Synthesis and serotonin receptor activity of the arylpiperazine alkyl/propoxy derivatives of new azatricycloundecanes

Article abstract of DOI:10.1016/j.ejmech.2008.03.019

A set of 36 arylpiperazine derivatives with two novel complex terminal imide fragments, 8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.0^2,6]undec-8-en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.0^2,6]undecane-3,5,8-trione, were s

Full text of DOI:10.1016/j.ejmech.2008.03.019

Available online at www.sciencedirect.com
European Journal of Medicinal Chemistry 44 (2009) 152e164
http://www.elsevier.com/locate/ejmech
Original article
Synthesis and serotonin receptor activity of the arylpiperazine
alkyl/propoxy derivatives of new azatricycloundecanes
b
a
A.J. Bojarski a, B. Kuran b, , J. Kossakowski , A. Kozio1 ,
*
c
c
´
E. Jagie11o-Wojtowicz , A. Chodkowska
a Department of Medicinal Chemistry, Institute of Pharmacology of the Polish Academy of Sciences, Sme˛tna 12, 31-343 Krako´w, Poland
b Department of Medical Chemistry, Medical University, Oczki 3, 02-007 Warszawa, Poland
c Department of Toxicology, Medical University, Chodz´ki 8, 20-093 Lublin, Poland
Received 18 June 2007; received in revised form 14 March 2008; accepted 20 March 2008
Available online 8 April 2008
Abstract
A set of 36 arylpiperazine derivatives with two novel complex terminal imide fragments, 8,11-dimethyl-3,5-dioxo-4-azatricy-
clo[5.2.2.02,6]undec-8-en-1-yl acetate and 1,11-dimethyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione, were synthesized and tested for their af-
finity for 5-HT1A and 5-HT2A receptors. The FujitaeBan analysis showed that the influence of structural modifications on the affinity for both
receptor subtypes is additive and that the activity of similar compounds could be predicted with high accuracy. Compounds 46, 48 and 18 out of
14 screened in a functional model of anxiety and depression demonstrated antidepressant activity in the forced swimming tests in mice, and were
devoid of neurotoxic effects (chimney test in mice).
Ó 2008 Elsevier Masson SAS. All rights reserved.
Keywords: Arylpiperazine; Azatricycloundecane; 5-HT1A receptor; 5-HT2A receptor; FujitaeBan analysis; Antidepressant activity
1. Introduction
exhibit anxiolytic- and/or antidepressant-like activity in some
behavioral models in rats [6e8]. On the basis of their structures,
we synthesized a series of new arylpiperazine derivatives with
two novel complex terminal imide fragments: 8,11-dimethyl-
3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl acetate and
1,11-dimethyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione.
Besides pyrimidynyl and oeOCH3ephenyl, 5 other classic
aryl groups, as well as such standard linkers as: propyl, butyl
and propoxyl were used (Table 1). In addition, benzylpipera-
zine derivatives were also investigated, since for some close
analogs a high 5-HT1A receptor affinity was reported [9,10].
Of the 36 new compounds, 25 were tested for their affinity
for 5-HT1A and 5-HT2A receptors. The influence of structural
modifications on serotonin activity was analyzed using a non-
parameter FujitaeBan method [11], and the binding constants
of the remaining 11 derivatives were predicted on the basis of
derived equations. In addition, the pharmacological properties
of several selected compounds were evaluated in one anxiety
test and one ‘‘behavioral despair’’ test.
The serotonergic system has been consistently implicated in
the pathophysiology of a number of psychiatric disorders in-
cluding depression and anxiety [1]. Of the 13 different serotonin
receptors belonging to GPCR superfamily [2], the 5-HT1A and
5-HT2A subtypes are most frequently considered to be the
targets for anxiolytic and antidepressant drugs [3]. Indeed, 5-
HT1A agonists and partial agonists (e.g. buspirone (1) and tando-
spirone) [4], as well as 5-HT2A antagonists (e.g. ritanserin and
mirtazapine) [5] demonstrate clinical effectiveness in the treat-
ment of either disorder. However, development of agents of this
type is still a topical subject of investigations and lies within the
area of our interest. In the group of previously investigated com-
pounds, several o-methoxyphenylpiperazines (2e4) showing
a similar 5-HT1A/5-HT2A binding profile as buspirone (Fig. 1)
* Corresponding author. Tel./fax: þ48 22 628 06 79.
E-mail address: bozena.kuran@am.edu.pl (B. Kuran).
0223-5234/$ - see front matter Ó 2008 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2008.03.019

A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
153
O
N
O
O
H3CO
N
O
N
N
N
N
N
N
O
O
OC2H5
buspirone 1
2
5-HT1A: Ki = 3.8 - 56.2 nMa
5-HT1A: Ki = 26 nM
5-HT2A: Ki = 2790 nM
5-HT2A: Ki = 851 - 1210 nMa
H3CO
N
O
H3CO
H3C
H3C
O
N
N
N
N
N
O
O
O
OAc
OCH3
3
4
5-HT1A: Ki = 22 nM
5-HT2A: Ki = 770 nM
5-HT1A: Ki = 31 nM
5-HT2A: Ki = 1390 nM
a
Fig. 1. Structure and affinity data for buspirone (1) and compounds 2e4. Range of Ki values taken from PDSB Ki Database (http://pdsp.med.unc.edu/kidb.php).
2. Chemistry
4. Results and discussion
The synthesis of the target compounds 18e53 started
with the preparation of appropriate imides in the DielseAl-
der reaction. Imides 5 and 7 were obtained in a reaction of
3,5-dimethylcyclohex-2-en-1-one with 1H-pyrrole-2,5-dione,
p-toluenosulphonic acid and isopropenyl acetate followed
by hydrolysis (Scheme 1). The N-hydroxyimides 10 and
11 were initially prepared by an analogous method using
1-hydroxy-substituted 1H-pyrrole-2,5-dione (Scheme 2). Un-
fortunately, targeted imides were obtained in low yield, and,
additionally, two by-products (8 and 9) were identified.
Therefore an alternative substrate, i.e. furan-2,5-dione, was
used, and the obtained two anhydrides were subsequently
condensed with hydroxylamine, giving N-hydroxyimides 10
and 11 with good yield (Scheme 3). The standard alkylation
procedure of intermediates 5, 7, 10 and 11 with 1,4-
dibromobutane or 1,3-dibromopropane led to 4-bromobutyl
(12, 13), 3-bromopropyl (14, 15) or 3-bromopropoxy (16,
17) derivatives which were then condensed with appropriate
amines to yield the final compounds 18e53 (Scheme 4).
In general, the tested compounds were more active for 5-
HT1A receptors (Ki ¼ 10e2730 nM) than for 5-HT2A ones
(Ki ¼ 102e9720 nM). Eleven ligands showed 5-HT1A affinity
below 100 nM, but benzyl and pyrimidinyl derivatives were
practically inactive. The highest Ki value was found for the
o-methoxyphenylpiperazine derivative 18, which was also
the most selective 5-HT1A/5-HT2A ligand (Ki ratio 5-HT2A
/
5-HT1A ¼ 74). As regards to 5-HT2A receptors, only four com-
pounds displayed Ki values below 200 nM, and among them
derivative 53 could be classified as a dual 5-HT1A/5-HT2A
agent of moderate activity.
A qualitative data analysis indicated that the affinities of the
investigated compounds strongly and systematically depended
on the 13 structural variables applied (eight aryl substituents,
three linkers and two imide terminals). To quantitatively deter-
mine that relationship, we applied a FujitaeBan analysis [11] e
a simple QSAR technique that directly relates structural fea-
tures to biological activity [15]. Using that non-parameter
method, compound affinity was expressed in a logarithmic
scale (pKi) as a sum of the calculated theoretical activity of
the arbitrarily chosen reference derivative 33 (m) and activity
contributions of the respective structural fragments (aAr,
aspacer and aimide).
3. Pharmacology
The 5-HT1A and 5-HT2A receptor affinities were determined
for 25 compounds (18e30, 33, 36, 39, 42e44, 46e48, 50 and
52e53) in in vitro studies on the basis of their ability to displace
[3H]-8-OH-DPAT [8-hydroxy-2-(di-n-propylamino)tetraline]
and [3H]-ketanserin [3-{2-[4-(4-fluorobenzoyl)piperidino]e-
thyl}quinazoline-2,4(1H,3H )-dione], respectively. The results
are presented in Table 1.
The neurotoxic effects of compounds showing significant
affinity for 5-HT1A receptors (Ki < 130 nM) were quantified
by the Boissier chimney test [12]. Next, potential anxiolytic
and antidepressant activities were evaluated by a four-plate
test [13] and a forced swimming test [14] in mice, respectively.
The effect of active compounds on the spontaneous locomotor
activity of mice was also tested.
pKi ¼ m þ aAr þ aspacer þ aimide
As shown in Table 2, the results of the FujitaeBan analysis
indicated that the effect of structural modifications on the
affinity for both receptor subtypes is additive and the majority
of activity contributions a are significant at a 95% confidence
level (t-test). The most negative values were obtained for aBz
and apyrimidinyl (from ꢀ0.554 to ꢀ0.705), which reflected the
above-mentioned, and confirmed previously observed
[16,17], poor affinity of benzyl and pyrimidinyl derivatives.
The contributions of pyridyl substituent were also negative
(apyridyl[5-HT1A] ¼ ꢀ0.145 and apyridyl[5-HT2A] ¼ ꢀ0.346)
when compared to the reference phenyl fragment (aPh ¼ 0).

