Synthesis and SAR studies of 1,4-diazabicyclo[3.2.2]nonane phenyl carbamates - subtype selective, high affinity α7 nicotinic acetylcholine receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2009.06.059

The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-diazabicyclo[3.2.2]nonane phenyl carbamate series of α7 nAChR agonists is described. The development of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selective, high affinity α7 agonists as excellent leads for further evaluation is discussed, along with key physicochemical and pharmacokinetic data highlighting their lead potential.

Full text of DOI:10.1016/j.bmcl.2009.06.059

Bioorganic & Medicinal Chemistry Letters 19 (2009) 4747–4751
Contents lists available at ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Synthesis and SAR studies of 1,4-diazabicyclo[3.2.2]nonane phenyl carbamates
– subtype selective, high affinity
a7 nicotinic acetylcholine receptor agonists
*
Christopher J. O’Donnell , Langu Peng, Brian T. O’Neill, Eric P. Arnold, Robert J. Mather, Steven B. Sands,
Alka Shrikhande, Lorraine A. Lebel, Douglas K. Spracklin, Frank M. Nedza
Neuroscience Medicinal Chemistry, Pfizer Global Research & Development, Eastern Point Road, Groton, CT 06340, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and SAR studies about the bicyclic amine, carbamate linker and aromatic ring of a 1,4-
Received 30 April 2009
Revised 10 June 2009
Accepted 15 June 2009
Available online 17 June 2009
diazabicyclo[3.2.2]nonane phenyl carbamate series of
of the medicinal chemistry strategy and SAR which led to the identification of 5 and 7aa as subtype selec-
tive, high affinity 7 agonists as excellent leads for further evaluation is discussed, along with key phys-
icochemical and pharmacokinetic data highlighting their lead potential.
a7 nAChR agonists is described. The development
a
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Alpha 7
Nicotinic acetylcholine receptor
nAChR
SAR
1,4-Diazabicyclo[3.2.2]nonane phenyl
carbamate
Agonist
MeO
N
OMe
Homomeric
a7 nicotinic acetylcholine receptor (nAChR) ago-
O
N
nists have been implicated as potential treatments for a variety
of attention and cognitive disorders and could be used to treat
the cognitive impairment associated with schizophrenia.1,2 Inter-
H
N
N
N
O
PHA-543,613
est in
a7 nAChR agonists as a target has greatly expanded over
the past decade, with a focus on identifying new ligands with im-
proved selectivity over other nicotinic receptor subtypes.1d Most of
the ligands described in the primary literature have evolved
around the quinuclidine core structure and include quinuclidine
amides (PHA-543,613),3 spirooxazolidinones (AR-R17779),4 as
well as quinuclidine ethers5 and quinuclidine carbamates (1 and
2, respectively).6 However, despite the richness in chemical matter,
GTS-21
O
H
O
O
Ar
O
N
Ar
NH
N
N
N
O
AR-R17779
1
2
Quinuclidine
ethers
Quinuclidine
carbamates
there is still a need for novel a7 nAChR agonists as it has been re-
ported that two of Pfizer’s Phase I clinical candidates in the quinu-
clidine amide series (PHA-543,613 and PHA-568,487)7 were
discontinued due to cardiovascular findings.8
When we initiated efforts targeting novel
quinuclidine carbamate 3 was identified from our compound file
7 Ki = 167 nM, 90% agonist activity (ag), Fig. 1).9,10 In the interest
of identifying novel chemical matter we utilized the following de-
sign criteria: (a) reverse the orientation of the carbamate to give 4
then (b) incorporate the nitrogen of the carbamate of 4 into a bicy-
clic ring system. These two design concepts were greatly enabled
by our previous use of 1,4-diazabicyclo[3.2.2]nonane in a quino-
lone antibiotic program11 and thus allowed us to quickly identify
a7 nAChR ligands,
1,4-diazabicyclo[3.2.2]nonane-(4-bromo)-phenyl carbamate 5 (a7
(a
Ki = 38 nM, 158% ag) as a lead structure.12,13 Herein we describe
structure–activity relationship (SAR) studies about the diamine
template, the carbamate linker and the aromatic ring. The results
of these studies further elucidated the key aspects of the
pharmacophore and resulted in the identification of a selective,
high affinity 7 nAChR agonist 7aa with good pharmacokinetic
properties and low hERG liability as an excellent tool with which
to explore 7 pharmacology.
a7 nAChR
a
* Corresponding author. Tel.: +1 860 715 4118; fax: +1 860 686 5158.
