Synthesis of new bridgehead substituted azabicyclo-[2.2.1]heptane and -[3.3.1]nonane derivatives as potent and selective α7 nicotinic ligands

Article abstract of DOI:10.1021/ol102170q

New azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives containing a pyridinyl substituent at the bridgehead position have been synthesized via an efficient ten chemical steps pathway. Both chemical series were then evaluated in vitro for their affinity at α7 nicotinic receptors revealing nanomolar potency with notably excellent selectivity over the α4β2 nicotinic subtype.

Full text of DOI:10.1021/ol102170q

ORGANIC
LETTERS
2010
Vol. 12, No. 21
5004-5007
Synthesis of New Bridgehead
Substituted Azabicyclo-[2.2.1]heptane
and -[3.3.1]nonane Derivatives as Potent
and Selective r7 Nicotinic Ligands
Franck Slowinski,*,† Omar Ben Ayad,† Julien Vache,‡ Mourad Saady,†
Odile Leclerc,† and Alistair Lochead‡
Sanofi-AVentis R&D, 1 AVenue Pierre Brossolette, 91385 Chilly-Mazarin Cedex, France
franck.slowinski@sanofi-aVentis.com
Received September 10, 2010
ABSTRACT
New azabicyclo[2.2.1]heptane and -[3.3.1]nonane derivatives containing a pyridinyl substituent at the bridgehead position have been synthesized
via an efficient ten chemical steps pathway. Both chemical series were then evaluated in vitro for their affinity at r7 nicotinic receptors
revealing nanomolar potency with notably excellent selectivity over the r4ꢀ2 nicotinic subtype.
In the past decade, intense efforts from both pharmaceutical
companies and academic groups have been engaged in identify-
ing new potent and selective R7 nicotinic receptor ligands. Such
compounds are expected to generate new promising treatments
for cognitive dysfunction related pathologies (e.g., Schizophre-
nia, Alzheimer’s disease).1 A number of chemical families have
been identified containing an azabicyclic moiety where the
nitrogen atom is positioned at the bridgehead.2 In most cases,
these molecules possess aromatic or heteroaromatic substituents
but not on the opposing bridgehead position of the azabicyclic
moiety (Figure 1).
† Exploratory Unit.
Figure 1. Examples of nitrogen-bridgehead azabicyclic R7 nicotinic
ligands.
‡ TSU Aging.
(1) (a) Martin, L. F.; Kem, W. R.; Freedman, R. Psychopharmacology
2004, 174, 54–64. (b) Olincy, A.; Stevens, K. E. Biochem. Pharmacol. 2007,
74, 1192–1201. (c) Dani, J. A. Biol. Psychiatry 2001, 49, 166–174. (d)
Sharma, G.; Vijayaraghavan, S. Curr. Med. Chem. 2008, 15, 2921–2932.
(2) For an overview of R7 nicotinic receptor ligands possessing an
azabicyclic moiety, see: (a) Romanelli, M. N.; Gratteri, P.; Guandalini, L.;
Martini, E.; Bonaccini, C.; Gualtieri, F. ChemMedChem 2007, 2, 746–767.
(b) Broad, L. M.; Sher, E.; Asties, P. C.; Zwart, R.; O’Neill, M. J. Drug
Future 2007, 32, 161–170. (c) Mazurov, A.; Hauser, T.; Miller, C. H. Curr.
Med. Chem. 2006, 13, 1657–1584.
In the literature, few examples of azabicyclo[2.2.1]heptane
derivatives of that kind, bearing an aromatic or a heteroaro-
matic group at the bridgehead position, are known.
Only oxadiazolyl (B and C), triazinyl (D), triazolyl (E and
F), and tetrazolyl (G) groups have been described,3 mostly
10.1021/ol102170q  2010 American Chemical Society
Published on Web 10/12/2010

