Design and synthesis of bridged piperidine and piperazine isosteres

Article abstract of DOI:10.1016/j.bmcl.2018.06.038

We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.

Full text of DOI:10.1016/j.bmcl.2018.06.038

Accepted Manuscript
Design and Synthesis of Bridged Piperidine and Piperazine Isosteres
Gaëtan Maertens, Oscar M. Saavedra, Vito Vece, Miguel A. Vilchis Reyes,
Sofiane Hocine, Esat Öney, Bertrand Goument, Olivier Mirguet, Arnaud Le
Tiran, Philippe Gloanec, Stephen Hanessian
PII:
S0960-894X(18)30526-2
https://doi.org/10.1016/j.bmcl.2018.06.038
BMCL 25919
DOI:
Reference:
Bioorganic & Medicinal Chemistry Letters
To appear in:
Received Date:
Accepted Date:
25 May 2018
17 June 2018
Please cite this article as: Maertens, G., Saavedra, O.M., Vece, V., Reyes, A.V., Hocine, S., Öney, E., Goument, B.,
Mirguet, O., Le Tiran, A., Gloanec, P., Hanessian, S., Design and Synthesis of Bridged Piperidine and Piperazine
Isosteres, Bioorganic & Medicinal Chemistry Letters (2018), doi: https://doi.org/10.1016/j.bmcl.2018.06.038
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Design and Synthesis of Bridged Piperidine
and Piperazine Isosteres
Leave this area blank for abstract info.
Gaëtan Maertensa, Oscar M. Saavedraa, Vito Vecea, Miguel A. Vilchis Reyesa, Sofiane Hocinea, Esat Öneya,
Bertrand Goumentb , Olivier Mirguetb, Arnaud Le Tiranb, Philippe Gloanecb, Stephen Hanessiana*

Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com
Design and Synthesis of Bridged Piperidine and Piperazine Isosteres
Gaëtan Maertensa, Oscar M. Saavedraa, Vito Vecea, Miguel A. Vilchis Reyesa, Sofiane Hocinea, Esat
Öneya, Bertrand Goumentb, Olivier Mirguetb, Arnaud Le Tiranb, Philippe Gloanecb, Stephen Hanessiana*
aDepartment of Chemistry, Université de Montréal, Station Centre-Ville, C.P. 6128, Montréal, QC, H3C 3J7, Canada.
bInstitut de Recherches Servier, 11 rue des Moulineaux 92150 Suresnes, France
ARTICLE INFO
ABSTRACT
Article history:
Received
Revised
We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine
bridged isosteres of pridopidine . The compounds were assessed against the D2 receptor in
agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and
the ADME profiles were studied.
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 Constrained amines
Keyword_2 C-arylation
Keyword_3 Oxabicyclic piperidines
Keyword_4 Oxabicyclic piperazines
Keyword_5 Dopaminergic activity
Among the multitude of heterocyclic small molecules1 that
affect the central nervous system are an important class
comprising piperidine2 and piperazine3 core structures. A classic
example is haloperidol (Haldol) (Figure 1), with a rich history of
antipsychotic activity, especially for the treatment of
schizophrenia.4 Haloperidol is known to act on therapeutically
relevant dopaminergic receptors5 such as D26 and D47, which are
responsible for its antipsychotic effects among other properties
related to a variety of psychiatric disorders.8 It is also well known
that the in vivo formation of the quaternary 4-(4-chlorophenyl)-
1-[4-(4-fluorophenyl)-4-oxobutyl]-pyridinium salts resulting
from metabolism of the piperidine subunit in haloperidol in
addition to reduction of the ketone function to the corresponding
benzylic alcohol are responsible for its toxicity and
extrapyramidal side effects.9,10
Huntington's Disease (HD). It has been shown that pridopidine’s
adverse effect profile is similar to that of placebo unlike classical
D2 receptor antagonists such as haloperidol which are associated
with severe adverse effects such as acute extrapyramidal
symptoms in patients with HD.9,10
Cl
O
S
O
N
F
N
HO
O
Haloperidol
Pridopidine
O
A: X = CH
B: X = N
X
N
OMe
OH
MeO
N
MeO
N
A large number of studies have been directed at understanding
the complex interplay between efficacy, selectivity, and toxicity
using haloperidol as the time-tested prototype among
antipsychotic drugs. Among these studies are scholarly examples
of the use of constrained azabicyclic analogs starting from readily
available materials such as tropinone10-12 and piperazines.12
N
O
3-oxa-9-azabicyclo-
[3.3.1]nonane
8-azabicyclo-
[3.2.1]nonane
8-azabicyclo-
[3.2.1]nonan-3-ol
N
MeO
N
N
O
N
MeO
O
O
Recently, a new class of N-propyl piperidine D2 ligands has
been disclosed acting as dopaminergic stabilizers. 13,14 The most
advanced is pridopidine (Figure 1) which has reached phase 3
clinical development for the symptomatic treatment of
MeO
HO
3-oxa-7,9-diazabicyclo-
[3.3.1]nonane
2-oxa-5-azabicyclo-
[2.2.2]octane
2-oxa-5-azabicyclo-
[2.2.2]octan-7-ol
Figure 1. Haloperidol and targeted scaffolds.