154
A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
Table 1
Structure, physical data and 5-HT1A and 5-HT2A binding affinities of compounds 18e53
O
N
O
O
H3C
O
CH3
CH3
imide
imide:
N
O
N
N
X
Ar
CH3
OAc
a
b
Compound
Ar
X
Imide
Yielda (%)
M.p.b (ꢁC)
Molecular formulac
Ki ꢂ SEM (nM)
5-HT1A
5-HT2A
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
a
o-OCH3ePh
Pyrimidyl
Pyridyl
Ph
eCH2e
eCH2e
eCH2e
eCH2e
eCH2e
eCH2e
eCH2e
eCH2e
eCH2e
eCH2e
eCH2e
eCH2e
e
a
a
a
a
a
a
b
b
b
b
b
b
a
a
a
a
a
a
b
b
b
b
b
b
a
a
a
a
a
a
b
b
b
b
b
b
75
57
50
78
80
80
73
67
75
78
80
89
75
78
80
78
88
89
87
85
89
86
80
78
85
88
87
86
80
82
85
60
78
61
85
83
182e184
154e155
164e165
173e174
168e169
234e235
209e210
156e157
197e198
193e194
192e193
263e264
165e166
149e150
164e165
169e170
176e177
231e232
173e175
155e157
179e180
220e221
180e181
269e270
165e166
165e166
199e200
178e179
142e143
149e150
164e165
168e170
189e190
175e176
136e137
152e153
C29H39O5N3
C26H35O4N5
C27H36O4N4
C28H37O4N3
C28H36O4N3F
C29H39O4N3
10 ꢂ 1
800 ꢂ 30
97 ꢂ 5
34 ꢂ 3
286 ꢂ 18
1416 ꢂ 75
25 ꢂ 3
1516 ꢂ 120
202 ꢂ 24
50 ꢂ 7
521 ꢂ 36
2730 ꢂ 158
35 ꢂ 4
e
737 ꢂ 49
6019 ꢂ 420
965 ꢂ 32
286 ꢂ 8
170 ꢂ 14
9720 ꢂ 650
522 ꢂ 38
3380 ꢂ 245
577 ꢂ 35
181 ꢂ 12
102 ꢂ 8
2092 ꢂ 143
1024 ꢂ 63
e
p-FePh
Benzyl
o-OCH3ePh
Pyrimidyl
Pyridyl
Ph
C27H37O4N3$HCl$3H2O
C24H33O3N5 1/2H2O
C25H34O3N4
C26H35O3N3
C26H34O3N3F
p-FePh
Benzyl
C27H37O3N3$HCl$2½H2O
C28H37O5N3$2HCl
C25H33O4N5$1/2H2O
C26H34O4N4$1/2H2O
C27H35O4N3
o-OCH3ePh
Pyrimidyl
Pyridyl
Ph
e
e
e
e
e
e
294 ꢂ 18
e
575 ꢂ 45
e
p-FePh
Benzyl
C27H34O4N3F
C28H37O4N3
e
e
e
o-OCH3ePh
Pyrimidyl
Pyridyl
Ph
e
e
C26H35O4N3
C23H31O3N5
44 ꢂ 3
e
429 ꢂ 56
e
e
C24H32O3N4
C25H33O3N3
e
e
e
344 ꢂ 12
e
e
292 ꢂ 24
e
e
p-FePh
Benzyl
e
e
C25H32O3N3F$1½H2O
C26H35O3N3$HCl$2½H2O
C28H37O6N3$2HCl$13/4H2O
C26H34O5N4$2HCl$2H2O
C27H35O5N3$2HCl$1/3H2O
C27H34O5N3F
o-OCH3ePh
Pyridyl
Ph
eOe
eOe
eOe
eOe
eOe
eOe
eOe
eOe
eOe
eOe
eOe
eOe
27 ꢂ 4
200 ꢂ 15
115 ꢂ 7
e
681 ꢂ 73
1836 ꢂ 72
375 ꢂ 19
e
p-FePh
o-FePh
m-ClePh
o-OCH3ePh
Pyridyl
Ph
C27H34O5N3F$2HCl$1/2H2O
C27H34O5N3Cl$2HCl$1H2O
C26H35O5N3$2HCl
C24H32O4N4$2HCl
C25H33O4N3$2HCl
C25H32O4N3F$2HCl$1½H2O
C25H32O4N3F$2HCl$1/2H2O
C25H32O4N3Cl$2HCl
80 ꢂ 9
37 ꢂ 3
124 ꢂ 14
e
1073 ꢂ 62
376 ꢂ 29
637 ꢂ 48
e
616 ꢂ 28
e
331 ꢂ 24
92 ꢂ 12
300 ꢂ 25
e
910 ꢂ 57
110 ꢂ 9
p-FePh
o-FePh
m-ClePh
Free base.
Salt.
Anal. C, H, N.
b
c
Both ortho-substituted aromatic moieties had a positive impact
on 5-HT1A affinity (ao-OCH ePh ¼ 0:459; ao-FePh ¼ 0.109), but
atom into the spacer structure was not relevant to affinities for
both those receptors.
Only two different imide terminals were investigated, and
their mutual relationship was established (in relation to imide
a) as strong negative contribution of imide b on 5-HT1A recep-
tors and favorable influence on 5-HT2A ones.
The results discussed above are in line with the general
view on the serotonin receptor affinity of arylpiperazine deriv-
atives; however, additional information on structural features
important for 5-HT2A activity (i.e. presence of imide b) should
be helpful in designing more active agents.
Excellent correlations between calculated and experimental
affinities were obtained for both receptors (r2 ¼ 0.957 and
3
they produced an opposite effect in the case of 5-HT2A recep-
tors (ao-OCH ePh ¼ ꢀ0:276; ao-FePh ¼ ꢀ0.258). Reverse influ-
3
ence was found for p-FePh, which was detrimental on 5-HT1A
and beneficial on 5-HT2A binding, whereas the m-ClePh sub-
stituent positively contributed to the affinity for either of those
serotonin receptors.
The highest activity contribution was found for the C4 alkyl
chain (in relation to the C3 spacer) for 5-HT1A subtype (aC4[5-
HT1A] ¼ 0.483); that fragment also showed positive contribution
to 5-HT2A receptors, but its value was lower (aC4[5-
HT2A] ¼ 0.168). On the other hand, introduction of an oxygen

A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
155
O
O
CH3
O
O
OAc
isopropenyl
acetate
H3C
H3C
NH
N H
NH
+
+
p-TSA
H3C
CH3
O
O
O
OAc
5
CH3
6
hydrolysis
O
CH3
O
O
H3C
H3C
NH
NH
+
O
O
OAc
CH3
5
7
Scheme 1. Synthesis of imides 5 and 7.
0.960 for 5-HT1A and 5-HT2A, respectively), and next, binding
constants of the remaining 11 compounds were predicted. The
results presented in Table 3 and Fig. 2 show that these addi-
tional compounds should display fairly low 5-HT1A affinity,
however, the predicted potencies of 40 and 52 towards 5-
HT2A receptors had relatively high values (pKi(pred.) ¼ 6.85
and 6.88, respectively). The experimentally measured affini-
ties of these two compounds (pKi(exp.) ¼ 7.06 and 6.94, respec-
tively) were close to the predicted ones, which confirmed the
quality and usefulness of the developed model.
As an integral part of our investigation, the therapeutic po-
tential of agents active in vitro (of Ki < 130 nM) was screened
in one dose (equivalent to 0.1 of LD50) in a functional test of
neurotoxicity and in two models of anxiety and depression in
mice. No neurotoxic effects were detected in the chimney test
for any of the 14 investigated compounds (18, 20, 21, 24, 27,
28, 30, 36, 42, 44, 46e48, 53), nor did any of them (adminis-
tered in the screening dose) show anxiolytic properties in the
four-plate test in mice. Strong antidepressant-like action was
observed for 46 and 48, while 18 only slightly shortened the to-
tal immobility time of mice. These effects seem to be specific,
since screened compounds did not affect the locomotor activity
with respect to the control group. Furthermore, it was found that
the antidepressant effects produced by 46 and 48 were dose-
dependent up to 0.0125 of LD50, and when given in doses of
2.5 and 5.0 mg/kg they revealed similar antidepressive profile
to imipramine in a dose 15 mg/kg (Table 4). It is rather unlikely
that the observed activity was mediated solely by 5-HT1A recep-
tors, since e in contrast to compound 18 ðKi5-HT ¼ 10 nMÞ
1A
and the other ligands tested e the two most in vivo active deriv-
atives showed only moderate affinity (Ki5-HT ¼ 80 and
1A
124 nM for 46 and 48, respectively). Indeed, many different re-
ceptor systems can be involved in antidepressant-like activity
observed in forced swimming test, and piperazine derivatives
may produce their effects via e.g. other serotonin [18], sigma
1 [19] and melanocortin-4 [20] receptors. The confirmation of
therapeutic potential and explanation of molecular mechanism
by which investigated compounds exerted their action require
further pharmacological studies.
5. Experimental
5.1. Chemistry
Melting points were determined in a capillary in Electro-
thermal 9100 apparatus and are uncorrected. The nuclear mag-
netic resonance spectra of protons (1H NMR) were recorded in
a Bruker AVANCE DMX400 spectrometer, operating at 200 or
1
400 MHz for H in CDCl3 or DMSO. Chemical shift values
are expressed in ppm (parts per million) in relation to
O
CH3
O
O
H3C
H3C
N OAc
OAc
OH
N
+
+
O
O
isopropenyl
acetate
p-TSA
O
O
OAc
CH3
hydrolysis
8
9
N OH
+
CH3
H3C
O
O
O
CH3
O
H3C
H3C
OH
N
N
+
+
O
O
OAc
CH3
10
11
Scheme 2. Synthesis of imides 8e11.

156
A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
O
O
CH3
O
O
OAc
isopropenyl
acetate
H3C
H3C
+
O
O
O
+
p-TSA
CH3
H3C
O
O
O
OAc
CH3
O
NH2OH
O
CH3
O
H3C
H3C
OH
N
+
OH
N
O
O
OAc
CH3
11
10
Scheme 3. Modified synthesis of imides 10 and 11.
tetramethylsilane as an internal standard and coupling con-
stants J are given in hertz.
A chromatographic column was filled with silica gel: Kie-
selgel 0.05e0.2 mm reinst (70e325 mesh ASTM) Merck.
ESI-MS spectra were recorded by a Mariner Perspective e
Biosystem.
Reactions were monitored by TLC on silica gel (plates with
a fluorescent indicator 254 nm, layer thickness 0.2 mm, Kie-
selgel G., Merck).
H-11), 1.79 (s, 3H, eCH3), 1.07 (dd, J ¼ 11.6, 4.4 Hz, 1H,
H(ax)-10), 0.89 (d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for
C14H17NO4: 63.87% C, 6.51% H, 5.32% N; found: 63.83%
C, 6.67% H, 5.39% N.
5.1.1.2. 1,11-Dimethyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-
trione (7). M.p. 175e175.5 ꢁC. 1H NMR (400 MHz, CDCl3) d:
8.96 (s, 1H, NH ), 3.21 (dd, J ¼ 9.2, 3.6 Hz, 1H, H-6), 2.75 (d,
J ¼ 9.6 Hz, 1H, H-2), 2.70 (m, 1H, H-7), 2.17 (m, 2H, H-9, H-
11), 2.09 (s, 1H, H-9), 1.96 (m, 1H, H(eq)-10), 1.31 (s, 3H,
eCH3), 1.10 (dd, J ¼ 14.0, 4.8 Hz, 1H, H(ax)-10), 1.0 (d,
J ¼ 7.2 Hz, 3H, eCH3). Anal. Calcd for C12H14NO3: 65.14%
C, 6.83% H, 6.33% N; found: 65.14% C, 6.69% H, 6.35% N.
5.1.1. Synthesis of imides 5 and 7
A mixture of 3,5-dimethylcyclohex-2-en-1-one (0.008 mol),
1H-pyrrole-2,5-dione (0.01 mol) and a catalytic amount of
pTSA ( p-toluenosulphonic acid) in isopropenyl acetate
(15 mL) was refluxed for 14 h. The boiling mixture was filtered
and the solvent was evaporated. The residue was crystallized
from hexane/ethyl acetate (60:40). A mixture of isomers (5
and 6) was hydrolyzed using anhydrous ethanol (10 mL) with
25% NH3 (2 mL). That mixture was refluxed for 50 min, and
when the reaction was finished the solvent was evaporated
and the crude product was recrystallized from anhydrous etha-
nol. Finally, the mixture of products 5 and 7 was separated by
column chromatography on silica gel, eluent: chloroform and
chloroform/methanol 100:0.5.
5.1.2. Synthesis of imides 10 and 11
Method 1. A mixture of 3,5-dimethylcyclohex-2-en-1-one
(0.05 mol), 1-hydroxy-1H-pyrrole-2,5-dione (0.04 mol) and
a catalytic amount of pTSA ( p-toluenosulphonic acid) in iso-
propenyl acetate (20 mL) was refluxed for 2 h. The boiling
mixture was filtered and the solvent was evaporated. The res-
idue was crystallized from hexane/ethyl acetate (60:40). The
crude product was hydrolyzed using anhydrous ethanol
(40 mL) with 25% NH3 (7 mL). The obtained mixture was
separated by column chromatography on silica gel, eluent:
chloroform and chloroform/methanol 100:0.5. Finally, four
solid products were isolated.
5.1.1.1. 8,11-Dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]un-
1
dec-8-en-1-yl acetate (5). M.p. 151 ꢁC. H NMR (400 MHz,
CDCl3) d: 8.29 (s, 1H, NH ), 5.83 (s, 1H, H-9), 3.91 (d,
J ¼ 8.2 Hz, 1H, H-2), 3.02 (m, 1H, H-6), 2.72 (m, 1H, H-7),
2.66 (m, 1H, H(eq)-10), 2.13 (s, 3H, eCOCH3), 2.01 (m, 1H,
5.1.2.1. 4-(Acetoxy)-8,11-dimethyl-3,5-dioxo-4-azatricyclo-
[5.2.2.02,6]undec-8-en-1-yl acetate (8). M.p. 146.7e
1
147 ꢁC. H NMR (400 MHz, CDCl3) d: 5.86 (s, 1H, H-9),
O
O
O
i
X
Br
X
N
N Ar
N
Y
N
N
( )n
( )n
HN
N
Ar
O
O
O
5, 7
Y = H
12, 13 X = CH2, n = 3
18 - 29 X = CH2, n = 3
10, 11 Y = OH
14, 15 X = CH2, n = 2
16, 17 X = O, n = 3
30 - 41 X = CH2, n = 2
42 - 53 X = O, n = 3
Scheme 4. Synthesis of compounds 12e53. (i) Acetonitrile, anhydrous K2CO3, 1,4-dibromobutane or 1,3-dibromopropane; (ii) acetone, anhydrous K2CO3, KI.

