SAR and biological evaluation of novel trans-3,4-dimethyl-4-arylpiperidine derivatives as opioid antagonists

Article abstract of DOI:10.1016/j.bmcl.2005.05.123

The phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. We have developed a SAR study around LY255582 by comparing the effect of the hydroxy group in the 2- and 4-position of the phenyl ring. Also, we have prov

Full text of DOI:10.1016/j.bmcl.2005.05.123

Bioorganic & Medicinal Chemistry Letters 15 (2005) 3844–3848
SAR and biological evaluation of novel
trans-3,4-dimethyl-4-arylpiperidine derivatives as opioid antagonists
b,
a
a
a
a
*
´
Nuria Dıaz, Mark Benvenga, Paul Emmerson, Ryan Favors, Michael Mangold,
Jamie McKinzie,a Nita Patel,a Steven Peters,a Steven Quimby,a Harlan Shannon,a
Miles Siegel,a Michael Statnick,a Elizabeth Thomas,a Joseph Woodland,a
Peggy Surfacea and Charles Mitcha
aDiscovery Research, Eli Lilly and Company, Indianapolis, IN 46285, USA
bLilly, S. A., Avenida de la Industria, 30, 28108 Alcobendas, Madrid, Spain
Received 18 March 2005; revised 27 May 2005; accepted 31 May 2005
Available online 1 July 2005
Abstract—The phenolic hydroxy group of opiate-derived ligands is of known importance for biological activity. We have developed
a SAR study around LY255582 by comparing the effect of the hydroxy group in the 2- and 4-position of the phenyl ring. Also, we
have proved that the 3-position of the phenyl ring is optimal for opioid activity. Furthermore, we have successfully replaced the
hydroxy group in LY255582 by carbamate and carboxamide groups. The new analogs have high affinity for the opioid receptors
comparable to the corresponding phenol. Carboxamide analog 12 has an improved metabolism profile and proved to be efficacious
in in vivo studies.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
intake and body weight gain in obese Zucker rats when
compared to the standard opioid antagonists naloxone,
naltrexone and nalmefene.4 The bioavailability of parent
LY255582 was <1% in both the rat and dog, primarily
because of extensive first pass metabolism.5 Our hypoth-
esis was that the phenol group played an important role
in this first pass metabolism. However, our previous
SAR in the piperidine scaffold had been based on the
3-phenol substitution by analogy to the morphine-type
structures. Traditional structure–activity relationship
of morphinans suggests that the phenolic hydroxyl
group in the 3-position was a strict requirement for
Opioid receptors are involved in a multitude of physio-
logical functions, such us GI motility, pain, appetite and
emotional state.1 Thus, selective opioid antagonists may
find uses in a number of therapeutic areas. The relative
safety of opioid antagonists makes them attractive as a
potential drug for the treatment of chronic diseases such
as obesity.
Zimmerman2 described the discovery of opioid antago-
nist activity in a series of trans-3,4-dimethyl-4-(3-
hydroxyphenyl)piperidines. These 4-phenylpiperidine
antagonists were structurally unique since opioid antag-
onists were generally analogs of morphine. This work
led to the discovery of LY255582 (1, Fig. 1).3
LY255582 is a centrally active antagonist which has a
high affinity for l, j, and d receptors (Ki: 0.18, 4.68
and 4.82 nM, respectively). This antagonist has shown
exceptional potency and durability in reducing food
Keywords: Opioid antagonist; trans-3,4-Dimethyl-4-arylpiperidine.
*
Corresponding author. Tel.: +34 91 663 34 62; fax: +34 91 623
3591; e-mail: diaz_nuria@lilly.com
Figure 1.
