New arylpiperazines with flexible versus partly constrained linker as serotonin 5-HT1A/5-HT7 receptor ligands

Article abstract of DOI:10.1002/ardp.201300011

A series of new long-chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl linker were synthesized and investigated in vitro as potential serotonin 5-HT_1A and 5-HT₇ receptor ligands. The compounds were prepared by a two-step procedure using naphthalimide and 2H-1,3-benzoxazine-2,4(3H)-dione as imides, and 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1,2,3,4-tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure included introduction of flexible penta- and hexamethylene chains as well as partly constrained m- and p-xylyl moieties. In general, the new compounds were more active at the 5-HT_1A than at the 5-HT₇ receptor, and the o-OMe-PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o-OMe-PhP series, except for a small binding reduction for ligands containing the m-xylyl moiety, there was no substantial change in the compounds' potency at both receptors, while for the THIQ derivatives a clear structure-activity relationship was visible only for the interaction of the compounds with the 5-HT₇ receptor, which strongly favored flexible analogs. New LCAP derivatives with flexible and partly constrained alkyl linker were tested as potential serotonin 5-HT_1A and 5-HT₇ receptor ligands. The spacer structure was modified by introduction of flexible penta- and hexamethylene chains and partly constrained m- and p-xylyl moieties. The new compounds were more active at the 5-HT_1A than at the 5-HT₇ receptor. o-OMe-PhP derivatives displayed higher affinities than their respective THIQ analogs. The spacer modifications had little effect on the observed in vitro activities. Copyright

Full text of DOI:10.1002/ardp.201300011

Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
339
Full Paper
New Arylpiperazines with Flexible versus Partly Constrained
Linker as Serotonin 5-HT1A/5-HT7 Receptor Ligands
1
Piotr Kowalski , Katarzyna Mitka , Jolanta Jaskowska , Beata Duszynska , and
1
1
2
´
´
Andrzej J. Bojarski2
1
´
Cracow University of Technology, Institute of Organic Chemistry and Technology, Krakow, Poland
2
´
Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, Krakow,
Poland
A series of new long-chain arylpiperazine (LCAP) derivatives with flexible and partly constrained alkyl
linker were synthesized and investigated in vitro as potential serotonin 5-HT1A and 5-HT7 receptor
ligands. The compounds were prepared by a two-step procedure using naphthalimide and 2H-1,3-
benzoxazine-2,4(3H)-dione as imides, and 1-(2-methoxyphenyl)piperazine (o-OMe-PhP) and 1,2,3,4-
tetrahydroisoquinoline (THIQ) as amine pharmacophores. Modifications of the spacer structure
included introduction of flexible penta- and hexamethylene chains as well as partly constrained
m- and p-xylyl moieties. In general, the new compounds were more active at the 5-HT1A than at the
5-HT7 receptor, and the o-OMe-PhP derivatives displayed higher affinities than their respective THIQ
analogs. The spacer modifications had little effect on the observed in vitro activities. Within the o-OMe-
PhP series, except for a small binding reduction for ligands containing the m-xylyl moiety, there was
no substantial change in the compounds’ potency at both receptors, while for the THIQ derivatives
a clear structure–activity relationship was visible only for the interaction of the compounds with the
5-HT7 receptor, which strongly favored flexible analogs.
Keywords: Arylpiperazines / NAN-190 / Serotonin 5-HT1A/5-HT7 receptor ligands / Structure–activity relationship (SAR)
Received: January 8, 2013; Revised: January 8, 2013; Accepted: March 18, 2013
DOI 10.1002/ardp.201300011
Introduction
selectivity and function at a given receptor protein [1, 5, 8, 10,
12]. Nevertheless, there is still the chemical space for further
investigations, especially within the central part of LACP, i.e.
a bridge connecting two terminal parts of a ligand molecule.
This issue was also a subject of our previous studies where
various linkers (n-butyl, cis/trans-but-2-enyl, o-xylyl, 1,4-cyclo-
hexyl) had been introduced to the LCAP structure and the
obtained affinity data on the respective derivatives displayed
different preferences at serotonin 5-HT1A and 5-HT7 receptor
subtypes [21]. While derivatives containing a flexible alkyl
chain and those with cyclohexyl moiety were the most active
at the 5-HT1A receptor, their analogs with trans-2-butenyl
spacer always displayed the highest affinity for the 5-HT7
receptor.
Long-chain arylpiperazines (LCAP) are one of the commonly
studied classes of bioactive compounds due to their large
spectrum of potential therapeutic applications [1–10].
Among them, a prominent place is occupied by pharmaco-
logical effects caused by interactions with different subtypes
of serotonin receptors, which are known to be involved in the
etiology of various mental diseases [1, 10].
Arylpiperazines are also a group of compounds for which
accumulated knowledge and published SAR studies provide
comprehensive data to design active ligands with a relatively
high degree of accuracy [2, 3, 11–20].
Indeed, a number of studies have been aimed at examining
the impact of LCAP structure modifications on the affinity,
The present communication describes the results of our
successive research on the impact of spacer structure on
5-HT1A and 5-HT7 receptor affinity. New compounds are struc-
tural analogs of the well-known serotonin 5-HT1A antagonist
NAN-190 (1) [22] and the previously reported 2H-1,3-benzox-
azine-2,4(3H)-dione derivative (2) [23], to which four different
Correspondence: Dr. Piotr Kowalski, Cracow University of Technology,
Institute of Organic Chemistry and Technology, 24 Warszawska Street,
´
31-155 Krakow, Poland
E-mail: kowapi@pk.edu.pl
Fax: þ48-12-6282037
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

340
P. Kowalski et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
O
O
N
N
N
N
N
H3CO
N
1, NAN-190
O
O
3
4
O
O
N
N
N
O
N
O
H3CO
O
O
2
n-Hex
n-Hex
N
N
N
HN
N
HN
H3CO
H3CO
5
6
7
8
Figure 1. Structures of the model compounds.
spacers, i.e. penthamethylene (a), hexamethylene (b), m-xylyl
(c) and p-xylyl (d), have been introduced. The first two sets of
compounds are structural analogs of NAN-190 (1) (9a–d) and 2
(10a–d), which contain a 1-(2-methoxyphenyl)piperazine
moiety (o-OMe-PhP) as an amine pharmacophore, whereas
in the remaining two groups (compounds 11a–d and 12a–
d) 1,2,3,4-tetrahydroisoquinoline (THIQ) isostere [18] was
used. Additionally, m-xylyl (13c–d) and p-xylyl (14c–d) deriva-
tives of simplified structure (without imide terminals) were
synthesized to test the influence of imide function on sero-
tonin receptors activity. The affinity of the new compounds is
discussed in relation to the previously obtained results for
parent molecules 1–8 (Fig. 1) [17, 21, 23–25].
had good solubility in acetone, while the disubstituted by-
products showed no solubility in several organic solvents and
could thus be easily separated by filtration. In the case of 1,5-
dibromopentane (a) and 1,6-dibromobutane (b), the reaction
was carried out for 48 h, whereas using a,a0-dichloro-m-
xylene (c) and a,a0-dichloro-p-xylene (d) it was completed after
24 h (Scheme 1). The reaction yields and physical properties
of the obtained N-(v-haloalkyl)imides 15a–d and 16a–d are
shown in Table 1.
