Synthesis and biological investigation of potential atypical antipsychotics with a tropane core. Part 1

Article abstract of DOI:10.1016/j.ejmech.2011.07.022

The synthesis, structure, in vitro and in vivo pharmacological activities of 3β-acylamine derivatives of tropane (4a-n, 5a-g, 6a,b, 8a-c) are described. Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine receptors 5-HT_1A, 5-HT_2A, and D₂. The most interesting agent 6b revealed very high affinity for the 5-HT_2A and D₂ receptors and high affinity for the 5-HT_1A receptor. The in vivo head twitch model was used to demonstrate antagonism of the 5-HT_2A receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced locomotor activity in mice. Molecular docking studies using a homology model of the 5-HT_1A receptor revealed a significant role of the N-8 atom of the tropane core in stabilising the ligand-receptor complex due to strong hydrogen bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT_2A receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D₂ receptor, strong hydrogen bonding of the amide moiety in the 3β position of the tropane nucleus with Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of atypical antipsychotic agents.

Full text of DOI:10.1016/j.ejmech.2011.07.022

European Journal of Medicinal Chemistry 46 (2011) 4474e4488
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and biological investigation of potential atypical antipsychotics
with a tropane core. Part 1
a
a
a
a
b
ꢀ
Tomasz S1owinski , Jacek Stefanowicz , Maciej Dawidowski , Jerzy Kleps , Stanis1aw Czuczwar ,
Marta Andres-Mach c, Jarogniew J. quszczki b c, Gabriel Nowak d e, Katarzyna Stachowicz d,
,
,
Bernadeta Szewczyk , Anna S1awinska , Aleksander P. Mazurek g, Andrzej Mazurek h,
e
e
f,
ꢀ
g
i
a,
*
ꢀ
Franciszek Plucinski , Irena Wolska , Franciszek Herold
a Department of Drug Technology and Pharmaceutical Biotechnology, Medical University of Warsaw, Banacha 1, 02-097 Warsaw, Poland
b Department of Pathophysiology, Medical University, Jaczewskiego 8, 20-090 Lublin, Poland
c Department of Physiopathology, Institute of Agriculture Medicine, Jaczewskiego 2, 20-950 Lublin, Poland
d Institute of Pharmacology, Polish Academy of Science, Sme˛tna 12, 31-343 Kraków, Poland
e Chair of Pharmacobiology, Jagiellonian University, Collegium Medicum, Medyczna 9, 30-688 Kraków, Poland
f Medical University of Warsaw, Department of Drug Chemistry, Banacha 1, 02-097 Warsaw, Poland
g National Medicines Institute, Chełmska 30/34, 00-725 Warsaw, Poland
h Medical University of Warsaw, Faculty of Pharmacy, Banacha 1, 02-097 Warsaw, Poland
i
ꢀ
Department of Crystallography, Faculty of Chemistry, Adam Mickiewicz University, Grunwaldzka 6, 60-780 Poznan, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis, structure, in vitro and in vivo pharmacological activities of 3
tropane (4aen, 5aeg, 6a,b, 8aec) are described.
Among the investigated compounds, several displayed very high (in nM) affinity for the monoamine
receptors 5-HT1A, 5-HT2A, and D2.
b-acylamine derivatives of
Received 12 May 2011
Received in revised form
30 June 2011
Accepted 12 July 2011
Available online 22 July 2011
The most interesting agent 6b revealed very high affinity for the 5-HT2A and D2 receptors and high
affinity for the 5-HT1A receptor. The in vivo head twitch model was used to demonstrate antagonism of
the 5-HT2A receptor subtype by this compound. In another test, 6b caused hypothermia in mice, which
was not attenuated by WAY 100635. In the climbing test, the compound did not significantly modify
climbing behaviour following apomorphine administration. Moreover, 6b significantly reduced loco-
motor activity in mice.
Molecular docking studies using a homology model of the 5-HT1A receptor revealed a significant role
of the N-8 atom of the tropane core in stabilising the ligandereceptor complex due to strong hydrogen
bonding with Asp116 located in the TMH 3 helix. Analogically, in a homology model of the 5-HT2A
receptor, the N-8 atom formed a hydrogen bond with Gly369. In another homology model of the D2
Keywords:
Atypical antipsychotic drugs
3b-aminotropane derivatives
5-HT1A, 5-HT2A, and D2 receptor ligands
Docking studies
receptor, strong hydrogen bonding of the amide moiety in the 3b position of the tropane nucleus with
Asp85 was observed. Compound 6b displayed a favourable Meltzer index (1.21) which is a feature of
atypical antipsychotic agents.
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
Successful pharmacotherapy of schizophrenia began in 1952
with the introduction of chlorpromazine. Subsequently, other
Schizophrenia is a chronic, devastating mental illness accom-
panied by positive (delusions, hallucinations, hyperactivity, dis-
organised speech), negative (avolition, anhedonia, social isolation,
suicidality, etc.) and cognitive (attentional impairment, memory
deficits) symptoms [1,2].
medications such as haloperidol were developed. These thera-
peutics are called ‘typical antipsychotics’ (Fig. 1) [3,4].
Typical antipsychotic drugs act mainly by antagonising D2
receptors, which contributes to many side effects, such as extra-
pyramidal symptoms (EPS) and tardive dyskinesia. Moreover, this
generation of therapeutics is successful only in suppressing of the
positive symptoms, and further is ineffective in one-third of treated
patients [5e7].
* Corresponding author. Tel.: þ48 22 5720638; fax: þ48225720631.
E-mail address: franciszek.herold@wum.edu.pl (F. Herold).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.07.022

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4475
A breakthrough in the pharmacotherapy of schizophrenia was
achieved by the introduction of the second generation of antipsy-
chotic drugs (called ‘atypical antipsychotics’). The first of these
agents was clozapine, followed by a number of other therapeutics:
olanzapine, risperidone, zotepine, sertindole, quetiapine and
ziprasidone (Fig. 1). The therapeutic effects of these drugs were
attributed to their strong antagonistic activity to D2 and 5-HT2A
receptors. Meltzer and coworkers found that a member of this
group should reveal an ideal pKi 5-HT2A/D2 ratio of approximately
ꢀ1.12. Clozapine demonstrates a Meltzer index of 1.19, whereas
chlorpromazine has a Meltzer index of 1.02 [8,9].
A major advantage of atypical antipsychotics is their effective-
ness in suppressing negative and cognitive symptoms [10e14].
However, it has been proven in many studies that they cause
numerous side effects [15,16]. The abovementioned drug, cloza-
pine, can provoke agranulocytosis, whereas administration of
olanzapine can lead to hyperglycaemia and increased appetite [17].
Ziprasidone, risperidone and quetiapine elevate the risk of malig-
nant ventricular arrhythmia [16].
The serotoninergic system plays an important role in regulating
the function of the prefrontal cortex (PFC), including emotional
control, cognitive behaviour and working memory. The pyramidal
neurons of the PFC possess numerous serotoninergic receptors,
such as 5-HT1A and 5-HT2A [18]. Many relevant preclinical data
indicate that 5-HT1A receptors can constitute an important bio-
logical target for new, improved antipsychotic drugs. Furthermore,
postsynaptic agonism is an essential feature of the therapeutic
profiles of atypical antipsychotics and is vital for suppressing both
the negative and cognitive symptoms of schizophrenia [19e24].
In the search for a new generation of antipsychotic drugs,
further receptors, such as dopaminergic D3, D4 and serotoninergic
5-HT2C have been explored [25,26]. As an outcome, new third
generation atypical antipsychotics have emerged, namely arpipra-
zole and bifeprunox (Fig. 1). Their mechanism of action is a result of
their affinity to many different monoamine receptors. Hence, ari-
piprazol acts mainly by binding to D2 (as a partial agonist) and D3
dopaminergic receptors, with simultaneous activity towards
5-HT1A (agonist), 5-HT2A (antagonist) and 5-HT2B serotoninergic
receptors [11e14,19,27e31]. Bifeprunox is also a partial D2 and
5-HT1A agonist with low affinity for 5-HT2A and 5-HT1C receptors
[10,32,33].
The aim of this work was the synthesis of acyl derivatives in the
chemical group of 3b-aminotropane as potential ligands for 5-HT1A,
5-HT2A and D2 receptors. Their binding affinity is presented
together with the results of in vivo functional profiling. The
outcome of the in vivo and in vitro investigations along with
docking studies enabled us to identify the key structural features
responsible for the activity and receptor selectivity of these
compounds, thus leading to novel agents with the desired atypical
antipsychotic action.
2. Results and discussion
2.1. Chemistry
The synthesis of target compounds was accomplished according
to Schemes 1 and 2. The 8-azabicyclo[3.2.1]oct-3b-ylamines 3aec
Cl
required for synthesis of the final compounds were obtained in
several steps. The starting 8-azabicyclo[3.2.1]octan-3-one deriva-
tives 1aec were synthesized from the respective amines (benzyl-,
furfuryl- or tetrahydrofurfurylamine) via a modified Robinson
condensation [34,35]. Subsequently, the ketones 1aec were con-
verted to the corresponding oximes 2aec, which were then sub-
jected to stereoselective BouveaulteBlanc reduction to furnish the
N
N
Cl
F
N
S
OH
O
Chloropromazine
Haloperidol
desired 8-azabicyclo[3.2.1]oct-3b-ylamines 3aec. Intermediates
C H3
N
1a,b, 2a,b and 3a,b have not been previously described, whereas
the benzyl derivatives 1c, 2c and 3c were obtained using a protocol
from the literature [35].
C H3
N
N
N
The target novel compounds 4aen, 5aeg and 6a,b were
synthesized by acylation of 8-azabicyclo[3.2.1]oct-3b-ylamines
N
N
Cl
3aec via the mixed anhydride method. Compound 4l was obtained
for in vitro comparative investigations according to procedures
from the literature [36]. The N-8-pyridinylmethyl derivatives 8aec
were obtained from the known intermediate 6c, via debenzylation
to amide 7, which was then alkylated with the appropriate pyr-
idinylmethyl chlorides (Scheme 1) [37].
C H3
N
N
H
S
H
Clozapine
Olanzapine
The compounds 14a,b with 3
for comparison of their in vitro receptor binding affinity with the
corresponding 3 derivatives. Initially, 1a was subjected to reduc-
tive amination with ammonium formate in the presence of 10% Pd/
C, with the intent of obtaining the -amine 9a. However, the
a configuration were synthesized
Cl
N
b
Cl
N
O
N
H
O
a
reaction proceeded to tetrahydrofurylmethyl derivative 9b. An
alternative approach employed tropinone 10 as a starting material,
which was subjected to reductive amination via the method
Aripiprazole
described by Allegretti and coworkers [38]. The resulting 3a -amine
11 was acylated with the appropriate carboxylic acids to give 12a or
12b, which were demethylated at the N-8 position by the Olofson
reagent to furnish 13a and 13b, respectively. Finally, 13a,b were
N-alkylated with 2-chloromethylofuran to give 14a,b, respectively.
The structures of all novel intermediates and final compounds
were confirmed by IR and 1H NMR spectroscopy and elemental
analysis (C, H, N). Detailed characterisation data is provided in the
N
NH
O
O
N
Bifeprunox
Fig. 1.

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4476
R
COOH
O
R
R
R
CHO
N
N
N
N
a
b
c
H
N
+
NH2
+
R
Ar
NH2
CHO
O
NOH
COOH
H
3a-c
H
O
4a-n
1a-c
2a-c
5a-g
6a-c
OMe
OMe
OMe
OMe
MeO
OMe
OMe
MeO
OMe MeO
OMe
MeO
Ar=
;
R=
O
a
OMe
OMe
4a
4b
MeO
4c
4d
4e
4f
4g
MeO
Cl
O2N
Cl MeO
NH2
Cl
MeO
F
Cl
4j
4i
4h
4k
4l
4m
4n
OMe
MeO
MeO
MeO
NH2
Cl
;
Ar=
R=
O
b
Cl
F
5d
5g
5f
5e
5a
5b
5c
OMe
MeO
;
R=
Ar=
c
6a
6b
6c
R
H
N
N
R=
d
e
H
N
H
N
N
N
N
6c
OMe
OMe
8c
8b
8a
OMe
OMe
H
O
8a-c
H
O
7
Scheme 1.
b
-derivatives. Reagents: (a) NH2OH
ꢁ
HCl, EtOH; (b) Na/EtOH or Na/BuOH; (c) ArCOOH, ClCOOC2H5, TEA, DMF; (d) 10% Pd/C, H2, MeOH; (e) 2-,3- or 4-
pyridinylmethylchloride hydrochloride, K2CO3, KI, acetone.
N
O
H
N
a
O
N H 2
9a
O
1a
N
O
H
N H 2
9b
H3C
H
H3
C
H3
C
N
N
N
N
N
b
a
c
d
O
H
H
H
H
O
NH
O
NH
O
O
NH
NH2
10
Ar
14a,b
Ar
11
Ar
13a,b
12a,b
Ar =
OMe
MeO
MeO
Cl
14a
14b
Scheme 2.
a-derivatives. Reagents: (a) HCOONH4, 10% Pd/C, MeOH/H2O; (b) ArCOCl, CHCl3, TEA or ArCOOH, ClCOOC2H5, TEA, DMF; (c) (1) ClCOOCHClCH3, ClCH2CH2Cl, (2) MeOH;
(d) 2-chloromethylfuran, K2CO3, acetone.

