4-Phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives, a novel class of selective δ-opioid agonists

Article abstract of DOI:10.1016/j.bmcl.2005.09.025

A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described herein. In vitro affinities for δ-, μ-, and κ-opioid receptors, as well as the functional activity in the [³⁵S]GTPγS assay ar

Full text of DOI:10.1016/j.bmcl.2005.09.025

Bioorganic & Medicinal Chemistry Letters 16 (2006) 146–149
4-Phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives, a novel
class of selective d-opioid agonists
a,b,
a,c
a,b
*
´
´
Andres A. Trabanco,
a,b
Shirley Pullan, Jose M. Alonso, Rosa M. Alvarez,a,b
Jose I. Andres, Inge Boeckx,a,c Javier Fernandez, Antonio Gomez,
Laura Iturrino,a,b Frans E. Janssens,a,c Joseph E. Leenaerts,a,c Ana I. De Lucas,a,b
Encarna Matesanz,a,b Theo Meerta,c and Thomas Stecklera,c
a,b
a,b
´
´
´
´
aDivision of Psychiatry, Research and Early Development Europe, Johnson & Johnson Pharmaceutical Research & Development,
Jarama 75, 47007 Toledo, 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 29 July 2005; revised 6 September 2005; accepted 12 September 2005
Available online 19 October 2005
Abstract—A novel series of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives has been prepared and their synthesis described
herein. In vitro affinities for d-, l-, and j-opioid receptors, as well as the functional activity in the [35S]GTPcS assay are reported.
The most potent and selective d-opioid agonist 18a exhibited a Ki of 18 nM, and was >258-fold and 28-fold selective over l- and
j-receptors, respectively; the compound is a full agonist with an EC50 value of 14 nM.
Ó 2005 Elsevier Ltd. All rights reserved.
CONEt2
Selective non-peptidic d-opioid agonists have been sub-
ject of great interest over the last 20 years as potential
analgesic agents that may lack some of the undesired ef-
fects of l-opioid agonists.1,2 Besides pain conditions,
this intensive research has led to the discovery of new
potential applications of d-opioid agonists to treat a
wide range of conditions, such as urinary incontinence,3
depression,4 neuroprotection,5 cocaine addiction,6 cardi-
ac ischemia7 amongst others.8
OH
H
MeO
N
N
N
N
H
1, TAN-67
2, SNC80
CONEt2
CONEt2
The discovery of non-peptidic d-opioid agonists TAN-
67 (1)9 and SNC80 (2)10 has contributed to the rapid
expansion of the opioid research based on the d-receptor
subtype (Fig. 1).11,12 We have recently described at
Johnson & Johnson PRD, new families of tropane deriv-
atives represented by compounds 313 and 4,14 showing
impressive potency and selectivity for the d receptor.
One possible drawback of compounds 1, 2, 3, and 4 is
their complex stereochemistry which makes their synthe-
sis difficult, requiring either chiral separations or enan-
tiomeric synthesis routes.
N
N
N
H
3
4
Figure 1. Set of selective non-peptidic d-opioid agonists 1–4.
High throughput binding screening of our corporate
compound collection against the human d-opioid recep-
tor resulted in the identification of the non-chiral
4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivative
(Fig. 2) as a weak to moderate d-opioid ligand
(Ki = 81 nM) with selectivity over l and j receptors
5
Keywords: Opioid; d agonist.
Corresponding author. Fax: +34 925 23 57 71; e-mail:
atrabanc@prdes.jnj.com
*
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.09.025