N-(v-Bromoalkyl)imides 16a and 16b were also obtained by
alkylation of imide 16 with 1,v-dibromoalkanes (a, b) in the
presence of K2CO3 and TBAB (tetrabutylammonium bromide)
as a PTC catalyst, in solvent-free conditions, according to
the method developed for solvent-free alkylation of imides
[26, 27] (see the Experimental section). The advantage of
this protocol is short reaction time (60 min), solvent-free
conditions and formation of a small quantity of disubstituted
by-products; on the other hand, the inconvenience is the use
of a threefold excess of dibromoalkanes (a, b).
Results and discussion
Chemistry
The synthesis of the compounds under study was carried out
by a two-step procedure according to the paths presented in
Schemes 1, 2, and 3. The structures of the obtained com-
pounds are shown in Fig. 2.
The second step, i.e. condensation of N-(v-alkyl)imides
15a–d and 16a–d with 1-(2-methoxyphenyl)piperazine (17)
or 1,2,3,4-tetrahydroisoquinoline (18), afforded compounds
9–12 (Scheme 2, Table 2). The condensation was carried out
at an ambient temperature in the presence of K2CO3 using
DMF as a solvent; under the same conditions, the reaction
of a-chloro-m-xylene (19) and a-chloro-p-xylene (20) with 17
or 18 yielded compounds 13c–d and 14c–d, respectively
(Scheme 3, Table 2).
In the first step, N-alkylation of imides 15 and 16 with 1,5-
dibromopentane (a), 1,6-dibromohexane (b), a,a0-dichloro-m-
xylene (c), and a,a0-dichloro-p-xylene (d) was conducted
(Scheme 1). The reaction, carried out at an ambient tempera-
ture in the presence of K2CO3 and DMF as a solvent, gave an
efficient yield of N-(v-haloalkyl)imides (15a–d and 16a–d). In
order to reduce formation of disubstituted by-products,
imides 15 and 16 were added stepwise to the reaction mixture
of dihaloalkanes a–d. N-(v-Haloalkyl)imides and disubsti-
tuted by-products were easily separated due to the difference
in their solubility. N-(v-Haloalkyl)imides (15a–d and 16a–d)
For biological experiments, free bases 9–14 were converted
into hydrochloride salts with ethanol saturated with HCl,
and their molecular weights were established on the basis of
an elemental analysis.
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
Arylpiperazines with Different Linkers as Serotonin Receptor Ligands
341
O
NH
O
X
15
R
X
X
,
,
,
(i)
R
X
R
R
O
15a, 16a
15b, 16b
15c, 16c
15d, 16d
NH
O
O
16
R
X
O
Br
N
15a, 15b
O
O
Br
Cl
Cl
16a, 16b
15c, 15d
16c, 16d
N
O
O
O
N
O
O
O
N
O
Conditions and Reagents:
(i) DMF, K2CO3, 24–48 h, room temp;
1,5-dibromopentane (a), 1,6-dibromohexane (b), α,α’-dichloro-m-xylene (c), or α,α’-dichloro-p-xylene (d).
Scheme 1. Synthesis of N-(v-haloalkyl)imides 15a–d and 16a–d.
(ii)
(i)
_
_
_ _
15a d, 16a d
_
_
11a d, 12a d
9a d, 10a d
Conditions and Reagents:
(i) DMF, K2CO3, 24–48 h, room temp, 1-(2-methoxyphenyl)piperazine hydrochloride (17),
(ii) DMF, K2CO3, 24–48 h, room temp, 1,2,3,4-tetrahydroisoquinoline (18).
Scheme 2. Synthesis of the investigated com-
pounds 9a–d, 10a–d, 11a–d, and 12a–d.
Cl
19
(ii)
(i)
14c,d
13c,d
Cl
20
Conditions and Reagents:
(i) DMF, K2CO3, 24–48 h, room temp, 1-(2-methoxyphenyl)piperazine hydrochloride (17),
(ii) DMF, K2CO3, 24–48 h, room temp, 1,2,3,4-tetrahydroisoquinoline (18).
Scheme 3. Synthesis of the investigated com-
pounds 13c–d and 14c–d.
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

342
P. Kowalski et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
AMINE
IMIDE
AMINE
AMINE
IMIDE
_
_
9b 12b
9a 12a
AMINE
IMIDE OR HYDROGEN
IMIDE OR HYDROGEN
_
_
9d 14d
9c 14c
IMIDE/HYDROGEN
O
AMINE
N
N
N
N
9a, 9b, 9c, 9d
H3CO
O
O
N
10a, 10b, 10c, 10d
11a, 11b, 11c, 11d
N
H3CO
O
O
O
N
N
O
O
O
12a, 12b, 12c, 12d
13c, 13d
N
N
N
O
N
N
H
H3CO
H
14c, 14d
Figure 2. Structures of the compounds obtained.
Biological evaluation
93 Ci/mmol, Amersham) as a radioligand. The experiment
was carried out in a 96-well plate using the MultiPROBE II
Liquid Handling System. After 1-h incubation at 378C, the
assay samples were rapidly filtered using a Unifilter harvester
and plates were subsequently washed with an ice-cold 50 mM
Tris buffer (pH 7.4). Radioactivity retained on the filters was
quantified on a Microbeta plate reader.
The investigated compounds were tested in competition
binding experiments for native 5–HT1A receptors and for
cloned human 5-HT7 ones according to the previously pub-
lished procedures [28, 29].
As regards 5-HT1A receptors, experiments were carried out
using membranes from rat hippocampus and [3H]-8-OH-DPAT
(8-hydroxy-2-(di-n-propylamino)tetralin; spec. act. 170 Ci/
mmol, NEN Chemical) as a radioligand. Following incu-
bation, the receptor preparations were rapidly filtered under
vacuum through GF/B glass fiber filters which were washed
extensively with an ice-cold 50 mM Tris buffer (pH 7.4) using
a Brandel harvester. Radioactivity was determined by liquid
scintillation counting in the Beckman LS 6500 apparatus [28].
Binding assays on membranes from HEK 293 cells stably
expressing human 5-HT7b receptors [29] were performed with
the use of [3H]-5-CT (5-carboxamidotryptamine; spec. act.
In both experiments 10 mM of serotonin was used for
nonspecific binding. Inhibition constants (Ki) were calculated
from the Cheng–Prushoff equation [30]. Results are expressed
as means of at least three separate experiments, each per-
formed for 7–9 concentrations of a compound, run in
triplicate.
At the same time, the two well-known reference serotonin
drugs buspirone and methiothepin were examined, and the
obtained results were consistent with our previous data as
well as with those reported in the literature [24, 31] (Table 3).
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
Arylpiperazines with Different Linkers as Serotonin Receptor Ligands
343
Table 1. Physical properties of N-(v-haloalkyl)imides 15a–d and 16a–d obtained in the reaction of imides 15 and 16 with dihaloalkanes
(a–d) in the presence of K2CO3 and DMF as a solvent.