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4477
Experimental Part. For in vivo and in vitro investigations, free bases
were converted into the corresponding water-soluble salts.
(Ki ¼ 103e507 nM), whereas the other compounds possessed weak
affinity (Ki > 1000 nM) for this receptor.
Analysing the influence of the substituents at the 3b position of
the tropane system in terms of 5-HT1A receptor binding affinity,
a substantial influence of the naphthyl moiety was observed. This
enhancing effect was greater for the 2-naphtyl (6b) compared to
the 1-naphtyl (6a) group. Furthermore, the presence of the
2-naphthyl moiety notably ameliorated the affinity for 5-HT2A
receptors (6b > 5g > 4n). The presence of this scaffold also affected
binding to D2 receptors, which was significant for compounds 6b
and 4n. The 2,3-dimethoxybenzoyl and 4-amino-5-chloro-2-
methoxybenzoyl substituents markedly influenced the affinity
towards 5-HT2A and D2 receptors, whereas the 2,3-
dimethoxybenzoyl group showed a greater affinity for D2 than
5-HT2A receptor binding (ligands 8a, 8b, 4b, 8c). The 4-amino-5-
chloro-2-methoxybenzoyl moiety in turn affected affinity towards
both receptors (4l and 5e).
2.2. Radioligand binding assays
As has been previously noted, ligands for the 5-HT1A, 5-HT2A and
D2 receptors seem to be of increasing therapeutic interest, and
compounds from different chemical groups have been extensively
studied in search for potentially new antipsychotics. In this work,
a
number of new derivatives of 3b-acylaminotropane were
designed, synthesized and subjected to in in vitro and in vivo
pharmacological testings (4aen, 5aeg, 6a,b, 8aec). In addition, two
3a-acylaminotropane derivatives (14a,b) were obtained and
investigated for comparative studies.
In the in vitro 5-HT1A receptor binding tests, high affinity
(Ki ¼ 304 nM) of the 2-naphthamide derivative 6b and moderate
affinity of the 1-naphthamide derivative 6a, (Ki ¼ 532 nM) was
confirmed, whereas the other compounds displayed weak binding
activities with Ki values of more than 1000 nM (Table 1). Ligands 6b,
5e, 5g, 4l and 4n revealed very high affinity towards the 5-HT2A
receptor, with Ki values ranging from 2.5 to 24 nM. Further deriv-
atives 5c, 4h, 6a and 5f displayed high binding activity to this
receptor (Ki ¼ 120e394 nM), whereas other compounds 4j, 4b and
8c revealed moderate to low affinities (Ki ¼ 500e1000 nM). Several
ligands (8a, 8b, 4l, 4b, 8c and 6b) demonstrated very high affinity
towards the D2 receptor with Ki values ranging from 9.3 to 82 nM.
Derivatives 5e, 4j, 4h and 4i displayed high binding activity
When the effect of the substituents at the N-8 position of the
tropane core on the affinity for D2 receptors was evaluated, it was
found that the substituents could be ranked in order of their
increasing
influence
as
follows: 3-
2-,
and
4-
pyridinylmethyl
>
furfuryl
>
benzyl > tetrahydrofurfuryl.
Furthermore, after analysing the substituent effect at N-8 on 5-HT2A
binding activity, the following order of amelioration was found:
benzyl
> tetrahydrofurfuryl > furfuryl > 2-, 3- and 4-
pyridinylmethyl.
The in vitro receptor binding studies indicated good affinity
towards all three investigated receptors (5-HT2A Ki ¼ 2.5 nM,
5-HT1A Ki ¼ 303 nM, D2 Ki ¼ 82 nM) only for compound 6b. This
observation is important for further structural modifications aim-
ing to develop new ligands with enhanced 5-HT1A binding activity.
The Meltzer index (pKi 5-HT2A/D2 ratio) for atypical antipsychotic
agents should value ꢀ1.12 [8,9]. This coefficient was estimated to be
1.17 for 5e, 1.34 for 5g and 1.21 for 6b.
Table 1
Binding affinities for dopamine D2 and serotonin 5-HT1A/5-HT2A receptors.
Ki (nM)
pKi ratio 5-HT2A/D2
D2
5-HT1A
6100
3000
19 000
9600
5-HT2A
6000
The 3a-acylaminotropane derivatives (14a,b) studied for their 5-
Compds
4a
b:
1000
26.3
652.5
1100
HT1A, 5-HT2A and D2 receptor affinity, in comparison with the 3
b
4b
4c
4d
744.5
analogues, were devoid of binding activity (Table 1).
1300
1100
7900
2.3. In vivo functional investigation
4e
4f
4g
68 800
13 200
52 200
57 300
4400
928.7
1100
174.9
1400
681.7
32 000
16.6
2300
24.1
2900
4300
2.3.1. Climbing behaviour in mice
4h
4i
4j
218.2
507.4
174.3
1.02
The evaluated substances were given at doses of 10 or 50 mg/
kg prior to the climbing test in mice. At the lower dose of 10 mg/
kg, the most effective substance for inhibiting climbing activity
was 4l, which proved effective at three time intervals (40, 50 and
60 min) following apomorphine (APO) administration. The second
active substance in this test was 4h showing an inhibitory action
upon the evaluated parameter only 120 min after the adminis-
tration of apomorphine. Substances 4b, 4j, 4n, 5e, 5g and 6b did
not significantly modify climbing behaviour throughout the total
observation period of 120 min. When given at 50 mg/kg, only the
effects of 4n and 6b did not reach statistical significance. Inter-
17 200
2100
4k
4l
4m
4n
5a
19 000
18.2
66 700
202.5
>100 000
16 000
2500
1.01
1.14
7100
2800
10 200
10 300
4600
3100
1100
120
5b
5c
>100 000
2400
5d
5e
12 400
103.3
10 100
5700
1100
6.2
394
12.3
393.8
2.5
1000
955.9
700
1.17
1.34
1.21
5f
5g
6a
4000
1200
2900
3100
3300
532
303.8
1400
3300
2500
estingly, 5e exhibited
a clear-cut inhibitory activity on the
6b
82.4
performance of mice in the climbing test at 30 and 40 min after
apomorphine injection. However, lethal effects were evident at
subsequent time intervals. The remaining substances 4b, 4h, 4j, 4l
and 5g produced significant inhibitory effects on climbing
behaviour, persisting up to 120 min following apomorphine
administration. Among the substances devoid of lethal activity,
substance 4b exhibited the shortest onset of action at 30 min after
apomorphine administration.
Climbing behaviour in mice has been documented to require both
D1 and D2 dopaminergic receptor activation, since selective agonists
of D1 or D2 receptors (SKF 38393 or quinpirole, respectively) failed to
produce this phenomenon when given alone. However,
8a
8b
8c
9.3
11.5
28.3
Compds
14a
14b
a:
>100 000
44 000
130
>100 000
>100 000
140
2500
7000
8.9
220
Clozapinea
Quetiapinea
Standards:
þButaclamol
Serotonin
1.17
0.99
180
230
0.5
2.6
Mianserine
5.0
a
Data from Ref. [39].

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4478
administration of either apomorphine (a mixed agonist) or a combi-
nation of selective agonists results in the induction of climbing
behaviour [40]. Consequently, the observed inhibition by some of the
evaluated substances on climbing behaviour in mice may have been
due to blockade of D2 dopaminergic receptors in vivo, which may be
inferred based on the results of the in vitro receptor studies.
effect on the hypothermia induced by compounds 4l (20 mg/kg), 4n
(20 mg/kg), 6b (5 mg/kg) (Table 4). At the same time, the decrease in
body temperature induced by 8-OH-DPAT (5 mg/kg) was completely
blocked by WAY 100635 (0.1 mg/kg) (Table 4). Compound 5e (20 mg/
kg) slightly decreased body temperature (Table 3) and enhanced
hypothermia induced by 8-OH-DPAT (5 mg/kg) in mice (Table 5).
Since the hypothermia induced by the examined compounds (4l, 4n
or 6b) was not attenuated by WAY 100635, this suggests that this
effect was not mediated through 5-HT1A somatodendritic receptors.
2.3.2. Head twitches in mice
The investigated compounds (4b, 4h, 4j, 4l, 4n, 5e, 5g and 6b)
administered i.p. at doses of 5, 10 and 20 mg/kg produced a signif-
icant, mostly dose-dependent decrease in the number of (ꢂ)-DOI-
induced head twitches in mice (Fig. 2):
2.3.4. Lower lip retraction in rats
Administration of 8-OH-DPAT induces lower lip retraction (LLR)
in rats, an effect connected with the stimulation of postsynaptic 5-
HT1A receptors [44,45]. LLR induced by 8-OH-DPAT is abolished by
5-HT1A receptor antagonists e.g., WAY 100635 or WAY 100135
[43,46]. Compounds 4l (10 and 20 mg/kg) and 6b (5, 10 and 20 mg/
kg) given alone did not evoke LLR in rats. Moreover, compounds 4n
(10 and 20 mg/kg) and 5e (10 and 20 mg/kg) given alone produced
weak and statistically non-significant LLR in rats, whereas 8-OH-
DPAT (1 mg/kg) induced 93% of the possible maximum effect. At the
same time, 4n (20 mg/kg) and 5e (10e20 mg/kg) inhibited LLR
induced by 8-OH-DPAT, showing the profile of a weak postsynaptic
5-HT1A receptor antagonist. In this model, WAY 100635 completely
abolished the effect of 8-OH-DPAT (Table 6).
4b by 33, 28 and 47%, respectively; F(3,36) ¼ 8.053, P < 0.0001
4j by 40, 40 and 45%, respectively; F(3,36) ¼ 10.16, P < 0.0001
4l by 68, 97 and 100%, respectively; F(3,36) ¼ 146.3, P < 0.0001
5e by 63 and 92%, respectively; F(3,34) ¼ 102.1, P < 0.0001
5g by 26, 63 and 73%, respectively; F(3,36) ¼ 29.55, P < 0.0001
6b by 81, 95 and 100%, respectively; F(3,36) ¼ 162.7, P < 0.0001
Compounds 4h (F(3,35) ¼ 0.2808,ns) and 4n (F(3,36) ¼ 4.855,
P < 0.01) were ineffective in this test (Table 2).
2.3.3. Body temperature in mice
Compounds 4l, 4n, 5e, 6b were tested in in vivo models commonly
used for evaluating functional 5-HT1A receptor activity. 8-OH-DPAT,
a 5-HT1A receptor agonist, induces hypothermia in mice, an effect
mediated through 5-HT1A somatodendritic receptors [41,42]. This
hypothermia is abolished by the 5-HT1A receptor antagonist WAY
100635 [43]. Compounds 4l, 4n, 6b, like 8-OH-DPAT, induced hypo-
thermia in mice (Table 3). WAY 100635 (0.1 mg/kg) did not have an
2.3.5. Locomotor activity in mice
Compound 4n and 6b significantly reduced locomotor activity
in mice (Table 4). The weak antidepressant-like effect demon-
strated in the forced swimming test by compounds 4n or 6b may
have been related to the reduction in locomotor activity induced by
these compounds (Table 7).
Fig. 2. Suppression of (ꢂ)-DOI (2.5 mg/kg)-induced head twitches by the investigated compounds 4b (A), 4h (B), 4j (C), 4l (D), 4h (E), 5e (F), 5g (G) and 6b (H) (5, 10 and 20 mg/kg)
given ip. in CD-1 mice. Values represent the number of head twitches (mean ꢂ SEM) during the 20 min test. Data presented are mean ꢂ SEM. *P<0.05, **P<0.01, ***P<0.0001 vs.
(ꢂ)-DOI-treated group.

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4479
Table 2
Climbing behaviour in mice.
Time
(min)
APO
(2.5 mg/kg)
APOþ4b
APOþ4h
APOþ4j
APOþ4l
APOþ4n
APOþ5e
APOþ5g
APOþ6b
(10 mg/kg)
(10 mg/kg)
(10 mg/kg)
(10 mg/kg)
(10 mg/kg)
(10 mg/kg)
(10 mg/kg)
(10 mg/kg)
10
20
30
40
50
60
120
8/8
8/8
8/8
7/8
8/8
8/8
7/8
7/8
8/8
4/8
5/8
6/8
6/8
7/8
7/8
7/8
8/8
5/8
6/8
4/8
3/8a
5/8
7/8
6/8
8/8
7/8
6/8
5/8
7/8
6/8
4/8
6/8
7/8
5/8
4/8
4/8
5/8
5/8
7/8
6/8
6/8
5/8
5/8
4/8
5/8
5/8
6/8
5/8
4/8
7/8
7/8
7/8
7/8
7/8
5/8
6/8
4/8
4/8
5/8
3/8a
2/8b
2/8b
5/8
Statistical analysis was performed using Fischer’s test with Yate’s correction for the control group treated with apomorphine (APO) at the appropriate time.
All investigated compounds were administered at a constant dose of 10 mg/kg 30 min before testing. APO was administered 10 min before testing.
a
P < 0.05.
P < 0.01.
b
2.3.6. Forced swimming test in mice
2.4.1. Docking to the 5-HT1A receptor
Compound 4n at a dose of 10 mg/kg (but not 20 mg/kg) reduced
the immobility time in the forced swim test by 9% (F(2,15) ¼ 5.804,
P < 0.05) (Fig. 3B). Compounds 4l (10 and 20 mg/kg) and 6b
(2.5 and 5 mg/kg) were ineffective in this test (Fig. 3A,C). 8-OH-
DPAT at doses of 1 mg/kg and 2 mg/kg reduced the immobility time
of mice by 45 and 57%, respectively (F(2,26) ¼ 52.94, P < 0.0001)
(data not shown).
Docking of ligands 4n, 5e, 6a and 6b to the 5-HT1A receptor
binding site revealed: (i) 6a located inside the receptor binding
pocket does not interact with its amino acid vicinity; (ii) on the
contrary, the protonated nitrogen atom N1 of the tropane ring of 6b
forms a strong hydrogen bond 1.744 Å in length with Asp116
located in the TMH3 helix (Fig. 4A). This interaction is commonly
considered to be crucial in the group of monoamine neurotrans-
mitter receptors; (iii) the protonated nitrogen atom N1 of the tro-
pane ring of 4n interacts via a hydrogen bond 2.633 Å in length
2.4. Molecular docking studies using models of the 5-HT1A, 5-HT2A
and D2 receptors
with Tyr390 and, additionally, there is a Ves interaction between
the naphthyl ring of the ligand and Val117 of the TMH3 receptor
helix; (iv), similarly, the protonated amine group of 5e forms
a hydrogen bond with Thr196 1.971 Å in length and the position of
5e inside the receptor binding pocket is additionally stabilised by
two Vecation (protonated N1 atom of the tropane ring) type
interactions with Phe361 and Tyr390 located in the TMH6 and
TMH7 receptor helices, respectively.
Four ligands 4n, 5e, 6a, 6b were docked to the binding sites of
the 5-HT1A, 5-HT2A and D2 receptor models [47]. The applied 3D
models of the 5-HT1A and 5-HT2A receptors were developed on the
basis of the X-ray structure of bovine rhodopsin and the homology
model of the D2 receptor was obtained by comparative modelling
using the crystal structure of the human b2-adrenergic receptor and
bovine rhodopsin as the templates [48,49]. The quite recently
reported X-ray structure of the human b2-adrenergic receptor
opens up new possibilities for modelling the correct structures of
dopamine receptors. Currently, the human b2-adrenergic receptor
is considered to be more homologous to dopamine receptors than
bovine rhodopsin [50].
2.4.2. Docking to the 5-HT2A receptor
Docking of ligands 4n, 5e, 6a and 6b to the 5-HT2A receptor-
binding pocket revealed that: (i) the protonated nitrogen atom N1
of the tropane ring of 6a is involved in a Vecation interaction with
Phe234. There are no hydrogen bonds; (ii) 6b forms a weak
hydrogen bond with Gly369 3.316 Å in length and the protonated
nitrogen atom N1 of the tropane ring takes part in a Vecation
Table 3
The effect of the tested compounds on body temperature in mice.
Treatment
Dose (mg/kg)
D
t ꢂ SEM (ꢃC)
Table 4
The effect of WAY 100635 on hypothermia induced by the tested compounds in
mice.
30 min
60 min
90 min
120 min
Vehicle
4l
e
ꢄ0.1 ꢂ 0.0
0.0 ꢂ 0.1 ꢄ0.0 ꢂ 0.0 ꢄ0.0 ꢂ 0.0
t ꢂ SEM (ꢃC)
5
ꢄ0.0 ꢂ 0.2 ꢄ0.3 ꢂ 0.2
0.1 ꢂ 0.1
0.1 ꢂ 0.1
Compound and dose (mg/kg)
D
10
20
e
ꢄ0.3 ꢂ 0.2 ꢄ0.2 ꢂ 0.1 ꢄ0.1 ꢂ 0.1 ꢄ0.1 ꢂ 0.1
ꢄ1.8 ꢂ 0.2b ꢄ1.0 ꢂ 0.2b ꢄ1.0 ꢂ 0.2b ꢄ0.9 ꢂ 0.2b
ꢄ0.0 ꢂ 0.1 ꢄ0.1 ꢂ 0.1 ꢄ0.0 ꢂ 0.0 ꢄ0.0 ꢂ 0.0
30 min
60 min
Vehicle
4n
Vehicle þ vehicle
ꢄ0.1 ꢂ 0.1
ꢄ1.7 ꢂ 0.1a
ꢄ1.3 ꢂ 0.3a
ꢄ0.1 ꢂ 0.1
ꢄ1.4 ꢂ 0.1a
ꢄ1.2 ꢂ 0.3a
ꢄ0.1 ꢂ 0.1
ꢄ1.5 ꢂ 0.2a
ꢄ1.3 ꢂ 0.4a
ꢄ0.1 ꢂ 0.1
ꢄ1.6 ꢂ 0.2a
ꢄ0.1 ꢂ 0.1b
ꢄ0.1 ꢂ 0.1
ꢄ0.9 ꢂ 0.2a
ꢄ0.8 ꢂ 0.2a
ꢄ0.1 ꢂ 0.1
ꢄ1.3 ꢂ 0.1a
ꢄ1.1 ꢂ 0.3a
ꢄ0.1 ꢂ 0.1
ꢄ0.9 ꢂ 0.2a
ꢄ0.9 ꢂ 0.4a
ꢄ0.1 ꢂ 0.1
ꢄ1.3 ꢂ 0.1a
ꢄ0.1 ꢂ 0.1b
5
20
e
ꢄ0.2 ꢂ 0.2
0.1 ꢂ 0.2
0.1 ꢂ 0.2
0.1 ꢂ 0.2
Vehicle þ 4l (20)
ꢄ1.3 ꢂ 0.3b ꢄ0.8 ꢂ 0.2b ꢄ0.4 ꢂ 0.2 ꢄ0.2 ꢂ 0.1
ꢄ0.0 ꢂ 0.1 ꢄ0.1 ꢂ 0.1 ꢄ0.0 ꢂ 0.0 ꢄ0.0 ꢂ 0.0
WAY 100635 (0.1) þ 4l (20)
Vehicle þ vehicle
Vehicle
5e
Vehicle þ 4n (20)
5
ꢄ0.1 ꢂ 0.0 ꢄ0.1 ꢂ 0.1
0.0 ꢂ 0.1
0.0 ꢂ 0.1
10
20
e
ꢄ0.2 ꢂ 0.1 ꢄ0.0 ꢂ 0.2 ꢄ0.1 ꢂ 0.2 ꢄ0.0 ꢂ 0.1
WAY 100635 (0.1) þ 4n (20)
Vehicle þ vehicle
ꢄ0.8 ꢂ 0.2a ꢄ0.3 ꢂ 0.1 ꢄ0.1 ꢂ 0.2 ꢄ0.1 ꢂ 0.2
Vehicle
6b
ꢄ0.1 ꢂ 0.0
ꢄ0.2 ꢂ 0.1
0.0 ꢂ 0.1 ꢄ0.0 ꢂ 0.0 ꢄ0.0 ꢂ 0.0
0.1 ꢂ 0.1 ꢄ0.1 ꢂ 0.1 ꢄ0.0 ꢂ 0.0
Vehicle þ 6b (5)
2.5
5
WAY 100635 (0.1) þ 6b (5)
Vehicle þ vehicle
ꢄ1.5 ꢂ 0.2a ꢄ0.9 ꢂ 0.3b ꢄ0.6 ꢂ 0.4a ꢄ0.5 ꢂ 0.3
Vehicle
8-OH-DPAT
WAY 100635 0.1
e
ꢄ0.0 ꢂ 0.1 ꢄ0.1 ꢂ 0.0 ꢄ0.1 ꢂ 0.1
0.2 ꢂ 0.1
Vehicle þ 8-OH-DPAT (5)
WAY 100635 (0.1)þ8-OH-DPAT(5)
5
ꢄ1.6 ꢂ 0.2b ꢄ1.3 ꢂ 0.1b ꢄ0.8 ꢂ 0.1b ꢄ0.5 ꢂ 0.1
0.1 ꢂ 0.1
0.1 ꢂ 0.1
0.1 ꢂ 0.1
0.1 ꢂ 0.1
WAY 100635 was administered (sc) 15 min before the investigated compounds,
n ¼ 7e8 mice per group. The test was performed 30 min after injection of the
tested compounds (ip). The absolute mean body temperatures were within
a range of 35.5 ꢂ 0.5ꢃC.
The tested compounds were administered (ip) 30 min before the test. 8-OH-DPAT
and WAY 100635 were injected subcutaneously (sc). The absolute mean body
temperatures were within a range of 35.5ꢂ0.5ꢃC; n¼6e8 mice per group.
a
a
P < 0.05.
P < 0.001 vs. respective vehicle þ vehicle group.
b
b
P < 0.001 vs. the respective vehicle.
P < 0.001 vs. respective vehicle þ compound group.

