Chemical modifications on 4-arylpiperazine-ethyl carboxamide derivatives differentially modulate affinity for 5-HT1A, D4.2, and α2A receptors: Synthesis and in vitro radioligand binding studies

Article abstract of DOI:10.1071/CH09353

A series of substituted 4-aryl-piperazine-ethyl heteroarylcarboxamides were prepared and tested in in vitro radioligand binding studies. The presence of a quinoxaline has a favourable impact in terms of serotonin 5-HT_1A versus dopamine D4.2 receptor selectivity. Compounds with a 3-CF₃ group at the distal phenyl ring are the most effective in terms of affinity and selectivity for 5-HT_1A versus D4.2 receptors. A 4-phenyl-1,2,3,6- tetrahydropyridine in place of the corresponding 4-phenyl-piperazine side chain is also favourable not only for the affinity for 5-HT_1A and D4.2 receptors but also in some cases for α_2A-adrenoceptors.

Full text of DOI:10.1071/CH09353

Full Paper
CSIRO PUBLISHING
Aust. J. Chem. 2010, 63, 56–67
www.publish.csiro.au/journals/ajc
Chemical Modifications on 4-Arylpiperazine-Ethyl
Carboxamide Derivatives Differentially Modulate Affinity
for 5-HT1A, D4.2, and α Receptors: Synthesis
2A
and In Vitro Radioligand Binding Studies
Amaury Graulich,A Marc Léonard,A Mélissa Résimont,A Xi-Ping Huang,B
Bryan L. Roth,B and Jean-François LiégeoisA,C
ADrug Research Center, Laboratory of Medicinal Chemistry, University of Liège,
Avenue de l’Hôpital 1 (B36), B-4000 Liège 1, Belgium.
BDepartment of Pharmacology, School of Medicine and Division of Medicinal Chemistry
and Natural Products, School of Pharmacy, University of North Carolina Chapel Hill
Medical School, 4072 Genetic Medicine Building, CB 7365, Chapel Hill, NC 27599, USA.
CCorresponding author. Email: JF.Liegeois@ulg.ac.be
A series of substituted 4-aryl-piperazine-ethyl heteroarylcarboxamides were prepared and tested in in vitro radioligand
binding studies. The presence of a quinoxaline has a favourable impact in terms of serotonin 5-HT1A versus dopamine
D4.2 receptor selectivity. Compounds with a 3-CF3 group at the distal phenyl ring are the most effective in terms of affinity
and selectivity for 5-HT1A versus D4.2 receptors. A 4-phenyl-1,2,3,6-tetrahydropyridine in place of the corresponding
4-phenyl-piperazine side chain is also favourable not only for the affinity for 5-HT1A and D4.2 receptors but also in some
cases for α2A-adrenoceptors.
Manuscript received: 20 June 2009.
Manuscript accepted: 13 August 2009.
Introduction
asthehippocampus[6] andprefrontalcortex.[7,8] Thehighestden-
sity of 5-HT1A receptors in rat brain is found in the hippocampus,
followed by the medial prefrontal cortex. The interaction of var-
ious atypical antipsychotic drugs with 5-HT1A receptors leading
to the modulation of external dopamine concentrations has been
proposed to be beneficial for improving negative symptoms and
cognition in patients with schizophrenia.[9] Alternatively, α2-
adrenergic receptor antagonism has also been proposed as an
explanation for the atypical antipsychotic potential of clozap-
ine. Thus, the combination of raclopride a D2 antagonist and
idazoxan an α2-antagonist also produces a comparable effect on
dopamine release in the prefrontal cortex.[10] Thus, selective or
mixed ligands for these receptors (5-HT1A and D4.2 receptors,
and α2A-adrenoceptors) would be of great interest.
