressant drug, increased d-opioid receptor binding
in frontal cortex and amygdala after 4 days of treatment
in rats.6 More recently Filliol et al. reported that d-opi-
oid receptor-knockout mice exhibited depressive-like
and anxiogenic-like responses in the forced swimming
and elevated plus-maze test, respectively.7
SNC80,8 a non-peptidic selective d-opioid agonist, has
shown both anxiolytic- and antidepressant-like activities
in behavioral models in rodents (Fig. 1). Perrine et al.
have shown that SNC80 produced dose-dependent anx-
iolytic effects in two paradigms of anxiety: the elevated
plus-maze and defensive burying models.9 Furthermore,
SNC80 suppresses ultrasonic vocalizations in rats in
response to air-puff stress,4 providing further evidence
CONEt2
H
MeO
N
N
Keywords: Opioid; d-Agonist; Antidepressant; Anxiolytic.
Corresponding author. Fax: +34 925 23 57 71; e-mail: atrabanc@
prdes.jnj.com
SNC80
*
Figure 1. Selective nonpeptidic delta opioid agonist SNC80.
0960-894X/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2007.05.012

A. A. Trabanco et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3860–3863
3861
Tr
N
N
N
N
N
NH
N
O
O
6
OH
OH
N
N
Tr
N
N
N
(ii)
(iii)
Ph
Ph
N
(i)
N
CO2Et
5
N
CO2Et
N
S
O
N
CO2Et
Ph
N
H
7
8
R2
NH
N
N
1
2
(iv)
(vi)
N
δ Ki = 18 nM
δ Ki = 3.2 nM
μ Ki = 980 nM
κ Ki = 346 nM
μ Ki = >4652 nM
κ Ki = 505 nM
N
N
δ [35S]GTPγS EC50 = 14 nM
δ [35S]GTPγS EC50 = 832 nM
NH
N
O
R1
O
R1
Figure 2. Compounds 1 and 2 and their binding affinities.
10
3a-q
R2
N
NH
N
H
for reduced stress responsivity following d-agonism. The
actions of SNC80 in animal models of depression have
been well characterized.9a,10 Thus SNC80 dose-depen-
dently reduced the duration of immobility in the forced
swim test in rats. Both anxiolytic- and antidepressant-
like effects could be significantly antagonized by naltrin-
dole, a selective d-opioid-receptor antagonist.
9
N
N
(vi)
(v)
N
N
R1
R1
O
O
O
O
11
4a-s
Scheme 1. Reagents and conditions: (i) n-BuLi, 1-tritylimidazole (6),
THF, À78 °C to rt, 2 h, 48%; (ii) AcOH (5% in MeOH), reflux, 6 h,
85%; (iii) AlCl3, benzene, 60 °C, 1 h, 77%; (iv) R1COCl, Et3N, DMF,
THF, rt, 2 h; (v) R1OCOCl, Et3N, CH2Cl2, rt, 2 h; (vi) NaH, THF, rt,
10 min, then R2Hal, reflux, 8 h, 56–87%.
We have recently disclosed a series of non-chiral/
non-peptidic 4-phenyl-4-[1H-imidazol-2-yl]-piperidine
derivatives as d-opioid ligands with good selectivity over
l- and j-receptors.11,12 This family of compounds has
the advantage of having no chiral centers and can be
easily synthesized from relatively cheap commercially
available reagents.
Selective reaction of 9 with the corresponding acid chlo-
rides or chloroformates gave compounds 10 and 11,
respectively. The alkylation of the imidazole nitrogen
in 10 and 11 was carried out by reaction with different
alkyl halides in THF, using sodium hydride as a base.
The targeted compounds 3a–o and 4a–o were obtained
in moderate to good yields.13
Compounds 1 and 2 were identified as the most promis-
ing representatives among the first set of analogues pre-
pared (Fig. 2). Thus, compound 1 was found to be the
most potent agonist found among all tested compounds
(EC50 = 14 nM), despite having only moderate binding
activity (Ki = 18 nM). Conversely, compound 2 showed
good binding affinity (Ki = 3.2 nM) but weak agonism
(EC50 = 832 nM).12
The pharmacological profile of the compounds was
determined in radioligand binding studies and func-
tional GTPcS assays. The binding affinities (Ki) of the
compounds against cloned human d-, l-, and j-recep-
tors were determined. The opioid binding affinities of
analogues of 3a–q and 4a–s are listed in Table 1.
These results prompted us to start a chemical explora-
tion around 4-phenyl-4-[1H-imidazol-2-yl]-piperidine
scaffold to further evaluate its potential. In order to ex-
pand our previous exploration around the piperidine
nitrogen a series of amides 3a–q and carbamates 4a–s
were prepared. The synthesis, binding affinities to l-,
d-, and j-opioid receptors, and preliminary pharmaco-
logical evaluation of these analogues in two in vivo anx-
iety and depression paradigms are reported.
