Parallel methods for the preparation and SAR exploration of N-ethyl-4-[(8-alkyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-aryl-methyl]-benzamides, powerful mu and delta opioid agonists

Article abstract of DOI:10.1016/j.bmcl.2004.09.004

Two parallel synthetic methods were developed to explore the structure-activity relationships (SAR) of a series of potent opioid agonists. This series of tropanylidene benzamides proved extremely tolerant of structural variation while maintaining excellent opioid activity. Evaluation of several representative compounds from this series in the mouse hot plate test revealed potent antinociceptive effects upon oral administration.

Full text of DOI:10.1016/j.bmcl.2004.09.004

Bioorganic & Medicinal Chemistry Letters 14 (2004) 5493–5498
Parallel methods for the preparation and SAR
exploration of N-ethyl-4-[(8-alkyl-8-aza-bicyclo[3.2.1]-
oct-3-ylidene)-aryl-methyl]-benzamides, powerful mu and
delta opioid agonists
Steven J. Coats,* Mark J. Schulz, John R. Carson, Ellen E. Codd, Dennis J. Hlasta,
Philip M. Pitis, Dennis J. Stone, Jr., Sui-Po Zhang, Ray W. Colburn and Scott L. Dax
Drug Discovery, Johnson and Johnson Pharmaceutical Research and Development, L.L.C., Welsh and McKean Roads,
PO Box776, Spring House, PA 19477-0776, USA
Received 6 August 2004; revised 1 September 2004; accepted 3 September 2004
Available online 29 September 2004
Abstract—Two parallel synthetic methods were developed to explore the structure–activity relationships (SAR) of a series of potent
opioid agonists. This series of tropanylidene benzamides proved extremely tolerant of structural variation while maintaining excel-
lent opioid activity. Evaluation of several representative compounds from this series in the mouse hot plate test revealed potent
antinociceptive effects upon oral administration.
Ó 2004 Elsevier Ltd. All rights reserved.
Morphine remains the analgesic of choice for severe
pain but the accompanyingconstipation, addiction lia-
bility, respiratory depression, and other unwanted side
effects drive the search for safer opioid agonists. The
ability to modulate the unwanted effects of a mu opioid
agonist by modifying its relative affinity for the delta
receptor has been postulated1 and later supported
experimentally.2
our efforts to develop both solution and solid-phase par-
allel synthetic approaches5 to this series is disclosed
herein, alongwith the evaluation of these compounds
with respect to opioid affinity, relative affinity for the
delta receptor, and their antinociceptive effects in rodent
models.
We knew from our earlier work3 that the 1S,5R config-
uration (as in Fig. 1) of 3 would, in general, display the
strongest affinity for the mu and delta opioid receptors;
however there are several cases where 1R,5S enantiomer
produced a more potent compound or opposite delta/
mu selectivity (Fig. 2). We had previously performed
the initial opioid bindingassay on the racemic mixture
We recently disclosed our delta/mu opioid agonist series
of tropanylidenes typified by N-ethyl-4-[(8-phenethyl-8-
aza-bicyclo[3.2.1]oct-3-ylidene)-phenyl-methyl]-benz-
amide (Fig. 1; 1).3 This compound was initially derived
metabolically from the powerful delta agonist N,N-
diethyl-4-[(8-phenethyl-8-aza-bicyclo[3.2.1]oct-3-ylidene)-
phenyl-methyl]-benzamide 2.
O
O
The unexpected discovery of potent mu opioid activity
in a series that was predicted to display delta selectivity
led us to explore analogs of 1 and hold constant this
newly found ethyl amide mu address.4 With the goal
of identifyingsafer opioid agonists to treat severe pain,
NEt2
NHEt
N
N
(CH2)2Ph
(CH2)2Ph
Keywords: Opioid; Delta; Mu; Parallel; Antinociception.
*
1
2
Correspondingauthor. Tel.: +1 215 628 5266; fax: +1 215 628
3297; e-mail: scoats@prdus.jnj.com
Figure 1. Initial tropanylidene opioid leads.
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.09.004