E-mail address: christopher.j.odonnell@pfizer.com (C.J. O’Donnell).
a
0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2009.06.059

4748
C. J. O’Donnell et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4747–4751
H
O
H
O
N
N
O
O
NH
a,b
c,d,e
N
N
N
NH
N
N
O
O
O
4
Br
Br
10
11
3
~ 3 : 1
9
Br
Br
O
O
N
O
O
N
NBoc
N
f,g
f,g
N
N
5
(SR-180711)
12
14
Figure 1. Approach used to discover the 1,4-diazabicyclo[3.2.2]nonane carbamate
series.
O
Br
N
N
N
NBoc
O
The synthesis of 1,4-diazabicyclo[3.2.2]nonane carbamates is
shown in Scheme 1. 1,4-Diazabicyclo[3.2.2]nonane14 6 was reacted
with arylchloroformate in the presence of DMAP and pyridine to
produce the desired carbamates 7, typically in 60–70% yield. Many
commercially available arylchloroformates were utilized to inves-
tigate the SAR in this series. In the instances where they were
not available, the corresponding phenol was easily converted to
the chloroformate by treatment with phosgene or triphosgene un-
der standard reaction conditions. Expansion of the SAR in the para-
position of the aromatic ring was accomplished starting with the 4-
bromophenyl carbamate analog 5 and converting it to the pinaco-
lato boronic ester 8 under Miyaura conditions in 49–64% yield.15
The resulting aryl boronic ester could then be elaborated to biaryl
analogs (7o and s–u) using standard Suzuki coupling conditions
with the appropriate aryl bromide in 49–72% yield.16
Synthesis of two novel diazabicyclic analogs, 1,5-diazabicy-
clo[4.2.2]decane carbamate 14 and 1,4-diazabicyclo[4.2.2]decane
carbamate 15 are described in Scheme 2. 1-Aza-bicy-
clo[3.2.2]nonan-4-one17 9 was reacted with hydroxylamine and
the resulting mixture of oxime isomers underwent Beckman rear-
rangement upon treatment with sulfuric acid (20% oleum) to give
amides 10/11 in 53% yield over two steps, in ca. 3:1 ratio as deter-
mined by 13C NMR peak heights. The mixture of amides was re-
duced with lithium aluminum hydride resulting in a 2.5:1 ratio
as an inseparable mixture of bicyclic amines as determined by
GC/MS. At this point, the major isomer was assigned as the isomer
with nitrogen adjacent to the bridgehead.18 Protection of the crude
mixture of amines as their corresponding tert-butylcarbamates al-
lowed for separation of the isomers via chromatography to afford
12 in 50% isolated yield and 13 in 14% yield (both over two steps).
Removal of the Boc group using HCl in methanol followed by cou-
13
15
Scheme 2. Reagents and conditions: (a) NH2OHꢀHCl, Na2CO3, MeOH, 60 °C; (b)
H2SO4, 100 °C, 53% for 2 steps; (c) LiAlH4, THF, rt to ";; (d) Boc2O, NaOH, THF, H2O;
(e) chromatography, 50% 12, 14% 13 (2 steps); (f) 1 M HCl, MeOH; (g) 4-
bromophenyl chloroformate, DMAP, pyridine, CH2Cl2, 54% 14, 56% 15 (2 steps).
pling of the resulting corresponding diamine with 4-bromophenyl
chloroformate gave 14 and 15 in 54% and 56% yield, respectively,
over two steps.
Homopiperazine and piperazine analogs 17, and 21–23 were
prepared utilizing the same conditions as described to prepare car-
bamate analogs
7 (Scheme 3). Hence, 1-(4-bromophenyl)-4-
methyl-1,4-diazepane-1-carboxylate 17 was prepared in 82% yield
from methyl homopiperazine 16. Piperazine analogs 21–23 were
prepared from 18 to 20 in 57%, 20%, and 45% yield, respectively.