____________________
We therefore conceived a series of carbon and oxygen bridged
bicyclic compounds related to pridopidine and derivatives such
as A and B (Figure 1)15 incapable of undergoing metabolism to
*
Corresponding author. Tel.: +1-514-343-6738; fax: +1-514-
343-5728; e-mail: stephen.hanessian@umontreal.ca.

quaternary pyridinium-type salts. Accordingly, we report on the
synthesis of representative members of bridged piperazines and
piperidines relying on stereoselective methods of C-arylation for
the latter class. In addition to the D2/D4 activity, we were
particularly interested in analogs having favorable ADME and
off-target (hERG) profiles.
NCO2Et
NCO2Et
a
b
H
I
OH
H
5
6
NCO2Et
c - e
N
Ar
Ar
H
H
7a: Ar = 2-(MeO)Ph
7b: Ar = 3-(MeO)Ph
7c: Ar = 4-(MeO)Ph
7d: Ar = 3,4-di(MeO)Ph
7e: Ar = 3,4,5-tri(MeO)Ph
8a: Ar = 2-(MeO)Ph
8b: Ar = 3-(MeO)Ph
8c: Ar = 4-(MeO)Ph
8d: Ar = 3,4-di(MeO)Ph
8e: Ar = 3,4,5-tri(MeO)Ph
Synthesis of analog 4 started by reaction between known
tropinone-derived ketone 116 and lithium bis(trimethylsilyl)amide
(LiHMDS)
in
the
presence
of
N-phenyl-
bis(trifluoromethanesulfonimide) (PhN(Tf)2)17 to generate the
corresponding triflic enol ether. This subsequently underwent a
Suzuki coupling18 with 2-methoxyphenylboronic acid, thus
delivering unsaturated intermediate 2 in 28% over two steps
(Scheme 1). Catalytic hydrogenation furnished the endo-aryl
azabicycle 3 as the sole isomer. It should be noted that at this
stage, a variety of reduction conditions (including the use of
different catalysts such as Raney nickel or diimide, while varying
temperatures, and solvents) all failed to produce the exo-C-aryl
isomer. A sequence consisting of hydrolysis of the carbamate 3
under basic conditions, followed by N-propionylation of the free
amine and reduction of the resulting amide function with LiAlH4
led to the desired 3-endo-(2-methoxyphenyl)-8-propyl-8-
azabicyclo[3.2.1]octane 4 in 30% over four steps. A single-
crystal X-ray analysis of the HCl salt of 4 allowed us to ascertain
its structure and stereochemistry (Scheme 1).
ORTEP representation
of 8a (HCl salt, hydrate)
Scheme 2. Reagents and conditions: (a) PPh3, I2, Imid., CH2Cl2, rt., 2h, 90%;
(b) Ar-MgBr, CoCl2, trans-N,N,N',N'-tetramethyl-1,2-cyclohexanediamine,
THF, 0°C to r.t., 3h-16h, 38-90%; (c) KOH, H4N2·H2O, (CH2OH)2, 160°C,
12h; (d) EtCOCl, 5N NaOH, CH2Cl2, r.t., 12h; (e) LiAlH4, THF, r.t., 12h, 34-
46% (3 steps).
NCO2Et
NCO2Et
a
HO
TsO
H
H
9
10
NCO2Et
b
NCO2Et
MeO
NCO2Et
a, b
c
H
O
O
7a
1
2
Scheme 3. Reagents and conditions: (a) TsCl, DMAP, Et3N, CH2Cl2, r.t., 48h,
69%; (b) NiBr2(glyme complex), 2-bromoanisole, 4,4’-di-tert-butyl-2,2’-
bipyridine, 4-ethylpyridine, KI, Mn, dimethylacetamide, 80°C, 18h, 60%.
NCO2Et
N
H
H
d-f
MeO
MeO
However, more steps were required to reach alcohol 923 in an
3
4
effective manner.