0960-894X/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2005.05.123

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N. Dıaz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3844–3848
3845
binding to opioid receptors, serving as a H-bonding
donor to a complementary site on the protein.6,7
in refluxing AcOH gave the racemic piperidine 17. Final-
ly, its alkylation with the enantiomerically pure brosy-
late (S)-A afforded compounds 2 and 3 which were
separated by chiral chromatography to give enantiomer-
ically pure 2A, 2B, 3A and 3B. The relative stereochem-
istry of methyl groups on carbons 30 and 40 is trans;
however, the absolute stereochemistry on these carbons
for 2A, 2B and 3A, 3B was not assigned (see Scheme 1).
We first wanted to know if the 3-position of the phenyl
ring was optimal for substitution. In addition, we have
studied replacements of the hydroxyl group to improve
the ADME profile of LY255582. For these purposes,
we synthesized and evaluated different trans-3,4-dimeth-
yl-4-arylpiperidine analogs of LY255582.
The 3-substituted phenyl ring piperidines 4, 10–12 were
synthesized from the common intermediate 18, prepared
from LY255582.13 The reductive elimination of the tri-
flate in a Pd-catalyzed reaction using NaHCO2 as a
reducing agent gave compound 4. On the other hand,
the carbonylation of the triflate using the same catalytic
system: Pd(OAc)2/dppf in the presence of methanol
gives the ester 10 which upon treatment with ammonia
leads to the carboxamide 12. Hydrolysis of 10 in the
presence of LiOH gives the carboxylic acid 11.
2. Chemistry
Mitch and co-workers developed a nine-step synthesis
for the preparation of these arylpiperidines8 and a few
years later Werner et al.9 published an improved synthe-
sis of LY255582. However, we desired a new synthetic
approach that would allow for the preparation of differ-
ent 4-arylpiperidines in a more effective way. Thus, we
implemented a new chemistry route where the key step
involves the Suzuki coupling between the racemic
vinyltriflate 1310 and the corresponding boronic acid
(Scheme 1). After some experimentation we found that
the best conditions for the coupling are the ones report-
ed by Fu:11 Pd(Ph3)4, K2CO3, DMA/THF, rt. The meth-
ylation of the allylamine 14 with dimethylsulfate at
ꢀ50 ꢁC gave the desired 3,4-dimethylenamine 15 in
excellent yield. Alkylation of the allylamine is regiospec-
ific at the c-position and occurs exclusively trans to the
C3-methyl substituent.12 The reduction of the enamine
using NaBH4 gave piperidine 16. N-demethylation with
phenyl chloroformate in refluxing toluene followed by
removal of both N- and O-protecting groups with HBr
Amine 5 was prepared from phenol 1 by the Smiles rear-
rangement.14 The treatment of 1 with 2-bromo-2-meth-
ylpropionamide in the presence of sodium hydride and
cesium carbonate in a mixture of NMP, DMPU and
dioxane at reflux gave 19, which was treated with acid
to give amine 5. Analogs 6–9 were synthesized starting
from 5 by reaction with the corresponding electrophile.
3. Results and discussion
Our effort was directed towards the analysis of the struc-
ture–activity relationship around the aryl domain by
Scheme 1. Reagents and conditions: (a) i—LDA, THF, ꢀ78 ꢁC, ii—N-phenyltriflimide, Et3N, CH2Cl2, ꢀ78 ꢁC, rt; (b) (OH)2BC6H4OMe, Pd(Ph3)4,
K2CO3, DMA, THF, rt; (c) i—n-BuLi, THF, ꢀ10 ꢁC, ii—Me2SO4, ꢀ50 ꢁC; (d) NaBH4, MeOH, rt; (e) PhO2CCl, toluene, 100 ꢁC; (f) i—HBr, HOAc,
reflux, ii—pH 10.5; (g) NaHCO3, A, DME, reflux.