In vitro characterization data of the SAR studies about the bicy-
clic ring of 7 are described in Table 1. The modification of the bicy-
clic ring system from the 1,4-diazabicyclo[3.2.2]nonane system to
the 1,5-diazabicyclo[4.2.2]decane system resulted in a 10-fold loss
in a7 nAChR potency along with a substantial decrease in agonist
activity (5 vs 14). Replacing the 1,4-diazabicyclo[3.2.2]nonane sys-
tem with the 1,4-diazabicyclo[4.2.2]decane systems resulted in a
20-fold loss in potency (5 vs 15). Attempts to replace the 1,4-diaza-
bicyclo[3.2.2]nonane ring system with diazamonocyclic ring sys-
tems resulted in complete loss of
functional activity (5 vs 17 and 21–23). This SAR highlights the
a7 nAChR binding affinity and
importance of the direction of the nitrogen lone pair interaction
with the a7 nAChR, as well as the relative position of this nitrogen
lone pair to the aryl portion of the molecule in order to maintain
good potency and functional activity.19
O
R
Br
a
b
NH
O
N
O
N
N
NH
N
O
a
a
6
7
N
N
O
17
16
B
Ar
O
O
O
Br
c
O
N
O
N
O
N
N
O
R1
HN
R2
R1
HN
R2
NH
R3
N
R3
8
7o, Ar = Ph, 63%
7s, Ar = 2-Pyr, 60%
7t, Ar = 3-Pyr, 72%
7u, Ar = 4-Pyr, 49%
18, R1=Me, R2=H, R3=H
19, R1=Me, R2=Me, R3=H
20, R1=Me, R2=H, R3=Me
21, R1=Me, R2=H, R3=H
22, R1=Me, R2=Me, R3=H
23, R1=Me, R2=H, R3=Me
Scheme 1. Reagents and conditions: (a) aryl chloroformate, DMAP, pyridine,
CH2Cl2, 60–70% (b) R = 4-Br, bis(pinacolato)diboron, PdCl2(dppf)ꢀCH2Cl2, dppf,
KOAc, DMSO, 100 °C, 49–64% (c) ArBr, PdCl2(dppf)ꢀCH2Cl2, dppf, K3PO4, 1,4-dioxane,
H2O, 70 °C, 49–72%.
Scheme 3. Reagents and conditions: (a) 4-bromophenyl chloroformate, DMAP,
pyridine, CH2Cl2, 82% for 17, 57% for 21, 20% for 22, 45% for 23.

C. J. O’Donnell et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4747–4751
4749
loss of functional activity (7a vs 26).23 Modifying the phenyl carba-
mate to a benzyl carbamate resulted in a 4.5ꢁ loss in potency (7a
vs 27)24 and replacement of the carbamate linker with sulfonamide
Table 1
In vitro SAR studies of different ring systems
7 agonist activityb
a4b2 IC50 (nM)
c
Compound
a
7 Kia (nM)
a
resulted in complete loss of
a
7 nAChR affinity (28).25 These studies
7 nAChR pharmacophore in that
5
14
15
17
21
22
23
38
383
763
>5710
>5000
>5000
>5000
158%
27%
nd
10%
<0.1%
<0.1%
nd
>5000
reveal some key elements to the
a
>10,000
>10,000
>10,000
>10,000
>10,000
>10,000
the heteroatoms of the carbamate are ideally suited for both
a7
nAChR potency and functional activity.
The SAR studies of a variety of mono-substituted analogs about
the aromatic ring of the carbamate of 7 are described in Table 3.
Substitution at the para-position of the aromatic ring in general re-
sulted in the most functionally active compounds whereas substi-
tution at the meta-position of the aromatic ring resulted in
nd = not determined.
a
GH4C1 cells binding assay, [125I]-BTX, all values represent an average of a six
point dose–response curve run in triplicate.9
b
improved a7 nAChR potency with a concomitant loss of a7 nAChR
All test compounds were measured at 32 lM and are reported as a %control
versus nicotine response at 50 l
M.10
functional activity (e.g., 7b vs 7c, 7d vs 7e, 5 vs 7g, 7i vs 7j, 7k vs 7l,
7o vs 7p, 7q vs 7r). The only exception to this general trend was
observed when the substituent was –C(O)Ph (7m vs 7n) in that
both potency and functional activity were improved in 7n. Substi-
tution at the ortho-position of the aromatic ring resulted in loss of
c
Rat brain homogenate binding assay, [3H]-Nic, all values represent an average of
a six point dose–response curve run in triplicate.