To study the effect of the aryl pharmacophore, we varied the
position of the methoxy group on the aryl moiety. Compounds
8b-e were prepared from 6 under the same conditions as for the
preparation of 8a (Scheme 2).
ORTEP
representation
of 4 (HCl salt)
Compound 12, incorporating an endo- tertiary alcohol, was
prepared from the known ethyl 3-hydroxy-3-(2-methoxyphenyl)-
8-azabicyclo-[3.2.1]octane-8-carboxylate 1112c as described
below in 15% yield over the three steps (Scheme 4).
Scheme 1. Reagents and conditions: (a) LiHMDS, PhN(Tf)2, THF, – 78°C
to r.t., 2h; (b) 2-methoxyphenylboronic acid, PdCl2(dppf)·CH2Cl2, 2N aq.
K2CO3, DMSO, 100°C, 1h, 28% (2 steps); (c) H2, Pd/C, EtOAc, r.t.; 12 h
(d) KOH, H4N2·H2O; (HOCH2)2, 150°C, 60h; (e) EtCOCl, 5N NaOH,
CH2Cl2, r.t., 12h; (f) LiAlH4, THF, r.t., 12h, 30% (4 steps).
OMe
OMe
a, b, c
NCO2Et
N
OH
OH
As mentioned above, our efforts to generate an exo-C-aryl
compound through hydrogenation reactions were unsuccessful.
To circumvent this problem, we envisaged a cobalt-based
coupling inspired from the work of Cossy and coworkers.19 To
this end, the known alcohol 520 was first reacted with PPh3 and I2
in the presence of imidazole to afford the iodide 6 (Scheme 2).
Treatment of 6 with 2-methoxyphenylmagnesium bromide in the
presence of a catalytic amount of CoCl2 and trans-N,N,N’,N’-
tetramethyl-1,2-cyclohexanediamine led to the exo-aryl
azabicyclic compound 7a in 38% yield over two steps. Finally, a
sequence consisting of deprotection of the amino group, followed
by propionylation and reduction of the amide led to the desired
azabicycle 8a in 34% yield over the three steps.
11
12
Scheme 4. Reagents and conditions: (a) KOH, H4N2·H2O, EtOH, reflux,
48h; (b) EtCOCl, 5N NaOH, DCM, r.t., 12h; (c) LiAlH4, Et2O, r.t., 12h,
15% (3 steps).
A similar approach as the one adopted to obtain 4 was used
for the synthesis of 7-endo-(2-methoxyphenyl)-9-propyl-3-oxa-9-
azabicyclo[3.3.1]-nonane 16. Ketone 1324 was first reacted with
LiHMDS and PhNTf2 to generate a triflic enol ether, which was
submitted to Suzuki coupling, yielding the unsaturated azabicycle
14 in 23% over two steps (Scheme 5). Catalytic hydrogenation of
the double bound led to 15 as the sole isomer. Interestingly, a
single-crystal X-ray analysis revealed that 15 adopted a chair-
boat conformation. Finally, the targeted 7-endo-(2-
methoxyphenyl)-9-propyl-3-oxa-9-azabicyclo[3.3.1]-nonane 16
was obtained after N-Boc removal, acylation of the free amine
and LiAlH4-mediated reduction of the amide to the
corresponding tertiary amine in 74% over four steps. We assume
Other alternative strategies can be applied to the
functionalization of bridged piperidines.21 For example, we used
a Ni-based coupling from the tosylate 10 according to Molander
and coworkers22 to generate intermediate 7a (Scheme 3).

NBoc
MeO
NBoc
N
MeO
a
a, b
c
N
Cl
Cl
F
N
F
O
O
O
O
O
13
14
21
22
OMe
OMe
H
H
NH
MeO
N
MeO
d - f
b
c, d
NBoc
N
N
N
O
O
O
O
23
24
15
16
Scheme 7. Reagents and conditions: (a) 2-methoxyaniline, diglyme, 165°C,
1h (b) H2 (60 psi), Pd(OH)2/C, 2N HCl, MeOH, rt, 15h, 44% (2 steps); (c)
Allyl iodide, K2CO3, MeCN, rt, 15h; (d) H2 (1 atm), Pd/C; MeOH, rt, 15h,
63% (2 steps).