A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
157
Table 2
Intercept (m), individual fragment contributions (a) and statistical data ob-
tained by the FujitaeBan analysis of 25 compounds
(s, 3H, eCH3), 1.13 (dd, J ¼ 14.0, 4.4 Hz, 1H, H(ax)-10), 0.99
(d, J ¼ 7.2 Hz, 3H, eCH3), ESI-MS m/z ¼ 236.25: 236.1 (100%).
Fragment
5-HT1A
5-HT2A
5.1.3. Synthesis of imides 10 and 11
m
a
6.800 ꢂ 0.105
0.459 ꢂ 0.068
ꢀ0.554 ꢂ 0.067
ꢀ0.145 ꢂ 0.067
0
6.306 ꢂ 0.079
ꢀ0.276 ꢂ 0.066
ꢀ0.705 ꢂ 0.065
ꢀ0.346 ꢂ 0.065
0
Method 2. A mixture of 3,5-dimethylcyclohex-2-en-1-one
(0.03 mol), furan-2,5-dione (0.04 mol) and a catalytic amount
of pTSA ( p-toluenosulphonic acid) in isopropenyl acetate
(15 mL) was refluxed for 8 h. The boiling mixture was filtered
and the solvent was evaporated. The residue was separated by
column chromatography on silica gel, eluent: chloroform.
The obtained product (5.4 g) was dissolved in methanol,
next an aqueous solution of hydroxylamine (6 mL), following
Fieser method [21], was added. The reaction mixture was
heated in a water bath at 70 ꢁC for 4 h. When the reaction
was completed, the mixture was cooled and left in a fridge.
The residue was separated by column chromatography on sil-
ica gel; developing system: chloroform/methanol from 100:0.2
to 100:5. Finally, 3.6 g of 10 and 1.5 g of 11 were obtained.
Ar
o-OMeePhP
1-PP
Pyridylpiperazine
PhP
p-FePhP
BzePhP
o-FePhP
m-ClePhP
C4
ꢀ0.353 ꢂ 0.067
ꢀ0.664 ꢂ 0.067
0.109 ꢂ 0.067a
0.270 ꢂ 0.067
0.483 ꢂ 0.095
0
0.157 ꢂ 0.065
ꢀ0.705 ꢂ 0.065
ꢀ0.258 ꢂ 0.065
0.127 ꢂ 0.065a
0.168 ꢂ 0.092a
0
Spacer
Imide
C3
C3eO
a
ꢀ0.001 ꢂ 0.091a
0.025 ꢂ 0.088a
0
0
b
ꢀ0.290 ꢂ 0.056
25
0.957
0.275 ꢂ 0.054
25
0.960
Number of compounds
Correlation coefficient (r2)
Standard error of regression
Calculated F0.01 ratio
a
0.108
31.09
0.079
33.48
5.1.4. Synthesis of alkyl derivatives 12e17
a did not pass the t-test at a 95% confidence level.
An appropriate imide (0.01 mol) was dissolved in acetoni-
trile (30 mL), next anhydrous K2CO3 (0.01 mol) and 1,4-di-
bromobutane (0.03 mol) or 1,3-dibromopropane (0.05 mol)
were added, respectively. The mixture was refluxed for 7e
15 h. When the reaction was completed, the mixture was
filtered and the solvent was evaporated. The residue was puri-
fied by column chromatography, eluent: chloroform.
4.02 (d, J ¼ 8.4 Hz, 1H, H-2), 3.09 (m, 1H,
H-6), 2.77 (s, 1H, H-7), 2.73 (m, 1H, H(eq)-10), 2.29 (s,
3H, H-10), 2.13 (s, 3H, eOCOCH3), 2.06 (m, 1H, H-11),
1.80 (s, 3H, eCH3), 1.12 (dd, J ¼ 12.0, 4.4 Hz, 1H, H(ax)
-
10), 0.91 (d, J ¼ 6.8 Hz, 3H, eCH3). ESI-MS m/z ¼ 321.3:
344.1 (100%), 322.2 (39%). Anal. Calcd for C16H19NO6:
59.80% C, 5.96% H, 4.36% N; found: 59.94% C, 5.58%
H, 4.30% N.
5.1.4.1. 4-(4-Bromobutyl)-8,11-dimethyl-3,5-dioxo-4-azatricy-
clo[5.2.2.02,6]undec-8-en-1-yl acetate (12). M.p. 70.3e
71 ꢁC. 1H NMR (200 MHz, CDCl3) d: 5.78 (s, 1H, H-9),
3.88 (d, J ¼ 8.2 Hz, 1H, H-2), 3.52e3.36 (m, 4H, H-10, H-
40), 2.97 (dd, J ¼ 8.2, 3.6 Hz, 1H, H-6), 2.77e2.65 (m, 2H,
H-7, H(eq)-10), 2.15 (s, 3H, eOCOCH3), 2.10e1.98 (m, 1H,
H-11), 1.77 (d, J ¼ 1.8 Hz, 3H, eCH3), 1.74e1.60 (m, 4H,
H-20, HeC30), 1.09 (dd, J ¼ 12, 4.6 Hz, 1H, H(ax)-10), 0.90
(d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for C18H24NBrO4:
54.27% C, 6.07% H, 3.52% N; found: 54.26% C, 6.24% H,
3.66% N.
5.1.2.2. 4-(Acetoxy)-1,11-dimethyl-4-azatricyclo[5.2.2.02,6]un-
decane-3,5,8-trione (9). M.p. 197e198 ꢁC. 1H NMR
(400 MHz, CDCl3) d: 3.27 (m, 1H, H-6), 2.83 (m, 1H,
H-2), 2.74 (m, 1H, H-7), 2.32 (s, 3H, H-10), 2.20 (m,
1H, H-9), 2.03e1.97 (m, 3H, H-9, H(eq)-10, H-11), 1.32
(s, 3H, eCH3), 1.16 (m, 1H, H(ax)-10), 1.02 (d,
J ¼ 7.2 Hz, 3H, eCH3), ESI-MS m/z ¼ 279.29: 302.1
(100%), 280.1 (24%). Anal. Calcd for C14H17NO5:
60.11% C, 6.13% H, 5.01% N; found: 59.95% C, 5.90%
H, 4.93% N.
5.1.4.2. 4-(4-Bromobutyl)-1,11-dimethyl-4-azatricyclo[5.2.2.02,6]-
undecane-3,5,8-trione (13). Yield 60%, oil. 1H NMR
(400 MHz, CDCl3) d: 3.43 (m, 2H, H-10), 3.34 (m, 2H, H-40),
3.09 (dd, J ¼ 9.4, 3.2 Hz, 1H, H-6), 2.63 (m, 2H, H-2, H-7),
2.13 (m, 1H, H-9), 1.91 (m, 3H, H-9, H(eq)-10, H-11), 1.72 (m,
2H, H-20), 1.61 (m, 2H, H-30), 1.27 (s, 3H, eCH3), 1.06 (dd,
J ¼ 14.4, 4.0 Hz, 1H, H(ax)-10), 0.93 (d, J ¼ 7.2 Hz, 3H,
eCH3). Anal. Calcd for C16H22NO3Br: 53.94% C, 6.22% H,
3.93% N; found: 53.79% C, 6.29% H, 3.98% N.
5.1.2.3. 4-Hydroxy-8,11-dimethyl-3,5-dioxo-4-azatricyclo-
[5.2.2.02,6]undec-8-en-1-yl acetate (10). M.p. 119e
1
120 ꢁC. H NMR (400 MHz, CDCl3) d: 5.76 (s, 1H, H-9),
3.86 (d, J ¼ 8.0 Hz, 1H, H-2), 2.99 (dd, J ¼ 8.0, 3.2 Hz,
1H, H-6), 2.72 (s, 1H, H-7), 2.65 (m, 1H, H(eq)-10), 2.11
(m, 4H, eOH, eOCOCH3), 2.03 (m, 1H, H-11), 1.74 (m,
3H, eCH3), 1.07 (m, 1H, H(ax)-10), 0.87 (d, J ¼ 6.8 Hz,
3H, eCH3). Anal. Calcd for C14H17NO5: 60.20% C,
6.09% H, 5.01% N; found: 60.36% C, 6.15% H, 4.96% N.
5.1.4.3. 4-(3-Bromopropyl)-8,11-dimethyl-3,5-dioxo-4-azatri-
cyclo[5.2.2.02,6]undec-8-en-1-yl acetate (14). Yield 60%,
5.1.2.4. 4-Hydroxy-1,11-dimethyl-4-azatricyclo[5.2.2.02,6
]
1
m.p. 106.9e107.2 ꢁC. H NMR (200 MHz, CDCl3) d: 5.78
1
undecane-3,5,8-trione (11). M.p. 189.5e190.4 ꢁC. H NMR
(400 MHz, CDCl3) d: 3.22 (dd, J ¼ 3.2, 8.8 Hz, 1H, H-6), 2.77
(d, J ¼ 9.2 Hz, 1H, H-2), 2.71 (m, 1H, H-7), 2.22 (m, 1H,
eOH ), 2.12 (m, 2H, H-9), 2.00 (m, 2H, H(eq)-10, H-11), 1.33
(s, 1H, H-9), 3.90 (d, J ¼ 8.4 Hz, 1H, H-2), 3.54 (t,
J ¼ 6.8 Hz, 2H, H-10), 3.28 (t, J ¼ 6.9 Hz, 2H, H-30), 2.98
(dd, J ¼ 3.2, 8.6 Hz, 1H, H-6), 2.76 (m, 1H, H-7), 2.72e2.60
(m, 1H, H(eq)-10), 2.15 (s, 3H, eOCOCH3), 2.11e1.90 (m,