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N. Dıaz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3844–3848
3846
Scheme 2. Reagents and conditions: (a) N-phenyltriflimide, Et3N, CH2Cl2, rt; (b) Pd(OAc)2, dppf, Et3N, NaHCO2, DMSO, 65 ꢁC; (c) Pd(OAc)2,
dppf, Et3N, CO, DMSO, MeOH, 65 ꢁC; (d) MeOH, NH3, NaCN; (e) LiOH 1 N, 0 ꢁC rt; (f) 2-bromo-2-methylpropionamide, NaH, Cs2CO3, NMP,
DMPU, dioxane, reflux; (g) 6 N HCl, EtOH, (h) CH2Cl2, pyridine, E.
changing the nature of the functional group or by
changing the position of the hydroxyl group. For that
purpose, we synthesized and evaluated compounds
2–12, which are shown in Table 1.
Compounds were tested for their affinities (Ki) towards
the cloned human l, j and d receptors expressed in Chi-
nese hamster ovary cells as measured by their abilities to
displace [3H]diprenorphine (l- and j-opioid receptor
Table 1. Binding data (Ki) and antagonist activity (Kb) of compounds 1–12
R
Ki (nM)
Kb (nM)
l
j
d
l
j
d
1
3-OH
2-OH
0.1
4.7
1340
1074
224.3
386
4.8
0.04
0.3
559.1
1.2
>2038
747.5
122.4
>2015
2A
2B
3A
3B
4
410
235
6993a
2381a
364.0a
3543a
169
40.5
18.8
1.3
23.1
1.6
0.7
0.3
0.4
nd
>1711
92.2
4-OH
30.4
376
7.7
88.3
40.6
15.7
9.8
H
3-NH2
749
47.1
24.7
14.3
25.8
nd
5
1.9
1.8
55.2
69.5
133
44.9
51.3
64.9
251
6
3-NHCONHMe
3-NHCOMe
3-NHSO2Me
3-NHCO2Me
3-NHCO2Et
3-CO2Me
3-CO2H
7
2.4
9.4
16.4
nd
8
192
9a
9b
10
11
12
1.0
1.2
10.6
12.3
2326
3015
12.7
14.2
24.6
1635
3507
6.4
0.1
0.1
34.6
nd
0.6
0.7
1.9
3.2
43.3
143
0.2
984
nd
1.9
1242
nd
2.8
3-CONH2
0.1
nd, not done.
a Ki affinities were measured using [3H]diprenorphine instead of [3H]bremazocine.

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N. Dıaz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3844–3848
3847
assays) or [3H]bremazocine (d-opioid receptor assay).15
Functional antagonist potency (Kb) of the compounds
was assessed by their ability to inhibit agonist-stimu-
lated activation of G-proteins using a [35S]GTPcS bind-
ing assay in CHO membranes containing each of the
cloned opioid receptor subtypes.16 No agonist activity
was detected for these compounds at concentrations
up to 10 lM.
3-OH group of morphine21 and naltrindole22 was re-
placed by alkyl, acetyl, aryl and/or heteroaryl groups;
these molecules had substantially lower affinity for opi-
oid receptors. Very recently, Neumeyer et al. reported
the successful replacement of the phenolic hydroxyl moi-
ety of morphinans by a 2-aminothiazole.23
Wentland et al. had reported the only carbon attach-
ment that has successfully replaced the prototypic
hydroxyl group. They found unexpectedly high affinity
for opioid receptors in cyclazocine analogs, where the
OH– was replaced by a carboxamide group24 (though
a significant decrease was observed on replacement of
hydroxy by carboxamide in morphine and naltrexone).25
Our primary goal for this study was to determine if the
phenolic group was mandatory and if its position on
carbon 3 of the phenyl ring was optimal. To accomplish
this goal, we evaluated aryl piperidines 2, 3 and 4.
The activity of both compounds 2A and2B for all three
receptors declines precipitously relative to compound 1.