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4480
Table 5
The effect of compound 5e and WAY 100635 on 8-OH-DPAT (5 mg/kg)-induced hypothermia in mice.
Treatment and dose (mg/kg)
D
t ꢂ SEM (ꢃC)
15 min
30 min
45 min
60 min
Vehicle þ vehicle
ꢄ0.1 ꢂ 0.2
ꢄ1.6 ꢂ 0.2b
ꢄ2.9 ꢂ 0.4d
ꢄ0.1 ꢂ 0.2
ꢄ1.6 ꢂ 0.2b
ꢄ0.2 ꢂ 0.1d
ꢄ0.1 ꢂ 0.3
ꢄ1.6 ꢂ 0.1b
ꢄ2.9 ꢂ 0.3d
ꢄ0.1 ꢂ 0.3
ꢄ1.6 ꢂ 0.1b
ꢄ0.1 ꢂ 0.0d
ꢄ0.0 ꢂ 0.1
ꢄ1.0 ꢂ 0.2a
ꢄ1.6 ꢂ 0.2c
ꢄ0.0 ꢂ 0.1
ꢄ1.0 ꢂ 0.2a
ꢄ0.1 ꢂ 0.2d
ꢄ0.1 ꢂ 0.1
ꢄ0.5 ꢂ 0.1
ꢄ0.6 ꢂ 0.1
ꢄ0.1 ꢂ 0.1
ꢄ0.5 ꢂ 0.1
ꢄ0.1 ꢂ 0.2d
Vehicle þ 8-OH-DPAT
5e (20) þ 8-OH-DPAT
Vehicle þ vehicle
Vehicle þ 8-OH-DPAT (5)
WAY 100635(0.1)þ8-OH-DPAT
Compound 5e was administered (ip) 45 min, while WAY 100635 (sc) 15 min prior 8-OH-DPAT, n ¼ 6e8 mice per group. The absolute mean initial body temperatures were
within a range of 36.0 ꢂ 0.5ꢃC.
a
P < 0.01.
b
P < 0.001 vs. respective vehicle þ vehicle group.
c
P < 0.01.
d
P < 0.001 vs. respective vehicle þ 8-OH-DPAT.
interaction with Trp336 (Fig. 4B); (iii) energetic stabilisation of 4n
located inside the receptor binding site results solely from Ve
with the essential receptor residues for neurotransmitter activity at
the D2 receptor, i.e. Asp85.
s
(Phe234) and Vecation interactions (Phe234); (iv) the protonated
amine group of 5e forms a relatively strong hydrogen bond with
Ser159 2.088 Å in length and the protonated nitrogen atom N1 of
the tropane ring is involved in Vecation interactions with Phe234
and Trp151.
3. Conclusions
A number of new 3b-acylamine derivatives of tropane were
designed and synthesized. Analysis of theresults of invitroradioligand
binding assays allowed for determining the influence of the substit-
2.4.3. Docking to the dopamine D2 receptor
uents at C-3 and N-8 of the tropane core on the affinity for the 5-HT1A
,
Docking of ligands 4n, 5e, 6a and 6b to the D2 receptor binding
pocket showed that: (i) 6a gains its energetic stabilisation inside
the receptor binding pocket solely due to a hydrogen bond between
the amide group of the ligand molecule and Asp85 2.124 Å in
length; (ii) similarly, the amide group of 6b forms a strong
hydrogen bond with Asp85 1.902 Å in length and, additionally, its
position is energetically stabilised as a result of a Vecation inter-
action with Phe81 (Fig. 4C); (iii) 4n is only bound to Asp85 via
a relatively strong hydrogen bond 2.030 Å in length, (iv) exclusively,
the protonated amine group of 5e forms a hydrogen bond with
Ser238 1.975 Å in length.
The analysis of the docking results, obtained for the particular
ligands, leads to the conclusion that 4n and 6b may possess greater
psychotropic activity than the other studied compounds. This is the
direct result of the strength of their binding, especially via
hydrogen bonds with the 5-HT1A and D2 receptors. Therefore, 4n
and 6b are expected to demonstrate high affinity for the D2
receptor. Moreover, 4n and 6b form these strong hydrogen bonds
5-HT2A and D2 receptors. The substituents in both positions were
ranked in order of their increasing influence on receptor binding.
Of all the tested compounds, 6b displayed very high (in nM)
affinity for all three investigated receptors and an ideal Meltzer
index (pKi 5-HT2A/D2 ratio) of 1.21, characteristic of atypical anti-
psychotics. The in vivo functional profiling of 6b revealed its
antagonism of the 5-HT2A receptor in the head twitch test. The
compound induced hypothermia in mice, which was not attenu-
ated by WAY 100635 administration, which suggested absent
presynaptic agonism of the 5-HT1A receptor. Furthermore, when
tested for D2 antagonism in the climbing test, the compound did
not significantly affect the behaviour of mice.
Moleculardockingstudiesof6b to homology models of the 5-HT1A
,
5-HT2A and D2 receptors provided very valuable data. Docking of the
compound to the model of the 5-HT1A receptor revealed a significant
role of the protonated N-8 nitrogen atom of the tropane moiety in
stabilisingtheligandereceptor complex by forming a strong hydrogen
bond with Asp116 located in the TMH 3 helix. Further, molecular
docking of 6b to the 5-HT2A receptor showed hydrogen bonding of the
protonated N-8 nitrogen atom with the Gly369 residue. In the D2
receptor model, the amide moiety in the 3b position of the tropane
nucleus formed a strong hydrogen bond with Asp85.
The results of these in vitro and in vivo investigations, along with
the molecular docking studies on the 5-HT1A, 5-HT2A and D2
receptors, have provided a valuable basis for further structural
Table 6
Induction of lower lip retraction (LLR) by the tested compounds and WAY 100635 (A)
and their effect on the 8-OH-DPAT (1 mg/kg)-induced LLR (B) in rats.
Treatment
Dose (mg/kg)
Mean ꢂ LLR score
A
B
Vehicle
4n
e
0.1 ꢂ 0.1
0.1 ꢂ 0.2
0.6 ꢂ 0.2
0.2 ꢂ 0.1
0.1 ꢂ 0.1
0.3 ꢂ 0.2
0.5 ꢂ 0.2
0.1 ꢂ 0.1
0.2 ꢂ 0.2
0.1 ꢂ 0.1
0.0 ꢂ 0.0
2.9 ꢂ 0.0
2.7 ꢂ 0.2
2.0 ꢂ 0.2b
2.6 ꢂ 0.2
2.7 ꢂ 0.2
2.4 ꢂ 0.1a
2.4 ꢂ 0.2a
2.7 ꢂ 0.2
2.6 ꢂ 0.2
2.6 ꢂ 0.2
0.3 ꢂ 0.2b
Table 7
10
20
10
20
10
20
5
10
20
0.1
Effect of 4n and 6b on locomotor activity in mice.
4l
Treatment (mg/kg)
Locomotor activity
5e
6b
Number of crossings ꢂ S.E.M. during
6 min
30 min
Vehicle
4n (10)
6b (5)
554 ꢂ 46
1514 ꢂ 173
566 ꢂ 68a
233 ꢂ 41a
WAY 100635
15 ꢂ 6.4a
321 ꢂ 212a
F(2,27) ¼ 15.04
P < 0.001
F(2,27) ¼ 57.94
P < 0.001
The investigated compounds were administered 15 min before the test (A) or
45 min before 8-OH-DPAT. n ¼ 6.
a
P < 0.05.
Compounds were injected i.p. 30 min before the test.
b
a
P < 0.01 vs. vehicle (A) or vs. vehicle þ 8-OH-DPAT (B).
P < 0.01 vs. vehicle group, (n ¼ 10).

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4481
Fig. 3. Effects of compounds 4l (A), 4n (B) and 6b (C) in the forced swimming test in Albino Swiss mice. Each bar represents the mean ꢂ SEM of 9e10 mice. All compounds were
injected 30 min before the test. *P < 0.05 vs. respective vehicle group (Dunnett’s test).
design, particularly of N-8 substituents, in the search for novel
potentially antipsychotic agents with multireceptor affinity based
4.2.2. 8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]octan-3-
one (1b)
on the structure of 3
b
-aminotropane.
Yield 13.6 g (53.7%). Bp 105e115 ꢃC/1.3 Tr; Mp (hydrochloride)
187.0e189.0 ꢃC, dec.; Anal. Calcd for C12H19NO2 ꢁ HCl: C 58.65%, H
8.20%, N 5.70%; Found: C 58.64%, H 8.18%, N 5.71%; IR (KBr) cmꢄ1 n
4. Experimental section
4.1. Synthetic procedures
All reagents and solvents were purchased from commercial
sources. Column chromatography was carried out on a Merck Silica
gel 60A (63e200
mm). Melting points were determined on an
Electrothermal 9100 apparatus with open capillary tubes and were
uncorrected. The IR spectra were obtained on a Shimadzu FTIR-
8300 spectrometer. NMR spectra were recorded on a Bruker
Advance DMX 400 WB (400 MHz) or a Varian Inova 500 (500 MHz)
spectrometer. Chemical shifts (d) were expressed in parts per
million relative to tetramethylsilane used as the internal reference.
Elemental analyses (C, H, N) were performed on a PerkineElmer
CHNO/S 2400 analyser and were within ꢂ0.4% of theoretical values.
Intermediates 1c, 2c and 3c (Scheme 1) were obtained following
literature protocols [35]. Compounds 6c and 7 have been previously
described [37]. Synthesis of 11 was performed according to
a procedure from the literature [38].
4.2. General procedure for synthesis of ketones (1a,b)
2,5-dimethoxytetrahydrofuran (16.0 g, 0.12 mol) was hydro-
lysed with diluted aqueous hydrochloric acid (200 mL H2O þ 1 mL
concentrated HCl) at 50 ꢃC for 75 min. The solution was cooled and
acetonedicarboxylic acid (19.0 g, 0.13 mol) and furfurylamine
(11.7 g, 0.12 mol) (for 1a) or tetrahydrofurfurylamine (12.1 g,
0.12 mol) (for 1b) were added. The pH of the resulting mixture was
adjusted to w4 with a 20% aqueous solution of NaOH and kept at
this value for 4 h by the portionwise addition of concentrated HCl.
After 24 h, the mixture was alkalised with a 20% aqueous solution of
NaOH and extracted with ethyl acetate (3 ꢁ 75 mL). The combined
organic extracts were dried with magnesium sulphate, filtered, and
the solvent was evaporated in vacuo to give crude 1a or 1b as an
yellow oil. The oil was subjected to distillation (1b) or distillation
followed by crystallisation (1a).
4.2.1. 8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]octan-3-one (1a)
Yield: 14.0 g (56.3%). Bp 102e105 ꢃC/0.34 Tr; Mp 24.8e25.3 ꢃC
(petroleum ether/diethyl ether 20:1 (v/v); hydrochloride: 179.0 ꢃC,
dec.); Anal. Calcd for C12H15NO2 ꢁ HCl: C 59.63%, H 6.67%, N 5.79%;
Found: C 59.66%, H 6.70%, N 5.70%; IR (KBr) cmꢄ1 n: 1718 (C]O); 1H
NMR (400 MHz, CDCl3): d 7.41 (C13H, 1H, s), 6.35 (C12H, 1H, s), 6.26
(C11H, 1H, s), 3.74 (C9H, 2H, s), 3.55 (C1H, C5H, 2H, bs), 2.72 (C2H,
C4Heq, 2H, dd, 2J ¼ 16.0 Hz, 3J ¼ 3.0 Hz), 2.22 (C2H, C4Hax, 2H, d),
2.11 (C6H, C7Heq, 2H, m), 1.64 (C6H, C7Hax, 2H, m).
Fig. 4. 6b molecule inside the: (A) 5-HT1A, (B) 5-HT2A, (C) D2 binding pocket. The
important receptor residues are shown as stick models and labelled. Black dashed line
denotes a hydrogen bond.