158
A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
Table 3
The observed and calculated affinity (pKi) for 5-HT1A and 5-HT2A receptors of compounds from the training set, and predicted pKi for the remaining compounds
Compound
5-HT1A
pKi
5-HT2A
pKi
Residual
Std. Err.
Residual
Std. Err.
Observed
Predicted
Observed
Predicted
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
8.00
6.10
7.01
7.47
6.54
5.85
7.60
5.82
6.69
7.30
6.28
5.56
7.46
8.06
6.14
7.12
7.40
6.59
5.89
7.70
5.78
6.76
7.04
6.23
5.53
7.46
5.54
6.52
6.80
6.00
5.29
7.10
5.18
6.17
6.44
5.64
4.93
7.46
6.52
6.80
5.99
7.05
7.41
7.10
6.16
6.44
5.64
6.69
7.05
ꢀ0.06
ꢀ0.04
ꢀ0.11
0.07
0.10
0.13
0.11
0.10
0.13
0.13
0.10
0.13
0.11
0.10
0.13
0.13
0.10
6.13
5.22
6.02
6.54
6.77
5.01
6.28
5.47
6.24
6.74
6.99
5.68
5.99
6.16
5.21
5.95
6.47
6.75
5.21
6.42
5.48
6.22
6.73
7.01
5.48
5.99
5.05
5.79
6.31
6.59
5.05
6.26
5.31
6.06
6.57
6.85
5.32
6.02
5.82
6.33
6.61
5.87
6.56
6.28
5.34
6.60
6.88
6.14
6.82
ꢀ0.02
0.01
0.06
0.08
0.10
0.08
0.08
0.10
0.10
0.07
0.10
0.09
0.07
0.10
0.10
0.08
0.08
0.02
ꢀ0.05
ꢀ0.04
ꢀ0.10
0.04
ꢀ0.20
ꢀ0.14
ꢀ0.01
0.02
ꢀ0.07
0.26
0.05
0.01
ꢀ0.02
0.20
0.00
0.04
ꢀ0.01
6.53
7.36
6.46
ꢀ0.27
0.25
0.10
0.10
0.10
6.24
6.37
6.53
ꢀ0.07
0.11
0.08
0.08
0.08
0.02
ꢀ0.04
7.57
6.70
6.94
0.11
0.18
0.14
0.10
0.12
0.10
6.17
5.74
6.43
0.15
ꢀ0.08
0.10
0.07
0.09
0.07
7.10
7.43
6.91
0.05
0.02
0.13
0.13
0.10
5.97
6.42
6.20
0.10
ꢀ0.13
ꢀ0.09
0.10
0.10
0.08
ꢀ0.20
6.21
ꢀ0.23
0.10
6.52
ꢀ0.07
0.08
6.64
7.04
ꢀ0.05
ꢀ0.02
0.13
0.13
6.04
6.96
ꢀ0.10
0.10
0.10
0.13
3H, H-11, H-20), 1.78 (d, J ¼ 1.6 Hz, 3H, eCH3), 1.08 (dd,
J ¼ 12, 4.6 Hz, 1H, H(ax)-10), 0.90 (d, J ¼ 7.0 Hz, 3H,
eCH3). Anal. Calcd for C17H22NO4Br: 53.14% C, 5.77% H,
3.64% N; found: 53.12% C, 5.54% H, 3.65% N.
H-9), 4.15e4.11 (m, 2H, H-10), 3.88 (d, J ¼ 8.4 Hz, 1H, H-
2), 3.60 (t, J ¼ 6.4 Hz, 2H, H-30), 2.98e2.95 (dd, J ¼ ¼ 8.4,
2.8 Hz, 1H, H-6), 2.77 (s, 1H, H-7), 2.71 (t, J ¼ 10.8 Hz,
1H, H(eq)-10), 2.17 (m, 5H, eOCOCH3, H-20), 2.05 (m, 1H,
H-11), 1.81 (s, 3H, eCH3), 1.13e1.09 (dd, J ¼ 12.0, 4.4 Hz,
1H, H(ax)-10), 0.90 (d, J ¼ 8.8 Hz, 3H, eCH3), ESI-MS m/
z ¼ 400.26: 422.1 (100%), 424.1 (96%). Anal. Calcd for
C17H22NBrO5: 51.01% C, 5.54% H, 3.50% N; found:
51.21% C, 5.28% H, 3.45% N.
5.1.4.4.
4-(3-Bromopropyl)-1,11-dimethyl-4-azatricyclo-
[5.2.2.02,6]undecane-3,5,8-trione (15). Yield 83%, m.p.
1
125.9e126.3 ꢁC. H NMR (400 MHz, CDCl3) d: 3.61 (m, 2H,
H-10), 3.32 (t, J ¼ 6.4 Hz, 2H, H-30), 3.15 (dd, J ¼ 9.2, 3.2 Hz,
1H, H-6), 2.70 (m, 2H, H-2, H-7), 2.19 (m, 1H, H-9), 2.15e
1.94 (m, 5H, H-9, H(eq)-10, H-11, H-20), 1.34 (s, 3H, eCH3),
1.13 (dd, J ¼ 14.4, 4.0 Hz, 1H, H(ax)-10), 1.00 (d, J ¼ 7.2 Hz,
3H, eCH3). Anal. Calcd for C15H20NO3Br: 52.64% C, 5.89%
H, 4.09% N; found: 52.41% C, 5.34% H, 4.47% N.
5.1.4.6.
4-(3-Bromopropoxy)-1,11-dimethyl-4-azatricyclo-
[5.2.2.02,6]undecane-3,5,8-trione (17). Yield 74%, m.p.
118e119 ꢁC. 1H NMR (400 MHz, CDCl3) d: 4.16 (t,
J ¼ 5.6 Hz, 2H, H-10), 3.65e3.57 (m, 2H, H-30), 3.15 (dd,
J ¼ 9.2, 2.8 Hz, 1H, H-6), 2.71 (m, 2H, H-2, H-7), 2.21e
2.17 (m, 3H, H-9, H-20), 2.05e1.97 (m, 3H, H-9, H(eq)-10,
H-11), 1.34 (s, 3H, eCH3), 1.16 (dd, J ¼ 13.6, 4.4 Hz, 1H,
H(ax)-10), 1.01 (d, J ¼ 6.8 Hz, 3H, eCH3). ESI-MS m/
5.1.4.5. 4-(3-Bromopropoxy)-8,11-dimethyl-3,5-dioxo-4- aza-
tricyclo[5.2.2.02,6]undec-8-en-1-yl acetate (16). Yield 80%,
1
m.p. 94e95 ꢁC. H NMR (400 MHz, CDCl3) d: 5.84 (s, 1H,

A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
159
B
A
18
8.0
7.0
6.0
5.0
8.0
52
7.0
40
6.0
5.0
5.0
6.0
7.0
8.0
5.0
6.0
7.0
8.0
Observed pKi
Observed pKi
Fig. 2. The correlation between the observed and calculated pKi (ꢃ), and the predicted pKi (B) of the remaining compounds, for (A) 5-HT1A and (B) 5-HT2A
receptors.
z ¼ 358.24: 382.1 (100%), 380.1 (97%). Anal. Calcd for
C15H20NO4Br: 50.29% C, 5.63% H, 3.91% N; found:
50.46% C, 5.26% H, 3.78% N.
compound was purified by column chromatography, eluent:
chloroform, chloroform/methanol 50:0.2.
5.1.5.1. 4-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-8,11-
dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl
acetate (18). Yield 75%, m.p. 111.2e112 ꢁC. 1H NMR
(200 MHz, CDCl3) d: 6.22 (m, 4H, H-arom.), 5.77 (s, 1H,
H-9), 3.82 (m, 4H, eOCH3, H-2), 3.42 (m, 2H, H-10),
3.08 (m, 4H, H-piper.), 2.94 (dd, J ¼ 8.4, 3.2 Hz, 1H, H-
6), 2.75 (m, 1H, H-7), 2.69 (m, 1H, H(eq)-10), 2.60 (m,
4H, H-piper.), 2.38 (t, J ¼ 6.6 Hz, 2H, H-40), 2.14 (s, 3H,
eOCOCH3), 2.02 (m, 1H, H-11), 1.76 (d, J ¼ 7.6 Hz, 3H,
eCH3), 1.49 (m, 4H, H-20, H-30), 1.07 (dd, J ¼ 12, 4.6 Hz,
1H, H(ax)-10), 0.88 (d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd
for C29H39O5N3: 68.34% C, 7.71% H, 8.24% N; found:
68.32% C, 7.75% H, 8.14% N.
5.1.5. Synthesis of 4-arylpiperazinyl derivatives of
N-substituted imides
To a mixture of N-bromoalkanyl/-alkanolimide (0.01 mol),
a powdered anhydrous K2CO3 (0.01 mol), a catalytic amount
of KI in acetone (30 mL) and an appropriate amine
(0.01 mol) were added. The reaction mixture was stirred at
room temperature for 10e20 h. Then, an inorganic residue
was filtered off and the solvent was evaporated. The obtained
Table 4
Antidepressive effects of compounds 18, 46 and 48 in the ‘‘forced swimming’’
test in mice
5.1.5.2.
4-{4-[4-(2-Pyrimidyl)piperazin-1-yl]butyl}-8,11-di-
Treatmenta
Dose (mg/kg ip)
The total
immobility timeb (s)
methyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl ace-
tate (19). Yield 57%, oil. 1H NMR (200 MHz, CDCl3) d:
8.30 (d, J ¼ 4.6 Hz, 2H, H-arom.), 6.47 (t, J ¼ 4.6 Hz, 1H,
H-arom.), 5.77 (s, 1H, H-9), 3.85 (m, 5H, H-2, H-piper.),
3.42 (t, J ¼ 6.6 Hz, 2H, H-10), 2.96 (dd, J ¼ 8.2, 3.2 Hz, 1H,
H-6), 2.75 (m, 1H, H-7), 2.69 (m, 1H, H(eq)-10), 2.48 (m,
4H, H-piper.), 2.36 (t, J ¼ 6.8 Hz, 2H, H-40), 2.15 (s, 3H,
eOCOCH3), 2.09e1.98 (m, 1H, H-11), 1.76 (d, J ¼ 1.8 Hz,
3H, eCH3), 1.49 (m, 4H, H-20, H-C30), 1.08 (dd, J ¼ 12,
4.6 Hz, 1H, H(ax)-10), 0.89 (d, J ¼ 6.8 Hz, 3H, eCH3). Anal.
Calcd for C26H35O4N5: 64.85% C, 7.33% H, 14.54% N;
found: 64.92% C, 7.33% H, 14.07% N.
Control
Imipramine
18
e
140.8 ꢂ 9.54
69.5 ꢂ 16.1*
15
5
10
113.8 ꢂ 18.2
71.7 ꢂ 22.7*
46
1.25
2.5
5
114.3 ꢂ 17.4
56.8 ꢂ 16.1*
48.3 ꢂ 18.7*
27.5 ꢂ 7.1*#
18.4 ꢂ 7.8*#
10
20
48
1.25
2.5
5
123.7 ꢂ 15.0
83.5 ꢂ 8.8*
63.5 ꢂ 10.1*
31.2 ꢂ 9.2*#
29.4 ꢂ 7.6*#
5.1.5.3. 4-{4-[4-(2-Pyridyl)piperazin-1-yl]butyl}-8,11-dimethyl-
10
20
3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl
acetate
(20). Yield 50%, oil. 1H NMR (200 MHz, CDCl3) d: 8.19
(m, 1H, H-arom.), 7.47 (m, 1H, H-arom.), 6.62 (m, 2H, H-
arom.), 5.77 (s, 1H, H-9), 3.87 (d, J ¼ 8.4 Hz, 1H, H-2), 3.53
*#p < 0.001; *comp. with control group; #comp. with imipramine.
a
Imipramine and investigated compounds were given 30 min before the test.
The data represent mean ꢂ SEM.
b