Compound Yield (%)
mp (8C)
Recryst. solvent
1H NMR (CDCl3), d ppm
15a
67
61–63a)
Ligroine
1.42–2.09 (6H, cluster, 3xCH2), 3.41 (2H, t, J ¼ 6.9 Hz, CH2-Br), 3.70
(2H, t, J ¼ 7.0 Hz, CH2-Nimide), 7.66–7.71 (2H, m, H-Ar), 7.88–7.95
(2H, m, H-Ar)
1.40–1.89 (8H, cluster, 4xCH2), 3.40 (2H, t, J ¼ 7.0 Hz, CH2-Br), 3.69
(2H, t, J ¼ 7.1 Hz, CH2-Nimide), 7.64–7.70 (2H, m, H-Ar), 7.85–7.92
(2H, m, H-Ar)
15b
49
55–57b)
Methanol
15c
15d
16a
57
75
71
129–130
153–155.5c)
81–83
Acetone–methanol
Acetone
4.55 (2H, s, CH2-Cl), 4.84 (2H, s, CH2-Nimide), 7.26–7.36 (3H, m, H-Ar),
7.43 (1H, s, H-Ar), 7.63–7.70 (2H, m, H-Ar), 7.83–7.91 (2H, m, H-Ar)
4.53 (2H, s, CH2–Cl), 4.83 (2H, s, CH2-imide), 7.26–7.49 (4H, m, H-Ar),
7.62–7.69 (2H, m, H-Ar), 7.82–7.90 (2H, m, H-Ar)
Methanol
1.51–2.01 (6H, cluster, 3xCH2), 3.42 (2H, t, J ¼ 7.1 Hz, CH2-Br), 4.05
(2H, t, J ¼ 7.5 Hz, CH2-Nimide), 7.22–7.46 (2H, m, H–Ar), 7.60–7.82
(1H, m, H-Ar), 8.07 (1H, dd, J ¼ 7.6, 1.9 Hz, H-Ar)
16b
56
58–60
Methanol
1.41–1.95 (8H, cluster, 4xCH2), 3.40 (2H, t, J ¼ 6.9 Hz, CH2-Br), 4.04
(2H, t, J ¼ 7.6 Hz, CH2-Nimide), 7.21–7.43 (2H, m, H-Ar), 7.65–7.82
(1H, m, H-Ar), 8.07 (dd, 1H, J ¼ 7.6, 2.0 Hz, H–Ar)
16c
16d
75
51
137–137
141–143
Acetone–ligroine
Acetone
4.56 (2H, s, CH2–Cl), 5.20 (2H, s, CH2-Nimide), 7.21–7.55 (6H, m, H-Ar),
7.60–7.79 (1H, m, H-Ar), 8.07 (1H, dd, J ¼ 7.5, 1.8 Hz, H-Ar)
4.54 (2H, s, CH2-Cl), 5.19 (2H, s, CH2-Nimide), 7.20–7.51 (6H, m, H-Ar),
7.59–7.78 (1H, m, H-Ar), 8.06 (1H, dd, J ¼ 7.6, 1.9 Hz, H-Ar)
a)
For 15a mp 59–618C (light petroleum) [34] and 59.5–608C (ethanol) [35] has been reported.
For 15b mp 58.5–59.58C [35] and 50–528C [36] has been reported.
For 15d mp 143–1468C [37] has been reported.
b)
c)
Table 2. Physical properties of the compounds obtained.
Compound
Base
mp (8C)
Hydrochloride
Yield (%)
Recryst. solvent
mp (8C)
9a
9b
9c
9d
70
75
74
57
53
52
47
72
72
71
79
64
43
60
47
68
86
89
61
76
135–137a)
66–68
Ethanol
Acetone–n-hexane
Butan-1-ol
Methanol
Acetone
Acetone
Acetone–methanol
Acetone
Acetone–water
–
Butan-1-ol
Acetone–water
Acetone
Acetone–water
Acetone–methanol
Acetone
Methanol–water
Methanol–water
–
195–197
203–204
245–248
128–130
124–126
134–135
84–86
65–70c)
119–120
69–71
234–237b); >2208C sublim.
161–164
205–207
10a
10b
10c
10d
11a
11b
11c
11d
12a
12b
12c
12d
13c
13d
14c
14d
>250b)
>240b)
194–197; >1808C sublim.
229–231; >2008C sublim.
226–228
>250b); >2108C sublim.
214–216; >1908C sublim.
218–222
235–238; >2108C sublim.
>240b); >2208C sublim.
202–204; >1708C sublim.
234–236; >1908C sublim.
175–177; >1508C sublim.
232–233; >1608C sublim.
Oil
143–145
129–130
79–81
67–70
122–124
145–146
64–65
82–83
Oil
Oil
–
a)
For 9a mp 133–134 8C (propan-2-ol) [36].
mp with decomposition.
Amorphous substance.
b)
c)
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

344
P. Kowalski et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
Table 3. The affinity dataa) on the serotonin 5-HT1A and 5-HT7 receptors of the investigated compounds.
o-OMe-PhP derivatives
Ki [nM] W SEM
5-HT1A
THIQ derivatives
Ki [nM] W SEM
5-HT7
5-HT1A
5-HT7
1, NAN-190
9a
9b
9c
9d
2
10a
10b
10c
10d
5
6
13c
13d
0.6 ꢀ 0.1b)
7.2 ꢀ 0.6e)
22 ꢀ 2
87 ꢀ 2c)
80 ꢀ 5
3
140 ꢀ 10d)
324 ꢀ 29
108 ꢀ 22
278 ꢀ 42
459 ꢀ 63
293 ꢀ 11f)
746 ꢀ 87
62 ꢀ 5
60 ꢀ 7
245 ꢀ 17
324 ꢀ 38
768 ꢀ 94
781 ꢀ 56
237 ꢀ 20
342 ꢀ 45
290 ꢀ 33
1060 ꢀ 132
1097 ꢀ 88
29,680
11a
11b
11c
11d
4
12a
12b
12c
12d
7
118 ꢀ 7
292 ꢀ 19
50 ꢀ 3
68 ꢀ 8
16 ꢀ 2
3.2 ꢀ 0.25f)
100 ꢀ 8
106 ꢀ 13
112 ꢀ 16
152 ꢀ 9
83 ꢀ 11
832 ꢀ 43
–
20 ꢀ 3
18 ꢀ 2.5
69 ꢀ 8
1141 ꢀ 121
572 ꢀ 49
>50,000d)
1240 ꢀ 60h)
3800 ꢀ 538
2005 ꢀ 176
34 ꢀ 3
168 ꢀ 14g)
1.5 ꢀ 0.3g)
182 ꢀ 14
121 ꢀ 17
8
14c
14d
–
573 ꢀ 95
5470 ꢀ 654
535 ꢀ 48
5350 ꢀ 870
a)
Buspirone and methiothepin were used as reference drugs for 5-HT1A (Ki ¼ 12 nM) and 5-HT7 (Ki ¼ 2.7 nM) receptors, respectively,
and the obtained affinities were comparable with those reported elsewhere [24, 31].
b)
Ki ¼ 0.55 nM according to Glennon et al. [22].
c)
Data from [21].
Data from [24].
d)
e)
Ki ¼ 5.0 nM according to Glennon et al. [38].
f)
Data from [23].
Data from [17].