5494
S. J. Coats et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5493–5498
on large scale. Olefin 6 was prepared in good yield from
N-carbethoxy-4-tropinone in the presence of LDA.
O
NHR1
R3
The one pot conversion of 6 to the carboxylic acid 7 in-
volved: dibromination, consumption of excess bromine
with sodium thiosulfate, and saponification of the
methyl ester and elimination of HBr by sodium hydr-
oxide. Removal of the ethyl carbamate was initially
carried out on the crude intermediate dibromide by
refluxingin ethanolic KOH. This was appealingin that
three synthetic steps could be carried out in a single
reaction pot. However we found the yields were im-
proved by the use of a two-pot approach usingNaOH
to give an intermediate vinyl bromide carboxylic acid
7, which was then treated with TMSI. Neutralization
and protection with FmocOSu gave (21g, 40%, seven
steps) key intermediate 8 necessary for our solid phase
analogprogram.
N
3
R2
Figure 2. Generic tropanylidene scaffold.
of compounds of type 3 and found that the data corre-
lated well with those obtained for the individual enantio-
mers. In consideration of these factors we chose to
prepare the more readily available racemic compounds
for initial in vitro screeningwhile sinlge enantiomers
of selected compounds were prepared for subsequent
profiling.
Our earlier work3 had shown that the secondary carb-
oxamido N-substituent could not deviate far in size from
ethyl without sharply decreasingmu receptor affinity.
Consequently we designed our parallel synthetic ap-
proach to hold this group constant as the ethyl amide.
Accordingly, FMPB resin9 was reacted with ethylamine
under reductive amination conditions to give secondary
amine resin 9 to which carboxylic acid 8 was coupled
using2-chloro-1,3-dimethylimidazolinium chloride
(Scheme 2). After shakingfor 24h, the resin slurry of
10 was filtered and the resin was washed two times with
dichloromethane. The combined filtrate containingex-
cess 11 was allowed to react with ethylamine followed
by Fmoc removal10 to produce the ethyl amide 12,
which was used in our parallel solution phase approach
described below.
Our original route to 1 relied on a McMurray coupling
as a key step in the synthetic sequence.6,7 This linear
route was quite efficient for the preparation of single
compounds but lacked the features necessary for facile
parallel analogconstruction. We therefore developed a
new synthetic route,8 which allowed us to easily generate
variation of the amide R1 group, the tropanylidene
nitrogen R2 substituent, and the olefinic R3 group of
racemic 3 (Fig. 2).
4-Bromomethyl methyl benzoate, 4 was allowed to
react with trimethyl phosphite to provide the Horner–
Emmons–Wittigprecursor 5 (Scheme 1). The use of tri-
methyl phosphite in place of higher homologs allowed
for a simple evaporative workup, which was quite useful
With versatile resin 10 in hand we began to prepare sets
of 96 compounds utilizingthe chemistry sequence out-
lined in Scheme 3. Removal of the Fmoc group was fol-
lowed by reductive amination with a variety of
aldehydes to give the resin bound vinyl bromides 13.
O
O
O
O
LDA
P(OMe)3
O
O
xylenes,
reflux
N-carbethoxy-
4-tropinone
Br
O
P(OMe)2
4
5
O
O
FMPB
N
Et
H
HO
Br
8, DIPEA
1. Br2, DCM, rt
H
Br
O
FMPB
N
Et
Cl-
2. Na2S2O3 (aq)
3. 3N NaOH
10
N
7
6
Cl
9
N
Fmoc
N
N+
N
EtO
O
EtO
Z= Cl, and/or
N+
O
O
O
HO
EtHN
Z
N
O
1. TMS-I
2. Na2CO3 / Fmo cOSu
Br
Br
Br
Filtrate from
formation of 10
N
Fmoc
N
N
Fmoc
11
12
H
8
Scheme 1. Preparation of a versatile tropanylidene.
Scheme 2. Loading 8 onto solid support.