As it can be deduced from the data shown in Table 1, in
general both chemical subseries, amides 3 and carba-
mates 4, showed affinities in the nanomolar range for
the d-opioid receptor and selectivities over l and j
receptors in the range of 10- to 100-fold. Regarding
the exploration of R1 a wide range of different groups
was tolerated in classes (3a–k and 4a–h) keeping a
reasonably good affinity and selectivity for the d-opioid
target. Due to their high potency and good selectivity,
compounds 3f (R1 = methoxymethyl), 3h (R1 = phenyl),
and 4b (R1 = ethyl) were selected as good representatives
to further study the influence of the R2 substituent. Thus
the introduction of a methyl substituent in the benzylic
position of 3f, 3h, and 4b resulted in compounds with
equal or slightly better affinity for the d-receptor (3l,
3n, and 4i, respectively). A similar trend was also ob-
served when the benzyl substituent was replaced by 4-
methoxycarbonylbenzyl. Thus, 3m, 3p and 4o showed
higher affinities for the d-opioid receptor than their
The route for the synthesis of compounds 3a–q and 4a–s
is outlined in Scheme 1 and is similar to the one previ-
ously reported by our group.12 Thus, reaction of the
2-lithium salt of 1-tritylimidazole (6) with the N-protected
piperidone 5 led to the corresponding addition product
7 in moderate yield. The trityl protecting group was
removed under acidic conditions to give the unprotected
imidazole derivative 8. The Friedel–Crafts reaction of 8
with benzene occurred with simultaneous hydrolysis of
the carbamate function affording the key intermediate
9 in good yield (77%). This compound was easily
obtained in 50–100 gram scale.

3862
A. A. Trabanco et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3860–3863
Table 1. Binding affinity of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives 3a–q and 4a–o to d-, l- and j-receptorsa,b
N
N
N
N
R2
R2
N
N
R1
O
R1
3a-q
O
O
4a-s
Compound R1
R2
d Ki (nM) l Ki (nM) j Ki (nM) l/d
j/d
3a
3b
3c
3d
3e
3f
Methyl
Ethyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
Benzyl
37
29
>465
>465
>465
>465
>4652
>465
>465
>4652
>465
>4652
>465
>4652
>4652
>4652
>465
>4652
>4652
>4652
2763
1008
n.t.
621
n.t.
n.t.
622
n.t.
124
284
n.t.
n.t.
>4652
65
>12
>52
>10
>20
>126
>63
>20
27
—
13
—
—
84
—
Isopropyl
Cyclopropyl
tert-Butyl
48
23
37
Methoxymethyl
Benzyl
Phenyl
7.4
23
3g
3h
3i
2.3
37
>2023 54
3,5-Dimethylphenyl
2,4,6-Trimethylphenyl
>13
>37
>16
7.7
—
—
3j
125
29
3k
3l
3,5-Trifluoromethylphenyl Benzyl
Methoxymethyl
Methoxymethyl
Phenyl
Phenyl
Phenyl
Phenyl
Methyl
Ethyl
a-Methylbenzyl
4-Methoxycarbonylbenzyl
a-Methylbenzyl
3-Methoxycarbonylbenzyl
4-Methoxycarbonylbenzyl
4-(N,N-Diethylaminocarbonyl)benzyl 158
3.7
5.9
2.3
85
>1257 >1257
>788 11
>2022 145
>5.5
>5002 95
3m
3n
3o
3p
3q
4a
4b
4c
4d
4e
4f
334
n.t.
88
—
0.93
n.t.
n.t.
171
>4652
188
201
121
84
>29
>245
747
—
—
Benzyl
Benzyl
19
3.7
2.9
9.3
1.8
7.4
9.3
12
46
>1064
20
n-Propyl
n-Butyl
Isopropyl
Cyclohexyl
tert-Butyl
Benzyl
Benzyl
Benzyl
>465
>465
>465
>465
>465
>465
>465
>4652
>4652
>465
>465
>465
>465
>465
>465
>465
>465
>160
>50
Benzyl
Benzyl
>258
>63
>50
112
16
4g
4h
4i
Benzyl
Benzyl
9.0
10
121
62
>39
Ethyl
Ethyl
a-Methylbenzyl
3-Methoxybenzyl
4-Methoxybenzyl
3-Fluorobenzyl
4-Fluorobenzyl
4-Hydroxybenzyl
4-Methoxycarbonylbenzyl
2-Naphthylmethyl
2-Pyridylmethyl
Cyclohexylmethyl
Cynnamyl
1.2
29
>378
>160
>388
>79
52
13
4j
366
201
>4652
n.t.