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4482
1728 (C]O); 1H NMR (hydrochloride) (500 MHz, CD3OD):
(C10H,1H, bs),4.26e4.48(C1H, C5H, 2H, m),3.97(C9H(2),1H, m), 3.86
(C9H(1), 1H, m), 3.10e3.28 (C13H, 2H, m), 2.32e2.64 (C2Heq, C4Heq
C6Heq, C7Heq, 4H, m), 2.10e2.30 (C6Hax, C7Hax, 2H, m), 1.88e2.08
(C2Hax, C4Hax, C11H(2), C12H(2), 5H, m), 1.65 (C11H(1), 1H, m).
d
4.60
4.4.2. 8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-
ylamine (3b)
,
Yield: 5.3 g (79.4%). Bp 113e120 ꢃC/0.8 Tr; Mp (ditartarate mono-
hydrate) 158.7e160.0 ꢃC;Anal.Calcd forC12H22N2O ꢁ 2(COO)2 ꢁ H2O:
C 47.06%, H 6.91%, N 6.86%; Found: C 47.31%, H 6.86%, N 6.82%; IR
(ditartarate monohydrate, KBr) cmꢄ1 n 2970 (NHas), 2885 (NHsym); 1H
4.3. General procedure for synthesis of oximes (2a,b)
NMR (400 MHz, D2O): d 4.22 (C10H, 1H, m), 4.11 (C1H, C5H, 2H, bs),
3.74 (C13H, 2H, m), 3.64 (C3H, 1H, m), 3.03 (C9H, 1H, dd, 2J ¼ 13.5 Hz,
3Jcis ¼ 2.5 Hz), 2.94 (C9H, 1H, dd, 2J ¼ 13.0 Hz, 3Jtrans ¼ 10.0 Hz), 2.16
(C2H, C4Heq, C11H, 5H, m), 2.02 (C6H, C7Heq, C12H, 6H, m), 1.94 (C6H,
C7Hax, 2H, pt), 1.80 (C2H, C4Hax, 2H, m), 1,47 (C11H, 1H, m).
To the solution of ketone 1a or 1b (0.05 mol) in ethanol (30 mL),
a solution of hydroxylamine hydrochloride (6.9 g, 0.1 mol) in H2O
(45 mL) was added. Subsequently, NaHCO3 (8.4 g, 0.1 mol) was
added portionwise and the resulting mixture was heated under
reflux for 30 min and stirred at room temperature for 24 h. Next,
H2O (20 mL) was added and the mixture was extracted with CHCl3
(3 ꢁ 75 mL). The combined organic extracts were dried with
magnesium sulphate, filtered, and the solvent was evaporated in
vacuo to give crude 2a or 2b as an yellow oil.
4.5. General procedure for synthesis of b-amides (4aen, 5aeg and
6a,b,c)
A solution of aromatic acid (5 mmol), ethyl chloroformate
(0.5 mL, 5 mmol) and triethylamine (0.75 mL, 5 mmol) in anhy-
drous DMF (30 mL) was stirred for 30 min at 0 ꢃC. Subsequently,
a solution of amine 3a, 3b or 3c (5 mmol) in anhydrous DMF (5 mL)
was added dropwise. The cooling bath was removed and stirring
was continued for 24 h. The solvent was evaporated in vacuo and
the residue was dissolved in CH2Cl2 (30 mL). The solution was
washed with a 5% aqueous solution of Na2CO3, dried with magne-
sium sulphate, filtered, and the solvent was evaporated in vacuo.
The residue was recrystallised (for solid compounds), purified by
column chromatography or treated with the appropriate acid to
form crystalline salts (for oily compounds), as described below.
4.3.1. 8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]octan-3-one oxime (2a)
The oil was crystallised. Yield: 60.3 g (74.1%). Mp 91.4e92.1 ꢃC
(acetone/hexane 5:1 (v/v)); Anal. Calcd for C12H16N2O2: C 65.43%, H,
7.32%, N 12.72%; Found: C 65.40%, H 7.28%, N 12.74%; IR (KBr) cmꢄ1
n
3179 (OH), 1007 (NO); 1H NMR (400 MHz, CDCl3):
d 9.76 (OH, 1H,
bs), 7.38 (C13H, 1H, s), 6.32 (C12H, 1H, s), 6.25 (C11H, 1H, s), 3.65
(C9H, 2H, s), 3.40 (C1H, C5H, 2H, bs), 3.00 (C2Heq, 1H, d,
2J ¼ 16.0 Hz), 2.62 (C4Hax, 1H, d, 2J ¼ 14.0 Hz), 2.26 (C4Heq, 1H, d),
2.15 (C2Hax, 1H, d), 2.01 (C6H, C7Heq, 2H, bs), 1.60 (C7Hax, 1H, m),
1.52(C6Hax, 1H, m).
4.3.2. 8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]octan-3-
one oxime (2b)
4.5.1. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-2-
methoxybenzamide (4a)
Crude 2b was used in subsequent reactions without further
Yield: 0.99 g (58.2%). Mp 110.9e111.9 ꢃC (ethyl acetate/diiso-
propyl ether, 10:1 (v/v)); Anal. Calcd for C20H24N2O3: C 70.57%, H
7.11%, N 8.23%; Found: C 70.56%, H 6.80%, N 8.11%; IR (KBr) cmꢄ1 n
purification. Yield: 10.7
g
(95.2%). Mp (hydrochloride)
222.5e224.5 ꢃC dec.; Anal. Calcd for C12H20N2O2 ꢁ HCl: C 55.27%, H
8.12%, N 10.74%; Found: C 54.94%, H 8.36%, N 10.66%; IR (KBr) cmꢄ1
3375 (NH), 1647 (C]O); 1H NMR (400 MHz, DMSO): 8.19 (C60H,
d
n
d
3235 (OH), 999 (NO). 1H NMR (hydrochloride) (500 MHz, CD3OD):
4.45, 4.20 (C1H, C5H, 2H, m), 4.37 (C10H, 1H, m), 3.96 (C9H(2), 1H,
1H, dd, 3J ¼ 8.0 Hz, 4J ¼ 1.5 Hz), 7.72 (NH, 1H, d, 3J ¼ 8.0 Hz), 7.42
(C40H, 1H, m, 3J ¼ 8.0 Hz, 4J ¼ 1.5 Hz), 7.40 (C13H, 1H, ps), 7.06 (C50H,
1H, t, 3J ¼ 7.5 Hz), 6.94 (C30H, 1H, d, 3J ¼ 8.5 Hz), 6.32 (C12H, 1H, t),
6.20 (C11H, 1H, d), 4.41 (C3H, 1H, m), 3.90 (C16H, 3H, s), 3.52 (C9H,
2H, s), 3.31 (C1H, C5H, 2H, bs), 2.05 (C2H, C4Heq, 2H, m), 1.96 (C6H,
C7Heq, 2H, m), 1.80 (C6H, C7Hax, 2H, m), 1.65 (C2H, C4Hax, 2H, m);
m), 3.84 (C9H(1), 1H, m), 3.37 (C13H(2), 1H, m), 3.29 (C13H(1), 1H,
m), 3.11, 2.95 (C2Heq, C4Heq, 2H, m), 2.54 (C6Heq, C7Heq, 2H, m), 2.32
(C6Hax, C7Hax, 2H, m), 2.18.
4.4. General procedure for synthesis of
b-amines (3a,b)
13C NMR (100 MHz, DMSO): 164.5 (C15), 157.6 (C20), 142.4 (C13),
d
132.8 (C40), 132.4 (C60), 121.7 (C10), 121.4 (C50), 111.4 (C30), 110.2
(C12), 108.2 (C11), 59.3 (C1, C5), 56.0 (C16), 49.6 (C9), 41.4 (C3), 39.1
(C2, C4), 26.1 (C6, C7).
To a refluxing mixture of oxime 2a or 2b (0.032 mol) in absolute
ethanol (120 mL), Na metal (7.0 g, 0.3 mol) was added portionwise
followedbyfurtherrefluxingfor4h. Thesolutionwasthencooledand
H2O (150 mL) was carefully added. The mixture was acidified with
concentrated aqueous HCl, the ethanol was evaporated in vacuo and
the resulting solutionwas washed with diethyl ether (2 ꢁ 50 mL). The
aqueous phase was alkalised with a saturated aqueous solution of
NaOH and extracted with diethyl ether (3 ꢁ 50 mL). The combined
organic extracts were dried with magnesium sulphate, filtered, and
the solvent was evaporated in vacuo to give crude 3a or 3b as an
yellow oil. The oil was subjected to distillation.
4.5.2. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-2,3-
dimethoxybenzamide (4b)
Yield: 0.97 g (52.7%). Mp 107.2e108.4 ꢃC (hexane/ethanol, 7:3
(v/v); hydrochloride: 215.4e215.7 ꢃC); Anal. Calcd for C21H26N2O4:
C 68.09%, H 7.07%, N 7.56%; Found: C 68.10%, H ax7.23%; N 7.47%; IR
(KBr) cmꢄ1
d
n
3364 (NH), 1651 (C]O); 1H NMR (400 MHz, CDCl3):
3
7.85 (NH, 1H, d, J ¼ 8.0 Hz), 7.66 (C60H, 1H, dd, 3J ¼ 8.0 Hz,
4J ¼ 1.5 Hz), 7.40 (C13H, 1H, d, J ¼ 1.0 Hz), 7.13 (C50H, 1H, t,
3J ¼ 8.0 Hz), 7.02 (C40, 1H, dd, 3J ¼ 8.5 Hz, 4J ¼ 1.0 Hz), 6.32 (C12H,
1H, dd, 3J1 ¼3.0 Hz, 3J2 ¼ 2.0 Hz), 6.21 (C11H,1H, d, 3J ¼ 3.0 Hz), 4.40
(C3H, 1H, 3k, 3Jaxeax ¼ 11.5 Hz, 3Jaxeeq ¼ 5.5 Hz), 3.88 (C17H, 3H, s),
3.83 (C16H, 3H, s), 3.53 (C9H, 2H, s), 3.31 (C1H, C5H, 2H, bs), 2.06
(C6H, C7Heq, 2H, dd, 2J ¼ 9.5 Hz, 3J ¼ 5.0 Hz), 1.93 (C2H, C4Heq, 2H,
4d, 2J ¼ 12.0 Hz, 3J1 ¼ 5.5 Hz, 3J2 ¼ 3.0 Hz), 1.80 (C6H, C7Hax, 2H, m),
3
4.4.1. 8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3
b
-ylamine (3a)
Yield: 5.0
g
(76.2%). Bp (102e120 ꢃC/0.4 Tr); Mp
(hydrochloride) > 186.8 ꢃC, dec. (ditartarate: 176.5e177.7 ꢃC); Anal.
Calcd for C12H18N2O ꢁ 2 HCl ꢁ H2O: C 48.50%, H 6.78%, N 9.42%;
Found: C 48.80%, H 6.96%, N 9.39%; IR (ditartarate, KBr) cmꢄ1 n 3020
(NHas), 2859 (NHsym); 1H NMR (400 MHz, D2O):
d
7.61 (C13H, 1H, s),
1.66 (C2H, C4Hax, 2H, m); 13C NMR (100 MHz, CDCl3):
d 164.5 (C15),
6.69 (C11H, 1H, s), 6.51 (C12H, 1H, s), 4.28 (C9H, 2H, s), 4.11 (C1H,
153.1 (C10), 152.7 (C30), 147.6 (C20), 142.3 (C13), 127.1 (C10), 124.6
(C50), 122.6 (C60), 115.3 (C40), 110.2 (C12), 108.2 (C11), 61.3 (C16),
59.2 (C1, C5), 56.2 (C17), 49.3 (C9), 41.3 (C3), 38.8 (C2, C4), 26.2 (C6,
C7). The C3H proton is axial. (see Section 4.16).
3
3
C5H, 2H, bs), 3.77 (C3H, 1H, m, Jaxeax ¼ 12.0 Hz, Jaxeeq ¼ 6.0 Hz),
2.42 (C2H, C4Heq, 2H, m), 2.28 (C6H, C7Heq, 2H, pd), 2.10 (C2H,
C4Hax, 2H, pd), 2.01 (C6H, C7Hax, 2H, m).