A. A. Trabanco et al. / Bioorg. Med. Chem. Lett. 16 (2006) 146–149
147
Ph
Ph
N
O
N
δ Ki = 81 nM
µ Ki = >465 nM
N
N
N
OH
13
N
Ph
N
N
κ
δ
Ki = 126 nM
35S]GTPγS EC50 = 1469 nM
(ii)
N
Ph
[
6
Ph
N
N
H
(i)
N
H
CO2Et
5
14
15
Figure 2. Binding affinities of compound 5.
(>5- and 1.5-fold, respectively). The compound was
found to be a weak agonist in our functional assays.
(v)
(iv)
(iii)
These results prompted us to start a limited chemical
exploration around 5 to evaluate its hit potential. The
synthesis and preliminary pharmacological evaluation
of these analogues are reported.
Ph
Ph
Ph
N
O
N
O
N
N
N
N
The preparation of analogues of compound 5 in which the
substitution of the imidazole nitrogen is different than
benzyl (12) is shown in Scheme 1. Thus, reaction of the
2-lithium salt of the commercially available 1-tritylimi-
dazole (7) with 1-carbethoxy-4-piperidone (6) led to the
corresponding addition product 8 in moderate yield.
The trityl-protecting group was removed under acidic
conditions to give the unprotected imidazole derivative
9. The Friedel–Crafts reaction of 9 with benzene occurred
with simultaneous hydrolysis of the carbamate function
affording the key intermediate 10 in good yield (77%).
N
N
S
N
Het
R
N
H
R
O
18
17
16
Scheme 2. Reagents and conditions: (i) n-BuLi, 1-benzylimidazole
(13), THF, À78 °C to rt, 2 h, 56%; (ii) AlCl3, benzene, 60 °C, 1 h, 54%;
(iii) RNCO, CH2Cl2, rt, 3 h, 80–90%; (iv) RSO2Cl or (RSO2)2O, Et3N,
CH2Cl2, À78 °C to rt, 8 h, 57–89%; (v) HetHal, Et3N, DMSO, 180 °C,
20 min, microwaves, 55–84%.
Ph
Ph
Selective reaction of 10 with phenylisocyanate gave 11 in
almost quantitative yield. The alkylation of the imidaz-
ole nitrogen in 11 was carried out by reaction with dif-
ferent alkyl halides in THF, using sodium hydride
as base. The targeted compounds 12 were obtained in
moderate to good yields.
N
N
N
N
(i)
O
N
O
N
N
NH
Ph
Ph
19
5
Scheme 3. Reagents and conditions: (i) NaH, DMF, rt, 1 h, then MeI,
60 °C, 6 h, 49%.
For the synthesis of modified analogues on the piperi-
dine nitrogen a similar synthetic strategy, starting from
1-benzyl imidazole, was followed. First, addition of
the corresponding lithiated heterocycle to 1-carbeth-
oxy-4-piperidone (6) gave the hydroxy derivative 14 in
56% yield. Then, Friedel–Crafts reaction with benzene
led to the 4-phenyl substituted piperidine 15. This piper-
idine intermediate (15) was transformed into the final
compounds 16, 17, and 18 under the standard reaction
conditions shown in Scheme 2.
Tr
N
NH
N
O
OH
OH
7
N
N
N
(ii)
(iii)
Tr
N
N
N
(i)
The preparation of the disubstituted urea 19 is shown in
Scheme 3 and was carried out by direct alkylation of 5
with methyl iodide.
CO2Et
CO2Et
CO2Et
6
R
N
NH
NH
The pharmacological profile of the compounds was
determined in radioligand binding studies and function-
al GTPcS assays. The binding affinities (Ki) of the com-
pounds against cloned human d, l and j receptors were
determined. Agonist potency values (EC50) were ob-
tained by monitoring the ability of test compounds to
activate [35S]GTPcS binding in comparison to the selec-
tive d agonist DPDPE in C6-Glioma cells expressing
cloned human d-opioid receptors. The opioid binding
affinities of analogues of 5 are listed in Table 1. Func-
tional data for a set of selected analogues of compound
5 are shown in Table 2.
N
N
(iv)
N
(v)
N
N
H
N
N
O
N
O
12
H
H
10
11
Scheme 1. Reagents and conditions: (i) n-BuLi, 1-tritylimidazole (7),
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) phenylisocyanate,
CH2Cl2, rt, 3 h, 95%; (v) NaH, THF, rt, 10 min, then RHal, reflux, 8 h,
56–87%.

