N,N-Dialkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides, potent, selective δ opioid agonists

Article abstract of DOI:10.1016/j.bmcl.2004.02.051

A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c, exhibited extremely high affinity for the δ opioid receptor with excellent selectivity versus the μ opioid receptor. They were full agonists at

Full text of DOI:10.1016/j.bmcl.2004.02.051

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2109–2112
N,N-Dialkyl-4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]-
benzamides, potent, selective d opioid agonists
John R. Carson,* Steven J. Coats, Ellen E. Codd, Scott L. Dax, Jung Lee,
Rebecca P. Martinez, Lou Anne Neilson, Philip M. Pitis and Sui-Po Zhang
Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, LLC, Welsh and McKean Roads,
PO 776, Spring House, PA 19477-0776, USA
Received 19 May 2003; accepted 10 February 2004
Abstract—A series of N,N-dialkyl-4-(9-aryltropanylidenemethyl)benzamides was prepared. The lead compounds, 15a and 15c,
exhibited extremely high affinity for the d opioid receptor with excellent selectivity versus the l opioid receptor. They were full
agonists at the d opioid receptor, as assessed by stimulation of GTPcS binding, and displayed antinociceptive activity.
Ó 2004 Elsevier Ltd. All rights reserved.
The discovery of multiple opioid subtypes in 19761 gave
rise to hopes that new pain relieving medications lacking
the side associated with morphine would be discovered.
Studies with the potent, d selective, cyclic peptide
DPDPE, that showed good antinociceptive activity
without concurrent effect on GI motility, amplified these
hopes.2 The discovery of the nonpeptide d agonists
BW373U863 (1a), TAN-674 (2), and SNC805 (1b) raised
enthusiasm even higher.
fallen short. SNC80 showed antinociceptive activity in
mice in the models predictive of efficacy in severe pain
but only by parenteral routes and only at high doses.6 In
addition, both BW373U86 and SNC80 induced convul-
sions in mice.7 These results challenged the potential of d
opioid agonists as therapeutic agents.
Meanwhile, the search for new d agonists has contin-
ued.8;9 The structures of new nonpeptide d agonists have
generally fallen into two classes, the compounds related
to TAN-67 from the GlaxoSmithKline group and the
structures related to SNC80 such as 3,10;11 4,12 and 5.13;14
Compounds of types 4 and 5 have shown impressive
potency and selectivity. The challenges facing the cre-
ators of new structural classes of d agonists, however,
have been to overcome issues regarding safety and effi-
cacy encountered with the first generation of nonpeptide
d agonists. With these objectives in mind, we prepared
and evaluated a series of N,N-dialkyl-4-[(8-azabi-
cyclo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides, 6,
which combine the structural features of 4 and 5.
O
NEt2
H
N
N
H
H3C
Y
N
CH3
N
H3C
2
1a Y = HO, BW373U86
1b Y = CH3O, SNC80
TAN-67
OH
Upon further investigation, however, the expectations
surrounding the nonpeptide d agonists as analgesics have
O
O
O
NR2R3
NR2R3
X
NR2R3
X
X
N
N
5
4
N
3
N
N
R1
R1
R1
* Corresponding author. Tel.: +1-215-628-5526; fax: +1-215-628-3297; e-mail: jcarson@prdus.jnj.com
Present address: Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.02.051