S. J. Coats et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5493–5498
5495
O
FMPB
N
Et
1. R3B(OH)2,
Pd(PPh3)4
Br
1. 25% pip / DMF
2. R2CHO
10
3
13
2. 50% TFA
DCM
(R1=Et)
Na(OAc)3BH
N
R2
Scheme 3. Solid phase parallel preparation of delta/mu opioid agonists.
A subsequent Suzuki reaction with a broad range of
boronic acids was followed by cleavage from support
to give functionalized tropanylidenes 3. We were also
successful with acylations and sulfonylations at the tro-
panylidene nitrogen as well as Stille reactions with the
vinyl bromide.
Basic groups such as 2-pyridyl (15) and 2-pyrazinyl
(16) behaved similarly in the bindingassays. While only
2-furanyl (17) is shown, we found that a broad range of
other small heterocycles could effectively replace the
olefinic R3 substituent of 3 such as 3-furanyl, 2-thio-
phenyl, 3-thiophenyl, and 4-isoxazolyl.
From this approach we were able to rapidly obtain 243
compounds, which were all purified by reversed-phase
HPLC, analyzed by LC/MS,11 and assayed in vitro
against the mu and delta opioid receptors. The tech-
niques used for the determination of delta and mu opi-
The R2 substituent of 3 was also tolerant of small
heterocyclic groups such as thienyl (14–16) and 4-imid-
azolo (19). Basic groups in the R2 position generally
led to a significant loss in opioid binding; unless
matched with an optimal R3 as in the case of 3-pyridyl
(21) and 2-pyridyl (22). Groups containingacid func-
tionality attached at R2, as in the case of 18, always
led to a significant loss in activity. As was found in re-
lated delta opioid agonists15 smaller groups at R2 were
optimal while larger groups (not shown) trended toward
a loss of opioid bindingaffinity.
12
oid receptor bindinghave been previously described.
Functional activity7 was measured by stimulation of
[35S]GTPcS bindingin a manner similar to that previ-
ously employed to study bradykinin receptors.13 With
select compounds, in vivo activity was assessed using
the mouse 48°C hot plate test,14 a stringent antinocicep-
tive model.
In our support of therapeutic team collaborations, we
have come to increasingrely on the development of par-
allel solution phase strategies, which allow multiple
sequential reactions to occur in a single reaction vessel
with little or no workup involved between synthetic
steps. Such sequences are, in many cases, more rapidly
developed relative to their solid phase counterparts. This
approach is well suited for the parallel preparation of
sets of compounds in a discovery SAR program.
We were quite surprised to find that 180 (74%) com-
pounds had a Ki of less than 50nM for either the delta
or mu receptors; more amazingly 102 (42%) compounds
had a Ki of less than 10nM for either the delta or mu.
Table 1 shows some selected compounds alongwith
their delta and mu bindingaffinity.
We were encouraged to find that the tropanylidene ethyl
benzamide series displayed a significantly improved
delta opioid bindingaffinity relative to morphine. As
shown in Table 1, substituted phenyl groups such as
3,4-methylenedioxy (14), 3-acetylamino (19 and 22),
and 3-acetyl (20) were all well tolerated in the olefinic
R3 position of 3 for both the mu and delta binding.
For the solution phase preparation of functionalized
tropanylidenes 3 we simply dispensed a dichloroethane
(DCE) solution of 12 to a set of microwave tubes, added
the aldehydes in DCE, added a DMF solution of so-
dium triacetoxy borohydride, and subjected the mixture
Table 1. Some representative tropanylidenes 3 (R1 = Et) from solid phase
Compd
R2
R3
Ki mu (nM)
Ki delta (nM)
mu/delta
Morphine
1
1.8
72
90
0.24
47
0.020
300
Benzyl
Benzyl
Phenyl
2
Phenyl (R1 = diethyl amide)
3,4-Methylenedioxyphenyl
2-Pyridyl
0.26
1.3
6.0
2.5
6.3
480
9.4
1.9
62
0.0055
0.42
1.6
14
15
16
17
18
19
20
21
22
3-Thienyl
2-Thienyl
3-Thienyl
3.1
3.8
17
2-Pyrazinyl
2-Furanyl
Phenyl
0.15
1.1
2-Methyl-propene
3-Carboxy phenyl
4-Imidazolo
2-Methyl-propene
3-Pyridyl
5.6
280
19
1.7
3-Acetylamino phenyl
3-Acetylphenyl
Phenyl
0.50
1.1
1.8
71
0.87
0.13
2-Pyridyl
3-Acetylamino phenyl
3.6
28