148
A. A. Trabanco et al. / Bioorg. Med. Chem. Lett. 16 (2006) 146–149
Table 1. Binding affinity of 4-phenyl-4-[1H-imidazol-2-yl]-piperidine derivatives to d, l, and j-receptorsa,b
N
N
R2
N
R1
Compound
R1
R2
d
Ki (nM)
l
Ki (nM)
j
Ki (nM)
l/d
j/d
5
N-Phenylaminocarbonyl
N-Phenylaminocarbonyl
N-Phenylaminocarbonyl
N-Phenylaminocarbonyl
N-Phenylaminocarbonyl
N-Phenylaminocarbonyl
N-Phenylaminocarbonyl
N-Phenylaminocarbonyl
N-Phenylaminocarbonyl
N,N-Methylphenylaminocarbonyl
Aminocarbonyl
Benzyl
81
72
>465
428
126
116
5.7
5.9
1.6
1.6
12a
12b
12c
12d
12e
12f
12g
12h
19
2-Fluorobenzyl
3-Fluorobenzyl
4-Fluorobenzyl
3-Methoxybenzyl
2-Pyridylmethyl
a-Methylbenzyl
Benzoyl
H
128
203
217
3074
43
>4652
>4652
3246
1877
2156
2059
46
>36
15
>23
15
11
9
1417
497
0.46
0.015
11
0.32
>465
1185
>4652
397
12
>1.2
3696
>465
9
>4652
>465
>4652
>4652
>4652
>4652
2520
—
—
Benzyl
Benzyl
>516
>51
>47
>29
87
44
3.4
16a
16b
16c
16d
16e
16f
16g
16h
16i
99
39
334
242
N-Ethylaminocarbonyl
N-Methylpiperazinylcarbonyl
N-(2-fluorophenyl)Aminocarbonyl
N-(3-fluorophenyl)Aminocarbonyl
N-(4-fluorophenyl)Aminocarbonyl
N-(2-methoxyphenyl)Aminocarbonyl
N-(3-methoxyphenyl)Aminocarbonyl
N-(4-methoxyphenyl)Aminocarbonyl
Methylsulfonyl
Benzyl
Benzyl
6.2
5.3
161
29
858
318
Benzyl
Benzyl
11
>160
1.5
25
3.3
29
97
>4652
1206
>4652
148
782
>160
12
Benzyl
Benzyl
31
46
>4652
1385
>150
30
Benzyl
Benzyl
152
44
46
>465
>4652
>4652
980
n.t.
>10
>101
>44
306
—
17a
17b
17c
18a
18b
18c
18d
Benzyl
Benzyl
2012
>4652
346
44
Aminosulfonyl
106
3.2
18
>44
108
28
N-Phenylaminosulfonyl
2-Pyrimidyl
2-Thiazolyl
Benzyl
Benzyl
>4652
>4652
>4652
235
505
>258
>58
>63
Benzyl
Benzyl
Benzyl
79
73
2533
n.t.
40
32
2-Benzothiazolyl
2-N-Methylbenzimidazolyl
—
138
1.7
0.29
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.
Table 2. Functional activity data for 5 and a set of selected analoguesa
As it can be deduced from the data shown in Table 1, in
general, most of the new analogues showed affinities in
the nanomolar range for the d-opioid target. Most com-
pounds were highly selective over l and j receptors in
the region of 10- to 100-fold. The introduction of elec-
tron-withdrawing (12a–c) or electron-donating (12d)
groups on the benzyl group of the hit 5 was well tolerat-
ed and led to compounds with comparable or slightly
lower affinity for the d receptor but, in general, higher
selectivity with respect to the other opioid receptors.
The attempts to replace the benzyl substituent in 5 by
other groups such as 2-pyridylmethyl (12e), benzoyl
(12g) or hydrogen (12h) resulted in a complete loss of
affinity for the d receptor. Surprisingly, the pyridyl
derivative 12e showed moderate binding affinity
(Ki = 46 nM) and selectivity (j/d 67-fold) for the j-opi-
oid receptor. Compound 12f, that presents a methyl sub-
stituent at the benzylic position, showed higher affinity
for the d-opioid receptor, with selectivity versus l and
j receptors being slightly better than that of 5.
Compound
d GTPcS
EC50 (nM)
5
19
1479
776
117
117
436
832
14
16b
16g
16h
17c
18a
18b
18c
98
26
a Agonism values (pEC50s) were measured in membranes expressing
human d receptors from three-parameter logistic curve fits of percent
stimulated [35S]GTPcS binding vs log(molar ligand).
To investigate the structure–activity relationship of this
series, the following structural modifications were made:
(a) substitution on the benzyl group of 5; (b) replace-
ment of the benzyl substituent; (c) modifications of the
urea substituents of compound 5; (d) substitution
of the urea functionality in 5 by sulfonamides and
2-aminoheterocyclic groups.
Regarding the influence of the substitution on the urea
functionality compound 19, a tetrasubstituted urea,
showed the highest affinity and selectivity for the d recep-

A. A. Trabanco et al. / Bioorg. Med. Chem. Lett. 16 (2006) 146–149
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tained are listed in Table 2. All the compounds tested were
found to be full agonists within a range of nanomolar
activities and were found to have no potential to antago-
nize DPDPE-induced [35S]GTPcS incorporation. Com-
pounds 18a and 18c were the most potent agonists,
EC50 = 14 and 26 nM, respectively, despite having only
moderate binding activity. Conversely, compounds 19
and 17c showed good binding affinity but weak agonism.
In summary, we have shown the viability and potential
of a new chemical class of selective d-opioid agonists
based on the 4-phenyl-4-[1H-imidazol-2-yl]-piperidine
scaffold. Further pharmacological characterization and
chemical exploration of the series in order to broaden
the SAR around its structure are currently in progress.
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The authors would like to gratefully acknowledge Ms.
Ilse Biesmans, Ms. Ilse Leenaerts, Ms. Carolien Jans-
sens, Ms. Alcira del Cerro, Mr. Luis Font, Mr. Alberto
Fontana, and Ms. Lieve Heilen for their experimental/
analytical work contribution.
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