derived from the transformation of the ester group of the
common intermediate A (except for F). Only one example
of an azabicyclo[3.3.1]nonane substituted with a phenyl
group at the bridgehead position (H) has been described with
moderate yield (Figure 2).4
the corresponding alcohol derivative 4 which was engaged
in a chlorination step leading to the 5-chloromethyl-2-
methoxy-pyridine 5. Substitution reaction with potassium
cyanide allowed access to the key synthon (6-methoxy-
pyridin-3-yl)acetonitrile 6 with 68% overall yield from 3 on
a multigram scale (Scheme 1).
Scheme 1. Synthesis of 6
Figure 2. Reported bridgehead (hetero)aromatic-substituted [2.2.1]-
and [3.3.1]-azabicyclic derivatives.
Generation of the 4-(6-chloropyridin-3-yl)-1-azabicyclo-
[2.2.1]heptane scaffold 1 was then achieved in a six-step
sequence described as follows: Double alkylation of 6 with
ethyl bromoacetate led to compound 7 in 79% yield. Under
hydrogenation conditions in the presence of Raney Nickel
as a catalyst, reduction of the cyano group of 7 and
concomitant intramolecular cyclization of the newly
generated terminal amino group on one of the ester
functions furnished the lactam 8 in 92% yield. Reduction
of both lactam and ester moiety using lithium aluminum
hydride (LAH) gave pyrrolidine 9 in 79% yield. Treatment
of the latter with concentrated hydrobromic acid with
heating led to the hydrolysis of the methoxy group of the
pyridine and to the exchange of the terminal alcohol to
bromide quantitatively (compound 10). Cyclization of 10
to the target azabicyclic[2.2.1]heptane scaffold was achieved
in 74% yield by treatment with potassium carbonate.
Finally, action of POCl3 under sealed tube conditions led
to the desired key chlorinated scaffold 1 (Scheme 2).
We wish here to report an efficient and concise synthesis
of new azabicyclo[2.2.1]heptane and -[3.3.1]nonane de-
rivatives bearing a 2-chloropyridin-5-yl substituent at the
bridgehead position. These were subsequently function-
alized with various substituents. To generate a library of
compounds, we focused our efforts on the synthesis of
both azabicyclic scaffolds 1 and 2 bearing a synthetically
valuable 2-chloropyridin-5-yl group at the bridgehead
position (Figure 3).
Synthesis of scaffold 2 started with the double 1,4-addition
of the above-described (6-methoxypyridin-3-yl)acetonitrile
6 on ethyl acrylate in the presence of Triton B following
Uyeo’s procedure5 with Su’s modifications.6 This step
afforded the compound 12 in quantitative yields. The
following steps were then the same as described above for
the preparation of scaffold 1 (Scheme 2).
A library of compounds were generated using scaffolds 1
and 2. Representative examples 17a-g and 18a,h were
synthesized via classical Suzuki-Miyaura coupling in mod-
Figure 3. Targeted scaffolds.
Although compound 6 is commercially available, we chose
to synthesize it for multigram accessibility and cost reasons.
Diisobutylaluminium (DIBAL) reduction of commercially
available 6-methoxynicotinic acid methyl ester 3 furnished
(3) (a) Orlek, B. S.; Blaney, F. E.; Brown, F.; Clark, M. S. G.; Hadley,
M. S.; Hatcher, J.; Riley, G. J.; Rosenberg, H. E.; Wadsworth, H. J.; Wyman,
P. J. Med. Chem. 1991, 34, 2726–2735. (b) Jenkins, S. M.; Wadsworth,
H. J.; Bromidge, S.; Orlek, B. S.; Wyman, P. A.; Riley, G. J.; Hawkins, J.
J. Med. Chem. 1992, 35, 2392–2406. (c) Orlek, B. S.; Cassidy, F.; Clark,
M. S. G.; Faulkner, R. E.; Collings, E. J.; Hawkins, J.; Riley, G. J. Bioorg.
Med. Chem. Lett. 1994, 4, 1411–1414.
(5) Hazama, N.; Irie, H.; Mizutani, T.; Shingu, T.; Takada, M.; Uyeo,
S.; Yoshitake, A. J. Chem. Soc. C 1968, 2947–2953.
(6) Su, D.-S.; Lim, J. L.; Markowitz, M. K.; Wan, B.-L.; Murphy, K. L.;
Reiss, D. R.; Harrell, C. M.; O’Malley, S. S.; Ransom, R. W.; Chang,
R. S. L.; Pettibone, D. J.; Tang, C.; Prueksaritanont, T.; Freidinger, R. M.;
Bock, M. G. Bioorg. Med. Chem. Lett. 2007, 17, 3006–3009.
(4) Badger, G. M.; Cook, J. W.; Walker, T. J. Chem. Soc. 1949, 1141–
1144.
Org. Lett., Vol. 12, No. 21, 2010
5005