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4483
4.5.3. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3
b
-yl)-2,4-
6.12%, N 7.49%; IR (KBR) cmꢄ1
n
3379 (NH), 1666 (C]O). 1H NMR
dimethoxybenzamide (4c)
(400 MHz, CDCl3):
d
8.07 (C60H, 1H, d, 4J ¼ 2.8), 7.60 (NH, 1H, d,
Yield: 0.90 g (48.6%). Mp 131.9e132.6 ꢃC (ethanol); Anal. Calcd for
C21H26N2O4: C 68.09%, H 7.07%, N 7.56%; Found: C 67.98%, H 6.95%, N
7.46%; IR (KBr) cmꢄ1 n 3387 (NH), 1635 (C]O); 1H NMR (400 MHz,
3J ¼ 8.0 Hz), 7.33 (C13H, 1H, bs), 7.28 (C40H, 1H, dd, 3J ¼ 8.8 Hz,
4J ¼ 2.8 Hz), 6.81 (C30H, 1H, d, 3J ¼ 8.8 Hz), 6.76 (C12H, 1H, d,
3J ¼ 1.5 Hz), 6.15 (C11H, 1H, t, 3J ¼ 3.0 Hz), 4.31 (C3H, 1H, 3k,
3Jaxeax ¼ 11.0 Hz, 3Jaxeeq ¼ 5.5 Hz), 3.83 (C16H, 3H, s), 3.45 (C9H, 2H,
s), 3.25 (C1H, C5H, 2H, bs), 1.99 (C6H, C7Heq, 2H, dd), 1.88 (C2H,
C4Heq, 2H, 4d, 2J ¼ 13.0 Hz), 1.75 (C6H, C7Hax, 2H, m), 1.59 (C2H,
CDCl3):
d
8.15 (C60H, 1H, d, 3J ¼ 9.0 Hz), 7.60 (NH, 1H, d, 3J ¼ 8.0 Hz),
7.40 (C13H, 1H, d), 6.58 (C50H, 1H, dd, 3J ¼ 9.0 Hz, 4J ¼ 2.5 Hz), 6.45
(C30H,1H, d, 4J ¼ 2.5 Hz), 6.32 (C12H,1H, pt), 6.20 (C11H,1H, m), 4.40
(C3H,1H, m), 3.87 (C16H, 3H, s), 3.83 (C17H, 3H, s), 3.52 (C9H, 2H, s),
C4Hax, 2H, m); 13C NMR (100 MHz, CDCl3): 162.8 (C15),155.7 (C20),
d
3.31 (C1H, C5H, 2H, bs), 2.05 (C2H, C4Heq, 2H, m), 1.94 (C6H, C7Heq
2H, m), 1.80 (C6H, C7Hax, 2H, m), 1.64 (C2H, C4Hax, 2H, m).
,
152.7 (C10), 141.9 (C13), 131.9 (C40), 131.6 (C60), 126.3 (C50), 122.8
(C10), 112.6 (C30), 109.8 (C12), 107.9 (C11), 58.8 (C1, C5), 56.0 (C16),
49.1 (C9), 41.2 (C3), 38.6 (C2, C4), 25.8 (C6, C7). The C3H proton is
axial (see Section 4.16).
4.5.4. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-2,5-
dimethoxybenzamide 4-toluenosulfonate (4d)
Yield: 1.33 g (47.5%). Mp 176.9e177.8 ꢃC (ethanol); Anal. Calcd
4.5.9. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-5-
for C28H34N2O7S: C 59.98%, H 6.47%, N 5.00%; Found: C 60.18%, H
fluoro-2-methoxybenzamide (4i)
6.19%, N 4.84%; IR (KBr) cmꢄ1
n
3306 (NH), 1627 (C]O); 1H NMR
Yield: 0.70 g (39.1%). Mp 116.4e117.8 ꢃC (diisopropyl ether/
ethyl acetate, 1:1 (v/v); hydrochloride: 235.8e237.9 ꢃC, dec.); Anal.
Calcd for C20H23N2O3F: C 67.02%, H 6.47%, N 7.82%; Found: C
(400 MHz, CD3OD):
d
7.70 (C20H, C80H, 2H, d, 3J ¼ 8.0 Hz), 7.66 (C60,
1H, bs), 7.43 (C13H, 1H, ps), 7.22 (C30H, C50H, 2H, d), 7.06 (C30H, C4;
H, 2H, bs), 6.75 (C11H, 1H, pd), 6.52 (C12H, 1H, pt), 4.46 (C3H, 1H,
m), 4.32 (C9H, 2H, s), 4.00 (C1H, C5H, 2H, bs), 3.88 (C16H, 3H, s),
3.77 (C17H, 3H, s), 2.43 (C2H, C4Heq, 2H, m), 2.35 (C18H, 3H, s), 2.21
(C6H, C7Hax, C6H, C7Heq 4H, pd), 2.01 (C2H, C4Hax, 2H, m).
67.03%, H 6.41%, N 7.89%; IR (KBr) cmꢄ1
n 3371 (NH), 1643 (C]O);
1H NMR (400 MHz, CDCl3):
d
7.87 (C60H, 1H, dd, JHeF ¼ 9.0 Hz,
3
4J ¼ 3.0 Hz), 7.74 (NH, 1H, d, 3J ¼ 8.0 Hz), 7.38 (C13H, 1H, m), 7.08
(C40H, 1H, m), 6.87 (C30H, 1H, dd, 3J ¼ 9.0 Hz, JHeF ¼ 4.0 Hz), 6.30
4
(C11H, 1H, m), 6.18 (C12H, 1H, m), 4.36 (C3H, 1H, m), 3.86 (C16H,
4.5.5. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3
b-yl)-3,4-
3H, s), 3.50 (C9H, 2H, s), 3.29 (C1H, C5H, 2H, d), 2.03 (C2H, C4Heq,
dimethoxybenzamide (4e)
2H, m), 1.92 (C6H, C7Heq, 2H, m), 1.77 (C6H, C7Hax, 2H, m), 1.63
(C2H, C4Hax, 2H, m).
Yield: 0.62 g (33.5%). Mp 161.7e163.5 ꢃC (hexane/ethanol,1:1 (v/
v)); Anal. Calcd for C21H26N2O4: C 68.09%, H 7.07%, N 7.56%; Found:
C 68.08%, H 7.16%, N 7.56%; IR (KBR) cmꢄ1 n 3388 (NH), 1624 (C]O);
4.5.10. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-4-
1H NMR (400 MHz, CDCl3):
d
7.39 (C13H, 1H, ps), 7.37 (C20H, 1H, s),
chloro-2-methoxybenzamide (4j)
7.20 (C60H, 1H, d), 6.84 (C50H, 1H, d, 3J ¼ 8.0 Hz), 6.32 (C12H, 1H, ps),
6.20 (C11H, 1H, ps), 5.94 (NH, 1H, d, 3J ¼ 8.0 Hz), 4.36 (C3H, 1H, m),
3.91 (C16H, C17H, 6H, s), 3.54 (C9H, 2H, s), 3.31 (C1H, C5H, 2H, ps),
Yield: 0.56 g (59.9%). Mp 106.6e107.8 ꢃC (diisopropyl ether);
Anal. Calcd for C20H23N2O3Cl: C 64.08%, H 6.18%, N 7.47%; Found: C
63.95%, H 6.30%, N 7.55%; IR (KBr) cmꢄ1 n 3387 (NH), 1647 (C]O);
2.05 (C2H, C4Heq, 2H, m),1.92 (C6H, C7Heq, 2H, m), 1.78 (C6H, C7Hax
2H, pq), 1.65 (C2H, C4Hax, 2H, pt).
,
1H NMR (400 MHz, CDCl3):
d
8.12 (C60H, 1H, d, 3J ¼ 8.5 Hz), 7.57 (NH,
1H, d, 3J ¼ 8.0 Hz), 7.40 (C13H,1H, m), 7.05 (C50H, 1H, dd, 3J ¼ 8.5 Hz,
4J ¼ 1.5 Hz), 6.94 (C30H, 1H, ps), 6.32 (C11H, 1H, pt), 6.20 (C12H, 1H,
pd), 4.38 (C3H, 1H, m), 3.91 (C16H, 3H, s), 3.52 (C9H, 2H, s), 3.31
(C1H, C5H, 2H, ps), 2.06 (C2H, C4Heq, 2H, m), 1.95 (C6H, C7Heq, 2H,
m), 1.80 (C6H, C7Hax, 2H, m), 1.64 (C2H, C4Hax, 2H, m); 13C NMR
4.5.6. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-3,5-
dimethoxybenzamide (4f)
Yield: 0.82 g (44.3%. Mp 200.5e203.4 ꢃC (diisopropyl ether/
ethanol, 5:1 (v/v)); Anal. Calcd for C21H26N2O4: C 68.09%, H 7.07%, N
(100 MHz, CDCl3): d
163.7 (C15),158.0 (C20),153.1 (C10),142.4 (C13),
7.56%; Found: C 67.92%, H 7.29%, N 7.63%; IR (KBR) cmꢄ1
n
3267
138.4 (C40), 133.7 (C60), 121.8 (C50), 120.4 (C10), 112.2 (C30), 110.2
(C12), 108.3 (C11), 59.3 (C1, C5), 56.4 (C16), 49.6 (C9), 41.6 (C3), 39.1
(C2, C4), 26.2 (C6, C7).
(NH), 1632 (C]O); 1H NMR (400 MHz, CDCl3):
d 7.39 (C13H, 1H, ps),
6.82 (C20H, C60H, 2H, d, 4J ¼ 2.0 Hz), 6.56 (C40H, 1H, t), 6.32 (C12H,
1H, pt), 6.20 (C11H, 1H, pd), 5.83 (NH, 1H, d, 3J ¼ 8.0 Hz), 4.33 (C3H,
1H, m), 3.81 (C16H, C17H, 6H, s), 3.54 (C9H, 2H, m), 3.32 (C1H, C5H,
2H, ps), 2.06 (C2H, C4Heq, 2H, m), 1.94 (C6H, C7Heq, 2H, m), 1.78
(C6H, C7Hax, 2H, pq), 1.63 (C2H, C4Hax, 2H, pt).
4.5.11. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-4-
chloro-2-nitrobenzamide (4k)
Yield: 0.42 g (21.5%) after column chromatography (CHCl3/
CH3OH 9:1, (v/v)); Mp 145.7e146.7 ꢃC; Anal. Calcd for
C19H20N3O4Cl: C 58.54%, H 5.17%, N 10.78%, Found: C 58.64%, H
4.5.7. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-3,4,5-
trimethoxybenzamide (4g)
5.18%, N 10.63%; IR (KBr) cmꢄ1
n
3229 (NH), 1632 (C]O); 1H NMR
4
Yield: 1.01 g (50.4%). Mp 198.5e201.6 ꢃC (diisopropyl ether/
(400 MHz, CDCl34):
d
8.01 (C30H, 1H, d, J ¼ 1.5 Hz), 7.61 (C50H, 1H,
ethanol, 5:1 (v/v)); Anal. Calcd for C22H28N2O5: C 65.98%, H 7.05%, N
dd, 3J ¼ 8.0 Hz, J ¼ 1.5 Hz), 7.40 (C60H, 1H, d, 3J ¼ 8.0 Hz), 7.38
(C13H, 1H, d, 3J ¼ 1.0 Hz), 6.32 (C12H, 1H, t, 3J ¼ 2.0 Hz), 6.19 (C11H,
1H, d, 3J ¼ 3.0 Hz), 4.29 (C3H, 1H, m), 3.71 (NH, 1H, d, 3J ¼ 8.5 Hz),
3.52 (C9H, 2H, s), 3.31 (C1H, C5H, 2H, ps), 2.07 (C2H, C4Heq, 2H, m),
1.96 (C6H, C7Heq, 2H, m), 1.77 (C6H, C7Hax, 2H, pq), 1.64 (C2H,
C4Hax, 2H, pt).
6.99%; Found: C 65.85%, H 6.90%, N 7.11%; IR (KBR) cmꢄ1
n
3263
(NH), 1628 (C]O); 1H NMR (400 MHz, CDCl3):
d 7.39 (C13H, 1H, d),
6.92 (C30H, C60H, 2H, s), 6.32 (C12H, 1H, dd), 6.20 (C11H, 1H, d), 5.84
(NH, 1H, d, 3J ¼ 8.5 Hz), 4.35 (C3H, 1H, m), 3.88 (C16H, C18H, 6H, s),
3.87 (C17H, 3H, s), 3.53 (C9H, 2H, s), 3.32 (C1H, C5H, 2H, ps), 2.07
(C2H, C4Heq, 2H, m), 1.96 (C6H, C7Heq, 2H, m), 1.79 (C6H, C7Hax, 2H,
pq), 1.68 (C2H, C4Hax, 2H, pt).
4.5.12. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-4-
amino-5-chloro-2-methoxy–benzamide (4l)
4.5.8. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3
b-yl)-5-
Yield: 1.01 g (51.8%). Mp 218.6e220.3 ꢃC (ethanol); Anal. Calcd
chloro-2-methoxybenzamide (4h)
for C20H24N3O3Cl: C 61.61%, H 6.20%, N 10.78%; Found: C 62.01%,
Yield: 1.25 g (66.7%). Mp 127.5e128.5 ꢃC (diisopropyl ether/ethyl
acetate, 1:1 (v/v); hydrochloride: 225.8e227.8 ꢃC, dec.); Anal. Calcd
for C20H23N2O3Cl: C 64.08%, H 6.18%, N 7.47%; Found: C 63.96%, H
H 6.11%, N 10.91%; IR (KBr) cmꢄ1
n 3382 (NH), 1633 (C]O), 1082
(AreCl); 1H NMR (400 MHz, CDCl3):
d
8.07 (C60H, 1H, s), 7.51
(NH, 1H, d, 3J ¼ 8.0 Hz), 7.39 (C13H, 1H, ps), 6.32 (C11H, 1H, ps),