Data from [25].
g)
h)
Results and discussion
The decreased activity of THIQ derivatives versus o-OMe-PhP
analogs at the 5-HT1A receptor is a known phenomenon
attributed to the properties of these amine fragments them-
selves [25]. As was shown in our previous papers, unsubsti-
tuted THIQ (7) is totally inactive (Ki > 50,000 nM), while o-
OMe-PhP (5) itself is a fairly potent 5-HT1A receptor ligand
(Ki ¼ 168 nM) [25]. Substitution of both those amines with
n-hexyl chains resulted in the enhancement of the affinities
of 6 and 8 due to hydrophobic interactions (Ki ¼ 1.5 and
1240 nM, respectively) [17, 25], which indicates that weaker
interactions of the amine moiety and the 5-HT1A receptor
binding site can be compensated by hydrophobic forces [17,
25, 32, 33]. Nevertheless, 5-HT1A binding results obtained in
the present study for o-OMe-PhP derivatives with no imide
function (13c and 13d) did not differ from the Ki values for
the unsubstituted o-OMe-PhP (5) molecule, showing lack of
engagement of the middle benzene group in the process
of binding with the 5-HT1A receptor (Table 3). Similar con-
clusions can be drawn on the basis of binding results
obtained for 5-HT7 receptor. Replacement of the polymethyl-
ene chain with a benzene group in o-OMe-PhP derivatives
13c–d did not affect 5-HT7 affinity, and in the case of THIQ
analogs 14c–d improved it. In each case, however, structure
simplification of parent 9c–d and 10c–d ligands led to a
decrease in affinity to both investigated serotonin receptors,
In general, all o-OMe-PhP derivatives (9a–d and 10a–d) were
active serotonin 5-HT1A receptor ligands with Ki values below
100 nM. At the same time, these compounds had lower, but
still significant, affinity for 5-HT7 receptors whose value oscil-
lated around 100 nM (Table 3). The 5-HT1A receptor preferred
ligands with a flexible n-alkyl spacer, whereas the 5-HT7 bind-
ing pocket more easily accommodated compounds with a
middle p-xylyl group; thus 9d and 10d showed the highest
activity in both sets of o-OMe-PhP derivatives (Ki ¼ 50 and
83 nM, respectively), which also exceeded the values pre-
sented by the parent compounds 1 and 2.
The replacement of 1-(2-methoxyphenyl)piperazine moiety
with 1,2,3,4-tetrahydroisoquinoline group (series 11a–d and
12a–d) decreased the affinity for both receptors. In these
series, ligands with an n-hexyl chain were the most active
for the 5-HT1A receptor, while the 5-HT7 receptor also pre-
ferred compounds with fully flexible n-alkyl linkers, but did
not discriminate between them (i.e. similar Ki values were
obtained for 11a and 11b, as well as for 12a and 12b).
Unfortunately, comparison of the obtained results with those
characterizing parent ligands 3 and 4 revealed unfavorable
tendency of diminishing affinity to both investigated recep-
tors (Table 3).
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
Arylpiperazines with Different Linkers as Serotonin Receptor Ligands
345
with a spatula for ca. 1 min. The reaction mixture was left at
ambient temperature. Within 15–20 min, the mixture was
slightly warmed up to 30–358C, and after another 30–40 min
the temperature dropped down, which indicated that the
reaction was completed. Next, the reaction mixture was poured
into 100 mL of water, and the products were extracted with
chloroform. After evaporation of the solvent and the excess
of dibromoalkane, crude products were purified in the same
manner as it was described above. The yields of N-(5-bromo-
pentyl)-2H-1,3-benzoxazine-2,4(3H)-dione (16a) and N-(6-bromo-
hexyl)-2H-1,3-benzoxazine-2,4(3H)-dione (16b) were 69 and 60%,
respectively.
which points to an important role exerted by the imide
function of LCAPs in the process of ligand recognition.
Summing up, the applied spacer modifications did not influ-
ence the preference of 5–HT1A binding over 5-HT7 one, as was
observed in our previous investigation [21]. Within o-OMe-PhP
series, except small binding reduction for ligands containing
the m-xylyl moiety (9c and 10c), there was no substantial
change in compounds potency at either receptor, and several
of the new compounds were characterized by dual 5-HT1A/5HT7
receptor activity. For the less active THIQ derivatives, clear SAR
was visible only for compound interactions with the 5-HT7
receptor, which favored flexible analogs.
General procedure for the synthesis of 9a–d,
10a–d, 11a–d, 12a–d, 13c–d, and 14c–d
A mixture of 0.01 mol of the respective N-(v-haloalkyl)imide
(15a–d or 16a–d), a-chloro-m-xylene (19) or a-chloro-p-xylene
(20), 0.01 mol of the respective amine 17 or 18, 0.02 mol of
anhydrous potassium carbonate (when a hydrochoride salt of
an amine was used, an equivalent of potassium carbonate was
also added) and a few crystals (ꢁ0.01 g) of potassium iodide in
20 mL of dimethylformamide was stirred with a magnetic stirrer
at room temperature. In the case of compound 15a, 15b, 16a, or
16b, the reaction time was 48 h, while for 15c, 15d, 16c, 16d, 19,
or 20 it was 24 h. Then the reaction mixture was poured into
100–150 mL of water, and the precipitate was either collected by
filtration or extracted with chloroform. Solid products were
purified by crystallization, and oils by column chromatography
using a mixture of chloroform/methanol (90:10) as eluent.
The yields and physical properties of 9a–d, 10a–d, 11a–d,
12a–d, 13c–d, and 14c–d are shown in Table 2.
Experimental
Melting points were determined on a Bo¨etius melting point
apparatus and are uncorrected. Elemental analyses were per-
formed on a Perkin–Elmer 2400 analyzer and the results are
within ꢀ0.4% of the calculated values. Infrared spectra were
recorded as pressed KBr discs on a Bio-Rad FTS 175B spec-
trometer. 1H NMR spectra were taken on a Varian 300 MHz
Mercury-VX spectrometer in CDCl3 using TMS as an internal
standard; chemical shifts are given in ppm (d). Mass spectra were
recorded using an Esquire 3000 mass spectrometer (Bruker
Daltonik, Bremen, Germany) equipped with an electrospray
source. ESI-MS spectra were registered in a positive-ion mode.
The reactions and purifications were monitored by TLC (UV
detection) on aluminum sheets coated with silica gel 60 F254
(Merck) using a chloroform/methanol (90:10) mixture as eluent.
All starting materials were purchased from commercial sources
(Sigma–Aldrich and Merck) and were used without further
purification.
Hydrochloride preparation
Free bases 9a–d, 10a–d, 11a–d, 12a–d, 13c–d, or 14c–d (100 mg)
were dissolved in 10 mL of acetone, treated with ethanol satu-
rated with HCl, and kept overnight in a refrigerator to give
colorless, crystalline products.
General procedure for preparation of N-(v-haloalkyl)-
imides 15a–d and 16a–d in the presence of a solvent
To a stirred suspension of 0.045 mol dihaloalkane a–d and
0.030 mol (4.14 g) of K2CO3 in 60 mL of DMF the appropriate
imide 15 or 16 (0.030 mol) was added in six portions at room
temperature over a period of 6 h. In the case of reaction of 1,5-
dibromopentane (a) or 1,6-dibromohexane (b), the reaction mix-
ture was stirred at room temperature for an additional 40–42 h,
and for 16–18 h while using a,a0-dichloro-m-xylene (c) or a,a0-
dichloro-p-xylene (d). Then the inorganic precipitate was filtered
off and the solvent and the excess of dihaloalkane was evapor-
ated under vacuum. The residue was extracted with acetone,
leaving insoluble disubstituted by-products. Crude products
were obtained from the acetone solution, and were then purified
by crystallization. Reaction yields and physical properties of
the obtained compounds are shown in Table 1.