108
25
4k
4l
Ethyl
Ethyl
12
17
5.9
51
>788
—
23
4m
4n
4o
4p
4q
4r
4s
Ethyl
Ethyl
>6.5
>101
>628
>0.7
>2.7
>3.2
>1.6
4.6
0.74
642
173
147
280
Ethyl
Ethyl
34
3116
n.t.
n.t.
n.t.
4.8
—
Ethyl
Ethyl
Ethyl
—
—
a The binding activity of compounds is represented as means of two-independent and confirmatory experiments. Only differences in pIC50 up to 0.6
(SD < 0.5) were considered as reproducible and were maintained. The Ki values represent the concentration giving half-maximal inhibition of
[3H]DPDPE (d), [3H]DAMGO (l), [3H]U69593 (j) to cloned human receptors.
b n.t., not tested.
corresponding unsubstituted analogues 3f, 3h and 4b.
The variation in the position of the methoxycarbonyl
substituent in 3p from position 4 to position 3 (3o) re-
sulted in a substantial decrease in affinity. The corre-
sponding 4-N,N-diethylcarboxamide derivative 3q was
also 170-fold less active than 3p. Attempts to replace
the benzyl group by other subtituents led to poorly ac-
tive compounds (4p–s). Compounds 3p and 4o stand
as the most potent compounds prepared within this ser-
ies so far, their binding affinities for the d-opioid recep-
tor being in the sub-nanomolar range.
and carbamates 4) was tested in several in vivo para-
digms predictable for anxiolytic and antidepressant
activities. Preliminary results for the amide 3h and car-
bamate 4b are shown in Table 2. Thus, compounds 3h
and 4b showed a statistically significant reduction in
both the number and duration of calls when tested in
the mouse neonatal ultrasonic vocalization test,14 as a
paradigm predictable for anxiolytic activity. Remark-
ably, the benzamide derivative 3h showed activity at a
dose of 1 mg/kg. Additionally 3h and 4b were tested in
the mouse tail suspension test.15 Both compounds de-
creased the duration of immobility in this test at
10 mg/kg and 30 mg/kg, respectively (lowest active
dose), therefore demonstrating antidepressant-like
effects.
Many compounds underwent functional testing in
([35S]GTPcS) and almost all showed agonistic activity.11
A representative compound of each subseries (amides 3

A. A. Trabanco et al. / Bioorg. Med. Chem. Lett. 17 (2007) 3860–3863
3863
Table 2. Effects of d-opioid agonists 3h and 4b on mice neonatal
Dierich, A.; LeMeur, M.; Valverde, O.; Maldonado, R.;
Kieffer, B. L. Nat. Genet. 2000, 25, 195.
ultrasonic vocalization and tail suspension testsa,b
8. (a) Calderone, S. N.; Rice, K. C.; Rothman, R. B.; Porreca,
F.; Flippen-Anderson, J. L.; Kayakiri, H.; Xu, H.; Becketts,
K.; Smith, L. E.; Bliski, E. J.; Davis, P.; Horvath, R. J.
J. Med. Chem. 1997, 40, 695; (b) Plobeck, N.; Delorme, D.;
Wei, Z.-Y.; Yang, H.; Zhou, F.; Schwarz, P.; Gawell, L.;
Gagnon, H.; Pelcman, B.; Schmidt, R.; Yue, S. Y.; Walpole,
C.; Brown, W.; Zhou, E.; Labarre, M.; Payza, K.; St-Onge,
S.; Kamassah, A.; Morin, P.-E.; Projean, D.; Ducharme, J.;
Roberts, E. J. Med. Chem. 2000, 43, 3878.
9. (a) Saitoh, A.; Kimura, Y.; Suzuki, T.; Kawai, K.; Nagase,
H.; Kamei, J. J. Pharmacol. Sci. 2004, 95, 374; (b) Perrine,
S. A.; Hoshaw, B. A.; Unterwald, E. M. Br. J. Pharmacol.
2006, 147, 864.
10. (a) Broom, D. C.; Jutkiewicz, E. M.; Folk, J. E.; Traynor,
J. R.; Rice, K. C.; Kenner, C.; Woods, J. H. Neuropsy-
chopharmacology 2002, 26, 744; (b) Broom, D. C.;
Jutkiewicz, E. M.; Folk, J. E.; Traynor, J. R.; Rice, K.
C.; Woods, J. H. Jpn. J. Pharmacol. 2002, 16, 1; (c)
Jutkiewicz, E. M.; Rice, K. C.; Wood, J. H.; Winsauer, P.
J. Behav. Pharmacol. 2003, 14, 509; (d) Jutkiewicz, E. M.
Diss. Abstr. Int. 2005, 65, 5097.