160
A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
(m, 4H, H-piper.), 3.42 (t, J ¼ 6.7 Hz, 2H, H-10), 2.96 (dd,
J ¼ 8.4, 3.2 Hz, 1H, H-6), 2.75 (m, 1H, H-7), 2.66 (m, 1H,
H(eq)-10), 2.53 (m, 4H, H-piper.), 2.37 (t, J ¼ 6.6 Hz, 2H, H-
40), 2.15 (s, 3H, eOCOCH3), 2.09e1.98 (m, 1H, H-11), 1.76
(d, J ¼ 1.4 Hz, 3H, eCH3), 1.49 (m, 4H, H-20, H-30), 1.08
(dd, J ¼ 12, 4.6 Hz, 1H, H(ax)-10), 0.89 (d, J ¼ 7.0 Hz, 3H,
eCH3). Anal. Calcd for C27H36O4N4: 67.48% C, 7.55% H,
11.66% N; found: 67.16% C, 7.57% H, 11.43% N.
J ¼ 9.2 Hz, 1H, H-7), 2.45 (m, 1H, H-2), 2.20 (m, 1H, H-9),
2.11e2.06 (m, 1H, H(eq)-10), 1.92 (m, 1H, H-11), 1.80e1.75
(m, 1H, H-9), 1.62 (m, 2H, H-30), 1.43 (m, 2H, H-20), 1.20 (s,
3H, eOCOCH3), 1.05 (dd, J ¼ 13.2, 4.8 Hz, 1H, H(ax)-10),
0.87 (d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for C27H37O4N3-
$HCl$3H2O: 58.10% C, 7.58% H, 7.53% N; found: 58.76% C,
6.99% H, 7.75% N.
5.1.5.8. 4-{4-[4-(2-Pyrimidyl)piperazin-1-yl]butyl}-1,11-dimethyl-
4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (25). Yield 67%,
m.p. 91e92 ꢁC. 1H NMR (400 MHz, CDCl3) d: 8.26 (d,
J ¼ 4.8 Hz, 2H, H-arom.), 6.45 (t, J ¼ 4.6 Hz, 1H, H-arom.),
3.80 (m, 4H, H-piper.), 3.45 (m, 2H, H-10), 3.10 (dd, J ¼ 9.2,
2.8 Hz, 1H, H-6), 2.69 (m, 1H, H-7), 2.65 (d, J ¼ 9.2 Hz, 1H,
H-2), 2.46 (t, J ¼ 4.6 Hz, 4H, H-piper.), 2.34 (t, J ¼ 7.0 Hz, 2H,
H-40), 2.16 (m, 1H, H-9), 1.95 (m, 3H, H-9, H(eq)-10, H-11),
1.48 (m, 4H, H-20, H-30), 1.31 (s, 3H, eCH3), 1.09 (dd, J ¼ 14,
4.4 Hz, 1H, H(ax)-10), 0.97 (d, J ¼ 6.8 Hz, 3H, eCH3). Anal.
Calcd for C24H33O3N5$1/2H2O: 64.26% C, 7.64% H, 15.61%
N; found: 64.34% C, 7.38% H, 14.69% N.
5.1.5.4. 4-[4-(4-Phenylpiperazin-1-yl)butyl]-8,11-dimethyl-3,
5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl
acetate
1
(21). Yield 78%, m.p. 111.8e112 ꢁC. H NMR (200 MHz,
CDCl3) d: 7.26 (m, 2H, H-arom.), 6.95 (m, 3H, H-arom.),
5.77 (s, 1H, H-9), 3.86 (d, J ¼ 8.4 Hz, 1H, H-2), 3.42 (t,
J ¼ 6.6 Hz, 2H, H-10), 3.19 (m, 4H, H-piper.), 2.95 (dd,
J ¼ 8.4, 3.2 Hz, 1H, H-6), 2.75 (m, 1H, H-7), 2.69 (m, 1H,
H(eq)-10), 2.58 (m, 4H, H-piper.), 2.38 (t, J ¼ 6.7 Hz, 2H, H-
40), 2.15 (s, 3H, eOCOCH3), 2.09e1.97 (m, 1H, H-11),
1.76 (d, J ¼ 1.8 Hz, 3H, eCH3), 1.49 (m, 4H, H-20, H-30),
1.08 (dd, J ¼ 12, 4.4 Hz, 1H, H(ax)-10), 0.89 (d, J ¼ 7.0 Hz,
3H, eCH3). Anal. Calcd for C28H37O4N3: 70.12% C, 7.78%
H, 8.76% N; found: 69.74% C, 7.53% H, 8.78% N.
5.1.5.9. 4-{4-[4-(2-Pyridyl)piperazin-1-yl]butyl}-1,11-dimethyl-
4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
(26). Yield
1
5.1.5.5. 4-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-8,11-
dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl
acetate (22). Yield 80%, m.p. 100.8e101 ꢁC. 1H NMR
(200 MHz, CDCl3) d: 6.90 (m, 4H, H-arom.), 5.77 (s, 1H,
H-9), 3.87 (d, J ¼ 8.4 Hz, 1H, H-2), 3.42 (t, J ¼ 6.7 Hz,
2H, H-10), 3.11 (m, 4H, H-piper.), 2.96 (dd, J ¼ 8.2,
75%, m.p. 125.8e126.2 ꢁC. H NMR (400 MHz, CDCl3) d:
8.18 (m, 1H, H-arom.), 7.47 (m, 1H, H-arom.), 6.61 (m, 2H,
H-arom.), 3.50 (m, 6H, H-10, H-piper.), 3.11 (dd, J ¼ 9.6,
2.8 Hz, 1H, H-6), 2.72 (m, 1H, H-7), 2.67 (d, J ¼ 9.2 Hz, 1H,
H-2), 2.53 (m, 4H, H-piper.), 2.38 (t, J ¼ 7.0 Hz, 2H, H-40),
2.18 (m, 1H, H-9), 1.97 (m, 3H, H-9, H(eq)-10, H-11), 1.51
(m, 4H, H-20, H-30), 1.33 (s, 3H, eCH3), 1.11 (dd, J ¼ 14.0,
4.4 Hz, 1H, H(ax)-10), 1.00 (d, J ¼ 7.2 Hz, 3H, eCH3). Anal.
Calcd for C25H34O3N4: 68.47% C, 7.81% H, 12.77% N; found:
68.70% C, 7.77% H, 12.66% N.
3.0 Hz, 1H, H-6), 2.75 (m, 1H, H-7), 2.66 (m, 1H, H(eq)
-
10), 2.57 (m, 4H, H-piper.), 2.37 (t, J ¼ 6.7 Hz, 2H, H-40),
2.15 (s, 3H, eOCOCH3), 2.09e1.98 (m, 1H, H-11), 1.76
(d, J ¼ 1.4 Hz, 3H, eCH3), 1.49 (m, 4H, H-20, H-30), 1.08
(dd, J ¼ 12, 4.6 Hz, 1H, H(ax)-10), 0.90 (d, J ¼ 7.0 Hz, 3H,
eCH3). Anal. Calcd for C28H36O4N3F: 67.58% C, 7.29%
H, 8.44% N; found: 67.80% C, 7.23% H, 8.33% N.
5.1.5.10. 4-[4-(4-Phenylpiperazin-1-yl)butyl]-1,11-dimethyl-4-
azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (27). Yield 78%,
1
m.p. 159.8e160.2 ꢁC. H NMR (400 MHz, CDCl3) d: 7.25
5.1.5.6. 4-[4-(4-Benzylpiperazin-1-yl)butyl]-8,11-dimethyl-3,5-
(m, 2H, H-arom.), 6.92 (d, J ¼ 8.0 Hz, 2H, H-arom.), 6.84
(t, J ¼ 7.2 Hz, 1H, H-arom.), 3.49 (m, 2H, H-10), 3.19 (t,
J ¼ 4.6 Hz, 4H, H-piper.), 3.11 (dd, J ¼ 9.2, 3.2 Hz, 1H, H-
6), 2.72 (d, J ¼ 2.8 Hz, 1H, H-7), 2.66 (d, J ¼ 9.2 Hz, 1H,
H-2), 2.58 (t, J ¼ 4.6 Hz, 4H, H-piper.), 2.38 (t, J ¼ 7.2 Hz,
2H, H-40), 2.18 (m, 1H, H-9), 1.97 (m, 3H, H-9, H(eq)-10,
H-11), 1.50 (m, 4H, H-20, H-30), 1.33 (s, 3H, eCH3), 1.11
(dd, J ¼ 4.8, 13.6 Hz, 1H, H(ax)-10), 0.99 (d, J ¼ 7.2 Hz, 3H,
eCH3). Anal. Calcd for C26H35O3N3: 71.37% C, 8.06% H,
9.60% N; found: 70.89% C, 8.36% H, 9.56% N.
dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl
acetate
1
(23). Yield 80%, m.p. 103.5e104.8 ꢁC. H NMR (200 MHz,
CDCl3) d: 7.30 (m, 5H, H-arom.), 5.75 (s, 1H, H-9), 3.85 (d,
J ¼ 8.4 Hz, 1H, H-2), 3.50 (s, 2H, H-50), 3.39 (t, J ¼ 6.8 Hz,
2H, H-10), 2.94 (dd, J ¼ 8.4, 3.2 Hz, 1H, H-6), 2.75 (m, 1H,
H-7), 2.65 (m, 1H, H(eq)-10), 2.46 (m, 8H, H-piper.), 2.31 (t,
J ¼ 7.0 Hz, 2H, H-40), 2.14 (s, 3H, eOCOCH3), 2.09e1.97
(m, 1H, H-11), 1.75 (d, J ¼ 1.4 Hz, 3H, eCH3), 1.44 (m,
4H, H-20, H-30), 1.08 (dd, J ¼ 12, 4.6 Hz, 1H, H(ax)-10), 0.89
(d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for C29H39O4N3:
70.56% C, 7.96% H, 8.51% N; found: 70.79% C, 7.79% H,
8.59% N.
5.1.5.11. 4-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-1,11-
dimethyl-4-azatricyclo[5.2.2.02,6
]
undecane-3,5,8-trione
1
(28). Yield 80%, m.p. 110.8e111.5 ꢁC. H NMR (400 MHz,
CDCl3) d: 6.94 (m, 2H, H-arom.), 6.86 (m, 2H, H-arom.),
3.49 (m, 2H, H-10), 3.11 (m, 5H, H-6, H-piper.), 2.71 (m,
1H, H-7), 2.66 (d, J ¼ 9.6 Hz, 1H, H-2), 2.57 (t, J ¼ 4.8 Hz,
4H, H-piper.), 2.38 (t, J ¼ 7.2 Hz, 2H, H-40), 2.18 (m, 1H,
H-9), 1.97 (m, 3H, H-9, H(eq)-10, H-11), 1.50 (m, 4H, H-20,
H-30), 1.33 (s, 3H, eCH3), 1.11 (dd, J ¼ 14, 4.4 Hz, 1H,
5.1.5.7. 4-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-1,11-di-
methyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (24). Yield
1
73%, m.p. 209e210 ꢁC. H NMR (400 MHz, DMSO) d: 10.75
(s, 1H, HCl), 7.04e6.89 (m, 4H, H-arom.), 5.31 (m, 4H, H-
piper.), 3.79 (s, 3H, eOCH3), 3.47 (d, J ¼ 9.2 Hz, 2H, H-10),
3.34 (m, 2H, H-40), 3.08 (m, 5H, H-6, H-piper.), 2.80 (d,