2110
J. R. Carson et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2109–2112
O
O
O
O
N
NEt2
OEt
X
X
a
a
X
X
b
b
CO
CONEt2
CO
11
COOEt
+
+
N
7
CH3
(CH2)2Ph
12
N
8
N
CH3
(CH2)2Ph
O
O
O
O
NEt2
OH
NEt2
X
X
X
c or d
NR2R3
c
X
10
9
13
N
H
14
N
N
(CH2)2Ph
R1
N
(CH2)2Ph
Scheme 1. Reagents and conditions: (a) TiCl4, Zn; (b) (1)
CCl3CH2OCOCl, (2) (2-Pr)2N-Et (Zn); (c) RCHO, NaBH(OAc)3 or
R1Br, K2CO3.
Scheme 2. Reagents and conditions: (a) TiCl4, Zn; (b) NaOH; (c) (1)
SOCl2, (2) R2R3NH, NaOH.
O
O
O
NEt2
NEt2
NR2R3
X
6
N
N
N
R1
R1
R1
16
15
The synthesis of compounds of type 6 was carried out
by condensation of an appropriately substituted
benzophenone 7 with tropinone under ÔMcMurrayÕ
conditions as shown in Scheme 1.15 Compounds with a
phenethyl group on the tropane nitrogen, varying in the
carboxamide functionality, were prepared by McMur-
ray condensation of N-phenethyl tropinone with ethyl 4-
benzoylbenzoate and conversion of the resulting ester to
the desired amides (Scheme 2). Compounds bearing a
phenolic group were prepared by cleavage of the cor-
responding methoxy compound with BBr3.
measured, and the efficacy relative to stimulation by
SNC80 was calculated. Antinociceptive activity was
assessed using the mouse abdominal irritant test
(MAIT).20
A general SAR for SNC80 and close relatives such as 3
and 4 has been put forward.21 One phenyl ring bearing
an N,N-diethylcarboxamide, the Portoghese ÔaddressÕ
function,22 is an obligatory feature for d agonists of this
class. They feature a second phenyl ring, which may or
may not bear an oxygenated function. The central het-
erocyclic ring, which on SNC80 is dimethylpiperazine,
may be varied10–14 leading to compounds such as 4 and
5, which may surpass SNC80 in potency and selectivity.
The optimal groups on the heterocyclic ring nitrogen
have been allyl and hydrogen. Groups which have
imparted good activity as Nsubstituents have generally
been five carbon atoms or less.12;13;23 An exception to
this rule is the (1,3)-benzodioxol-5-ylmethyl group,
which conferred high d opioid affinity to a piperazine,
albeit, resulting in little antinociceptive activity.24
Compound 9 (X ¼ H) was separated into enantiomers,
15a and 16a, by chiral HPLC. Other enantiomerically
pure compounds (15 and 16) were prepared by alkyl-
ation or reductive alkylation of the enantiomers of 15a
and 16a. Compounds 15d and 16d were also prepared by
classical resolution as ditoluoyltartrate salts. The abso-
lute configuration of 16d was assigned by vibrational
circular dichroism16;17 and the assignment of configura-
tion of 16a was made by conversion to 16d.
Certain compounds of type 6 showed exceptional
potency and selectivity. Compound 15a, with a Ki value
of 23 pM, was 400 times as potent as SNC80 and 13
times as potent as the analogous compound of type 5. It
was 37,000-fold selective for d over l receptor binding.
The N-allyl compound, 15c, was similarly of higher
affinity than analogous compounds within this struc-
tural class, and nearly as selective. These compounds
were full agonists at the d opioid receptor, as assessed by
GTPcS binding. Compounds with the 1R,5S (15)
stereochemistry had higher affinity for the d opioid
The opioid properties of the N,N-dialkyl-4-[(8-azabi-
cylo[3.2.1]-oct-3-ylidene)phenylmethyl]benzamides, 6,
were examined (Table 1). Methodology used for the
binding studies has been described.18 Functional activity
was measured by stimulation of [35S]GTPcS binding.
The procedure for these studies was adapted from that
previously employed to study signal transduction path-
ways associated with bradykinin receptors.19 The stim-
ulation of [35S]GTPcS binding in Chinese hamster ovary
cells (CHO) transfected with the human d opioid
receptor following treatment with test compound was