In the case of compound 3, where the hydroxyl group
has been moved to the 4-position of the phenyl ring, iso-
mer 3A shows higher affinity (for l and d receptors) than
isomer 3B; however, 300-fold lower than those observed
with LY255582. This activity is similar to that of com-
pound 4, the deshydroxy derivative. These results sug-
gest that the hydroxyl group in the 3-position is of
importance for the molecular interaction of the aryl-
piperidines with the opioid receptors. Recently, Kim
et al. have published similar findings showing the need
for a specific phenolic position in 5-phenylmorphans.17
We prepared and tested the carboxamide derivative 12.
Carboxymethoxy analog 10 and carboxylic acid 11,
which were intermediates in the synthesis of the carbox-
amide, were also tested. While the ester and acid 10 and
11 had substantially diminished affinity for opioid recep-
tors relative to their 3-OH counterpart, compound 12
showed high affinity at the three opioid receptors, com-
parable to its OH– counterpart (Ki: 0.18, 12.73 and
6.38 nM, respectively). Compound 12 displayed potent
in vitro l, j and d antagonist activity (Kb: 0.1, 1.9 and
2.8 nM, respectively), which was similar to the antago-
nist potency of 1 (Kb: 0.04, 0.3 and 1.2 nM, respectively).
Our second goal was to find replacements of the hydrox-
yl group that would retain the essential H-bond donat-
ing properties of the 3-phenol in LY255582 but have
an improved ADME profile, thus we prepared com-
pounds 5–12 to evaluate this hypothesis.
During the preparation of this paper, Bourdonnec
et al.26 published that the carboxamide group was an
effective isostere in vitro of the phenolic OH moiety in
this trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidine
scaffold.
We first prepared aniline 5, as the amino group is known
to mimic the hydroxy group at the site of some recep-
tors.18 In fact, Wentland et al. have successfully replaced
OH by amino groups in their cyclazocine analogs.19 In
our case, we also found that aniline 5 had significant
affinity for l, j and d receptors, however, it was 20-,
11- and 10-fold less potent than LY255582, respectively.
4. Pharmacology and metabolism
We next wanted to study if carboxamide 12 was active
in vivo and if it could provide us with a better profile
than LY255582 (1).
Opioid antagonist activity in vivo was measured in the
tail-flick assay, measuring the compoundÕs ability to
block morphine-induced analgesia.27 Phenol 1 exhibited
higher potency (ED50sc: 0.017 mg/kg) than 12 (ED50sc:
0.024 mg/kg) when administered by the subcutaneous
route. However, carboxamide 12 showed better oral
Next, we tested analogs 6–9. Urea 6 shows similar affin-
ity across the three receptors compared to aniline 5.
Amide 7 and sulfonamide 8,20 although active at l, j
and d receptors, had lower affinity than aniline 5.
On the other hand, carbamates 9a and9b showed im-
proved potency across the three receptors compared to
aniline 5 (9a; Ki: 1.0, 10.6 and 14.2 nM for l, j and d,
respectively), though these analogs are less potent than
LY255582 (10-, 2- and 3-fold less potent) they do retain
significant potency. Furthermore, carbamates displayed
potent in vitro antagonist activity for the three opioid
receptors (9a, Kb: 0.1, 0.6 and 1.9 nM for l, j and d,
respectively).
potency (ED50po: 0.15 mg/kg) than
0.26 mg/kg). This result might be due to an improved
metabolism of compound 12.
1
(ED50po:
In fact, the studies of the metabolism in rat liver slices
after 24 h show that carboxamide 12 was 27% metabo-
lized while phenol 1 was 98% metabolized. The de-
creased metabolism of compound 12 was found to
correspond to an improved oral bioavailability (%F)28
in rats compared to compound 1 (%F = 32% and
2.5%, respectively)
Continuing with the effort of looking for suitable
replacements for the phenolic group we prepared and
evaluated analogs 10–12, where the OH was replaced
by a carbon attachment. There are very few papers that
describe any type of carbon attachment at the position
of the prototypic phenolic OH. For example, when
Compound 12 was evaluated for its effect on food con-
sumption in fasted male Long–Evans rats.29 Oral
administration of a 3 mg/kg dose of 12 resulted in a sta-
tistically significant reduction of the cumulative amount

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N. Dıaz et al. / Bioorg. Med. Chem. Lett. 15 (2005) 3844–3848
3848
16a and 16b were achieved through combination of 1D
and 2D experiments. 1D-NOESY confirmed the relative
trans stereochemistry of the methyl groups in carbons 30
and 40. See also Ref. 9.
of food consumed, as measured over 1- and 2-h time
periods. In contrast, oral administration of a 3 mg/kg
dose of LY255582 was inactive over the same time
periods.