Scheme 2
.
Synthesis of Scaffold 1 and 2
Table 1. Suzuki-Miyaura Coupling Reaction on 1 and 2
a Boronic acid pinacol ester was used instead of boronic acid.
b Subsequent salification was performed providing 17c as its hydrobromide
salt. c Subsequent salification was performed providing 17b as its hydro-
chloride salt.
erate to good yields. Compounds 17b and 17e were
subsequently salified to hydrochloride and hydrobromide salt,
respectively, to obtain satisfactory purity (Table 1).
In vitro evaluation of these compounds as R7 nicotinic
receptor ligands was then performed on tissues from rat brain
following Marks and Collins’ protocol.7
the hundred-nanomolar range. This trend which should
be confirmed with a wider range of analogues is the
subject of a future study. The functional activity of
examples from this publication is under study and will
be published elsewhere.
Selectivity versus the R4ꢀ2 nicotinic receptor, the other
major nicotinic receptor subtype present in the brain, was
also evaluated following a protocol described by Anderson
and Hall.9 Of the five tested compounds, three (17c-e)
were inactive as ligand on the R4ꢀ2 nicotinic receptor
(IC50 > 10 000 nM), whereas compounds 17b and 17g
exhibited R4ꢀ2 nicotinic receptor affinity with IC50 values,
respectively, of 4150 and 1960 nM. In these cases, R7
selectivity versus the R4ꢀ2 subtype is more than 100-
fold (Table 2).
All examples possessed potent R7 nicotinic receptor
affinities with IC50 values from 5 nM (17g) to 1.045 µM
(17f). More precisely, six of nine examples (17a-d, 17g,
18h) exhibited activity with IC50 below 50 nM. These
primary activities are comparable or better than the in vitro
activity of the SSR180711, an R7 nicotinic receptor partial
agonist we previously developed (advanced clinical phases),
used as our reference drug compound.8 In terms of
structure-activity relationship, an influence of the size
of the azabicyclic moiety has been observed by comparing
IC50 of 17a with its superior homologue 18a. The latter
appeared to be 10-fold less potent but still had affinity in
In summary, we have developed an efficient and concise
synthesis of two new chemical series of pyridinyl bridge-
(7) (a) Marks, M. J.; Collins, A. C. Mol. Pharmacol. 1982, 22, 554–
564. (b) Marks, M. J.; Stitzel, J. A.; Romm, E.; Wehner, J. M.; Collins,
A. C. Mol. Pharmacol. 1986, 30, 427–436.
(8) For more informations on the SSR180711, see: (a) Biton, B.; et al.
Neuropsychopharmacology 2007, 32, 1–16. (b) Pichat, P.; et al. Neurop-
sychopharmacology 2007, 32, 17–34.
(9) (a) Anderson, D. J.; Arneric, S. P. Eur. J. Pharmacol. 1994, 253,
261–267. (b) Hall, M.; Zerbe, L.; Leonard, S.; Freedman, R. Brain Res.
1993, 600, 127–133.
5006
Org. Lett., Vol. 12, No. 21, 2010

from scaffolds 1 and 2 by means of a Suzuki-Miyaura
coupling reaction. These final compounds were then
evaluated by in vitro biological tests and exhibited highly
potent activity (nanomolar range) as R7 nicotinic ligands
with an excellent selectivity versus the R4ꢀ2 nicotinic
receptor. This synthesis opens an efficient general access
to (hetero)aromatic bridgehead substituted azabicyclo-
[2.2.1]heptane and -[3.3.1]nonane with the nitrogen atom
at the opposing bridgehead position.
Table 2. In Vitro Evaluation of Compounds 17a-g and 18a,h as
R7 Nicotinic Receptor Ligands and Selectivity vs the R4ꢀ2
Subtypea
R7 receptor
R4ꢀ2 receptor
compound
IC50 (nM) ( SD
IC50 (nM)
SSR180711
17a
30 ( 5
23
>10 000
n.d.
17b
37
4150
17c
17d
17e
17f
17g
18a
14
9
>10 000
>10 000
>10 000
n.d.
1960
n.d.
Acknowledgment. We wish to thank Annick Coste, Marie
Mattera, Xavier Vige´, and Olivier Bergis (Sanofi-Aventis
R&D Chilly-Mazarin, France) for biological evaluations and
Patrice Gervais, Soizic Chartrain, Marianne Gentric, Christe`le
Guibout, He´le`ne Olivan, and Isabelle Salliot-Maire from the
analytical department (Sanofi-Aventis R&D Chilly-Mazarin,
France) for precious support.
596 ( 19
1045 ( 146
5 ( 0.3
260
18h
21
n.d.
a SD: Standard deviation. The results with no SD were only performed
once but with SSR180711 as the internal reference drug compound
exhibiting reproducible values; n.d.: not determined; R7 ligands: in vitro
evaluation was performed on OFA male rat brain tissues in the presence of
[3H]-R-bungarotoxine at 1 nM concn; R4ꢀ2 ligands, in vitro evaluation was
performed on Sprague Dawley rat brain tissues in the presence of [3H]-
cytisine at 1 nM concn.
Supporting Information Available: Experimental pro-
cedures and structural characterization data for all compounds
prepared. This material is available free of charge via the
Internet at http://pubs.acs.org.
headsubstitutedazabicyclo[2.2.1]heptaneand-[3.3.1]nonane.
We were therefore able to generate a library of compounds
OL102170Q
Org. Lett., Vol. 12, No. 21, 2010
5007