The SAR studies about the carbamate linker of 7 are described in
Table 2. Replacing the carbamate linker with a urea linker resulted
in a 10-fold loss in potency (5 vs 24)21 and replacing the carbamate
a
7 nAChR potency when compared to the same substituent in
either the meta- or para-position (7f vs 7e or 7d and 7h vs 7g or
5). In most cases where the 7 Ki < 100 nM the selectivity over
the 4b2 nAChR was >50x (compounds 5, 7a–n, 7p–7r). The only
exception to this was observed with 7c where the selectivity over
the
4b2 nAChR was 30ꢁ. Interestingly, it appears as though meta-
substitution began to illicit 4b2 nAChR affinity (7e, 7g, and 7n).
linker with an amide resulted in a complete loss of
a7 nAChR affin-
a
ity (25).22 The carbonyl oxygen may be replaced by sulfur without
a
loss of a7 nAChR affinity; however this modification did result in a
a
Table 2
a
In vitro SAR studies about the carbamate linker
Additionally, when the para-position of the aromatic ring was
substituted with a phenyl ring (7o), modest potency, and good
functional activity were maintained. However, while this modifica-
N
N
tion resulted in good selectivity over the
a4b2 nAChR, it did result
in measurable
a
3b4 nAChR activity (IC50 = 3770 nM).26 Replacing
Compound
Substituent
a
7 Kia (nM)
a
7 agonist activityb
the 4-phenyl ring with pyridine heterocycles resulted in com-
pounds with modest potency and good functional activity; how-
ever this modification did not result in improved selectivity over
Br
Br
O
O
5
38
158%
nd
the
7u = 2640 nM).
The SAR trends in Table 3 revealed that meta-substituted phenyl
carbamate analogs were more potent at 7 nAChR then similarly
a3b4 nAChR (a3b4 IC50’s, 7s = 4630 nM, 7t = 3810 nM,
O
a
24
25
7a
26
27
28
328
substituted analogs at the para- or ortho-position, and para-substi-
tuted phenyl carbamate analogs had improved agonist activity over
similarly substituted analogs at the meta- or ortho-position. There-
fore we hypothesized that 3,4-disubstituted analogs would result in
more potent and functionally active analogs. The SAR trends re-
vealed that 3,4-disubstituted phenyl analogs were equipotent to
the 3-phenyl substituted analogs but had similar functional activity
to the 4-phenyl substituted analogs (Table 4). For example, the 4-
bromo-3-chlorophenylcarbamate analog 7v was equipotent to the
3-chlorophenylcarbamate analog 7e and displayed similar func-
tional activity as the 4-bromophenyl carbamate analog 5. Similarly,
7z was equipotent to 7n with similar functional activity to 5. All of
N
H
Br
O
>5000
739
1.7%
99%
28%
nd
O
O
the 3,4-disubstituted analogs displayed weak
a
4b2 and
a
3 nAChR
S
749
affinity; however, they were still >50ꢁ selective for the
a7 nAChR.
O
The naphthyl carbamate analog 7aa provided the best combined
attributes of compounds within this series.
O
O
Selected physicochemical properties, selectivity, ADME, and
pharmacokinetic data for compounds 5 and 7aa are highlighted
in Table 5. Both 5 and 7aa displayed excellent aqueous solubility,
good permeability, good/excellent in vitro metabolic stability and
high selectivity versus the 5-HT3 receptor.19 One differentiating
feature of the two compounds is highlighted by their affinity to
the hERG ion channel, with 5 displaying greater inhibitory activity
versus 7aa. Both compounds displayed excellent brain penetration
3350
>4720
O
O
S
nd
Br
and CSF concentrations well above their
compounds would serve as excellent lead structures to explore
in vivo
7 nAChR pharmacology.13
We have described the synthesis and detailed SAR of a ser-
ies of 1,4-diazabicyclo[3.2.2]nonane phenyl carbamates that are
a7 Ki. As such, both of the
nd = not determined.