ORTEP
representation
of 15
26. Aqueous acidic conditions served to hydrolyze the acetal
(78% over 3 steps). An intramolecular Mitsunobu reaction
allowed us to selectively obtain the bridged bicyclic morpholine
analog 27. PCC-mediated oxidation furnished ketone 28 in 86%
yield over 2 steps, whose structure was ascertained by single-
crystal X-ray analysis. At this stage, the 2-methoxyphenyl moiety
was introduced through a Grignard addition, leading to a 2:1
mixture of benzylic alcohols 29a and 29b in 99% yield. After
separation of the two isomers by chromatography, the nosyl
group was removed according to Nargund and coworkers27 and
the propyl chain was installed as described above, yielding
alcohols 30a and 30b in 66% and 59% yield respectively over
three steps.
Scheme 5. Reagents and conditions: (a) LiHMDS, PhN(Tf)2, THF, – 78°C to
r.t., 2h; (b) 2-methoxyphenylboronic acid, PdCl2(dppf)·CH2Cl2, 2N aq.
K2CO3, DMSO, 100°C, 1h, 23% (2 steps); (c) H2, Pd/C, EtOAc, r.t. 12h; (d)
TFA, CH2Cl2, r.t., 12h; (e) EtCOCl, 5N NaOH, CH2Cl2, r.t., 12h; (f) LiAlH4,
THF, r.t., 12h, 74% (4 steps).
that the chair-boat conformation is maintained based on NMR
data.
The Cossy cobalt-based coupling strategy was also applied to
the synthesis of exo-C-aryl 3-oxa-9-azabicyclo[3.3.1]nonane
bicyclic morpholine 20. The known alcohol 1724 was first
converted into the corresponding exo-iodo intermediate 18 under
Appel conditions (Scheme 6). A cobalt-mediated coupling
between 18 and 2-methoxyphenylmagnesium bromide led to
compound 19 in 42% yield. Finally, TFA-mediated deprotection
of the N-Boc group followed by N-propionylation and reduction
of the intermediate amide led to the azabicycle 20 in 39% yield
over three steps.
a, b
c, d
N3
O
NHNs
O
O
O
O
O
Ph
Ph
26
25
e
NNs
O
NNs
O
O
HO
27
28
NBoc
NBoc
a
b
H
I
NNs
O
OMe
HO
MeO
HO
H
O
f
O
NNs
O
17
18
HO
NBoc
N
c - e
29a
29b
H
H
O
19
O
N
O
OMe
OMe
OMe
HO
MeO
g - i
20
N
O
Scheme 6. Reagents and conditions: (a) PPh3, I2, Imid., CH2Cl2, 0 ºC to r.t.,
2h, 43%; (b) 2-methoxyphenylmagnesium bromide, CoCl2, trans-N,N,N',N'-
tetramethyl-1,2-cyclohexanediamine, THF, 0 ºC to r.t., 3h, 42%; (c) TFA,
CH2Cl2, r.t., 36h; (d) EtCOCl, 5N NaOH, CH2Cl2, r.t., 12h; (e) LiAlH4,
THF, r.t., 12h, 39% (3 steps).
HO
30b
30a
Scheme 8. Reagents and conditions: (a) H2, Pd/C, MeOH, 18h, rt; (b) o-
NsCl, Et3N, DMAP, CH2Cl2, r.t., 6h; (c) 1N HCl, CH2Cl2/MeOH 1:1, 3h,
78% (3 steps); (d) PPh3, DIAD, dioxane, r.t., 2h; (e) PCC, CH2Cl2, r.t., 18h,
86% (2 steps); (f) 2-methoxyphenylmagnesium bromide, THF, 0°C, 1h,
29a/29b: 2:1, 99%; (g) 3-mercaptopropionic acid, LiOH·H2O, DMF, r.t., 4h
(h) EtCOCl, 5N NaOH, CH2Cl2, rt. 12h; (i) LiAlH4, THF, rt., 12h, 59 % for
30a, 66 % for 30b (3 steps).
We then focused on a prototypical bridged piperazine analog
(Scheme 7). The known dichlorinated morpholine 21, prepared
according to Revesz and coworkers,25 was first submitted to an
SN2 reaction involving 2-methoxyaniline.
A
subsequent
Finally, a reductive dehydroxylation performed on 29a in the
presence of BF3·OEt2 and triethylsilane, followed by the
deprotection of the amine yielded intermediates 31a and 31b in
67% global yield in a ratio of 1.5:1 in favor of 31b (Scheme 9).