J. R. Carson et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2109–2112
Table 1. Structure–activity relationships of d opioid agonists
2111
d Ki
(nM)
l Ki
(nM)
d GTPcS
%I MAIT
150 lmol/
kg po
Compd
R1
N-R2,R3
X
EC50 (nM)
Rel. eff.
8a
8b
CH3
CH3
N-Et2
N-Et2
N-Et2
N-Et2
N-Et2
N-Et2
N-Et2
N-Et2
3-CH3O
3-OH
4-CH3O
4-OH
4-OH
H
5.9
693
65
3
0.87
0.87
0.85
0.86
0.96
0.87
0.76
1.02
0.60
3.5
727
1499
194
8c
8d
CH3
CH3
27
9
1.89
0.58
0.39
2.62
0.01
9a
H
n-Pr
442
289
5
26.7
93.3
26.7
40
10a
10b
10c
43
27
2-(4-Fluorophenyl)ethyl
(1,3)-Benzodioxol-5-yl-
methyl
H
393
H
22.4
0.2
10d
10e
10f
10g
10h
10i
2-Oxo-2-phenylethyl
3-Phenylpropyl
2-Phenoxyethyl
2-(2-Thienyl)ethyl
2-(1H-Indol-3yl)-ethyl
2-Cyclohexylethyl
2-Phenethyl
2-Phenethyl
2-Phenethyl
2-Phenethyl
2-Phenethyl
2-Phenethyl
2-Phenethyl
N-Et2
N-Et2
H
H
H
H
H
H
H
H
H
H
H
H
H
6.31
0.56
0.38
13.12
3.48
1.36
7.39
49.01
2.94
16.61
3.2
9643
104
630
1281
337
451
644
103
229
294
291
276
571
173
112
0.68
0.88
0.84
0.78
0.91
0.92
0.82
0.92
0.9
13.3
N-Et2
N-Et2
623
1348
16
N-Et2
N-Et2
228
14a
14b
14c
14d
14e
14f
14g
N-n-Pr2
N-2-Pr2
3557
5041
1081
403
N-Ethyl,2-methylallyl
N-Bis-(2-methoxyethyl)
N-Ethyl,2-hydroxyethyl
Pyrrolidinyl
cis-2,6-Dimethyl-
piperidinyl
Morpholinyl
N-Et2
33
0.71
0.77
0.86
548
1463
10,000
24.1
10.97
14h
14i
15a
15b
15c
15d
16a
16b
16c
16d
1b
2-Phenethyl
2-Phenethyl
H
H
3-CH3O
35.2
1.36
0.023
5.7
237
417
350
218
0.76
0.8
N-Et2
N-Et2
H
855
1.8
153
0.5
1.02
0.87
1.05
0.82
1.00
0.85
0.83
0.88
86.7
80
CH3
Allyl
H
2910
322
N-Et2
N-Et2
H
0.025
0.24
0.36
4.5
100
100
86.7
90
2-Phenethyl
H
CH3
H
72.3
34
53
N-Et2
N-Et2
H
2310
9730
H
149
177
1387
Allyl
2-Phenethyl
Allyl
N-Et2
N-Et2
H
0.32
42.1
1.7
4400
317
100
90
H
3-CH3O
N-Et2
N-Et2
1300
3a
3b
H
Allyl
H
H
H
H
35
24
>10,000
11,565
5040
458
21
0.76
0.81
0.95
1.07
N-Et2
N-Et2
N-Et2
5a
5b
H
Allyl
0.3
0.5
12
12
3650
receptor than compounds with the 1S,5R configuration
(16). In general, the SAR pattern seen with SN80 ana-
logues was followed.15 An exception was the N-R1
phenethyl compound (15d). The compound with this
large group on nitrogen had a d Ki of 0.23 nM and was
active in the MAIT test. In an attempt to follow up on
this finding, some amide variations (14a–i) were pre-
pared. They were less potent and selective than the N,N-
diethyl compound (15d). Some other large groups were
tried on the tropanylidene nitrogen leading to com-
pounds 10b–i. Only the (1,3)-benzodioxol-5-ylmethyl
group (10c) led to high affinity d binding although this
compound lacked antinociceptive activity.
receptor. The only compound, which elicited Ôstraub tailÕ
behavior, characteristic of l opioid agonists, was 15d.
In summary, we have prepared a series of N,N-dialkyl-
4-[(8-azabicyclo[3.2.1]-oct-3-ylidene)phenylmethyl]ben-
zamides (6). The lead compounds (15a,c) bind with
exceptionally high affinity to the d opioid receptor and
are also highly selective for d versus l opioid binding.
They are full d agonists and are antinociceptive in the
mouse abdominal irritant test. Importantly, they appear
to have a lower convulsant liability than earlier d agon-
ists.
References and notes
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type 6 was administered orally to 15 mice at a dose of
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