A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
161
H(ax)-10), 0.99 (d, J ¼ 7.2 Hz, 3H, eCH3). Anal. Calcd for
C26H34O3N3F: 68.55% C, 7.52% H, 9.22% N; found:
68.39% C, 7.80% H, 9.30% N.
2H2O: 65.66% C, 7.34% H, 11.78% N; found: 65.01% C,
7.40% H, 11.28% N.
5.1.5.16. 4-[3-(4-Phenylpiperazin-1-yl)propyl]-8,11-dimethyl-
5.1.5.12. 4-[4-(4-Benzylpiperazin-1-yl)butyl]-1,11-dimethyl-4-
3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl
acetate
azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (29). Yield 89%,
(33). Yield 78%, m.p. 95e95.5 ꢁC. 1H NMR (400 MHz,
CDCl3) d: 7.26 (t, J ¼ 8.0 Hz, 2H, H-arom.), 6.92 (d,
J ¼ 8.4 Hz, 2H, H-arom.), 6.85 (t, J ¼ 7.2 Hz, 1H, H-arom.),
5.77 (s, 1H, H-9), 3.86 (d, J ¼ 8.4 Hz, 1H, H-2), 3.47 (t,
J ¼ 7.2 Hz, 2H, H-10), 3.18 (t, J ¼ 4.8 Hz, 4H, H-piper.),
2.96 (dd, J ¼ 8.4, 2.8 Hz, 1H, H-6), 2.75 (m, 1H, H-7), 2.69
(m, 1H, H(eq)-10), 2.56 (t, J ¼ 4.6 Hz, 4H, H-piper.), 2.31 (t,
J ¼ 7.2 Hz, 2H, H-30), 2.15 (s, 3H, eOCOCH3), 2.03 (m,
1H, H-11), 1.77 (s, 3H, eCH3), 1.70 (m, 2H, H-20), 1.08
(dd, J ¼ 12, 4.4 Hz, 1H, H(ax)-10), 0.89 (d, J ¼ 6.8 Hz, 3H,
eCH3). Anal. Calcd for C27H35O4N3: 69.65% C, 7.58% H,
9.03% N; found: 69.47% C, 7.54% H, 9.12% N.
1
m.p. 263.5e264.4 ꢁC. H NMR (400 MHz, CDCl3) d: 7.64
(m, 2H, H-arom.), 7.47 (m, 3H, H-arom.), 4.19 (m, 2H, H-
40), 3.96 (m, 4H, H-piper.), 3.60e3.40 (m, 6H, H-10, H-50,
H-piper.), 3.22 (m, 1H, H-6), 3.10 (m, 2H, H-piper.), 2.70
(m, 1H, H-7), 2.19 (m, 1H, H-9), 1.98 (m, 2H, H-9, H(eq)
-
10), 1.77 (m, 1H, H-11), 1.60 (m, 4H, H-20, H-30), 1.33 (s,
3H, eCH3), 1.14 (dd, J ¼ 14, 4.0 Hz, 1H, H(ax)-10), 0.99 (d,
J ¼ 7.2 Hz, 3H, eCH3). Anal. Calcd for C27H37O3N3-
$HCl$2½H2O: 60.83% C, 7.75% H, 7.88% N; found:
60.93% C, 7.69% H, 7.89% N.
5.1.5.13. 4-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl}-8,11-
dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl ace-
5.1.5.17. 4-{3-[4-(4-Fluorophenyl)piperazin-1-yl]propyl}-8,11-
dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl ace-
1
tate (30). Yield 75%, m.p. 165e166 ꢁC. H NMR (200 MHz,
1
CDCl3) d: 13.49 (s, 1H, HCl), 7.99 (m, 1H, H-arom.), 7.40 (t,
J ¼ 7.9 Hz, 1H, H-arom.), 7.06 (m, 2H, H-arom.), 5.85 (s, 1H,
H-9), 4.81 (m, 2H, H-30), 4.03e3.82 (m, 6H, eOCH3, H-2, H-
piper.), 3.78e3.4 (m, 6H, H-10, H-piper.), 3.09 (m, 3H, H-6,
H-piper.), 2.88e2.56 (m, 2H, H-7, H(eq)-10), 2.14e1.99 (m,
6H, eOCOCH3, H-11, H-20), 1.84e1.79 (m, 3H, eCH3),
1.11e1.03 (dd, J ¼ 11.6, 5 Hz, 1H, H(ax)-10), 0.89 (d,
J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for C28H37O5N3$2HCl:
59.15% C, 6.91% H, 7.39% N; found: 59.56% C, 6.73% H,
7.44% N.
tate (34). Yield 88%, m.p. 99e100 ꢁC. H NMR (400 MHz,
CDCl3) d: 6.96 (m, 2H, H-arom.), 6.82 (m, 2H, H-arom.),
5.78 (s, 1H, H-9), 3.88 (d, J ¼ 8.3 Hz, 1H, H-2), 3.47 (t,
J ¼ 7.1 Hz, 2H, H-10), 3.10 (s, 4H, H-piper.), 2.95 (dd,
J ¼ 8.0, 2.7 Hz, 1H, H-6), 2.75 (s, 1H, H-7), 2.69 (m, 1H,
H(eq)-10), 2.58 (m, 4H, H-piper.), 2.35 (t, J ¼ 7.0 Hz, 2H, H-
30), 2.15 (s, 3H, eOCOCH3), 2.01 (m, 1H, H-11), 1.77 (s,
3H, eCH3), 1.70 (m, 2H, H-20), 1.08 (dd, J ¼ 12, 4.4 Hz, 1H,
H(ax)-10), 0.89 (d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for
C27H34O4N3F: 67.06% C, 7.09% H, 8.69% N; found: 67.03%
C, 6.87% H, 8.82% N.
5.1.5.14. 4-{3-[4-(2-Pyrimidyl)piperazin-1-yl]propyl}-8,11-di-
methyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl ace-
tate (31). Yield 78%, oil. 1H NMR (200 MHz, CDCl3) d:
8.30 (d, J ¼ 4.8 Hz, 2H, H-arom.), 6.47 (t, J ¼ 4.7 Hz, 1H,
H-arom.), 5.77 (s, 1H, H-9), 3.91e3.74 (m, 5H, H-2, H-piper.),
3.42 (t, J ¼ 6.7 Hz, 2H, H-10), 2.96 (dd, J ¼ 8.4, 3.2 Hz, 1H,
H-6), 2.75 (m, 1H, H-7), 2.72e2.61 (m, 1H, H(eq)-10), 2.47
(t, J ¼ 5.1 Hz, 4H, H-piper.), 2.35 (t, J ¼ 6.8 Hz, 2H, H-30),
2.15 (s, 3H, eOCOCH3), 2.12e1.94 (m, 1H, H-11), 1.76 (d,
J ¼ 1.4 Hz, 3H, eCH3), 1.58e1.38 (m, 2H, H-20), 1.08 (dd,
J ¼ 12, 4.4 Hz, 1H, H(ax)-10), 0.90 (d, J ¼ 7.2 Hz, 3H,
eCH3). Anal. Calcd for C25H33O4N5$1/2H2O: 63.01% C,
7.19% H, 14.69% N; found: 63.28% C, 7.26% H, 13.71% N.
5.1.5.18. 4-[3-(4-Benzylpiperazin-1-yl)propyl]-8,11-dimethyl-
3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl
acetate
(35). Yield 89%, m.p. 91e92 ꢁC. 1H NMR (400 MHz,
CDCl3) d: 7.30 (m, 4H, H-arom.), 7.26e7.23 (m, 1H, H-
arom.), 5.75 (s, 1H, H-9), 3.83 (d, J ¼ 8.4 Hz, 1H, H-2),
3.50 (s, 2H, H-40), 3.40 (t, J ¼ 7.12 Hz, 2H, H-10), 2.93 (dd,
J ¼ 8.4, 2.8 Hz, 1H, H-6), 2.74 (m, 1H, H-7), 2.68 (m, 1H,
H(eq)-10), 2.45 (m, 8H, H-piper.), 2.29 (t, J ¼ 7.2 Hz, 2H, H-
30), 2.14 (s, 3H, eOCOCH3), 2.02 (m, 1H, H-11), 1.75 (s,
3H, eCH3), 1.64 (m, 2H, H-20), 1.08 (dd, J ¼ 12, 4.4 Hz,
1H, H(ax)-10), 0.88 (d, J ¼ 7.2 Hz, 3H, eCH3). Anal. Calcd
for C28H37O4N3: 70.12% C, 7.78% H, 8.76% N; found:
70.30% C, 7.82% H, 8.88% N.
5.1.5.15.
4-{3-[4-(2-Pyridyl)piperazin-1-yl]propyl}-8,11-di-
methyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl ace-
tate (32). Yield 80%, oil. 1H NMR (400 MHz, CDCl3) d:
8.18 (d, J ¼ 3.6 Hz, 1H, H-arom.), 7.47 (m, 1H, H-arom.),
6.61 (m, 2H, H-arom.), 5.77 (s, 1H, H-9), 3.86 (d,
J ¼ 8.0 Hz, 1H, H-2), 3.53e3.46 (m, 6H, H-10, H-piper.),
2.97 (dd, J ¼ 8.4, 3.2 Hz, 1H, H-6), 2.75 (m, 1H, H-7),
2.72e2.66 (m, 1H, H(eq)-10), 2.50 (t, J ¼ 4.8 Hz, 4H, H-
piper.), 2.34 (t, J ¼ 7.2 Hz, 2H, H-30), 2.15 (s, 3H,
eOCOCH3), 2.03 (m, 1H, H-11), 1.77 (m, 3H, eCH3), 1.70
(m, 2H, H-20), 1.08 (dd, J ¼ 12, 4.4 Hz, 1H, H(ax)-10), 0.88
(d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for C26H34O4N4$1/
5.1.5.19.
4-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl}-
1,11-dimethyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
(36). Yield 87%, m.p. 106e107 ꢁC. 1H NMR (400 MHz,
CDCl3) d: 6.90 (m, 4H, H-arom.), 3.83 (s, 3H, eOCH3),
3.52 (t, J ¼ 7.2 Hz, 2H, H-10), 3.06 (m, 5H, H-6, H-piper.),
2.68 (m, 1H, H-7), 2.63 (m, 5H, H-2, H-piper.), 2.36 (t,
J ¼ 7.0 Hz, 2H, H-30), 2.15 (m, 1H, H-9), 1.94 (m, 3H, H-
9, H(eq)-10, H-11), 1.70 (m, 2H, H-20), 1.30 (s, 3H, eCH3),
1.08 (dd, J ¼ 4.8, 13.6 Hz, 1H, H(ax)-10), 0.96 (m, 3H,
eCH3). Anal. Calcd for C26H35O4N3: 68.85% C, 7.78% H,
9.26% N; found: 69.05% C, 8.04% H, 9.20% N.