In continuation of our work on a series of naphthalene
carboxamides,[11,12] we observed that the replacement of the
naphthalene ring by nitrogen-containing aromatic heterocycles
was differentially favourable for the affinity for D4.2 receptors
(J.-F. Liégeois, pers. comm.).The naphthalene moiety represents
a particularly lipophilic group and appears in several medic-
inal programs. N-[2-(4-phenylpiperazin-1-yl)ethyl]-2-naphthyl
carboxamide 1 (Fig. 1) is not structurally so far from these
molecules and is claimed to be a 5-HT1A ligand.[13] In our
hands, this compound possesses effectively a high affinity for
5-HT1A receptors (affinity for the receptor, Ki = 14 4 nM) but
also a high affinity for dopamine D4.2 receptors (Ki = 8 1 nM)
(J.-F. Liégeois, pers. comm.). Similarly, WAY100635 (Fig. 1),
Medicinal chemistry research is often focussed on either the dis-
covery of a pharmacological tool for exploring a specific target
or the development of a new drug based on a new therapeutic
strategy. In the first case, selective agents are generally required
for studying the role of the corresponding target. In the second
case, drugs acting on several sites have also great interest.[1]
Recently, multireceptor affinity strategy was put forward as an
innovativeapproachtothediscoveryofnewdrugcandidates.[1–3]
This is clearly the case of clozapine (Fig. 1). Partially owing
to its toxicological potential, but also because its unique thera-
peutic benefit for schizophrenic patients is important, clozapine
has inspired the development of numerous medicinal chem-
istry programs. In parallel, clozapine’s biological potential was
extensively explored. The hypothesis of an adequate ratio of
affinity for serotonin 5-HT2A receptors versus dopamine D2
receptors (high affinity for serotonin 5-HT2A receptors com-
bined with a low affinity for dopamine D2 receptors)[4] led to
the development of the second generation of antipsychotic drugs
while, in parallel, other interaction sites of the molecule (e.g.
dopamine D4 receptors) were the targets for extensive devel-
opment programs.[5] Importantly, in vivo microdialysis studies
and radioligand binding studies have demonstrated the benefi-
cial combination of several neuronal interactions.[1] Thus, for
instance, serotonin 5-HT1A partial agonism is likely involved in
the ability of clozapine and other atypical antipsychotic drugs to
increase dopamine release in several important brain areas such
© CSIRO 2010
10.1071/CH09353
0004-9425/10/010056

Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives
57
Me
N
impact of a steric constraint. Biological evaluation was done by
invitroradioligandbindingstudieswithhumanclonedreceptors.
Chemistry
The target compounds were synthesized by reaction of the
appropriate primary amine with the appropriate acyl chlo-
ride (2-quinoline, 3-quinoline, or 2-quinoxaline) as described
in Scheme 1. The crude amines were obtained following a
Gabriel procedure using the appropriate N-substituted phthal-
imides, which were synthesized by reaction of an adequate
N-phenylpiperazine with N-(2-bromoethyl)phthalimide in the
presence of potassium carbonate. The N-arylpiperazine deriva-
tives were obtained from commercial sources, whereas N-(2-
bromoethyl)phthalimide was purchased or prepared in house
following classical methods and further characterized. Most
N-substituted phthalimides are known. Nevertheless, they were
used after purification and crystallization followed by a classical
N
N
Cl
N
H
Clozapine
O
N
N
N
H
1
analytical characterization (e.g. H NMR, elemental analysis).
ThisinformationissummarizedseparatelyintheAccessoryPub-
lication. Target compounds were mainly isolated as the base and
further characterized.
1
MeO
N
O
Receptor Binding Studies
N
In vitro binding experiments were conducted on human cloned
receptors expressed in appropriate cells and used as mem-
brane preparations. The radioligands used were [3H]-8-OH-
DPAT (0.25 nM), [3H]-MK912 (0.7 nM), and [3H]-YM-09151–
2 (0.2 nM) for 5-HT1A, α2A, and D4.2 receptors, respectively.
Experimentalproceduresforfiltrationandradioactivitycounting
used previously described methodology[18] and are summarized
below in the Experimental section.
N
H
BP897
O
N
The experimental data for quinoxaline, 2-quinoline, and
3-quinoline derivatives are reported in Tables 1–3 respectively.