5496
S. J. Coats et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5493–5498
O
NHEt
1. R2CHO,
Na(OAc)3BH
Br
µw 120 oC, 6 min
R3B(OH)2
12
3 (R1 = Et)
2. water quench;
concentrate
Pd(PPh3)4, NMP
µw 180 oC, 10 min
23
N
R2
Scheme 4. Solution phase parallel preparation of delta/mu opioid agonists.
to microwave irradiation for 6min at 120°C (Scheme 4).
Simply quenchingthe reductive amination reaction with
water and subsequent concentration allowed us to di-
rectly perform a microwave assisted Suzuki reaction
on crude 23. This critical findingallowed us to rapidly
prepare analogs of type 3 more quickly and efficiently
than the above solid phase approach.
assayed in vitro against the mu and delta opioid recep-
tors. Of these, 123 (64%) compounds had a Ki of less
than 10nM for either the delta or mu receptors. An
additional advantage of the parallel solution phase ap-
proach was that it allowed us to rapidly scale up selected
compounds for further in vivo studies usingthe same
solution phase sequence.
From this parallel solution phase approach16 we rapidly
obtained a total of 192 compounds, which were all puri-
fied by reversed-phase HPLC, analyzed by LC/MS, and
In our exploration of the R2 position of 3 we found
that 3-furanyl provided the broadest in vitro opioid
activity of all substituents investigated. Table 2 shows
Table 2. Tropanylidene 3 (R1 = Et, R2 = 3-furanyl); a highly potent series
Compd
R3
Ki mu (nM)
Ki delta (nM)
mu/delta
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
3-Amino-5-carboxy phenyl
5-(1H-Tetrazole)
Cyano
9100
83
56
210
0.30
0.94
3.4
160
0.40
3.3
13
1.0
12
3-Nitro-5-carboxy phenyl
2-Pyrazinyl
9.9
28
2.9
8.0
2.3
3.9
3.0
3.1
1.6
1.5
4.5
0.37
1.2
3.0
1.5
0.33
1.3
7.9
2100
2.4
4.1
3.6
5.4
2.4
2.4
2.0
7.0
5.5
3.3
5.2
1.0
6.5
0.20
9.3
1.2
5.9
1.1
3-Carboxy phenyl
4-Carboxy phenyl
4-(3-Phenylpropionic acid)
5-Pyrimidinyl
3.5
5.3
12
3.0
6.9
50
0.78
2.3
4-Sulfamoyl phenyl
4-Methanesulfonyl phenyl
4-N,N-Dimethyl benzamide
2-Pyridyl
16
3.1
6.7
45
2.0
4.6
10
4-Pyridyl
H
3-Pyridyl
2.2
110
1.2
1.8
1.3
2.6
4.1
1500
1.9
1.9
71
6.0
93
0.40
1.2
4-(3,5-Dimethyl-isoxazol-4-yl)
4-Benzamide
3.9
2.0
3-(3-Amino) phenyl
3-Hydroxy-3-pyridyl
3-(1H-Tetrazol-5-yl) phenyl
Br
0.52
0.73
0.80
0.46
20
3-Methoxy-3-pyridyl
3-Aminomethyl phenyl
3-Hydroxymethyl phenyl
3-Acetylamino phenyl
4-Acetylamino phenyl
4-Hydroxy-3-methoxy phenyl
4-Hydroxymethyl phenyl
3-(3-Cyano) phenyl
3-Acetyl phenyl
0.81
1.2
0.80
0.59
19
0.15
0.50
0.34
0.30
2.7
3.3
1.3
1.7
1.1
1.5
4.0
3.7
1.7
51
0.60
0.40
0.33
1.1
4-Acetyl phenyl
3,4-Methylenedioxyphenyl
4-Nitro phenyl
3-Quinolyl
0.23
20
3-Fluoro phenyl
4-Fluoro phenyl
0.40
1.4
4-(N,N-dimethylamino) phenyl
2,6-Dimethyl phenyl
8.7
1.3
1.4