N-{5-[4-(2-Methoxyphenyl)piperazin-1-
yl]pentyl}phthalimide 9a
1
Base: colorless plates; H NMR d: 1.50–1.95 (6H, cluster, 3xCH2),
2.41 (2H, t, J ¼ 7.0 Hz, CH2-Npip), 2.58–2.69 (4H, m, 2xCH2), 3.03–
3.15 (4H, m, 2xCH2), 3.70 (2H, t, J ¼ 6.9 Hz, CH2-Nimide), 3.86
(3H, s, OCH3), 6.89–7.02 (4H, m, H-Ar), 7.63–7.80 (2H, m, H-Ar),
7.85–7.91 (2H, m, H-Ar); ESI-MS: m/z 408 (MH)þ; IR (KBr) cmꢂ1
:
2931, 2815, 1766, 1711, 1394, 1239. Anal. calcd. for C24H29N3O3
HCl 0.5H2O (452.98): C, 63.64; H, 6.90; N, 9.28. Found: C, 63.77;
H, 6.67; N, 9.22.
N-{6-[4-(2-Methoxyphenyl)piperazin-1-
yl]hexyl}phthalimide 9b
Base: colorless needles; 1H NMR d: 1.42–1.80 (8H, cluster, 4xCH2),
2.39 (2H, t, J ¼ 7.1 Hz, CH2-Npip), 2.57–2.69 (4H, m, 2xCH2), 3.04–
3.15 (4H, m, 2xCH2), 3.69 (2H, t, J ¼ 7.1 Hz, CH2-Nimide), 3.86
(3H, s, OCH3), 6.90–7.00 (4H, m, H-Ar), 7.64–7.80 (2H, m, H-Ar),
Preparation of N-(v-haloalkyl)imides 16a and 16b in
solvent-free conditions
A powdered mixture of 1.63 g (0.01 mol) of 2H-1,3-benzoxazine-
2,4(3H)-dione (16), 4.14 g (0.03 mol) of anhydrous potassium
carbonate and 0.32 g (0.001 mol) of TBAB was placed in a reac-
tion vessel. Then, three equivalents of 1,5-dibromopentane (a) or
1,6-dibromohexane (b) were added and the mixture was stirred
7.85–7.91 (2H, m, H-Ar); ESI-MS: m/z 422 (MH)þ; IR (KBr) cmꢂ1
:
2939, 2813, 1768, 1713, 1397, 1237. Anal. calcd. for C25H31N3O3
2HCl (494.45): C, 60.73; H, 6.73; N, 8.50. Found: C, 60.66; H, 6.91;
N, 8.43.
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

346
P. Kowalski et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
(2H, s, CH2-Nimide), 6.88–6.98 (4H, m, H-Ar), 7.22–7.43
(6H, m, H-Ar), 7.56–7.79 (1H, m, H-Ar), 8.09 (1H, dd, J ¼ 7.6,
N-{3-([4-(2-Methoxyphenyl)piperazin-1-
yl]methyl)benzyl}phthalimide 9c
1.9 Hz, H-Ar, m, H-Ar); ESI-MS: m/z 458 (MH)þ; IR (KBr) cmꢂ1
:
Base: pale yellow needles; 1H NMR d: 2.63–2.72 (4H, m, 2xCH2),
3.02–3.15 (4H, m, 2xCH2), 3.56 (2H, s, CH2-Npip), 3.85 (3H, s, OCH3),
4.85 (2H, s, CH2-Nimide), 6.89–6.99 (4H, m, H-Ar), 7.22–7.30 (3H, m,
H-Ar), 7.41 (1H, s, H-Ar), 7.63–7.81 (2H, m, H-Ar), 7.85–7.91 (2H, m,
H-Ar); ESI-MS: m/z 442 (MH)þ; IR (KBr) cmꢂ1: 2933, 2815, 1766,
1714, 1394, 1240. Anal. calcd. for C27H27N3O3 HCl (477.98): C,
67.85; H, 5.90; N, 8.79. Found: C, 67.89; H, 5.76; N, 8.73.
2936, 2820, 1759, 1699, 1472, 1346, 1240. Anal. calcd.
for C27H27N3O4 2HCl H2O (548.46): C, 59.13; H, 5.70; N, 7.66.
Found: C, 59.29; H, 5.77; N, 7.50.
N-[5-(1,2,3,4-Tetrahydroisoquinolin-2-yl)pentyl]phthalimide
11a
Base: pale yellow needles; 1H NMR d: 1.49–1.96 (6H, cluster,
3xCH2), 2.54 (2H, t, J ¼ 7.3 Hz, CH2-NTHIQ), 2.72–2.91
(4H, m, 2xCH2), 3.64 (2H, s, CH2), 3.70 (2H, t, J ¼ 6.9 Hz,
CH2-Nimide), 6.95–7.15 (4H, m, H-Ar), 7.63–7.80 (2H, m, H-Ar),
N-{4-([4-(2-Methoxyphenyl)piperazin-1-
yl]methyl)benzyl}phthalimide 9d
Base: pale yellow plates; 1H NMR d: 2.55–2.67 (4H, m, 2xCH2),
3.00–3.12 (4H, m, 2xCH2), 3.54 (2H, s, CH2-Npip), 3.83 (3H, s, OCH3),
4.83 (2H, s, CH2-Nimide), 6.87–6.97 (4H, m, H-Ar), 7.33–7.47
(4H, m, H-Ar), 7.63–7.80 (2H, m, H-Ar), 7.85–7.91 (2H, m, H-Ar);
ESI-MS: m/z 442 (MH)þ; IR (KBr) cmꢂ1: 2934, 2805, 1767, 1716,
1396, 1239. Anal. calcd. for C27H27N3O3 HCl (477.98): C, 67.85;
H, 5.90; N, 8.79. Found: C, 67.66; H, 5.97; N, 8.59.
7.84–7.90 (2H, m, H-Ar); ESI-MS: m/z 349 (MH)þ; IR (KBr) cmꢂ1
:
2929, 2815, 1768, 1714, 1394. Anal. calcd. for C22H24N2O2 HCl
(384.90): C, 68.65; H, 6.55; N, 7.28. Found: C, 68.69; H, 6.68;
N, 7.10.
N-[6-(1,2,3,4-Tetrahydroisoquinolin-2-yl)hexyl]phthalimide
11b
Base: pale yellow oil; 1H NMR d: 1.45–1.81 (8H, cluster, 4xCH2),
2.49 (2H, t, J ¼ 7.4 Hz, CH2-NTHIQ), 2.70–2.90 (4H, m, 2xCH2), 3.60
(2H, s, CH2), 3.69 (2H, t, J ¼ 6.9 Hz, CH2-Nimide), 7.00–7.12
(4H, m, H-Ar), 7.63–7.79 (2H, m, H-Ar), 7.84–7.91 (2H, m, H-Ar);
ESI-MS: m/z 363 (MH)þ; IR (KBr) cmꢂ1: 2933, 2812, 1766, 1715,
1384. Anal. calcd. for C23H26N2O2 HCl 0.5H2O (407.94): C, 67.72;
H, 6.92; N, 6.87. Found: C, 67.58; H, 6.99; N, 7.02.