Compound
Ultrasonic vocalization Tail suspension
(LAD, mg/kg)
(LAD, mg/kg)
<1
10
N
N
Ph
N
O
N
Ph
3h
4b
10
30
N
Ph
N
O
OEt
a LAD, lowest active dose tested.
b All compounds were dosed subcutaneously.
11. (a) Steckler, T. H. W.; Janssens, F. E.; Leenaerts, J. E.;
´
Fernandez-Gadea, F. J.; Gomez-Sanchez, A.; Meert, T. F.
WO2004/089372 A1; (b) Janssens, F. E.; Leenaerts, J. E.;
´
´
In summary, we have shown the potential of a new
chemical class of selective d-opioid agonists based on
the 4-phenyl-4-[1H-imidazol-2-yl]-piperidine scaffold.
These compounds have shown for the first time anxio-
lytic- and antidepressant-like effects in two behavioral
paradigms. Further pharmacological characterization
and chemical exploration of the series in order to broad-
en the SAR around its structure are currently in
progress.
´
Fernandez-Gadea, F. J.; Gomez-Sanchez, A.; Meert, T. F.
WO2003/033486 A1.
´
´
12. Trabanco, A. A.; Pullan, S.; Alonso, J. M.; Alvarez, R. M.;
´
´
´
Andres, J. I.; Fernandez, J.; Gomez, A.; Iturrino, L.;
Janssens, F. E.; Leenaerts, J. E.; De Lucas, A. I.; Matesanz,
E.Meert, T.; Steckler, T. Bioorg. Med. Chem. Lett. 2006, 16,
146.
13. Compound 3h: white solid; mp 122.7 °C;. 1H NMR (CDCl3,
400 MHz) d 7.38–7.26 (m, 6H), 7.23–7.20 (m, 5H), 7.15 (br
d, J = 7.6, Hz, 2H), 7.08 (br s, 1H), 6.70 (br s, 1H), 6.59 (dd,
J = 8.3, 1.6 Hz, 2H), 4.59 (s, 2H), 4.48 (br d, J = 12.7 Hz,
1H), 3.86 (br t, J = 12.4 Hz, 1H), 3.61 (br d, J = 12.8 Hz,
1H), 3.18 (br t, J = 11.6 Hz, 1H), 2.57 (br d, J = 12.9 Hz,
1H), 2.42 (br d, J = 12.7 Hz, 1H), 2.31 (br t, J = 11.1 Hz,
1H), 1.85 (br t, J = 10.4 Hz, 1H). 13C NMR (CDCl3,
100 MHz) d 170.6, 150.3, 145.9, 136.4, 135.7, 132.4, 130.0,
129.5, 128.8, 128.6, 127.9, 127.6, 127.5, 127.4, 126.3, 122.1,
49.7, 45.8, 44.0, 39.6, 39.1, 35.1; HRMS Calcd for
C28H28N3O (M+1): 422.2232. Found 422.2291; Anal. Calcd
for C28H27N3O: C, 79.78; H, 6.46; N, 9.97. Found: C, 79.56;
H, 6.57; N, 9.85. Compound 4b: white solid; mp 164.8 °C;
1H NMR (CDCl3, 400 MHz) d 7.35–7.27 (m, 3H), 7.23–7.19
(m, 3H), 7.15 (br d, J = 7.9 Hz, 2H), 7.07 (s, 1H), 7.01–6.97
(m, 2H), 6.68 (s, 1H), 4.59 (s, 2H), 4.12 (q, J = 7 Hz, 2H),
4.08–3.71 (m, 2H), 3.52 (br s, 1H), 3.22 (br s, 1H), 2.71–2.64
(m, 2H), 2.13 (br s, 1H), 1.99 (br s, 1H), 1.24 (t, J = 7.1 Hz,
3H). 13C NMR (CDCl3, 100 MHz) d 156.0, 150.4, 146.4,
133.9, 129.4, 128.6, 128.5, 127.4, 126.3, 121.9, 120.3, 61.6,
49.6, 43.8, 41.4, 41.2, 15.1; HRMS Calcd for C24H28N3O2
(M+1): 390.2182. Found 390.2206; Anal. Calcd for
C24H27N3O2: C, 74.01; H, 6.99; N, 10.79. Found: C,
74.19; H, 6.98; N, 10.81.
Acknowledgments
The authors gratefully acknowledge Mr. Jose M. Alon-
so, Ms. Ilse Biesmans, Dr. J. Adriaan Bouwknecht, Dr.
Laura Iturrino, Mr. Joseph E. Leenaerts, Ms. Ilse Lena-
erts, Ms. Carolien Janssens, Ms. Alcira del Cerro, Mr.
Luis Font, Mr. Alberto Fontana, and Ms. Lieve Heylen
for their experimental/analytical contribution.
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