a
GH4C1 cells binding assay, [125I]-BTX, all values represent an average of a six
point dose–response curve run in triplicate.9
a
b
All test compounds were measured at 32
lM and are reported as a %control
versus nicotine response at 50
l
M.10

4750
C. J. O’Donnell et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4747–4751
Table 3
In vitro SAR studies for compounds 5, 7a–u
R3
R2
O
N
O
N
R1
R1
R2
R3
a
7 Kia (nM)
a
7 agonist activityb
a4b2 IC50 (nM)
c
Compound
7a
7b
7c
7d
7e
7f
H
H
H
H
H
Cl
H
H
Br
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
F
H
Cl
H
H
Br
H
H
Me
H
OMe
H
C(O)Ph
H
Ph
H
OPh
H
H
H
H
F
H
Cl
H
H
Br
H
H
Me
H
OMe
H
C(O)Ph
H
Ph
H
OPh
H
2-Pyridyl
3-Pyridyl
4-Pyridyl
739
537
35
79
32
868
38
9.5
725
178
25
201
79
95
11
215
9
212
13
354
203
207
99%
100%
47%
145%
77%
nd
158%
70%
nd
202%
46%
126%
26%
35%
98%
111%
9%
241%
40%
174%
189%
191%
1040
1780
1065
>5000
3505
>5000
>5000
3935
>5000
>5000
>5000
>5000
>5000
>5000
2615
>5000
>10,000
5030
>10,000
>5000
>5000
>5000
5
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
7q
7r
7s
7t
7u
nd = not determined.
a
GH4C1 cells binding assay, [125I]-BTX, all values represent an average of a six point dose–response curve run in triplicate.9
b
c
All test compounds were measured at 32
lM and are reported as a %control versus nicotine response at 50 l
M.10
Rat brain homogenate binding assay, [3H]-Nic, all values represent an average of a six point dose–response curve run in triplicate.20
Table 4
In vitro
a
7 binding and functional activity and
a
4b2 and
a3b4 nAChR binding affinity for compounds 5, 7v–aa
R3
R2
O
N
O
N
R2
R3
a
7 Kia (nM)
a
7 agonist activityb
a
4b2 IC50 (nM)
a3 IC50 (nM)
c
d
Compound
5
H
Cl
Cl
Me
H
Cl
F
Br
Br
H
Br
Cl
Cl
Cl
H
36
33
32
50
79
31
86
11
16
158%
203%
77%
>5000
7120
3505
7220
>5000
4980
6980
2615
2040
>6480
2090
nd
4020
>5000
4750
9960
nd
7v
7e
7w
7d
7x
7y
7n
7z27
83%
146%
195%
110%
98%
C(O)Ph
C(O)Ph
Br
201%
1390
R3
7aa
23
175%
9880
4910
R2
nd = not determined.
a
GH4C1 cells binding assay, [125I]-BTX, all values represent an average of a six point dose–response curve run in triplicate.9
All test compounds were measured at 32 lM and are reported as a %control versus nicotine response at 50 l
M.10
b
c
Rat brain homogenate binding assay, [3H]-Nic, all values represent an average of a six point dose–response curve run in triplicate.20
IMR32 cells binding assay, [3H]-Epibatidine, all values represent an average of a six point dose–response curve run in triplicate.26
d
subtype selective, high affinity agonists of the
a
7 nAChR. Opti-
nAChR pharmacophore: the direction of the nitrogen lone pair;
the situating of the oxygen atoms of the carbamate functional
mization of the SAR resulted in the identification of 5 and 7aa,
which have excellent physical chemical properties and, as a re-
sult, display favorable in vitro and in vivo pharmacokinetic
properties. Additionally, compound 7aa was characterized by
having the potential for an improved cardiosafety profile due
to its low affinity for hERG. The data presented herein also
group for
a7 nAChR potency and functional activity; and the
simultaneous substitution at the meta- and para-position of
the aromatic ring being optimal for potency and functional
activity. These findings will prove useful in the discovery of
additional subtype selective compounds suitable for clinical
development.
serve to emphasize the many important elements of the
a7

C. J. O’Donnell et al. / Bioorg. Med. Chem. Lett. 19 (2009) 4747–4751
4751
Table 5
9. GH4C1 cells binding assay was performed as previously described with slight
modification (see Ref. 12): Quik, M.; Choremis, J.; Komourian, J.; Lukas, R. J.;
Puchacz, E. J. Neurochem. 1996, 67, 145. The data reported in the tables
represents the average of three six point dose–response curves that were run in
a single assay. Compound 5 was used as an internal standard in each assay and
had a Ki = 38.3 3.6 nM (n = 27).