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4484
6.26 (C30H, 1H, s), 6.20 (C12H, 1H, pd), 4.44 (NH2, 2H, s), 4.38
(C3H, 1H, m), 3.81 (C16H, 3H, s), 3.51 (C9H, 2H, s), 3.29 (C1H,
C5H, 2H, ps), 2.04 (C2H, C4Heq, C6H, C7Heq, 4H, m), 1.78 (C6H,
C7Hax, 2H, pq), 1.60 (C2H, C4Hax, 2H, pt); 13C NMR (100 MHz,
4.5.17. N-(8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]oct-
3b
-yl)-5-chloro-2-methoxybenzamide (5c)
Yield: 1.31 g (69.3%). Mp 101.7e102.0 ꢃC (diisopropyl ether);
Anal. Calcd for C20H27N2O3Cl: C 63.40%, H 7.18%, N 7.39%; Found: C
CDCl3):
d
163.9 (C15), 157.6 (C20), 153.2 (C10), 146.8 (C40), 142.4
63.51%, H 7.17%, N 7.41%; IR (KBr) cmꢄ1 n 3386 (NH),1647 (C]O); 1H
(C13), 133.3 (C60), 112.8 (C50), 111.8 (C10), 110.2 (C11), 108.2 (C12),
98.0 (C30), 59.4 (C1, C5), 56.2 (C16), 49.6 (C9), 41.4 (C3), 39.2 (C2,
C4), 26.2 (C6, C7).
NMR (400 MHz, CDCl3):
d
8.13 (C60H, 1H, d, 4J ¼ 3.0 Hz), 7.66 (NH,
1H, bs), 7.36 (C40H, 1H, dd, 3J ¼ 9.0 Hz, 4J ¼ 3.0 Hz), 6.88 (C30H, 1H, d,
3J ¼ 9.0 Hz), 4.36 (C10H, 1H, m), 4.04 (C3H, 1H, m), 3.92 (C6H, 3H, s),
3.88 (C13H, 1H, pq, 2J ¼ 3J ¼ 8.0 Hz), 3.76 (C13H, 1H, pq), 3.52, 3.36
(C1H, C5H, 2H, ps), 2.50 (C9H, 2H, bs), 1.90 (C2H, C4Heq, C11H, 5H,
m), 1.86 (C6H, C7Heq, C12H, 6H, m), 1.84 (C6H, C7Hax, 2H, pt), 1.78
4.5.13. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-1-
naphthamide (4m)
Yield: 0.39 g (21.6%). Mp 167.5e168.2 ꢃC (diisopropyl ether/
acetone, 8: 4 (v/v)); Anal. Calcd for C25H24N2O2 ꢁ HCl ꢁ 1.5H2O: C
65.16%, H 6.61%, N 6.61%; Found: C 65.27%, H 6.85%, N 6.49%; IR
(C2H, C4Hax, 2H, pd); 13C NMR (100 MHz, CDCl3):
d 163.3 (C]O),
156.2 (C20), 132.3 (C40), 132.2 (C60), 126.9 (C50), 123.3 (C10), 113.0
(C30), 78.7 (C10), 68.4 (C13), 60.5, 60.4 (C1, C5), 57.5 (C9), 56.5
(OCH3), 41.5 (C3), 38.3 (C2,C4), 30.5 (C11), 26.4 (C6, C7), 25.6 (C12).
(KBr) cmꢄ1
d
n
3275 (NH), 1635 (C]O); 1H NMR (400 MHz, CDCl3):
3
8.24 (C80H, 1H, d, J ¼ 8.5 Hz), 7.87 (C40H, C50H, 2H, dd), 7.52
(C20H,C30H, C70H, 3H, m), 7.42 (C60H, 1H, t, 3J ¼ 7.5 Hz), 7.39 (C13H,
1H, ps), 6.31 (C11H, C12H, 2H, pd), 5.92 (NH, 1H, d, 3J ¼ 7.5 Hz), 4.48
(C3H, 1H, m), 3.60 (C9H, 2H, s), 3.38 (C1H, C5H, 2H, ps), 2.12 (C2H,
C4Heq, 2H, m), 2.03 (C6H, C7Heq, 2H, m), 1.89 (C6H, C7Hax, 2H, pq),
1.81 (C2H, C4Hax, 2H, pt).
4.5.18. N-(8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]oct-
3b
-yl)-5-fluoro-2-methoxybenzamide (5d)
Yield: 1.37 g (75.7%). Mp 111.0e111.7 ꢃC (diisopropyl ether);
Anal. Calcd for C20H27N2O3F: C 66.28%, H 7.51%, N 7.73%; Found: C
66.27%, H 7.48%, N 7.73%; IR (KBr) cmꢄ1
n 3379 (NH), 1651 (C]O);
3
1H NMR (400 MHz, CDCl3):
d
7.84 (C60H, 1H, dd, JHeF ¼ 9.5 Hz,
3
4.5.14. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3
b-yl)-2-
4J ¼ 3.0 Hz), 7.71 (NH, 1H, d, J ¼ 8.0 Hz), 7.07 (C40H, 1H, m), 6.85
(C30H,1H, dd, 3J ¼ 9.0 Hz, 3J ¼ 4.0 Hz), 4.30 (C10H,1H, m), 3.95 (C3H,
1H, m), 3.86 (C16H, 3H, s), 3.85 (C13H, 1H, pq), 3.75 (C13H, 1H, pq),
naphthamide (4n)
Yield: 0.71 g (39.4%). Mp 190.8e191.4 ꢃC (ethyl acetate); Anal.
Calcd for C23H24N2O2 ꢁ HCl ꢁ H2O: C 66.58%, H 6.51%, N 6.75%;
3.41, 3.28 (C1H, C5H, 2H, ps), 2.43 (C9H, 2H, pd, 1.89 (C2H, C4Heq
,
Found: C 66.60%, H 6.54%, N 6.66%; IR (KBr) cmꢄ1
n
3240 (NH),
C6H, C7Hax, C6H, C7Heq, C12H, 8H, m), 1.69 (C2H, C4Hax, C11H, 5H,
1624 (C]O); 1H NMR (400 MHz, CDCl3):
d
8.25 (C10H, 1H, ps),
m), 1.45 (C11H, 1H, m); 13C NMR (100 MHz, CDCl3):
d 163.28 (C]O),
7.86 (C30H, C40H, C80H, 3H, m), 7.80 (C50H, 1H, dd, 3J ¼ 8.5 Hz,
4J ¼ 1.5 Hz), 7.54 (C60H, C70H, 2H, m), 7.41 (C13H, 1H, d,
3J ¼ 1.0 Hz), 6.46 (C11H, 1H, d, 3J ¼ 3.0 Hz), 6.40 (NH, 1H, d,
3J ¼ 8.5 Hz), 4.50 (C3H, 1H, m), 3.72 (C9H, 2H, s), 3.46 (C1H, C5H,
157.3 (d, 1JCeF ¼ 239.8, C50), 153.7 (C20), 123.4 (d, JCeF ¼ 6.9, C10),
3
2
2
118.9 (d, JC-F ¼ 23.5, C40), 118.6 (d, JCeF ¼ 25.7, C60), 112.9 (d,
3J ¼ 7.5, C30), 79.0 (C10), 68.3 (C13), 60.3, 60.0 (C1, C5), 57.5 (C9),
56.7 (OCH3), 41.6 (C3), 38.5 (C2, C4), 30.4 (C11), 26.4 (C6, C7), 25.6
(C12).
2H, ps), 2.15 (C2H, C4Heq, 2H, m), 2.03 (C6H, C7Heq, C2H, C4Hax
,
4H, m), 1.93 (C6H, C7Hax, 2H, pq); 13C NMR (100 MHz, CDCl3):
d
167.1 (C]O), 151.1 (C10), 142.9 (C13), 134.9 (C40a), 132.7 (C20),
4.5.19. N-(8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]oct-
131.8 (C80a), 129.1 (C80), 128.6 (C40), 127.9 (C50), 127.8 (C60), 127.5
(C70), 126.9 (C30), 123.7 (C10), 110.8 (C11), 110.3 (C12), 59.7 (C1, C5),
48.6 (C9), 41.7 (C3), 37.7 (C2, C4), 26.0 (C6, C7).
3b
-yl)-4-amino-5-chloro-2-methoxybenzamide (5e)
Yield: 1.50 g (74.0%). Mp 216.0e225.0 ꢃC, dec. (ethanol); Anal.
Calcd for C20H28N3O3Cl: C 51.46%, H 6.48%, N 9.00%; Found: C
51.52%, H 6.58%, N 8.87%; IR (KBr) cmꢄ1 n 3386 (NH), 1643 (C]O);
4.5.15. N-(8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]oct-
1H NMR (500 MHz, DMSO): 7.65 (C60H, 1H, s), 7.54 (NH, 1H, d,
d
3
b
-yl)-benzamide (5a)
3J ¼ 8.0 Hz), 6.47 (C30H, 1H, s), 5.87 (NH2, 2H, s), 4.08 (C10H, 1H, m),
3.82 (C3H, 1H, m), 3.82 (C16H, 3H, s), 3.73 (C13H, 1H, pq), 3.59
(C13H, 1H, m), 3.31e3.20 (C1H, C5H, 2H, bs), 2.44 (C9H, 1H, dd),
2.33 (C9H, 1H, dd, 2J ¼ 13.0 Hz, 3J ¼ 5.0 Hz), 1.87 (C2H, C4Heq, C11H,
3H, m), 1.74 (C6H, C7Heq, 2H, m), 1.65 (C6H, C7Hax, 2H, m), 1.55
(C2H, C4Hax, C11H, C12H, 5H, m); 13C NMR (125 MHz, DMSO):
Yield: 1.20 g (76.2%). Mp 138.7e140.2 ꢃC (diisopropyl ether/
ethanol, 10:1 (v/v)); Anal. Calcd for C19H26N2O2: C 72.58%, H
8.33%, N 8.91%; Found: C 72.49%, H 8.26%, N 8.96%; IR (KBr) cmꢄ1
n
3263 (NH), 1632 (C]O); 1H NMR (400 MHz, CDCl3):
d
7.70
(C20H, C60H, 2H, d, J ¼ 7.0 Hz), 7.46 (C40H, 1H, t, 3J ¼ 7.0 Hz), 7.39
(C30H, C50H. 2H, t, 3J ¼ 7.5 Hz), 5.96 (NH, 1H, d, 3J ¼ 7.5 Hz), 4.32
(C10H, 1H, m), 3.96 (C3H, 1H, m), 3.85 (C13H, 1H, pq,
2J ¼ 3J ¼ 7.0 Hz), 3.73 (C13H, 1H, pq), 3.42, 3.31 (C1H, C5H, 2H,
ps), 2.46 (C9H, 2H, m), 1.96 (C2H, C4Heq, C11H, 5H, m), 1.85 (C6H,
3
d
162.7 (C]O), 157.2 (C20), 148.2 (C40), 131.4 (C60), 110.7 (C10), 108.8
(C50), 97.5 (C30), 78.8 (C10), 66.9(C13), 58.9, 59.5 (C1, C5), 55.8 (C9),
55.7 (OCH3), 40.6 (C3), 37.1 (C2, C4), 29.5 (C11), 26.2, 26.5 (C6, C7),
24.9 (C12).
C7Heq, C12H, 6H, m), 1.72 (C2H, C4Hax, 2H, pd), 1.67 (C6H, C7Hax
2H, pt), 1.51 (C11H, 1H, m).
,
4.5.20. N-(8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]oct-
3b
-yl)-1-naphthamide (5f)
4.5.16. N-(8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]oct-
Yield: 1.70 g (93.6%) after column chromatography (ethyl
3b
-yl)-3-methoxybenzamide (5b)
Yield: 1.00 g (57.8%). Mp 105.8e108.2 ꢃC (diisopropyl ether/
ethanol,10:0.6 (v/v)); Anal. Calcd for C20H28N2O3: C 69.74%, H 8.19%,
N 8.13%; Found: C 69.68%, H 8.19%, N 8.16%; IR (KBr) cmꢄ1
3267
(NH), 1632 (C]O); 1H NMR (400 MHz, CDCl3): 7.30 (C50H, 1H, t),
acetate/methanol, 6:4 (v/v)). Mp 153.0e157.1 ꢃC; Anal. Calcd for
C23H28N2O2 ꢁ HCl ꢁ 2H2O: C 63.22%, H 7.61%, N 6.41%; Found: C
63.27%, H 7.50%, N 6.71%; IR (KBr) cmꢄ1 n 3275 (NH), 1636 (C]O);
n
1H NMR (500 MHz, CDCl3):
d
8.24 (C80H, 1H, dt, 3J ¼ 7.5 Hz,
d
4J ¼ 5J ¼ 1.0 Hz), 7.86 (C40H, C50H, 2H, m), 7.52 (C20H, C30H, C70H, 3H,
m), 7.42 (C60H, 1H, dd, 3J1 ¼ 8.5 Hz, 3J2 ¼ 7.0 Hz), 5.87 (NH, 1H, d,
3J ¼ 8.5 Hz), 4.42 (C10H, 1H, m), 3.94 (C3H, 1H, m), 3.85 (C13H, 1H,
m), 3.73 (C13H, 1H, m), 3.42e3.33 (C1H, C5H, 2H, pt), 2.48 (C9H, 1H,
7.27 (C20H, 1H, t), 7.20 (C60H, 1H, d, 3J ¼ 7.0 Hz), 7.00 (C40H, 1H, dd,
3J ¼ 8.0 Hz), 5.95 (NH, 1H, d, 3J ¼ 8.0 Hz), 4.29 (C10H, 1H, m), 3.97
(C3H,1H, m), 3.86 (C13H, 1H, pq, 2J ¼ 3J ¼ 7.0 Hz), 3.82 (C16H, 3H, s),
3.74 (C13H, 1H, pq), 3.45, 3.32 (C1H, C5H, 2H, ps), 2.48 (C9H, 2H, m),
1.98 (C2H, C4Heq, C11H, 5H, m), 1.86 (C6H, C7Heq, C12H, 6H, m), 1.73
(C2H, C4Hax, 2H, pd), 1.68 (C6H, C7Hax, 2H, pt), 1.13 (C11H, 1H, m).
dd), 2.43 (C9H, 1H, dd, 2J ¼ 13.0 Hz, 3J ¼ 7.5 Hz), 1.98 (C6H, C7Heq
,
C11H, 4H, m), 1.84 (C6H, C7Hax, 2H, m), 1.78 (C2H, C4Hax, C2H,
C4Heq, 4H m), 1.67 (C12H, 2H, m), 1.51 (C11H, 1H, m).