Installation of the propyl chain provided the bridged bicyclic
morpholines 32a and 32b in 76% and 78% yield respectively
over the two steps.
hydrogenation in the presence of Pearlman’s catalyst delivered
the amine 23 in 39% over two steps. Finally, a sequence
comprising allylation of the amine using allyl iodide and
potassium carbonate as a base, followed by catalytic reduction of
the allyl group led to the desired 7-(2-methoxyphenyl)-9-propyl-
3-oxa-7,9-diazabicyclo-[3.3.1]nonane 24 in 64% yield over the
two steps
All compounds synthesized were tested at two doses (0.1 and
10 µM) on the dopamine D2 receptor for agonist and antagonist
activity as well as on the dopamine D4 receptor as an agonist (see
Table 1; Supporting Information). The compounds were also
tested against hERG, on Caco-2 cells for passive diffusion and
efflux, and on human, rat, and mouse microsomes for metabolic
stability.
To the best of our knowledge, the synthesis of 7-aryl-2-oxa-5-
azabicyclo[2.2.2]octanes have not been previously reported. The
synthesis commenced with the known intermediate 25 which
could be prepared from D-glucose, according to Herdewijn and
coworkers26 (Scheme 8). We first reduced the azide to the
corresponding primary amine by catalytic hydrogenation.
Nosylation of the free amine provided the protected compound

References and notes
NNs
O
NH
O
OMe
HO
MeO
H
a, b
NH
O
1.
For relevant reviews, see: (a) Vitaku, E.; Smith, D.T.; Njardarson, J.T.
J. Med. Chem. 2014, 57(24), 10257-10274. (b) Taylor, R. D.;
MacCoss, M.; Lawson, A.D.G. J. Med. Chem. 2014, 57(14), 5845-
5859. (c) Zhang, T.Y. Adv. Heterocycl. Chem. 2017, 121, 1-12.
For recent monograph about piperidine in medicinal chemistry, see:
Vardanyan, R.S. Piperidine-Based Drug Discovery.
MeO
H
29a
31a
31b
2.
3.
OMe
H
N
O
H
N
O
Elsevier:Amsterdam. 2017.
c, d
MeO
For recent reviews on piperazines in medicinal chemistry, see: (a)
Rathi, A.K.; Syed, R.; Shin, H.S.; Patel, R.V. Expert Opin. Ther. Pat.
2016, 26(7), 777-797. (b) Shaquiquzzaman, M.; Verma, G.; Marella,
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Alan, M. M. Eur. J. Med. Chem. 2015, 102, 487-529. (c) Al-Ghorbani,
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Pharm. Res. 2015, 7(5), 281-307. (d) Patel, R.V.; Park, S.W. Mini-Rev.
Med. Chem. 2013, 13(11), 1579-1601. (e) Wu, Y.J. Progress in
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32a
32b
Scheme 9. Reagents and conditions: (a) BF3.OEt2, Et3SiH, CH2Cl2, – 78°C,
4h (b) 3-mercaptopropionic acid, LiOH·H2O, DMF, r.t., 4h, 31a/31b: 1.5:1,
67% (2 steps); (c) EtCOCl, 5N NaOH, CH2Cl2, r.t. 12h; (d) LiAlH4, THF,
r.t., 12h, 76 % for 32a, 78% for 32 b (2 steps).
Reference compounds A and B from Pettersson and
coworkers15 were active as agonists on the D2R at the two doses
consistent with the literature data. We then tested the two
compounds against hERG and found that only the piperazine
derivative B significantly blocked the K channel at the 10 µM
level. Both A and B proved to be permeable on Caco-2 cells,
were not prone to efflux and were found to be stable in the
presence of human microsomes. However, they were
significantly metabolized in rat and mice microsomes (see Table
1, Supporting Information)
4.
5.
For recent reviews on haloperidol, see: (a) Tyler, M.W.; Zaldivar-Diez,
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Unfortunately, the tropane analogues 4, 8a-e and 12 were all
inactive on D2 and D4 receptors as agonists and antagonists. As
depicted in the ORTEP representation of 8a (Scheme 2), the
tropane bridged-ring is projecting the aromatic and propyl
substituents in a pseudo trans-diequatorial orientation mimicking
the conformation of the corresponding piperidine or piperazine
derivatives. The ethano bridge may thus be responsible for
abolishing the agonist activity on the D2 receptor. The tropane
derivatives 8a-e, 12 showed an unfavorable profile vis-à-vis
hERG at 1 µM. Passive permeability was maintained, while the
microsomal stability tended to significantly erode across species
for 8a-d vs A. Interestingly, both 8a and endo-hydroxy
containing tropane 12 improved human microsomal stabilities
compared to A and B, while maintaining adequate permeability
and efflux profiles.
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The bicyclic morpholine analogues 20 and 24 were also
devoid of activity on the D2 and D4 dopaminergic receptors.
Significantly, the bridged morpholino-piperazine 24 ADME and
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The new 7-aryl-2-oxa-5-azabicyclo[2.2.2]octane derivatives
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