13. LY255582 was enantiomerically pure, see Ref. 9.
14. Weidner, J. J.; Weintraub, P. M.; Schnettler, R. A.; Peet,
N. P. Tetrahedron 1997, 53, 6303.
15. Rodgers, G.; Hubert, C.; McKinzie, J.; Suter, T.; Statnick,
M.; Emmerson, P.; Stancato, L. Assay Drug Dev. Technol.
2003, 1, 627.
16. DeLapp, D. W.; McKinzie, J. H.; Sawyer, B. D.;
Vandergriff, A.; Falcone, J.; McClure, D.; Felder, C. C.
J. Pharmacol. Exp. Ther. 1999, 289, 946.
17. Kim, I. J.; Dersch, C. M.; Rothman, R. B.; Jacobson,
A. E.; Rice, K. C. Bioorg. Med. Chem. 2004, 12, 4543.
18. Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147.
19. Wentland, M. P.; Ye, Y.; Cioffi, C. L.; Rongliang, L.;
Zhou, Q.; Xu, G.; Duan, W.; Dehnhardt, C. M.; Sun, X.;
Cohen, D. J.; Bidlack, J. M. J. Med. Chem. 2003, 46, 838,
and literature cited therein.
5. Conclusions
From these early SAR findings, it seems reasonable to
conclude that the hydroxyl group on carbon 3 of the
aromatic ring of 1 plays an important role in binding
to opioid receptors. We have been successful in the bio-
isosteric replacement of the hydroxyl group by a carbox-
amide group (analog 12). Carbamates 8 also show high
receptor affinity. We have demonstrated that carboxam-
ide 12 improved the pharmacokinetic properties of
LY255582 and also was efficacious in reducing food
consumption in rats. Further evaluation of carboxamide
12 is on going.
20. Portoghese replaced the hydroxy group of opiate-derived
ligands by a sulfonamide group, the new analogs were
found inactive, see: McCurdy, C. R.; Jones, R. M.;
Portoghese, P. S. Org. Lett. 2000, 2, 819.
Acknowledgments
21. Hedberg, M. H.; Johansson, A. M.; Fowler, C. J.;
Terenius, L.; Hakcsell, U. Bioorg. Med. Chem. Lett.
1994, 4, 2527.
22. Kubota, H.; Tothman, R. B.; Dersch, C.; McCullough,
K.; Pinto, J.; Rice, K. C. Bioorg. Med. Chem. Lett. 1998, 8,
799.
´
We thank Pilar Lopez for the separation of compounds
2A, 2B, 3A and 3B and Paloma Vidal for the structural
elucidation of 16.
References and notes
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28. The bioavailability was determined using Long–Evans rats
(n = 3). It was a crossover study (po ꢀ10 mg/kg to iv
ꢀ1 mg/kg). Formulation for oral arm: 1% CMC, 0.5%
SLS, 0.085% Povidone. Formulation for iv arm: 50%
PEG, 1% ethanol in saline.
29. The male Long–Evans rats had been fasted for 18 h prior
to testing. The weight of food consumed was measured for
groups of six rats treated with test substance and
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10. Intermediate 13 can be prepared and stored for long
periods of time, thus it can be used as a common
intermediate in the synthesis of different aryl piperidines.
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12. The regiochemistry and stereochemistry was confirmed
through analysis of intermediates 16. Full assignments of