Selected physicochemical properties, ADME, and pharmacokinetic data for 5 and 7aa
Br
O
O
10. Xenopus oocytes were harvested surgically and treated with collagenase
(1.3 mg/mL) for 3 h to remove the follicular layer. The oocytes were injected
with 10–50 ng of rat alpha7 neuronal nicotinic receptor cRNA and stored in
N
O
N
O
N
N
5
7aa
Barth’s saline for up to
2 weeks. Electrophysiological recordings were
performed 4–10 days later using two-electrode voltage clamp. The oocytes
were placed in the recording chamber and superfused with Ringer’s saline (in
mM: 115 NaCl, 2.5 KCl, 0.4 BaCl2, 0.1 CaCl2, 10 HEPES, pH 7.5) containing
agonists or antagonists. Electrodes are filled with 3 M KCl. Holding potential
(Vh) = ꢂ60 or ꢂ90 mV. Currents induced by the application of drugs were
digitized by a Data Translation a/d board and analyzed with AXODATA software.
Compound
5
7aa
MW
325.21
2.9
2.1
33
>65
296.37
3.1
2.3
33
>65
12/48
8%
>3160
12.0
61
5290
463
11.6
343
cLog P
Log Da
TPSA
Aq Solubility (
Caco-2 AB/BA
All test compounds were tested at 32
nicotine at 50 M. Data is reported as a % nicotine response with the nicotine
response defined as 100%. For comprehensive reference on the
lM and are compared to a test dose of
l
g/ml)
l
10/26
46%
a
hERG, %inh @ 10
l
Mb
characterization of nicotinic receptors in oocytes see: Chavez-Noriega, L. E.;
Crona, J. H.; Washburn, M. S.; Urrutia, A.; Elliott, K. J.; Johnson, E. C. J. Pharmacol.
Exp. Ther. 1997, 280, 346.
c
5-HT3 IC50 (nM)
>3160
<6.8
>105
5461
648
HLM Clintd (ml/min/kg)
T1/2 (min)
11. McGuirk, P. R.; Jefson, M. R.; Mann, D. D.; Elliott, N. C.; Chang, P.; Cisek, E. P.;
Cornell, C. P.; Gootz, T. D.; Haskell, S. L.; Hindahl, M. S.; LaFleur, L. J.; Rosenfeld,
M. J.; Shryock, T. R.; Silvia, A. M.; Weber, F. H. J. Med. Chem. 1992, 35, 611.
12. O’Donnell, C. J.; O’Neill, B. T. U.S.02/177591, 2002.
Braine (ng/g)
Plasmae (ng/ml)
Brain/plasma
CSFe (nM)
9.1
774
13. Concurrent to our work, scientists at Sanofi-Aventis also arrived at the same
compound (5, SR 180711) and have reported detailed in vitro and in vivo data
on this compound: (a) Gallet, T.; Jegham, S.; Lardenois, P.; Lochead, A.; Nedelec,
A. WO00/58311, 2000.; (b) Biton, B.; Bergis, O. E.; Galli, F.; Nedelec, A.; Lochead,
A. W.; Jegham, S.; Godet, D.; Lanneau, C.; Santamaria, R.; Chesney, F.;
Léonardon, J.; Granger, P.; Debono, M. W.; Bohme, G. A.; Sgard, F.; Besnard,
F.; Graham, D.; Coste, A.; Oblin, A.; Curet, O.; Vigé, X.; Voltz, C.; Rouquier, L.;
Souilhac, J.; Santucci, V.; Gueudet, C.; Francon, D.; Steinberg, R.; Griebel, G.;
Oury-Donat, F.; George, P.; Avenet, P.; Scatton, B. Neuropsychopharmacology
2007, 32, 1; (c) Pichat, P.; Bergis, O. E.; Terranova, J.-P.; Urani, A.; Duarte, C.;
Santucci, V.; Gueudet, C.; Volts, C.; Steinberg, R.; Stemmelin, J.; Oury-Donat, F.;
Avenet, P.; Griebel, G.; Scatton, B. Neuropsychopharmacology 2007, 32, 17; (d)
Barak, S.; Arad, M.; De Levie, A.; Black, M. D.; Griebel, G.; Weiner, I.
Neuropsychopharmacology 2009, 1.
a
Partition coefficient measured in 1-octanol/aqueous buffer @ pH 7.4.
b
The percent inhibition of binding of [3H]dofetilide to hERG stably expressed on
HEK293 cells.
c
HEK293 cells expressing h 5-HT3 binding assay, [3H]-LY278584, all values
represent an average of a six point dose–response curve run in triplicate.28
d
Determined using pooled liver microsomes in phosphate buffer @ pH 7.4 and
1
l
M substrate concentration, with sampling made at the 30 min time point.