N-{5-[4-(2-Methoxyphenyl)piperazin-1-yl]pentyl}2H-1,3-
benzoxazine-2,4(3H)-dione 10a
Base: colorless solid; 1H NMR d: 1.45–1.87 (6H, cluster, 3xCH2),
2.43 (2H, t, J ¼ 7.2 Hz, CH2-Npip), 2.59–2.71 (4H, m, 2xCH2),
3.04–3.16 (4H, m, 2xCH2), 3.86 (3H, s, OCH3), 4.06 (2H,
t, J ¼ 7.6 Hz, CH2-Nimide), 6.90–7.00 (4H, m, H-Ar), 7.21–
7.47 (2H, m, H-Ar), 7.60–7.79 (1H, m, H-Ar), 8.08 (1H, dd,
J ¼ 7.6, 1.9 Hz, H-Ar); ESI-MS: m/z 424 (MH)þ; IR (KBr) cmꢂ1
:
N-{3-[(1,2,3,4-Tetrahydroisoquinolin-2-
2943, 2815, 1762, 1700, 1471, 1351, 1238. Anal. calcd. for
C24H29N3O4 HCl H2O (477.99): C, 60.31; H, 6.75; N, 8.79.
Found: C, 59.96; H, 6.42; N, 9.03.
yl)methyl]benzyl}phthalimide 11c
Base: pale yellow plates; 1H NMR (CDCl3) d: 2.70–2.88 (4H,
m, 2xCH2), 3.62 (2H, s, CH2), 3.66 (2H, s, CH2-NTHIQ), 4.85
(2H, s, CH2-Nimide), 7.05–7.12 (4H, m, H-Ar), 7.30–7.34
(3H, m, H-Ar), 7.44 (1H, s, H-Ar), 7.72–7.79 (2H, m, H-Ar), 7.87–
7.92 (2H, m, H-Ar); ESI-MS: m/z 383 (MH)þ; IR (KBr) cmꢂ1: 2951,
2804, 1768, 1714, 1393. Anal. calcd. for C25H22N2O2 HCl (418.92):
C, 71.68; H, 5.53; N, 6.69. Found: C, 71.53; H, 5.72; N, 6.76.
N-{6-[4-(2-Methoxyphenyl)piperazin-1-yl]hexyl}2H-1,3-
benzoxazine-2,4(3H)-dione 10b
Base: colorless solid; 1H NMR d: 1.40–1.86 (8H, cluster, 4xCH2),
2.43 (2H, t, J ¼ 7.2 Hz, CH2-Npip), 2.58–2.70 (4H, m, 2xCH2), 3.04–
3.15 (4H, m, 2xCH2), 3.85 (3H, s, OCH3), 4.03 (2H, t, J ¼ 7.7 Hz,
CH2-Nimide), 6.88–6.95 (4H, m, H-Ar), 7.20–7.43 (2H, m, H-Ar), 7.59–
7.80 (1H, m, H-Ar), 8.07 (1H, dd, J ¼ 7.6, 1.9 Hz, H-Ar); ESI-MS:
m/z 438 (MH)þ; IR (KBr) cmꢂ1: 2942, 2817, 1764, 1693, 1472, 1391,
1241. Anal. calcd. for C25H31N3O4 HCl H2O (492.01): C, 61.03;
H, 6.97; N, 8.54. Found: C, 61.34; H, 6.74; N, 8.59.
N-{4-[(1,2,3,4-Tetrahydroisoquinolin-2-
yl)methyl]benzyl}phthalimide 11d
Base: colorless needles; 1H NMR (CDCl3) d: 2.71–2.93
(4H, m, 2xCH2), 3.61 (2H, s, CH2), 3.64 (2H, s, CH2-NTHIQ), 4.84
(2H, s, CH2-Nimide), 7.01–7.11 (4H, m, H-Ar), 7.36–7.39 (4H,
m, H-Ar), 7.44 (1H, s, H-Ar), 7.68–7.78 (2H, m, H-Ar), 7.86–7.92
(2H, m, H-Ar); ESI-MS: m/z 383 (MH)þ; IR (KBr) cmꢂ1: 2897, 2805,
1773, 1710, 1395. Anal. calcd. for C25H22N2O2 HCl H2O (436.93):
C, 68.72; H, 5.77; N, 6.41. Found: C, 68.58; H, 5.55; N, 6.60.
N-{3-([4-(2-Methoxyphenyl)piperazin-1-
yl]methyl)benzyl}2H-1,3-benzoxazine-2,4(3H)-dione 10c
1
Base: colorless solid; H NMR d: 2.57–2.69 (4H, m, 2xCH2), 3.02–
3.13 (4H, m, 2xCH2), 3.57 (2H, s, CH2-Npip), 3.84 (3H, s, OCH3),
5.21 (2H, s, CH2-Nimide), 6.89–6.98 (4H, m, H-Ar), 7.26–7.49
(6H, m, H-Ar), 7.59–7.81 (1H, m, H-Ar), 8.09 (1H, dd, J ¼ 7.5,
1.9 Hz, H-Ar); ESI-MS: m/z 458 (MH)þ; IR (KBr) cmꢂ1: 2938,
2808, 1763, 1708, 1469, 1383, 1240. Anal. calcd. for
C27H27N3O4 HCl H2O (512.00): C, 63.34; H, 5.91; N, 8.21.
Found: C, 63.14; H, 5.72; N, 8.00.
N-[5-(1,2,3,4-Tetrahydroisoquinolin-2-yl)pentyl]2H-1,3-
benzoxazine-2,4(3H)-dione 12a
Base: colorless solid; 1H NMR (CDCl3) d: 1.47–1.79 (6H, cluster,
3xCH2), 2.52 (2H, t, J ¼ 7.3 Hz, CH2-NTHIQ), 2.71–2.89 (4H,
m, 2xCH2), 3.61 (2H, s, CH2), 4.06 (2H, t, J ¼ 7.6 Hz,
CH2-Nimide), 7.02–7.10 (4H, m, H-Ar), 7.21–7.46 (2H, m, H-Ar),
7.60–7.81 (1H, m, H-Ar), 8.07 (1H, dd, J ¼ 7.6, 1.8 Hz, H-Ar);
ESI-MS: m/z 365 (MH)þ; IR (KBr) cmꢂ1: 2941, 2860, 1756, 1690,
1470, 1360. Anal. calcd. for C22H24N2O3 HCl (400.90): C, 65.91;
H, 6.29; N, 6.99. Found: C, 65.80; H, 6.12; N, 7.23.