N
OMe
N
N
Impact of Modifications on Serotonin 5-HT1A
Receptor Affinity
Most of the compounds tested in this work possess a significant
affinityfor5-HT1A receptors, althoughthepresenceofanitrogen
heterocycle compared with a naphthalene moiety significantly
reduces the lipophilicity. Indeed, when measuring the log kꢀIAM, a
high-performance liquid chromatography (HPLC) approach for
experimental lipophilicity measurement,[19–21] the determined
values were 3.39, 2.49, 2.66, and 2.94 for the naphthalene (1),
the quinoxaline (2), the 3-quinoline (32), and the 2-quinoline
(17) derivatives, respectively. This parameter is quite important
inthecontextnotonlyofadrugdevelopmentintermsofbioavail-
ability but also in the context of pharmacological investigation
when aqueous solutions are required. In a series of dopamine D3
ligands reported in the literature, the replacement of the naph-
thalene ring by a nitrogen-containing aromatic heterocycle led
to a decrease in lipophilicity parallel to a significant reduction in
affinity for this receptor.[22] In fact, the affinity was reduced by
10, 30, and 36 times for the 3-quinoline, the 2-quinoxaline, and
the 2-quinoline, respectively.[22] In the present work, compared
with the naphthalene analogue (1), the affinity was reduced by
23, 2, and 2 times for the 3-quinoline (32), the 2-quinoxaline (2),
and the 2-quinoline (17), respectively. Therefore, the impact of
such modulations leads to significant variations depending on
the receptor that cannot be readily generalized.
WAY100635
Fig. 1. Chemical structure of different dopaminergic and serotonergic
ligands.
a classical 5-HT1A ligand frequently used in many pharmaco-
logical investigations, has also been reported to possess a
high potency for dopamine D4 receptors.[14] Otherwise, BP897
(Fig. 1), with a butyl linker between the naphthamide and the
basic nitrogen, described as a dopamine D3 receptor partial ago-
nist or as an antagonist,[15,16] was also found to have a high
5-HT1A affinity (Ki = 3 0 nM). This fact was also recently
reported by others.[17] Thus, we were interested in developing
less lipophilic compounds related to compound 1 (Fig. 1) and
then in examining the impact of moieties of lesser lipophilicity
on the affinity for several receptors such as 5-HT1A and D4.2
receptors and α2A-adrenoceptors. In the present work, nitrogen-
containing aromatic heterocycles were used to replace the carbon
ring and we also explored different chemical modifications on
the distal aromatic ring. The last one was monosubstituted by
atoms or groups with different electronic, steric, or lipophilic
properties.Analogues possessing a tetrahydropyridine instead of
a piperazine nucleus were also prepared in order to evaluate the
Otherwise, we observe that the impact of the nitrogen posi-
tion on the affinity for 5-HT1A receptors is somewhat different.
Although possessing two nitrogens and thus having a reduced

58
A. Graulich et al.
O
O
(a)
Y
N
N
N
X
Br
R1
O
O
Y
H2N
(b)
(c)
N
X
R1
Y
O
X
R1
N
R2
N
H
Scheme 1. Reagents and conditions: (a) N-(un)substituted-4-arylpiperazine (or 4-phenyl-1,2,3,6-tetrahydropyridine), K2CO3, reflux;
(b) NH2NH2, EtOH, reflux; (c) acyl chloride, Et3N, EtOAc, rt. R1: H, 2-Cl, 3-Cl, 4-Cl, 2-F, 3-F, 4-F, 2-Me, 3-Me, 4-Me, 2-OMe, 3-OMe,
4-OMe, 3-CF3. R2: 2-quinolinyl, 3-quinolinyl, 2-quinoxalinyl. X–Y: N–CH2 or C=CH.