Rat in vivo pharmacology: male Sprague-Dawley rats (n = 3) were treated with
e
5 mg/kg s.c. of test compound. Brain, Plasma, and CSF (cerebral spinal fluid) were
assessed at 1 h post dose.
14. (a) Mikhlina, E. E.; Rubtsov, M. V. Zh. Org. Khim. 1963, 33, 2167; (b) Rubtsov, M.
V.; Mikhlina, E. E.; Vorob’eva, V. Ya.; Yanina, A. D. Zh. Org. Khim. 1964, 34, 2222.
15. Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60, 7508.
16. For experimental details along with full characterization date see Ref. 12.
17. Mendoza, J. S.; Jagdmann, G. E.; Gosnell, P. A. Bioorg. Med. Chem. Lett. 1995, 5,
2211.
Acknowledgments
The authors thank Dr. Bruce N. Rogers, Dr. Christopher J. Helal,
Dr. Jacob B. Schwarz, and Dr. Amy B. Dounay for their helpful sug-
gestions in preparing this manuscript.
18. Characteristic NMR signals for the major isomer: 1H NMR, 3.37 ppm, 2H (N–
CH2); 13C NMR/DEPT experiments, 46.0 ppm (CH–N), 32.9 ppm (N–CH2–)
25.9 ppm (N–CH2CH2).
19. Horenstein, N. A.; Leonik, F. M.; Papke, R. L. Mol. Pharmacol. 2008, 74, 1496.
20. Rat brain homogenate binding assay was performed as previously described,
see: (a) Lippiello, P. M.; Fernandes, K. G. Mol. Pharmacol. 1986, 29, 448; (b)
Anderson, D. J.; Arneric, S. P. Eur. J. Pharm. 1994, 253, 261. The data reported in
the tables represents the average of three six point dose–response curves that
were run in a single assay. Nicotine was used as an internal standard in each
assay and had an IC50 = 1.65 0.47 nM (n = 12).
21. Compound 24 was prepared by reacting 1,4-diazabicyclo[3.2.2]nonane with 4-
bromophenylisocyanate in 14% yield.
22. Compound 25 was prepared by reacting 1,4-diazabicyclo[3.2.2]nonane with 2-
(4-bromophenyl)acetyl chloride in 41% yield.
23. Compound 26 was prepared by reacting 1,4-diazabicyclo[3.2.2]nonane with
phenylchlorothionocarbonate using the conditions to prepare 7 in 58% yield.
24. Compound 27 was prepared from benzylchloroformate using the conditions to
prepare 7 in 15% yield.
25. Compound 28 was prepared by reacting 1,4-diazabicyclo[3.2.2]nonane with 4-
bromophenylsulfonylchloride in 41% yield.
References and notes
1. (a) Lyon, E. R. Psychiat. Serv. 1999, 50, 1346; (b) Simosky, J. K.; Stevens, K. E.;
Freedman, R. Curr. Drug Targ.—CNS & Neurol. Dis. 2002, 1, 149; (c) Leonard, S.;
Gault, J.; Hopkins, J.; Logel, J.; Vianzon, R.; Short, M.; Drebing, C.; Berger, R.;
Venn, D.; Sirota, P.; Zerbe, G.; Olincy, A.; Ross, R. G.; Adler, L. E.; Freedman, R.
Arch. Gen. Psychiat. 2002, 59, 1085; (d) Lightfoot, A. P.; Kew, J. N. C.; Skidmore, J.
Prog. Med. Chem. 2008, 46, 131.
2. (a) Olincy, A.; Stevens, K. E. Biochem. Pharmacol. 2007, 74, 1192; (b) Levin, E. D.;
Simon, B. B. Psychopharmacology 1998, 138, 217.
3. Wishka, D. G.; Walker, D. P.; Yates, K. M.; Reitz, S. C.; Jia, S.; Myers, J. K.; Olson,
K. L.; Jacobsen, E. J.; Wolfe, M. L.; Groppi, V. E.; Hanchar, A. J.; Thornburgh, B. A.;
Cortes-Burgos, L. A.; Wong, E. H. F.; Staton, B. A.; Raub, T. J.; Higdon, N. R.; Wall,
T. M.; Hurst, R. S.; Walters, R. R.; Hoffmann, W. E.; Hajos, M.; Franklin, S.; Carey,
G.; Gold, L. H.; Cook, K. K.; Sands, S. B.; Zhao, S. X.; Soglia, J. R.; Kalgutkar, A. S.;
Arneric, S. P.; Rogers, B. N. J. Med. Chem. 2006, 49, 4425.