N-{4-([4-(2-Methoxyphenyl)piperazin-1-
yl]methyl)benzyl}2H-1,3-benzoxazine-2,4(3H)-dione 10d
1
Base: colorless solid; H NMR d: 2.56–2.68 (4H, m, 2xCH2), 3.00–
3.12 (4H, m, 2xCH2), 3.56 (2H, s, CH2-Npip), 3.83 (3H, s, OCH3), 5.19
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
Arylpiperazines with Different Linkers as Serotonin Receptor Ligands
347
(8H, m, H-Ar); ESI-MS: m/z 238 (MH)þ; IR for hydrochloride
(KBr) cmꢂ1: 3029, 2922, 2540, 2492, 2415, 1454. Anal. calcd.
for C17H19N HCl (273.80): C, 74.57; H, 7.36; N, 5.12. Found: C,
74.50; H, 7.42; N, 5.20.
N-[6-(1,2,3,4-Tetrahydroisoquinolin-2-yl)hexyl]2H-1,3-
benzoxazine-2,4(3H)-dione 12b
Base: colorless plates; 1H NMR (CDCl3) d: 1.45–1.79 (8H, cluster,
4xCH2), 2.51 (2H, t, J ¼ 7.4 Hz, CH2-NTHIQ), 2.71–2.89 (4H,
m, 2xCH2), 3.61 (2H, s, CH2), 4.04 (2H, t, J ¼ 7.6 Hz, CH2-Nimide),
7.03–7.12 (4H, m, H-Ar), 7.21–7.46 (2H, m, H-Ar), 7.60–7.81 (1H,
m, H-Ar), 8.07 (1H, dd, J ¼ 7.6, 1.8 Hz, H-Ar); ESI-MS: m/z 379
(MH)þ; IR (KBr) cmꢂ1: 2934, 2859, 1758, 1689, 1470, 1361.
Anal. calcd. for C23H26N2O3 HCl (414.17): C, 66.58; H, 6.56;
N, 6.75. Found: C, 66.77; H, 6.40; N, 6.61.
The study was partly supported by the Polish Ministry of Science and
Higher Education (MNiSW), grant no. 2-P05F-019-30.
The authors have declared no conflict of interest.
References
N-{3-[(1,2,3,4-Tetrahydroisoquinolin-2-
yl)methyl]benzyl}2H-1,3-benzoxazine-2,4(3H)-dione 12c
Base: colorless solid; 1H NMR (CDCl3) d: 2.73–2.88 (4H, m, 2xCH2),
3.63 (2H, s, CH2), 3.67 (2H, s, CH2-NTHIQ), 5.21 (2H, s, CH2-Nimide),
7.01–7.12 (4H, m, H-Ar), 7.26–7.53 (6H, m, H-Ar), 7.59–7.81 (1H,
m, H-Ar), 8.07 (1H, dd, J ¼ 7.8, 1.9 Hz, H-Ar); ESI-MS: m/z 399
(MH)þ; IR (KBr) cmꢂ1: 2912, 2804, 1747, 1698, 1469, 1387,
1343. Anal. calcd. for C25H22N2O3 HCl (434.91): C, 69.04;
H, 5.33; N, 6.44. Found: C, 68.98; H, 5.51; N, 6.34.
[1] S. J. Oh, H. J. Ha, D. Y. Chi, H. K. Lee, Curr. Med. Chem. 2001, 8,
999–1034.
[2] P. Coudert, C. Rubat, M. Bastide, R. Malhuret, J. Chopineau,
J. Pharm. Belg. 1995, 50, 445–454.
´
[3] V. Soskic, J. Joksimovic, Curr. Med. Chem. 1998, 5, 493–512.
´
ˇ
[4] J. Penjisevic, V. Sukalovic, D. Andric, S. Kostic-Rajacic,
ˇ
´
´
´
´
ˇ ´
V. Soskic, G. Roglic, Arch. Pharm. (Weinheim) 2007, 340,
ˇ
ˇ
456–465.
´
´
´
´
´
´
ˇ ´
´
´
[5] M. Tomic, M. Kundakovic, B. Butorovic, B. Janac, D. Andric,
G. Roglic, D. Ignatovic, S. Kostic-Rajacic, Bioorg. Med. Chem.
N-{4-[(1,2,3,4-Tetrahydroisoquinolin-2-
´
´
yl)methyl]benzyl}2H-1,3-benzoxazine-2,4(3H)-dione 12d
Base: pale yellow solid; 1H NMR (CDCl3) d: 2.71–2.92 (4H,
m, 2xCH2), 3.61 (2H, s, CH2), 3.65 (2H, s, CH2-NTHIQ), 5.20
(2H, s, CH2-Nimide), 7.00–7.11 (4H, m, H-Ar), 7.21–7.48 (6H,
m, H-Ar), 7.59–7.80 (1H, m, H-Ar), 8.07 (1H, dd, J ¼ 7.6, 1.9 Hz,
H-Ar); ESI-MS: m/z 399 (MH)þ; IR (KBr) cmꢂ1: 2900, 2804, 1756,
1698, 1467, 1390, 1348. Anal. calcd. for C25H22N2O3 HCl
0.5H2O (443.92): C, 67.64; H, 5.45; N, 6.31. Found: C, 67.69;
H, 5.60; N, 6.21.
Lett. 2004, 14, 4263–4266.
[6] J. C. Gonzalez-Gomez, L. Santana, E. Uriarte, J. Brea,
M. Villazon, M. I. Loza, M. De Luca, M. E. Rivas, G. Y.
Montenegro, J. A. Fontenla, Bioorg. Med. Chem. Lett. 2003,
13, 175–178.
[7] M. L. Lopez-Rodriguez, B. Benhamu, M. J. Morcillo, I. Tejada,
D. Avila, I. Marco, L. Schiapparelli, D. Frechilla, J. Del Rio,
Bioorg. Med. Chem. Lett. 2003, 13, 3177–3180.
[8] M. Leopoldo, Curr. Med. Chem. 2004, 11, 629–661.
3-{[4-(2-Methoxyphenyl)piperazin-1-yl]methyl}toluene 13c
Base: colorless plates; 1H NMR d: 2.35 (3H, s, CH3), 2.59–
2.71 (4H, m, 2xCH2), 3.04–3.16 (4H, m, 2xCH2), 3.54 (2H,
s, CH2-Npip), 3.84 (3H, s, OCH3), 6.89–6.98 (4H, m, H-Ar), 7.11–
7.24 (4H, m, H-Ar); ESI-MS: m/z 297 (MH)þ; IR (KBr) cmꢂ1: 2933,
2804, 1490, 1240. Anal. calcd. for C19H24N2O HCl (332.87):
C, 68.56; H, 7.57; N, 8.42. Found: C, 68.60; H, 7.49; N, 8.52.
´
[9] C. Teran, L. Santana, E. Uriarte, Y. Fall, L. Unelius, B.-R. Tolf,
Bioorg. Med. Chem. Lett. 1998, 8, 3567–3570.
[10] M. L. Lopez-Rodriguez, D. Ayala, B. Benhamu, M. J. Morcillo,
A. Viso, Curr. Med. Chem. 2002, 9, 443–469.
[11] D. E. Nichols, C. D. Nichols, Chem. Rev. 2008, 108, 1614–1641.
[12] H. Pessoa-Mahana, R. Araya-Maturana, C. B. Saitz, D. C.
Pessoa-Mahana, Mini. Rev. Med. Chem. 2003, 3, 77–93.