ꢀ
T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4485
4.5.21. N-(8-Tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]oct-
4.7. General procedure for synthesis of b-amides (8aec)
3
b
-yl)-2-naphthamide (5g)
Yield: 1.00 g (55.0%). Mp 176.3e178.1 ꢃC (ethyl acetate); Anal.
A mixture of 7 (1.02 g, 3.5 mmol), 2-chloro-, 3-chloro of 4-
chloromethypyridine hydrochloride (0.57 g, 3.5 mmol), anhy-
drous K2CO3 (0.96 g, 7.5 mmol) and KI (catalytic amount) was
refluxed in anhydrous acetone (50 mL) for 1 h. The solids were
filtered off and the filtrate was evaporated in vacuo. The residue
was dissolved in CH2Cl2 (30 mL), washed with water, dried with
magnesium sulphate and evaporated in vacuo. The resulting thick
oil was dissolved in ethanol and treated with saturated ethanolic
hydrogen chloride. The precipitated dihydrochlorides 8aec were
filtered and washed with cold acetone.
Calcd for C23H28N2O2 ꢁ HCl ꢁ 1.5H2O: C 64.55%, H 7.54%, N 6.55%;
Found: C 64.24%, H 7.22%, N 6.37%; IR (KBr) cmꢄ1 n 3279 (NH), 1636
(C]O); 1H NMR (500 MHz, CDCl3):
d
8.23 (C10H, 1H, s), 7.85 (C40H,
C50H, C80H, 3H, m), 7.79 (C30H, 1H, dd, 3J ¼ 8.5 Hz, 4J ¼ 2.0 Hz), 7.53
(C60H, C70H, 2H, m), 6.27 (NH,1H, d, 3J ¼ 8.5 Hz), 4.40 (C10H, 1H, m),
3.99 (C3H, 1H, m), 3.87 (C13H, 1H, m), 3.75 (C13H, 1H, m),
3.48e3.55 (C1H, C5H, 2H, ps), 2.51 (C9H, 2H, m), 1.99 (C2H, C4Heq
,
C11H, 4H, m), 1.94 (C6H, C7Heq, 2H, m), 1.85 (C6H, C7Hax, 2H, m),
1.76 (C2H, C4Hax, C12H, 4H m), 1.53 (C11H, 1H, m); 13C NMR
(125 MHz, CDCl3):
d
166.7 (C]O), 134.6 (C20), 132.6 (C40a), 132.0
(C80a), 128.8 (C80), 128.3 (C40), 127.5 (C60), 127.7 (C50), 127.2 (C70),
126.6 (C30), 123.5 (C10), 78.7 (C10), 68.1 (C13), 59.8, 59.9 (C1, C5),
56.8 (C9), 41.7 (C3), 37.7 (C2, C4), 30.2 (C11), 26.3, 26.4 (C6, C7), 25.4
(C12).
4.7.1. N-(8-Pyridin-2-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-2,3-
dimethoxybenzamide dihydrochloride (8a)
Yield: 0.77 g (48.0%). Mp 186.3e191.0 ꢃC (ethanol); Anal. Calcd
for C22H27N3O3 ꢁ 2HCl ꢁ H2O: C 55.93%, H 6.61%, N 8.89%; Found: C
55.65%, H 6.92%, N 8.89%; IR (KBr) cmꢄ1 n 3271 (NH), 1632 (C]O);
4.5.22. N-(8-Benzyl-8-azabicyclo[3.2.1]oct-3
b
-yl)-1-naphthamide
1H NMR (500 MHz, CD3OD):
d
8.94 (C60H, 1H, bd, 3J ¼ 5.0), 8.51
(6a)
(C40H,1H, bt), 8.35 (Cc’’H,1H, bd), 8.00 (C50H, 1H, bt), 7.29 (C60H,1H,
4
Yield: 0.48 g, (26.0%). Mp 177.7e178.1 ꢃC (ethyl acetate); Anal.
Calcd for C25H26N2O ꢁ HCl ꢁ H2O: C 70.66%, H 6.83%, N 6.59%;
Found: C 70.57%, H 6.87%, N 6.51%; IR (KBr) cmꢄ1 n 3282 (NH), 1631
dd, 3J ¼ 7.5 Hz, J ¼ 2.0 Hz), 7.19 (C40H, 1H, dd, 3J ¼ 8.0 Hz,
4J ¼ 2.0 Hz), 7.16 (C50H, 1H, t, 3J ¼ 8.0 Hz), 4.73 (C9H, 2H, bs), 4.54
(C3H, 1H, tt, 3Jaxeax ¼ 11.0 Hz, 3Jaxeeq ¼ 6.5 Hz), 4.22 (C1H, C5H, 2H,
bt), 3.90 (C13H, 3H, s), 3.89 (C12H, 3H, s), 2.59 (C6H,C7Heq, 2H, bs),
2.32 (C6H, C7Heq, C2H, C4Heq, C2H, C4Hax, 6H, m).
(C]O); 1H NMR (400 MHz, CDCl3):
d
8.24 (C80H, 1H, dd, 3J ¼ 7.0 Hz,
4J ¼ 2.5 Hz), 7.89 (C40H, 1H, m), 7.61e7.43 (C20H, C30H, C70H, 3H, m),
3
7.41 (C20H, C60H, 2H, d, J ¼ 7.0 Hz), 7.34 (C30H, C50H, 2H, t,
3J ¼ 7.0 Hz), 7.28 (C40H, 1H, t), 5.84 (NH, 1H, d, 3J ¼ 8.5 Hz), 4.50
4.7.2. N-(8-Pyridin-3-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-2,3-
(C3H, 1H, m), 3.59 (C9H, 2H, s), 3.31 (C5H, 2H, ps), 2.13 (C2H, C4Heq
,
dimethoxybenzamide dihydrochloride (8b)
2H, m), 2.03 (C6H, C7Heq, 2H, m), 1.86 (C6H, C7Hax, 2H, pq), 1.67
Yield: 1.08 g (67.5%). Mp 171.6e186.0 ꢃC (ethanol); Anal. Calcd
for C22H27N3O3 ꢁ 2HCl ꢁ 3H2O: C 51,97%, H 6.94%, N 8.26%; Found:
C 51.91%, H 6.58%, N 8.28%; IR (KBr) cmꢄ1 n 3364 (NH), 1651 (C]O);
(C2H, C4Hax, 2H, pt); 13C NMR (100 MHz, CDCl3):
d 169.03 (C]O),
140.1 (C10), 135.0 (C40a), 133.8 (C10), 130.6 (C40), 130.2 (C80a), 128.8
(C20, C60), 128.5 (C50), 128.4 (C30, C50), 127.2 (C60), 127.0 (C40), 126.6
(C70), 125.5 (C20), 124.9 (C30, C80), 59.0 (C1, C5), 56.5 (C2), 42.3 (C3),
38.8 (C2, C4), 26.7 (C6, C7).
1H NMR (500 MHz, CD3OD):
d
9.38 (C20H, 1H, s), 9.07 (C60H, 1H, d,
3J ¼ 8.0 Hz), 9.01 (C40H, 1H, d, J ¼ 5.5 Hz), 8.23 (C50H, 1H, dd,
3J1 ¼ 8.5 Hz, 3J2 ¼ 5.5 Hz), 7.28 (C60H, 1H, d, 3J ¼ 6.5 Hz), 7.18 (C40H,
1H, dd, 3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz), 7.15 (C50H, 1H, t, 3J ¼ 8.0 Hz), 4.61
(C9H, 2H, bs), 4.54 (C3H, 1H, tt), 4.15 (C1H, C5H, 2H, bt), 3.89 (C13H,
3
4.5.23. N-(8-Benzyl-8-azabicyclo[3.2.1]oct-3b-yl)-2-naphthamide
(6b)
3H, s), 3.88 (C12H, 3H, s), 2.60 (C6H,C7Heq, 2H, M), 2.32 (C6H, C7Hax
C2H, C4Heq, C2H, C4Hax, 6H, m).
,
Yield: 0.68 g (36.6%). Mp 193.5e194.2 ꢃC (ethyl acetate); Anal.
Calcd for C25H26N2O ꢁ HCl ꢁ H2O: C 70.66%, H 6.83%, N 6.59%;
Found: C 70.89%, H 6.81%, N 6.48%; IR (KBr) cmꢄ1 n 3263 (NH), 1651
4.7.3. N-(8-Pyridin-4-ylmethyl-8-azabicyclo[3.2.1]oct-3b-yl)-2,3-
(C]O); 1H NMR (400 MHz, CDCl3):
d
8.26 (C10H, 1H, ps), 7.89 (C30H,
dimethoxybenzamide dihydrochloride (8c)
C40H, C80H, 3H, m), 7.82 (C50H, 1H, dd, 3J ¼ 9.0 Hz, 4J ¼ 1.5 Hz), 7.561
Yield: 0.75 g (47.8%). Mp 226.2e227.0 ꢃC (ethanol/diethyl ether);
Anal. Calcd for C22H27N3O3 ꢁ 2HCl ꢁ 0.5H2O: C 57.02%, H 6.53%, N
(C60H, C70H, 2H, m), 7.42 (C20H, C60H, 2H, d, 3J ¼ 7.0 Hz), 7.35 (C30H,
3
C50H, 2H, t, J ¼ 7.0 Hz), 7.28 (C40H, 1H, t), 6.13 (NH, 1H, d,
9.07%; Found: C 57.02%, H 6.31%, N 9.07%; IR (KBr) cmꢄ1
n
3398
3J ¼ 8.0 Hz), 4.45 (C3H, 1H, m), 3.59 (C9H, 2H, s), 3.31 (C1H, C5H),
2H, ps), 2.12 (C2H, C4Heq, 2H, m), 1.99 (C6H, C7Heq, 2H, m), 1.83
(C6H, C7Hax, 2H, pq), 1.17 (C2H, C4Hax, 2H, pt); 13C NMR (100 MHz,
(NH), 1662 (C]O); 1H NMR (500 MHz, CD3OD):
d
9.03 (C20H, C60H,
4
2H, dd, 3J ¼ 5.5 Hz, J ¼ 1.0 Hz), 8.58 (C30H, C50H, 2H, 3J ¼ 7.0 Hz),
7.29 (C60H, 1H, dd, 3J ¼ 7.5 Hz, J ¼ 1.5 Hz), 7.19 (C40H, 1H, dd,
4
CDCl3):
d
166.9 (C]O), 140.1 (C20), 134.8 (C40a), 132.8 (C10), 132.2
3J ¼ 6.0 Hz, 4J ¼ 2.0 Hz), 7.16 (C50H, 1H, t, 3J ¼ 8.0 Hz), 4.69 (C9H, 2H,
bs), 4.54 (C3H, 1H, tt), 4.14 (C1H, C5H, 2H, bt), 3.90 (C13H, C12H, 6H,
s), 2.56 (C6H, C7Heq, 2H, m), 2.42 (C2H, C4Heq, 2H, m), 2.28 (C2H,
C4Hax, C6H, C7Hax, 4H, m).
(C80a), 129.1 (C80), 128.8 (C20, C60), 128.6 (C40), 128.4 (C30, C50), 127.9
(C50), 127.8 (C60), 127.4 (C70), 127.0 (C40), 126.9 (C30), 123.7 (C10), 59.1
(C1, C5), 56.6 (C9), 42.3 (C3), 38.9 (C2, C4), 26.7 (C6, C7).
4.6. Synthesis of N-(8-azabicyclo[3.2.1]oct-3
b
-yl)-2,3-
4.8. Synthesis of 8-tetrahydrofuran-2-ylmethyl-8-azabicyclo[3.2.1]
dimethoxybenzamide (7)
oct-3a-ylamine (9b)
The starting N-(8-benzyl-8-azabicyclo[3.2.1]oct-3
b
-yl)-2,3-
Compound 1a (8.8 g, 0.04 mol) was dissolved in a mixture of
methanol (115 mL) and H2O (13 mL). Subsequently, HCOONH4
(26.0 g, 0.4 mol) and 10% Pd/C (5.2 g) were added and the mixture
was stirred for 24 h. The catalyst was filtered off and the filtrate was
evaporated in vacuo. The residue was treated with 30% aqueous
solution of NaOH (20 mL) and stirred for 5 min. The mixture was
extracted with diethyl ether (5 ꢁ 30 mL) and the combined organic
layers were dried with magnesium sulphate and evaporated in
vacuo. The residue was subjected to distillation. Yield: 2.0 g (22.3%).
Bp 112e120 ꢃC/0.6 Tr; Mp (hydrochloride) > 310 ꢃC, dec.; Anal.
dimethoxybenzamide 6c was synthesized from amine 3c and 2,3-
dimethoxybenzoic acid following the general procedure
described in Section 4.5. The synthesis of compound 6c has been
previously described [37].
Compound 6c (5.8 g, 14 mmol) was dissolved in methanol
(50 mL) and catalytically hydrogenated (5.8 g of 10% Pd/C, 10 atm of
H2, 24 h). The catalyst was filtered off and the filtrate was evapo-
rated in vacuo to furnish 3.73 g (91.6%) of crude 7, which was used
in subsequent reactions without further purification.

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4486
Calcd for C12H21N2O ꢁ 2HCl: C 50.89%, H 8.54%, N 9.89%; Found: C
50.89%, H 8.20%, N 9.86%; IR (KBr) cmꢄ1
3357 (NHas), 3298
(NHsym), 1067 (CO); 1H NMR (400 MHz, CDCl3):
3.85 (C10H, 1H,
4.11.1. 8-Azabicyclo[3.2.1]oct-3a-yl-2,3-dimethoxybenzamide
n
hydrochloride (13a)
d
Yield: 2.1 g (86.2%). Mp 236.7e237.2 ꢃC (methanol/diethyl
ether); Anal. Calcd for C16H22N2O3 ꢁ HCl ꢁ H2O: C 55.73%, H 7.31%,
m), 3.77 (C13H(1), 1H, q, 2J ¼ 3J ¼ 7.5 Hz), 3.65 (C13H(2), 1H, q), 3.20
(C1H, 1H, ps), 3.10 (C5H, 1H, ps), 3.12 (C3H, 1H, m), 2.38 (C9H(1), 1H,
dd, 2J ¼ 13 Hz, 3J ¼ 7 Hz), 2.31 (C9H(2), 1H, dd, 2J ¼ 13 Hz,
3J ¼ 4.5 Hz), 2.06 (C2H, C4Heq, 2H, m), 1.90 (C11H(1), 1H, m), 1.88
(C6H, C7Hax, C6H, C7Heq, 4H, pd), 1.76 (C12H, 2H, m), 1.45 (C11H(2),
1H, m), 1,30 (C2H, C4Hax, 2H, pd), 1.23 (NH2, 2H, bs).
N 8.12%; Found: C 55.82%, H 7.15%, N 7.96%; IR (KBr) cmꢄ1
n
3380
(NH), 1635 (C]O); 1H NMR (400 MHz, CD3OD):
d
8.71 (NþH2, 2H,
d), 7.34 (C60H, 1H, dd, 3J ¼ 7.5 Hz, J ¼ 1.5 Hz), 7.21 (C40H, 1H, dd,
3J ¼ 8.0 Hz, 4J ¼ 2.0 Hz), 7.17 (C50H, 1H, t, 3J ¼ 8.0 Hz), 4.23 (C3H, 1H,
t, 3J1 ¼ 5.5 Hz, 3J2 ¼ 0.0 Hz), 4.08 (C1H, C5H, 2H, ps), 3.95 (C12H, 3H,
s), 3.91 (C11H, 3H, s), 2.37 (C2H, C4Heq, C6H, C7Heq, 4H, m), 2.22
(C2H, C4Hax, C6H, C7Hax, 4H, m).
4
4.9. Synthesis of 8-methyl-8-azabicyclo[3.2.1]oct-3a-yl-2,3-
dimethoxybenzamide (12a)
4.11.2. 8-Azabicyclo[3.2.1]oct-3a-yl-5-chloro-2-methoxybenzamide
hydrochloride (13b)
A solution of 2,3-dimethoxybenzoic acid (3.64 g, 21 mmol) and
thionyl chloride (5 mL, 69 mmol) in anhydrous benzene was
refluxed for 3 h. The mixture was evaporated in vacuo and traces of
thionyl chloride were coevaporated with benzene (2 ꢁ 20 mL). The
residue was dissolved in anhydrous CHCl3 (50 mL) and added
dropwise to a stirred, cooled (w0 ꢃC) solution of 8-methyl-8-
Yield: 1.8 g (70.6%). Mp 228.4e229.5 ꢃC, dec. (methanol); Anal.
Calcd for C15H19N2O2Cl ꢁ HCl ꢁ 0.3H2O: C 53.42%, H 6.18%, N 8.31%;
Found: C 53.42%, H 5.87%, N 8.00%; IR (KBr) cmꢄ1 n 3383 (NH), 1651
(C]O); 1H NMR (400 MHz, CD3OD):
d
8.62 (NþH2, 2H, pd), 7.80
(C60H, 1H, d, 4J ¼ 2.5 Hz), 7.49 (C40H, 1H, dd, 3J ¼ 9.0 Hz, 4J ¼ 2.5 Hz),
7.18 (C30H, 1H, d, 3J ¼ 9.0 Hz), 4.22 (C3H, 1H, pt), 4.09 (C1H, C5H, 2H,
azabicyclo[3.2.1]oct-3a-ylamine 11 (2.8 g, 20 mmol) and triethyl-
ps), 4.00 (C11H, 3H, s), 2.40 (C2H, C4Heq, 2H, m), 2.36 (C6H, C7Heq
2H, m), 2.28 (C6H, C7Hax, 2H, m), 2.20 (C2H, C4Hax, 2H, pd).
,
amine (3.0 mL, 20 mmol) in anhydrous CHCl3 (75 mL). The mixture
was stirred at room temperature for 24 h, washed with a 5%
aqueous solution of Na2CO3 (2 ꢁ 30 mL), dried with magnesium
sulphate and evaporated in vacuo. Yield: 4.2 g (68.9%). Mp
71.7e73.8 ꢃC (ethyl acetate; hydrochloride: 218.7e220.3 ꢃC); Anal.
Calcd for C17H24N2O3 ꢁ HCl ꢁ H2O: C 56.90%, H 7.58%, N 7.81%;
Found: C 57.24% H 7.37%, N 7.88%; IR (KBr) cmꢄ1 n 3386 (NH), 1638
4.12. General procedure for synthesis of a-amides (14a,b)
To a suspension of 14a or 14b (5 mmol) in acetone (40 mL),
K2CO3 (2.7 g, 20 mmol) was added and the mixture was stirred for
5 min. Subsequently, a solution of 2-chloromethylfuran (0.8 mL,
8 mmol) in acetone (10 mL) was added, the mixture was refluxed
for 4 h and evaporated in vacuo. To the residue was added H2O
(10 mL), followed by extraction with CH2Cl2 (3 ꢁ 20 mL). The
combined organic layers were dried with magnesium sulphate and
evaporated in vacuo.
(C]O); 1H NMR (400 MHz, CDCl3):
d
8.55 (NH, 1H, bd, 3J ¼ 7.0 Hz),
4
7.72 (C60H, 1H, dd, 3J ¼ 8.0 Hz, J ¼ 1.0 Hz), 7.17 (C50H, 1H, t), 7.07
(C40H, 1H, dd, 3J ¼ 8.0 Hz, 4J ¼ 8.0 Hz), 4.35 (C3H, 1H, pq, J4-
3
3
3
¼ 7.0 Hz, Jeqꢄeq ¼ 7.0 Hz, Jaxeax ¼ 7.0 Hz), 3.36 (C13H, 3H, s),
NeH
3.93 (C12H, 3H, s), 3.40 (C1H, C5H, 2H, bs), 2.51 (C2H, C4Heq, 2H, m),
2.45 (C9H, 3H, s), 2.22 (C6H, C7Heq, 2H, m), 2.00 (C6H, C7Hax, 2H,
m), 1.81 (C2H, C4Hax, 2H, m).
4.12.1. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3a-yl)-2,3-
dimethoxybenzamide (14a)
The residue was macerated (diisopropyl ether/ethanol, 7.5:1 (v/
v)). The solution was decanted from the tarry sediment and
concentrated in vacuo. The residue was subjected to column
chromatography (CH2Cl2/CH3OH, 9:1 (v/v)) and further purified by
recrystallisation. Yield: 0.6 g (32.3%). Mp 96.9e98.3 ꢃC (diisopropyl
ether); Anal. Calcd for C21H26N2O4: C 68.09%, H 7.07%, N 7.56%;
Found: C 68.11%, H 6.94%, N 7.57%; IR (KBr) cmꢄ1 n 3391 (NH), 1651
4.10. Synthesis of 8-methyl-8-azabicyclo[3.2.1]oct-3a-yl-5-chloro-
2-methoxybenzamide (12b)
The compound was obtained from 11 (0.7 g, 5 mmol) and 5-
chloro-2-methoxybenzoic acid (0.93 g, 5 mmol) following the
procedure described in Section 4.5. Yield: 0.96 g (62,1%). Mp
154.2e156.1 ꢃC (diisopropyl ether/ethanol, 10:1 (v/v)); Anal. Calcd
for C16H21N2O2Cl: C 62.23%, H 6.85%, N 9.07%; Found: C 62.20%, H
(C]O); 1H NMR (400 MHz, CDCl3):
d
8.34 (NH, 1H, d, 3J ¼ 7.0 Hz),
7.72 (C60H, 1H, dd, 3J ¼ 8.0 Hz, 4J ¼ 1.0 Hz), 7.39 (C13H, 1H, d), 7.16
(C50H, 1H, t, 3J ¼ 8.0 Hz), 7.05 (C40H, 1H, dd, 3J ¼ 8.0 Hz, 4J ¼ 1.0 Hz),
6.32 (C12H, 1H, t, 3J ¼ 2.5 Hz), 6.21 (C11H, 1H, d, 3J ¼ 2.5 Hz), 4.34
(C3H,1H, q, 3J1 ¼7.0 Hz, 3J2 ¼ 0.0 Hz), 3.95 (C17H, 3H, s), 3.92 (C16H,
6.57%, N 9.05%; IR (KBr) cmꢄ1
n
3410 (NH), 1647 (C]O); 1H NMR
(400 MHz, CDCl3):
d
8.42 (NH, 1H, d, 3J ¼ 7.0 Hz), 8.15 (C60H, 1H, d,
4J ¼ 3.0 Hz), 7.34 (C40H, 1H, dd, 3J ¼ 9.0 Hz, 4J ¼ 3.0 Hz), 6.89 (C30H,
1H, d, 3J ¼ 9.0 Hz), 4.28 (C3H, 1H, q, 3J ¼ 7.0 Hz), 3.97 (C12H, 3H, s),
3.15 (C1H, C5H, 2H, ps), 2.28 (C9H, 3H, s), 2.23 (C2H, C4Heq, 2H, m),
3H, s), 3.55 (C9H, 2H, s), 3.24 (C1H, C5H, 2H, bs), 2.32 (C2H, C4H, eq
,
2H, 4d, 2J ¼ 14.5 Hz, 3J1 ¼7.0 Hz, 3J2 ¼ 4.0 Hz), 2.14 (C6H, C7H, eq, 2H,
m), 1.91 (C6H, C7H, ax, 2H, m), 1.72 (C2H, C4H, ax, 2H, d, 2J ¼ 14.5 Hz,
3J ¼ 0.0 Hz). The C3H proton is equatorial (see Section 4.16).
2.15 (C6H, C7Heq, 2H, m), 1.83 (C6H, C7Hax, 2H, m), 1.68 (C2H, C4Hax
2H, m).
,
4.12.2. N-(8-Furan-2-ylmethyl-8-azabicyclo[3.2.1]oct-3a-yl)-5-
4.11. General procedure for synthesis of N-demethylated
a-amides
chloro-2 methoxybenzamide (14b)
(13a,b)
Yield: 0.75 g (40.7%) after column chromatography (CH2Cl2/
CH3OH, 9:1 (v/v)). Mp 145.8e147.5 ꢃC (diisopropyl ether); Anal.
Calcd for C20H23N2O3Cl: C 64.08%, H 6.18%, N 7.47%; Found: C
64.00%, H 6.50%, N 7.52%; IR (KBr) cmꢄ1 n 3414 (NH), 1643 (C]O);
To a cooled (w0 ꢃC) solution of 12a or 12b (7.5 mmol) in
ClCH2CH2Cl (30 mL), 2-chloroethyl chloroformate (0.8 mL,
7.5 mmol) in ClCH2CH2Cl (15 mL) was added. The mixture was
stirred at room temperature for 2 h and concentrated in vacuo. The
residue was dissolved in methanol and the solution was refluxed
for 1.5 h. After subsequent evaporation of the mixture to about half
of the volume, diethyl ether (10 mL) was added and the resulting
precipitate was filtered.
1H NMR (400 MHz, CDCl3):
d
8.44 (NH,1H, d, 3J ¼ 7.0 Hz), 8.15 (C60H,
4
1H, d, J ¼ 3.0 Hz), 7.36 (C13H, 1H, bs), 7.35 (C40H, 1H, dd,
4J ¼ 3.0 Hz), 6.90 (C30H, 1H, d, 3J ¼ 9.0 Hz), 6.30 (C12H, 1H, t,
3J ¼ 2.5 Hz), 6.19 (C11H, 1H, d, 3J ¼ 3.0 Hz), 4.30 (C3H, 1H, q,
3J1 ¼ 7.0 Hz, 3J2 ¼ 0.0 Hz), 3.97 (C16H, 3H, s), 3.53 (C9H, 2H, s), 3.26
(C1H, C5H, 2H, bs), 2.27 (C2H, C4H, eq, 2H, 4d, 2J ¼ 14.5 Hz,