162
A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
5.1.5.20.
4-{3-[4-(2-Pyrimidyl)piperazin-1-yl]propyl}-1,11-di-
(s, 1H, HCl), 7.60 (s, 2H, H-arom.), 7.45 (s, 3H, H-arom.), 4.32
(m, 2H, H-30), 3.54 (m, 8H, H-10, H-40, H-piper.), 3.36 (m, 3H,
H-6, H-piper.), 2.95 (m, 2H, H-piper.), 2.79 (m, 1H, H-2), 2.44
(m, 1H, H-7), 2.19 (m, 1H, H-9), 2.06 (d, J ¼ 18.8 Hz, 1H, H-
9), 1.88 (m, 4H, H(eq)-10, H-11, H-20), 2.00 (s, 3H, eCH3), 1.03
(m, 1H, H(ax)-10), 0.87 (d, J ¼ 4.4 Hz, 3H, eCH3). Anal. Calcd
for C26H35O3N3$HCl$2½H2O: 60.16% C, 7.96% H, 8.09% N;
found: 60.51% C, 7.29% H, 8.09% N.
methyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (37). Yield
85%, m.p. 165.8e166.2 ꢁC. 1H NMR (400 MHz, CDCl3)
d: 8.26 (d, J ¼ 4.8 Hz, 2H, H-arom.), 6.44 (t, J ¼ 4.7 Hz,
1H, H-arom.), 3.77 (t, J ¼ 4.6 Hz, 4H, H-piper.), 3.52 (t,
J ¼ 7.0 Hz, 2H, H-10), 3.10 (dd, J ¼ 3.2, 9.6 Hz, 1H, H-6),
2.69 (m, 1H, H-7), 2.65 (d, J ¼ 9.6 Hz, 1H, H-2), 2.43 (t,
J ¼ 5.0 Hz, 4H, H-piper.), 2.32 (t, J ¼ 6.8 Hz, 2H, H-30),
2.16 (m, 1H, H-9), 1.95 (m, 3H, H-9, H(eq)-10, H-11),
1.70 (m, 2H, H-20), 1.31 (s, 3H, eCH3), 1.10 (dd,
J ¼ 13.6, 4.8 Hz, 1H, H(ax)-10), 0.97 (d, J ¼ 7.2 Hz, 3H,
eCH3). Anal. Calcd for C23H31O3N5: 64.92% C, 7.34%
H, 16.46% N; found: 64.42% C, 7.24% H, 15.96% N.
5.1.5.25. 4-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propoxy}-
8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-
1
1-yl acetate (42). Yield 85%, m.p. 165.8e166.2 ꢁC. H NMR
(400 MHz, CDCl3) d: 13.47 (s, 1H, HCl), 8.20 (d, J ¼ 7.6 Hz,
1H, H-arom.), 7.46 (t, J ¼ 8.0 Hz, 1H, H-arom.), 7.06 (m, 2H,
H-arom.), 5.86 (s, 1H, H-9), 5.03 (m, 2H, H-piper.), 4.40 (m,
2H, H-piper.), 4.16 (m, 2H, H-10), 4.07 (s, 3H, eOCH3), 3.91
(d, J ¼ 8.0 Hz, 1H, H-2), 3.68e3.41 (m, 6H, H-30, H-piper.),
3.04 (dd, J ¼ 8.0, 3.2 Hz, 1H, H-6), 2.76 (m, 1H, H-7), 2.69
(t, J ¼ 11.6 Hz, 1H, H(eq)-10), 2.32 (m, 2H, H-20), 2.15 (s, 3H,
eOCOCH3), 2.05 (m, 1H, H-11), 1.81 (s, 3H, eCH3), 1.11
(dd, J ¼ 12, 4.4 Hz, 1H, H(ax)-10), 0.89 (d, J ¼ 6.8 Hz, 3H,
eCH3). Anal. Calcd for C28H37O6N3$2HCl$13/4H2O: 54.59%
C, 7.06% H, 6.82% N; found: 54.63% C, 7.30% H, 6.85% N.
5.1.5.21.
4-{3-[4-(2-Pyridyl)piperazin-1-yl]propyl}-1,11-di-
methyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (38). Yield
1
89%, m.p. 93.3e94 ꢁC. H NMR (400 MHz, CDCl3) d: 8.18
(m, 1H, H-arom.), 7.46 (m, 1H, H-arom.), 6.61 (m, 2H, H-
arom.), 3.54 (m, 6H, H-10, H-piper.), 3.12 (dd, J ¼ 9.2,
3.2 Hz, 1H, H-6), 2.72 (m, 1H, H-7), 2.67 (d, J ¼ 9.6 Hz, 1H,
H-2), 2.52 (t, J ¼ 4.6 Hz, 4H, H-piper.), 2.36 (t, J ¼ 7.0 Hz,
2H, H-30), 2.18 (m, 1H, H-9), 1.98 (m, 3H, H-9, H(eq)-10, H-
11), 1.74 (m, 2H, H-20), 1.33 (s, 3H, eCH3), 1.11 (dd,
J ¼ 13.6, 4.8 Hz, 1H, H(ax)-10), 1.00 (d, J ¼ 6.8 Hz, 3H,
eCH3). Anal. Calcd for C24H32O3N4: 67.90% C, 7.60% H,
13.20% N; found: 66.83% C, 7.72% H, 13.03% N.
5.1.5.26. 4-{3-[4-(2-Pyridyl)piperazin-1-yl]propoxy}-8,11-di-
methyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl ace-
1
tate (43). Yield 88%, m.p. 165e166 ꢁC. H NMR (400 MHz,
5.1.5.22. 4-[3-(4-Phenylpiperazin-1-yl)propyl]-1,11-dimethyl-
4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
CDCl3) d: 13.25 (s, 1H, HCl), 8.22 (d, J ¼ 5.2 Hz, 1H, H-
arom.), 8.01 (t, J ¼ 7.0 Hz, 1H, H-arom.), 7.10e7.03 (m, 2H,
H-arom.), 5.85 (s, 1H, H-9), 4.59 (m, 2H, H-piper.), 4.26 (m,
2H, H-piper.), 4.15 (m, 2H, H-10), 3.91 (d, J ¼ 8.4 Hz, 1H, H-
2), 3.76 (m, 2H, H-piper.), 3.50e3.40 (m, 2H, H-30), 3.27
(m, 2H, H-piper.), 3.04 (m, 1H, H-6), 2.76 (s, 1H, H-7), 2.69
(t, J ¼ 10.6 Hz, 1H, H(eq)-10), 2.32 (m, 2H, H-20), 2.15 (s, 3H,
eOCOCH3), 2.05 (m, 1H, H-11), 1.81 (s, 3H, eCH3), 1.11
(dd, J ¼ 12, 4.8 Hz, 1H, H(ax)-10), 0.90 (d, J ¼ 6.8 Hz, 3H,
eCH3). Anal. Calcd for C26H34O5N4$2HCl$2H2O: 52.79% C,
6.82% H, 9.47% N; found: 52.50% C, 6.79% H, 9.57% N.
(39). Yield
1
86%, m.p. 132e132.8 ꢁC. H NMR (400 MHz, CDCl3) d:
7.25 (t, J ¼ 7.9 Hz, 2H, H-arom.), 6.91 (d, J ¼ 8.4 Hz, 2H,
H-arom.), 6.84 (t, J ¼ 7.2 Hz, 1H, H-arom.), 3.54 (t,
J ¼ 7.2 Hz, 2H, H-10), 3.18 (t, J ¼ 4.8 Hz, 4H, H-piper.),
3.11 (dd, J ¼ 3.2, 9.2 Hz, 1H, H-6), 2.71 (m, 1H, H-7),
2.65 (d, J ¼ 9.2 Hz, 1H, C2eH), 2.57 (t, J ¼ 4.8 Hz, 4H, H-
piper.), 2.36 (t, J ¼ 7.0 Hz, 2H, H-30), 2.17 (m, 1H, H-9),
1.97 (m, 3H, H-9, H(eq)-10, H-11), 1.73 (m, 2H, H-20), 1.33
(s, 3H, eCH3), 1.10 (dd, J ¼ 13.2, 5.2 Hz, 1H, H(ax)-10),
0.99 (d, J ¼ 7.2 Hz, 3H, eCH3). Anal. Calcd for
C25H33O3N3: 70.89% C, 7.85% H, 9.92% N; found:
70.503% C, 7.78% H, 10.03% N.
5.1.5.27. 4-[3-(4-Phenylpiperazin-1-yl)propoxy]-8,11-dimethyl-
3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl
acetate
5.1.5.23. 4-{3-[4-(4-Fluorophenyl)piperazin-1-yl]propyl}-1,11-di-
methyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (40). Yield
80%, oil. 1H NMR (400 MHz, CDCl3) d: 6.95 (m, 2H, H-
arom.), 6.87 (m, 2H, H-arom.), 3.55 (t, J ¼ 7.2 Hz, 2H, H-10),
3.12 (m, 5H, H-6, H-piper.), 2.72 (m, 1H, H-7), 2.67 (d,
J ¼ 9.2 Hz, 1H, C2eH), 2.59 (m, 4H, H-piper.), 2.37 (t,
J ¼ 7.0 Hz, 2H, H-30), 2.19 (m, 1H, H-9), 1.96 (m, 3H, H-9,
H(eq)-10, H-11), 1.74 (m, 2H, H-20), 1.34 (s, 3H, eCH3), 1.12
(dd, J ¼ 13.2, 4.8 Hz, 1H, H(ax)-10), 0.99 (d, J ¼ 7.2 Hz, 3H,
eCH3). Anal. Calcd for C25H32O3N3F$1½H2O: 64.08% C,
7.53% H, 8.97% N; found: 64.27% C, 6.91% H, 8.93% N.
(44). Yield 87%, m.p. 199e200 ꢁC. 1H NMR (400 MHz,
CDCl3) d: 13.40 (s, 1H, HCl), 7.90 (d, J ¼ 7.2 Hz, 2H, H-arom.),
7.53 (m, 3H, H-arom.), 5.86 (s, 1H, H-9), 4.80 (m, 2H, H-piper.),
4.35e4.22 (m, 4H, H-10, H-piper.), 3.91 (d, J ¼ 8.0 Hz, 1H,
H-2), 3.75 (m, 2H, H-piper.), 3.67 (m, 2H, H-30), 3.50e3.45 (m,
2H, H-piper.), 3.06 (m, 1H, H-6), 2.76 (s, 1H, H-7), 2.69 (t,
J ¼ 10.6 Hz, 1H, H(eq)-10), 2.29 (m, 2H, H-20), 2.14 (s, 3H,
eOCOCH3), 2.06 (m, 1H, H-11), 1.81 (s, 3H, eCH3), 1.11 (dd,
J ¼ 12, 4.8 Hz, 1H, H(ax)-10), 0.89 (d, J ¼ 6.8 Hz, 3H, eCH3).
Anal. Calcd for C27H35O5N3$2HCl$1/3H2O: 57.86% C, 6.77%
H, 7.50% N; found: 57.40% C, 6.80% H, 7.38% N.
5.1.5.24. 4-[3-(4-Benzylpiperazin-1-yl)propyl]-1,11-dimethyl-
(41). Yield
78%, m.p. 278e279 ꢁC. 1H NMR (400 MHz, DMSO) d: 11.75
5.1.5.28.
4-{3-[4-(4-Fluorophenyl)piperazin-1-yl]propoxy}-
4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-
1
1-yl acetate (45). Yield 86%, m.p. 103e104 ꢁC. H NMR