`
[13] M. A. Siracusa, L. Salerno, M. N. Modica, V. Pittala, G. Romeo,
M. E. Amato, M. Nowak, A. J. Bojarski, I. Mereghetti, A.
4-{[4-(2-Methoxyphenyl)piperazin-1-yl]methyl}toluene 13d
Base: colorless needles; 1H NMR d: 2.34 (3H, s, CH3), 2.58–2.70
(4H, m, 2xCH2), 3.03–3.15 (4H, m, 2xCH2), 3.54 (2H, s, CH2-Npip),
3.85 (3H, s, OCH3), 6.89–6.98 (4H, m, H-Ar), 7.07–7.31 (4H, m, H-Ar);
ESI-MS: m/z 297 (MH)þ; IR (KBr) cmꢂ1: 2936, 2811, 1500, 1454, 1236.
Anal. calcd. for C19H24N2O HCl 0.5H2O (341.88): C, 66.75; H, 7.67;
N, 8.19. Found: C, 66.81; H, 7.89; N, 8.01.
Cagnotto, T. Mennini, J. Med. Chem. 2008, 51, 4529–4538.
´
[14] M. L. Lopez-Rodrıguez, M. J. Morcillo, E. Fernandez, M. L.
Rosado, L. Pardo, K. Schaper, J. Med. Chem. 2001, 44, 198–207.
´
´
´
[15] P. Zajdel, G. Subra, P. Verdie, A. J. Bojarski, B. Duszynska,
K. Basista, J. Obniska, J. Martinez, M. Pawłowski, Eur. J. Med.
Chem. 2009, 44, 800–808.
´
[16] P. Zajdel, G. Subra, A. J. Bojarski, B. Duszynska, M. Pawłowski,
J. Martinez, J. Comb. Chem. 2004, 6, 761–767.
3-[(1,2,3,4-Tetrahydroisoquinolin-2-yl)methyl]toluene 14c
Base: pale yellow oil; 1H NMR d: 2.35 (3H, s, CH3), 2.69–2.96
(4H, m, 2xCH2), 3.64 (4H, s, CH2 þ CH2-NTHIQ), 7.03–7.26
(8H, m, H-Ar); ESI-MS: m/z 238 (MH)þ; IR for hydrochloride
(KBr) cmꢂ1: 3031, 2923, 2538, 2492, 2427, 1454. Anal. calcd.
for C17H19N HCl (273.80): C, 74.57; H, 7.36; N, 5.12. Found: C,
74.59; H, 7.30; N, 4.91.
[17] J. L. Mokrosz, M. J. Mokrosz, S. Charakchieva-Minol, M. H.
´
Paluchowska, A. J. Bojarski, B. Duszynska, Arch. Pharm.
(Weinheim) 1995, 328, 143–148.
´
[18] J. L. Mokrosz, A. J. Bojarski, S. Charakchieva-Minol, B. Duszynska,
M. J. Mokrosz, M. H. Paluchowska, Arch. Pharm. (Weinheim)
1995, 328, 604–608.
4-[(1,2,3,4-Tetrahydroisoquinolin-2-yl)methyl]toluene 14d
Base: pale yellow oil; 1H NMR d: 2.35 (3H, s, CH3), 2.66–2.95
(4H, m, 2xCH2), 3.64 (4H, s, CH2 þ CH2-NTHIQ), 7.02–7.34
´
[19] R. A. Medina, J. Sallander, B. Benhamu, E. Porras, M. Campillo,
L. Pardo, M. L. Lopez-Rodrıguez, J. Med. Chem. 2009, 52, 2384–
´
´
2392.
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com

348
P. Kowalski et al.
Arch. Pharm. Chem. Life Sci. 2013, 346, 339–348
´
[20] P. Kowalski, T. Kowalska, A. J. Bojarski, B. Duszynska,
J. Heterocyclic Chem. 2007, 44, 889–893.
´ ´
[29] M. H. Paluchowska, R. Bugno, B. Duszynska, E. Tatarczynska,
´
A. Nikiforuk, T. Lenda, E. Chojnacka-Wojcik, Bioorg. Med.
Chem. 2007, 15, 7116–7125.
´
[21] A. J. Bojarski, B. Duszynska, M. Kołaczkowski, P. Kowalski,
T. Kowalska, Bioorg. Med. Chem. Lett. 2004, 14, 5863–5866.
[30] Y. Cheng, W. H. Prusoff, Biochem. Pharmacol. 1973, 22, 3099–
3108.
[22] R. A. Glennon, N. A. Naiman, R. A. Lyon, M. Titeler, J. Med.
Chem. 1988, 31, 1968–1971.
[31] D. R. Thomas, S. A. Gittins, L. L. Collin, D. N. Middlemiss,
G. Riley, J. Hagan, I. Gloger, C. E. Ellis, I. T. Forbes, A. M.
Brown, Br. J. Pharmacol. 1998, 124, 1300–1306.
´
[23] M. J. Mokrosz, P. Kowalski, T. Kowalska, Z. Majka, B. Duszynska,
A. J. Bojarski, A. Fruzinski, J. Karolak-Wojciechowska,
´
´
A. Wesołowska, A. Kłodzinska, E. Tatarczynska, E. Chojnacka-
Wojcik, Arch. Pharm. (Weinheim) 1999, 332, 373–379.
´
´
[32] M. J. Mokrosz, A. J. Bojarski, B. Duszynska, E. Tatarczynska,
A. Kłodzinska, A. Deren-Wesołek, S. Charakchieva-Minol,
´
´
´
´
´
E. Chojnacka-Wojcik, Bioorg. Med. Chem. 1999, 7, 287–295.
´
[24] J. L. Mokrosz, A. Deren-Wesołek, E. Tatarczynska, B. Duszynska,
A. J. Bojarski, M. J. Mokrosz, E. Chojnacka-Wojcik, J. Med.
´
´
´
[33] A. J. Bojarski, M. J. Mokrosz, Pharmazie 1999, 54, 828–830.
Chem. 1996, 39, 1125–1129.
[34] J. F. Constant, B. M. Carden, J. Lhomme, J. Heterocyclic Chem.
1985, 22, 1035–1040.
[25] J. L. Mokrosz, M. J. Mokrosz, A. J. Bojarski, S. Charakchieva-
Minol, Pharmazie 1994, 49, 781–782.
[35] L. S. Payne, J. Boger, Synth. Commun. 1985, 15, 1277–1290.
´
´
[26] P. Kowalski, J. Jaskowska, A. J. Bojarski, B. Duszynska,
[36] A. Mary, D. Z. Renko, C. Guillou, C. Thal, Bioorg. Med. Chem.
1998, 6, 1835–1850.
J. Heterocyclic Chem. 2008, 45, 209–214.
´
[27] J. Jaskowska, P. Kowalski, J. Heterocyclic Chem. 2008, 45, 1371–
1375.
[37] K. Paul, C. D. Blonton, J. Pharm. Sci. 1976, 65, 1527–1530.
[38] R. A. Glennon, N. A. Naiman, M. E. Pierson, J. D. Smith, A. M.
Ismaiel, M. Titeler, R. A. Lyon, J. Med. Chem. 1989, 32, 1921–
1926.
[28] A. J. Bojarski, M. T. Cegła, S. Charakchieva-Minol, M. J.
´
Mokrosz, M. Mackowiak, S. Misztal, J. L. Mokrosz, Pharmazie
1993, 48, 289–294.
ß 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.archpharm.com