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T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
4487
3J1 ¼ 6.6 Hz, 3J2 ¼ 3.0 Hz), 2.14 (C6H, C7H, eq, 2H, m), 1.88 (C6H, C7H,
ax, 2H, m), 1.68 (C2H, C4H, ax, 2H, d, 2J ¼ 14.5 Hz, 3J ¼ 0.0 Hz). The
C3H proton is equatorial. (see Section 4.16).
The effects of the tested compounds given alone on rectal body
temperature in mice (measured with an Ellab thermometer) were
recorded 30, 60, 90 and 120 min after administration. In an inde-
pendent experiment, the effect of WAY 100635 (0.1 mg/kg) on the
hypothermia induced by compounds 4l, 4n, 5e, 6b or 8-OH-DPAT
was tested. WAY 100635 was administered 15 min before 4l, 4n, 5e,
6b or 8-OH-DPAT and rectal body temperature was recorded 30 min
and 60 min after injection of the tested compounds. The results
4.13. In vitro experiments
All compounds were tested for their affinities towards 5-HT1A
,
5-HT2A and D2 receptors according to procedures described previ-
ously [51].
were expressed as a change in body temperature (Dt) with respect
to the basal body temperature, measured at the beginning of the
experiment.
4.14. In vivo experiments
4.14.4. Lower lip retraction (LLR) in rats
All the experimental procedures were approved by the Local
Bioethics Commissions at the Institute of Pharmacology, Polish
Academy of Sciences in Kraków and Medical University in Lublin.
LLR was assessed according to the method described by
Berendsen et al. [44]. The rats were individually placed in cages
(30 ꢁ 25 ꢁ 25 cm) and they were scored three times at 15, 30 and
45 min after the administration of the tested compounds as
follows: 0 ¼ lower incisors not visible, 0.5 ¼ partly visible,
1 ¼ completely visible. The total maximum score amounted to 3/
rat. In a separate experiment, the effect of the studied compounds
on LLR induced by 8-OH-DPAT (1 mg/kg) was tested. The
compounds were administered 45 min before 8-OH-DPAT, and the
animals were scored 15, 30 and 45 min after 8-OH-DPAT
administration.
4.14.1. Climbing test
Each animal was placed in a plastic box with a metal grid.
Climbing behaviour was assessed at 10 min intervals up to 1 h
starting 10 min after apomorphine injection and the last test was
performed 120 min after apomorphine administration. All obser-
vations were made in a blind fashion by an observer unaware of the
specific drug treatments. The examined compounds were admin-
istrated intraperitoneally at doses of 10, 50 and 100 mg/kg, 20 min
before apomorphine injection. Of note, the studied compounds at
doses of 50 and 100 mg/kg produced side effects in mice (including
somnolence, muscle flaccidity and ataxia), which made it impos-
sible to perform the climbing test. In such a situation, the animals
were considered to be unable to perform the test. Qualitative
variables from the climbing test were compared by using the
Fisher’s exact probability test. Differences among values were
considered statistically significant if P < 0.05. Statistical tests were
performed using commercially available GraphPad Prism version
4.0 for Windows (GraphPad Software, San Diego, CA, USA).
4.14.5. Locomotor activity in mice
The spontaneous locomotor activity of mice was recorded by
a photoresistor actometer (24 cm in diameter, illuminated by two
light beams), which were connected to a counter for the recording
of light beam interruptions. The mice were placed individually in
the actometer, and the number of light beam crossings was counted
twice: during the first 6 min, i.e. at the time equal to the observa-
tion period in the forced swimming test, and during a 30 min
experimental session.
4.14.6. Forced swimming test in mice (Porsolt test)
4.14.2. Head twitches in mice
The experiment was carried out according to the method of
Porsolt et al. [53]. Briefly, the mice were individually placed in
a glass cylinder (25 cm high, 10 cm in diameter) containing 6 cm of
water maintained at 23e25 ꢃC, and were left there for 6 min. A
mouse was regarded as immobile when it remained floating on
water, making only small movements to keep its head above the
surface. The total duration of immobility was measured by an
experimenter during the final 4 min of a 6 min test session, after
a 2 min habituation period.
In order to habituate mice to the experimental environment,
each animal was randomly transferred to a 12 cm (diame-
ter) ꢁ 20 cm (height) glass cage lined with sawdust 20 min before
treatment. Head twitches in mice were induced by (ꢂ)-DOI (2.5
mg/kg). Immediately after treatment, the number of head twitches
was counted for 20 min [52]. The investigated compounds were
administered 30 min before (ꢂ)-DOI at doses of 5, 10 and 20 mg/
kg.
4.14.3. Body temperature in mice
4.14.7. Statistical analysis
The experiments were performed on male Albino Swiss mice
(24e28 g). The animals were kept at room temperature (20 ꢂ 1 ꢃC)
on a natural dayenight cycle (AprileMay) and were housed under
standard laboratory conditions. They had free access to food and
tap water before the experiment. Each experimental group con-
sisted of 6e8 animals/dose, and all the animals were used only
once. 8-Hydroxy-2-(di-n-propylamino)tetralin hydrobromide (8-
OH-DPAT, Research Biochemical Inc.) and N-{2-[4-(2-
methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexane
carboxamide trihydrochloride (WAY 100635, synthesized by Dr. J.
Boksa, Institute of Pharmacology, Polish Academy of Sciences,
Kraków, Poland) were used as aqueous solutions. Compounds 4l,
4n, 5e, 6b were suspended in a 1% aqueous solution of Tween 80. 8-
OH-DPAT and WAY 100635 were injected subcutaneously (sc) and
4l, 4n, 5e, 6b were given intraperitoneally (ip) in a volume of 10 ml/
kg (mice). The obtained data were analyzed by Dunnett’s test
(when only one drug was given) or by the NewmaneKeuls test
(when two drugs were administered).
The obtained data were presented as the mean ꢂ S.E.M.
Comparisons between groups were carried out by a one-way
analysis of variance (ANOVA) followed by intergroup comparisons
using Dunnett’s test (when only one drug was given).
4.15. X-ray structure analysis
Crystal data for C20H23N2O3Cl (4h): triclinic, space group P-1,
a ¼ 9.0182(6), b ¼ 9.2275(5), c ¼ 12.3417(5) Å,
a
¼ 107.779(4),
b
¼
94.391(4),
g
¼
102.281(5)ꢃ,
V
¼
944.47(9)Å3,
Z
¼
2,
Dx ¼ 1.318 Mg/m3, T ¼ 293 K. Data were collected with a Oxford
Difraction KM4CCD difractometer using graphite monochromated
MoK
3854(0.035), observed (I > 2
ters: 3854/0/235, absorption correction: multi-scan, goodness-of-
a
radiation. Reflections: collected: 11 287, unique (Rint):
s(I)): 2558, data/restraints/parame-
fit on F2: 1.032, R(F) (I > 2 (I)): 0.0443, wR(F2) (all data): 0.1386,
s
Max/min. Dr (e/Å3): 0.257/ꢄ0.256. Atom labelling is shown in
Fig. 5. The deposition number CCDC 831789 for 4h contain the

ꢀ
4488
T. Słowinski et al. / European Journal of Medicinal Chemistry 46 (2011) 4474e4488
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J. Neurosci. 25 (2005) 10831e10843.
Fig. 5. The molecular structure of 4h shows an intramolecular hydrogen bond between
the O atom of the methoxy group and the NH of the amide group leading to a six-
membered ring. The piperidine moiety adopts a chair conformation. The substituent
at N8 is in an equatorial (b) position.
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J. Neurochem. 76 (2001) 1521e1531.
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R3eR5.
supplementary crystallographic data for this paper. These data can
be obtained free of charge via www.ccdc.cam.ac.uk/data_request/
cif, or by emailing data_request@ccdc.cam.ac.uk, or by contacting
The Cambridge Crystallographic Data Centre, 12, Union Road,
Cambridge CB2 1EZ, UK; fax: þ44 1223 336033.
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599e608.
4.16. 1H NMR investigation for
compounds
b (4b, 4h) and a (14a, 14b)
The analysis of the splitting pattern of the multiplet for the
proton CH3 of 4b suggests its axial orientation. The signal appears
as a multiplet (12 lines), formed by three partially overlapping
quartets. Splitting into triplets (3J ¼ 11.5 Hz) is attributed to the
spinespin coupling with the two neighbouring axial protons C2H
and C4H. Splitting of the components of the triplet into quartets
(3J ¼ 5.5 Hz) is a result of the spin interactions with neighbouring
equatorial C2H and C4H protons and with the NH proton.
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On the contrary, the shape of the multiplet of the proton CH3 of
14a suggests its equatorial position. Moreover, the six-membered
ring of the tropane nucleus does not seem to be a ‘clear’ cyclo-
hexane structure, which can be inferred from the analysis of the
splitting patterns of the multiplets of the C3H, C2H and C4H
protons. The signal of the CH3 proton is a quartet with two vicinal
coupling constants. The first of these (3J1 ¼ 7.0 Hz) results from
spinespin interactions with protons C2H, C4H and NH. The second
vicinal coupling constant (3J2 ¼ 0.0 Hz) is attributed to coupling
with two axial protons C2H and C4H. According to the Karplus
curve, these coupling constants correspond to the dihedral angles
HE-C3-C2, HE-C2-C3w30ꢃ and HE-C3-C2, HA-C2-C3w80ꢃ [54,55].
This interpretation is further confirmed by the analysis of the
shapes of the multiplets of protons C2H, C4Heq and C2H, C4Hax. The
signals of the first of the above pairs appear as four doublets
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3
3
(2Jaxeeq ¼ 14.5 Hz, J2eqe3eq ¼ 7.0 Hz, J2eqe1eq ¼ 4.0 Hz) and as
3
a doublet (2Jaxeeq ¼ 14.5 Hz, J3eqe2,4ax ¼ 0.0 Hz) for the latter.
ꢀ
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The above assumptions are also valid for compounds 4h and
14b.
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