Table 1. Affinity of 2-quinoxaline derivatives for human cloned 5-HT1A, α2A, and D4.2 receptors
O
O
N
R
N
N
N
N
N
N
N
H
N
H
2–15
16
Compound
R
5-HT1A affinity
α2A affinity
D4.2 affinity
SelectivityB
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
H
2-F
3-F
4-F
28
13
11
37
9
1
1
6
18A
49A
36A
4A
51A
11A
15A
55A
21A
10A
3A
48A
9A
8A
41A
53A
27A
55A
180
44A
53A
244 71
32A
45A
28A
>18
>38
>45
>14
8
>150
>15
22
>167
>18
>250
51
>71
1.5
2-Cl
3-Cl
4-Cl
2-Me
3-Me
4-Me
3-CF3
2-OMe
3-OMe
4-OMe
–
25 15
3
3.3
33
11
3
1
4
1
1
28 0.9
2
3
7
1
0
3
163
2
10A
329 91
4
0A
1
316
3
53A
>125
AKi (in nM, mean s.d.; n ≥ 2 if unspecified) or percentage of inhibition at 1 µM.
BSelectivity is obtained by dividing Ki D4.2 by Ki 5-HT1A. A value of 500 nM was chosen for compounds having low affinity and thus the selectivity is
superior to the mentioned value.
lipophilicity, the quinoxaline derivatives have higher affinity
for 5-HT1A receptors. A significant difference is observed
between both quinoline isomers. The 2-substituted deriva-
tives possess generally a higher affinity than the 3-substituted
ones.
Otherwise, the nature and the position of the substituent on
the distal aromatic ring differentially influence the binding to the
5-HT1A receptor sites. An electron-withdrawing atom or group
is better tolerated in position 3 than 2 and 4. Nevertheless, in
the latter position, a fluorine atom leads to a significant affinity

Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives
59
Table 2. Affinity of 2-quinoline derivatives for human cloned 5-HT1A, α2A, and D4.2 receptors
O
O
N
R
N
N
N
N
N
H
N
H
17–30
31
Compound
R
5-HT1A affinity
α2A affinity
D4.2 affinity
SelectivityA
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
H
2-F
3-F
4-F
31
29
23
170 37
19 11
12
282 40
16
9
185 57
8
5
13
614 78
10
6
4
1
46A
244 26
51A
16A
384 63
27A
17A
339 55
39A
11A
17A
291 23
24A
15A
112 12
85 0.7
50A
3.6
2.9
>22
0.4
67 12
2-Cl
3-Cl
4-Cl
2-Me
3-Me
4-Me
3-CF3
2-OMe
3-OMe
4-OMe
–
77
32A
61
9
6
4
3
>42
0.2
4
15.9
0.4
>63
16.7
>38
<1
3
1
65 19
138 27
82
58A
1
2
1
5
78 46
54A
19A
1
150 21
61 17
6.3
AKi (in nM, mean s.d.; n ≥ 2 if unspecified) or percentage of inhibition at 1 µM.
BSelectivity is obtained by dividing Ki D4.2 by Ki 5-HT1A. A value of 500 nM was chosen for compounds having low affinity and thus the selectivity is
superior to the mentioned value.
in the quinoxaline series (5). The presence of a group with
steric hindrance has also a favourable impact on the affinity for
5-HT1A receptors.A methyl group is more favourable in position
3 (10, 25, 40) than 2 (9, 24, 39) and 4 (11, 26, 41). Regarding
the methoxy group, the presence in position 2 (13, 28, 43) and
3 (14, 29, 44) is significantly more favourable than in position
4 (15, 30, 45). In another study, such an electron-withdrawing
group decreases binding to 5-HT1A and D2 receptors.[23] In the
present series, a slight advantage in terms of affinity is observed
for the 2-substituted analogues (13, 28, 43). In position 3, the
compromise of an electron-withdrawing character and steric hin-
drance found in the CF3 group (12, 27, 42) increase the affinity
for 5-HT1A receptors.