S. J. Coats et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5493–5498
Table 3. Selected compounds prepared as single enantiomers
5497
Compd
R2
R3
Stereochemistry
Ki mu (nM)
Ki delta (nM)
63
64
65
66
67
68
69
70
71
72
73
74
75
76
2-Pyridyl
4-N,N-Dimethyl benzamide
1S,5R
1R,5S
1S,5R
1R,5S
1S,5R
1R,5S
1S,5R
1R,5S
1S,5R
1R,5S
1S,5R
1R,5S
1S,5R
1R,5S
14
100
2.8
680
17
0.20
0.50
1.5
2-Methyl-propene
3-Thiophenyl
2-Methyl-propene
3-Thiophenyl
3-Furanyl
3-Acetyl phenyl
4-Hydroxy methyl phenyl
3-Carboxy phenyl
3-(1H-Tetrazol-5-yl) phenyl
Cyano
28
2.0
17
2.2
30
0.70
31
80
58
24
12
3100
2.6
2.3
0.20
39
0.90
1.1
3-Furanyl
Br
0.30
29
all of the compounds we prepared where the R2 of tro-
panylidene 3 is 3-furanyl and the R1 is again held con-
stant as ethyl. The compounds are listed in order of
increasingClog P, which ranges from 1.5 to 6. The vari-
ety of substituents tolerated at R3 is quite impressive as
we found that acidic, basic, neutral, large, and small
groups all result in high affinity compounds. To our
knowledge this level of broad substitution, which re-
tains single digit nanomolar binding, is unprecedented
in the opioid area.
References and notes
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3. Carson, J. R.; Coats, S. J.; Codd, E. E.; Dax, S. L.; Lee, J.;
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(a) Barn, D. R.; Caulfield, W. L.; Cottney, J.; McGurk,
K.; Morphy, J. R.; Rankovic, Z.; Roberts, B. Bioorg. Med.
Chem. Lett. 2001, 9, 2609–2624; (b) Cottney, J.; Rankovic,
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A number of homochiral analogs of 3 were prepared by
one of two routes, which we have previously described.3
As can be seen in Table 3 the most active isomer in every
case is the 1S,5R enantiomer; however the 1R,5S enantio-
mer in many cases also displays potent opioid binding
and in some cases the selectivity for the opioid receptors
is reversed.
Many compounds underwent functional testingand al-
most all showed agonist activity. A subset was tested or-
ally at 150lmol/kgin the mouse 48 °C hot plate test. We
found that compounds 15, 17, 20, and 73 provided ro-
bust antinociception and most induced Straub tail, a
behavior often associated with mu opioid agonist activ-
ity. The 3- and 4-carboxy phenyl tropanylidenes 29 and
30 provided little or no analgesic effects in the same test-
ingparadigm most likely due to poor oral absorption or
brain penetration. We observed no instances of convul-
sions17 or deaths with these compounds.
In summary, we have developed an efficient solid and
solution phase approach for SAR exploration in the
tropanylidene series of opioid agonists. In a collabora-
tion that lasted a little over one year, 435 compounds
were prepared for in vitro screeningand over 60 com-
pounds were resynthesized on larger scale to support
further testing. We discovered that significant polarity
could be introduced into the tropanylidene scaffold
while maintainingexcellent bindingaffinity and in
many cases oral in vivo efficacy. This scaffold has proven
to be an excellent opioid template as 225 unique
compounds displayed potent bindingaffinity with Ki
values of less than 10nM for either the delta or mu
opioid receptors.
9. An electron rich aldehyde resin, 1.06mmol/g, Irori,
catalogno. USR200-06.
10. Sheppeck, J. E., II; Kar, H.; Hong, H. Tetrahedron Lett.
2000, 41, 5329–5333.
11. Greater than 95% of compounds tested in vitro were
greater than 95% pure based on integration of the total
absorption chromatogram (190–360nM). The minimum
purity tested in vitro was 85%.

5498
S. J. Coats et al. / Bioorg. Med. Chem. Lett. 14 (2004) 5493–5498
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16. Representative procedure: To a solution of 4-[(8-aza-
bicyclo[3.2.1]oct-3-ylidene)-bromo-methyl]-N-ethyl-benz-
amide, 12 (10mg, 0.029mmol) and the appropriate
aldehyde (0.087mmol) in dichloroethane (0.5mL) was
added sodium triacetoxyborohydride (12mg, 0.058mmol)
in dimethylformamide (100lL) and acetic acid (5lL). The
reaction mixture was irradiated (lw) at 120°C for 6min.
After quenchingwith water, the mixture was concentrated
in vacuo. To the resultingresidue in N-methyl pyrrolid-
inone (0.3mL) was added potassium carbonate (12mg,
0.087mmol) in water (100lL), the appropriate boronic
acid (0.087mmol), and tetrakis(triphenylphosphine)palla-
dium (1.5mg, 0.001mmol) in N-methyl pyrrolidinone
(100lL). The reaction mixture was irradiated (lw) at
180°C for 10min. After quenchingwith water, the mixture
was absorbed onto diatomaceous earth and eluted with
5% methanol/ethyl acetate. The eluate was concentrated to
a residue and purified by reversed-phase chromatography
to furnish the product as a trifluoroacetate salt.
17. Hong, E. J.; Rice, K. C.; Calderon, S.; Woods, J. H.;
Traynor, J. R. Analgesia 1998, 3, 269–276.