26. IMR32 cells binding assay was performed as previously described, see: (a)
Donnelly-Roberts, D. L.; Puttfarcken, P. S.; Kuntzweiler, T. A.; Briggs, C. A.;
Anderson, D. J.; Campbell, J. E.; Piattoni-Kaplan, M.; McKenna, D. G.; Wasicak, J.
T.; Holladay, M. W.; Williams, M.; Arneric, S. P. J. Pharmacol. Exp. Ther. 1998,
285, 777; (b) Sullivan, J. P.; Decker, M. W.; Brioni, J. D.; Donnelly-Roberts, D.;
Anderson, D. J.; Bannon, A. W.; Kang, C.-H.; Adams, P.; Piattoni-Kaplan, M.;
Buckley, M. J.; Gopalakrishnan, M.; Williams, M.; Arneric, S. P. J. Pharmacol. Exp.
Ther. 1994, 271, 624. The data reported in the tables represents the average of
three six point dose–response curves that were run in a single assay. 3-
Bromocytisine was used as an internal standard in each assay and had an
IC50 = 15.6 1.76 nM (n = 3).
4. Mullen, G.; Napier, J.; Balestra, M.; DeCory, T.; Hale, G.; Macor, J.; Mack, R.;
Loch, J., III; Wu, E.; Kover, A.; Verhoest, P.; Sampognaro, A.; Phillips, E.; Zhu, Y.;
Murray, R.; Griffith, R.; Blosser, J.; Gurley, D.; Machulskis, A.; Zongrone, J.;
Rosen, A.; Gordon, J. J. Med. Chem. 2000, 43, 4045–4050.
5. Tatsumi, R.; Seio, K.; Fujio, M.; Katayama, J.; Horikawa, T.; Hashimoto, K.;
Tanaka, H. Bioorg. Med. Chem. Lett. 2004, 14, 3781.
6. (a) Macor, J. E.; Wu, E. WO97/30998, 1997.; (b) Guendisch, D.; Andrae, M.;
Munoz, L.; Tilotta, M. C. Bioorg. Med. Chem. 2004, 12, 4953.
7. Walker, D. P.; Wishka, D. G.; Piotrowski, D. W.; Jia, S.; Reitz, S. C.; Yates, K. M.;
Myers, J. K.; Vetman, T. N.; Margolis, B. J.; Jacobsen, E. J.; Acker, B. A.; Groppi, V.
E.; Wolfe, M. L.; Thornburgh, B. A.; Tinholt, P. M.; Cortes-Burgos, L. A.; Walters,
R. R.; Hester, M. R.; Seest, E. P.; Dolak, L. A.; Han, F.; Olson, B. A.; Fitzgerald, L.;
Staton, B. A.; Raub, T. J.; Hajós, M.; Hoffmann, W. E.; Li, K. S.; Higdon, N. R.; Wall,
T. M.; Hurst, R. S.; Wong, E. H. F.; Rogers, B. N. Bioorg. Med. Chem. 2006, 14,
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8. Rogers, B. N. Agonists of alpha 7 nAChRs for the Potential Treatment of Cognitive
Deficits in Schizophrenia, Nicotinic Acetylcholine Receptors as Therapeutic Targets:
Emerging Frontiers in Basic Research and Clinical Sciences; San Diego, CA, Oct. 31-
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27. The chloroformate used to prepare 7z was prepared in three-steps from 2-
bromo-5-hydroxybenzaldehyde (Harmata, M.; Kahraman, M. J. Org. Chem.
1999, 64, 4949). 2-Bromo-5-hydroxybenzaldehyde was reacted with phenyl
magnesium
bromide
in
THF
at
rt
to
give
4-bromo-3-
(hydroxy(phenyl)methyl)phenol in 88% yield. Swern oxidation provided (2-
bromo-5-hydroxyphenyl)-(phenyl)methanone in 22% yield which was treated
with phosgene to give the desired chloroformate.
28. Wong, D. T.; Robertson, D. W.; Reid, L. R. Eur. J. Pharmacol. 1989, 166, 107.