A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
163
(400 MHz, CDCl3) d: 6.96 (m, 2H, H-arom.), 6.86 (m, 2H,
H-arom.), 5.83 (s, 1H, H-9), 4.06 (m, 2H, H-10), 3.87 (d,
J ¼ 8.4 Hz, 1H, H-2), 3.10 (t, J ¼ 4.8 Hz, 4H, H-piper.),
2.95 (dd, J ¼ 8.4, 3.2 Hz, 1H, H-6), 2.77 (m, 1H, H-7),
2.71 (m, 1H, H(eq)-10), 2.60 (m, 6H, H-30, H-piper.), 2.15
(s, 3H, eOCOCH3), 2.04 (m, 1H, H-11), 1.88 (m, 2H, H-
20), 1.80 (s, 3H, eCH3), 1.09 (dd, J ¼ 12, 4.8 Hz, 1H,
H(ax)-10), 0.90 (d, J ¼ 7.2 Hz, 3H, eCH3). Anal. Calcd for
C27H34O5N3F: 64.91% C, 6.86% H, 8.41% N; found:
64.93% C, 6.93% H, 8.46% N.
7.19 (m, 1H, H-arom.), 6.90 (m, 1H, H-arom.), 4.43 (m, 2H,
H-10), 4.01 (m, 4H, H-piper.), 3.59 (m, 2H, H-30), 3.47 (m,
2H, H-piper.), 3.30 (m, 2H, H-piper.), 3.11 (m, 2H, H-6, H-7),
2.70 (m, 1H, H-2), 2.01 (m, 5H, H-9, H-11, H-20), 1.83 (m,
1H, H(eq)-10), 1.17 (s, 3H, eCH3), 0.86 (m, 4H, H(ax)-10, e
CH3). Anal. Calcd for C24H32O4N4$2HCl: 56.14% C, 6.67%
H, 10.91% N; found: 56.23% C, 6.73% H, 10.63% N.
5.1.5.33. 4-[3-(4-Phenylpiperazin-1-yl)propoxy]-1,11-dimethyl-
4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
(50). Yield
78%, m.p. 189e190 ꢁC. 1H NMR (400 MHz, CDCl3) d:
12.99 (s, 1H, HCl), 7.95 (m, 2H, H-arom.), 7.54 (m, 3H, H-
arom.), 4.85 (m, 2H, H-10), 4.04 (m, 4H, H-piper.), 3.80 (m,
2H, H-30), 3.67 (m, 4H, H-piper.), 3.32 (m, 1H, H-6), 2.81
(m, 1H, H-2), 2.72 (m, 1H, H-7), 2.21 (m, 3H, H-9, H-20),
2.06 (m, 2H, H-9, H-11), 2.00 (m, 1H, H(eq)-10), 1.33 (s, 3H,
eCH3), 1.15 (dd, J ¼ 13.6, 4.0 Hz, 1H, H(ax)-10), 1.00 (d,
J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for C25H33O4N3$2HCl:
58.59% C, 6.88% H, 8.20% N; found: 58.60% C, 6.88% H,
8.02% N.
5.1.5.29. 4-{3-[4-(2-Fluorophenyl)piperazin-1-yl]propoxy}-8,11-
dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-1-yl ace-
1
tate (46). Yield 80%, m.p. 142e143 ꢁC. H NMR (400 MHz,
CDCl3) d: 13.13 (s, 1H, HCl), 7.53 (m, 1H, H-arom.), 7.27e
7.14 (m, 3H, H-arom.), 5.85 (s, 1H, H-9), 4.17 (m, 4H, H-10,
H-piper.), 3.92 (d, J ¼ 7.2 Hz, 1H, H-2), 3.69 (m, 6H, H-piper.),
2.35 (m, 2H, H-30), 3.04 (m, 1H, H-6), 2.76 (s, 1H, H-7), 2.71
(m, 1H, H(eq)-10), 2.34 (m, 2H, H-20), 2.14 (s, 3H, eOCOCH3),
2.05 (m, 1H, H-11), 1.81 (s, 3H, eCH3), 1.10 (m, 1H, H(ax)-10),
0.90 (d, J ¼ 6.4 Hz, 3H, eCH3). Anal. Calcd for C27H34O5N3-
F$2HCl$1/2H2O: 55.71% C, 6.41% H, 7.23% N; found:
55.67% C, 6.00% H, 7.13% N.
5.1.5.34.
4-{3-[4-(4-Fluorophenyl)piperazin-1-yl]propoxy}-
1,11-dimethyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
(51). Yield 61%, m.p. 175e176 ꢁC. 1H NMR (400 MHz,
CDCl3) d: 12.96 (s, 1H, HCl), 8.00 (m, 2H, H-arom.), 7.22
(m, 2H, H-arom.), 4.87 (m, 2H, H-10), 4.41e4.28 (m, 4H,
H-piper.), 3.83e3.67 (m, 6H, H-30, H-piper.), 3.33 (m, 1H,
H-6), 2.57 (m, 1H, H-2), 2.62 (m, 1H, H-7), 2.21 (m, 2H,
H-9, H-20), 2.00 (m, 3H, H-9, H(eq)-10, H-11), 1.33 (s, 3H,
eCH3), 1.14 (m, 1H, H(ax)-10), 1.00 (d, J ¼ 5.2 Hz, 3H,
eCH3). Anal. Calcd for C25H32O4N3F$2HCl$1½H2O:
54.00% C, 6.66% H, 7.56% N; found: 53.83% C, 6.20%
H, 7.31% N.
5.1.5.30.
4-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propoxy}-
8,11-dimethyl-3,5-dioxo-4-azatricyclo[5.2.2.02,6]undec-8-en-
1
1-yl acetate (47). Yield 82%, m.p. 149e150 ꢁC. H NMR
(400 MHz, CDCl3) d: 13.26 (s, 1H, HCl), 7.66 (s, 1H, H-
arom.), 7.54 (d, J ¼ 7.6 Hz, 1H, H-arom.), 7.42 (t,
J ¼ 7.6 Hz, 1H, H-arom.), 7.33 (d, J ¼ 7.6 Hz, 1H, H-arom.),
5.86 (s, 1H, H-9), 4.49 (m, 2H, H-piper.), 4.20 (m, 2H, H-
piper.), 3.93 (m, 2H, H-10), 3.80e3.40 (m, 7H, H-2, H-30, H-
piper.), 3.05 (m, 1H, H-6), 2.76 (s, 1H, H-7), 2.70 (m, 1H,
H(eq)-10), 2.32 (m, 2H, H-20), 2.14 (s, 3H, eOCOCH3), 2.06
(m, 1H, H-11), 1.81 (s, 3H, eCH3), 1.11 (dd, J ¼ 12, 4.0 Hz,
1H, H(ax)-10), 0.90 (d, J ¼ 6.4 Hz, 3H, eCH3). Anal. Calcd
for C27H34O5N3Cl$2HCl$1H2O: 53.43% C, 6.31% H, 7.00%
N; found: 53.53% C, 6.56% H, 7.27% N.
5.1.5.35. 4-{3-[4-(2-Fluorophenyl)piperazin-1-yl]propoxy}-
1,11-dimethyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
(52). Yield 85%, m.p. 136e137 ꢁC. 1H NMR (400 MHz,
CDCl3) d: 12.79 (s, 1H, HCl), 7.34 (m, 1H, H-arom.), 7.14
(m, 3H, H-arom.), 4.30 (m, 2H, H-10), 4.05e3.95 (m, 2H,
H-piper.), 3.68 (m, 2H, H-30), 3.60e3.46 (m, 6H, H-piper.),
3.28 (m, 1H, H-6), 2.79 (m, 1H, H-2), 2.72 (s, 1H, H-7),
2.36 (m, 1H, H-9), 2.21 (m, 2H, H-20), 2.05e1.97 (m, 3H,
H-9, H(eq)-10, H-11), 1.33 (s, 3H, eCH3), 1.18e1.13 (m,
1H, H(ax)-10), 1.00 (d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd
for C25H32O4N3F$2HCl$1/2H2O: 55.66% C, 6.45% H,
7.79% N; found: 55.70% C, 6.13% H, 8.05% N.
5.1.5.31. 4-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propoxy}-
1,11-dimethyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
(48). Yield 85%, m.p. 164e165 ꢁC. 1H NMR (400 MHz,
CDCl3) d: 13.20 (s, 1H, HCl), 8.20 (d, J ¼ 7.6 Hz, 1H, H-
arom.), 7.46 (t, J ¼ 7.8 Hz, 1H, H-arom.), 7.06 (m, 2H, H-
arom.), 5.05 (m, 2H, H-10), 3.35 (m, 4H, H-piper.), 4.07 (s,
3H, eOCH3), 3.70e3.60 (m, 6H, H-30, H-piper.), 3.31 (m,
1H, H-6), 2.80 (d, J ¼ 8.4 Hz, 1H, H-2), 2.72 (s, 1H, H-7),
2.23 (m, 1H, H-9), 2.21 (m, 2H, H-20), 2.05e1.97 (m, 3H,
H-9, H(eq)-10, H-11), 1.33 (s, 3H, eCH3), 1.14 (dd, J ¼ 14,
4.4 Hz, 1H, H(ax)-10), 1.00 (d, J ¼ 6.8 Hz, 3H, eCH3).
Anal. Calcd for C26H35O5N3$2HCl: 57.56% C, 6.87% H,
7.46% N; found: 57.38% C, 6.75% H, 7.68% N.
5.1.5.36. 4-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propoxy}-
1,11-dimethyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione
(53). Yield 83%, m.p. 152e153 ꢁC. 1H NMR (400 MHz,
CDCl3) d: 12.90 (s, 1H, HCl), 7.54 (s, 1H, H-arom.), 7.37
(m, 3H, H-arom.), 4.35 (m, 4H, H-10, H-piper.), 3.19e3.52
(m, 8H, H-30, H-piper.), 3.30 (m, 1H, H-6), 2.79
(d, J ¼ 8.8 Hz, 1H, H-2), 2.71 (s, 1H, H-7), 2.32 (m, 1H,
H-9), 2.18 (m, 2H, H-20), 2.06e1.97 (m, 3H, H-9, H(eq)-10,
H-11), 1.33 (s, 3H, eCH3), 1.15 (dd, J ¼ 14.4, 3.6 Hz, 1H,
5.1.5.32.
4-{3-[4-(2-Pyridyl)piperazin-1-yl]propoxy}-1,11-di-
methyl-4-azatricyclo[5.2.2.02,6]undecane-3,5,8-trione (49). Yield
1
60%, m.p. 168e170 ꢁC. H NMR (400 MHz, DMSO) d: 10.61
(s, 1H, HCl), 8.14 (m, 1H, H-arom.), 7.84 (m, 1H, H-arom.),
H
(ax)-10), 1.00 (d, J ¼ 6.8 Hz, 3H, eCH3). Anal. Calcd for

164
A.J. Bojarski et al. / European Journal of Medicinal Chemistry 44 (2009) 152e164
C25H32O4N3Cl$2HCl: 54.90% C, 6.27% H, 7.68% N; found:
54.95% C, 6.07% H, 7.71% N.
Antidepressant properties were assessed by a ‘‘forced
swimming’’ test according to Porsolt et al. [14], at 30 min after
administration of investigated compounds in doses of 0.1e
0.00635 of their LD50 or imipramine in a dose of 15 mg/kg
ip. The mice were individually placed and forced to swim in
a glass cylinder (27 ꢄ 16 cm) containing 15 cm of water
(25 ꢁC). The mice were left in the cylinder for 6 min. After
the first 2 min, the total duration of immobility was measured
during a 4-min test. A mouse was judged to be immobile when
it remained floating passively, making slow movements to
keep its head above the water.
5.2. Serotonin 5-HT1A and 5-HT2A binding assays
Radioligand studies with native 5-HT1A and 5-HT2A recep-
tors were conducted according to the methods described previ-
ously [22]. Briefly, the following were used: for 5-HT1A assays e
rat hippocampal membranes, [3H]-8-OH-DPAT (170 Ci/mmol,
NEN Chemicals) and 5-HT (10 mM) for non-specific binding;
for 5-HT2A assays e [3H]-ketanserin (88.0 Ci/mmol, NEN
Chemicals) and methysergide (1 mM) for non-specific binding.
5.3. Pharmacology
References
The experiments were carried out on male Albino Swiss
mice (20e24 g) kept at a room temperature of 18e20 ꢁC
on a natural dayenight cycle, with free access to food and
water. Permission to carry out animal tests and experiments
was issued by the Ethical Board at the Medical University
of Lublin. The investigated compounds were administered in-
traperitoneally (ip) as suspensions in 1% Tween 80 at a con-
stant volume of 0.1 mL/10 g body weight of mice. Control
animals received the some volume of a solvent. The com-
pounds were administered in doses equivalent to 0.1 or
0.05 of their LD50. Each experimental group consisted of
eight animals.
Motor coordination in a ‘‘chimney test’’ was measured ac-
cording to the method of Boissier et al. [12], at 30 min after
administration of the investigated compounds in a dose equiv-
alent to 0.1 of their LD50. The mice had to climb up backwards
in a plastic tube (inner diameter: 3 cm, length: 25 cm). The
mice that were unable to perform the three tasks within 60 s
were considered to display motor impairment. The motor im-
pairment was quantified as percentage of animals which failed
to complete the test.
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