Interestingly, the presence of the 1,2,3,6-tetrahydropyridine
ring instead of the piperazine moiety is highly favourable for
5-HT1A affinity, particularly for the quinoxaline (16) and the
3-quinoline (32) analogues. Compared with the phenylpiper-
azine analogues, the affinity is 7, 3, and 11 times higher for the
quinoxaline (2 versus 16), the 2-quinoline (17 versus 31), and
the 3-quinoline (32 versus 46) analogues respectively. In the lit-
erature, a study on a series of D3 ligands reported no significant
difference between both chains in terms of affinity for the studied
receptors.[24] The rigidity conferred on this part of the molecule
must facilitate some interactions in the receptor sites that com-
pensate for the negative impact of the nitrogen-containing
heterocycle. The replacement of the sp3 nitrogen by an sp2 car-
bon leads to spatial constraints without a huge impact in terms of
basicity.The nitrogen close to the aromatic ring is not sufficiently
basic to be protonated at physiological pH and the electron lone
pair is not sufficiently available for hydrogen bonding.
Impact of Modifications on α -Adrenoceptor Affinity
2
A weak interaction appears in the three groups in piperazine
series when a substituent, whatever its steric or electronic char-
acter, is at position 2. In this series, contrary to the interaction for
5-HT1A receptors, thequinoxalineanaloguespresentlessaffinity
than the 2- and 3-quinoline derivatives. Otherwise, the pres-
ence of the tetrahydropyridine side chain (16, 31, 46) increases
the interaction for these sites compared with the corresponding
phenylpiperazine analogues (2, 17, 32) but the impact is less
pronounced in the quinoxaline (2 versus 16) series than in the 2-
(17 versus 31) and 3-quinoline (32 versus 46) series.
Impact of Modifications on Dopamine D4.2
Receptor Affinity
The higher affinity for these receptor sites is found in the 2-
and 3-quinolinyl series. Contrary to the 5-HT1A receptors, the
quinoxaline analogues present lesser affinity than the 2- and 3-
quinoline derivatives. In the quinoxaline series, only compounds
possessing a substituent with steric hindrance such as a chlorine
(6), a methyl (9), or a methoxy (13) at position 2 of the dis-
tal phenyl ring have medium affinity. In the quinoline series, it
appears that a chlorine in position 4 (23, 38) is well tolerated.
This observation can also be found in the literature.[25] A subtle
difference appears between the 2- and 3-quinoline analogues,
generally in favour of the latter. The electronic and steric para-
meters together seem involved because the methyl group has a
less favourable impact on D4.2 receptor affinity.A substituent in
position 3 is less well tolerated in both series except for the pres-
ence of a methyl group. Similarly to the presence of a substituent

60
A. Graulich et al.
Table 3. Affinity of 3-quinoline derivatives for human cloned 5-HT1A, α2A, and D4.2 receptors
O
O
N
R
N
N
N
H
N
H
N
N
32–45
46
Compound
R
5-HT1A affinity
α2A affinity
D4.2 affinity
SelectivityB
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
H
2-F
3-F
4-F
315 72
63 23
23A
202 24
47A
104 13
58 2.4
82 9.7
0.3
0.9
1.3
0.1
0.7
5
0.1
1.6
4.1
0.6
23
66
320
4
5
10A
45
4
2-Cl
3-Cl
4-Cl
2-Me
3-Me
4-Me
3-CF3
2-OMe
3-OMe
4-OMe
–
49 10
22
256 21
25A
21A
33 2.8
5
120
2
215 55
46 18
28 7.5
42 10
59 17
200
6
14
5
33A
217 15
10A
22A
132
5
341 48
25 3.5
316 24
31A
15
15
40
4
5
3
350 16
24A
12A
1.7
7.9
–
2019 561
23
9
173
6
34
5
1.5
AKi (in nM, mean s.d.; n ≥ 2 if unspecified) or percentage of inhibition at 1 µM.
BSelectivity is obtained by dividing Ki D4.2 by Ki 5-HT1A. A value of 500 nM was chosen for compounds having low affinity and thus the selectivity is
superior to the mentioned value.
in position 4, the 3-quinolinyl analogues have a higher affinity
than the 2-quinoline analogues. The presence of a substituent in
position 2 is also favourable compared with the unsubstituted
analogues. Regarding these receptor sites, the favourable impact
of a tetrahydropyridine side chain is less pronounced compared
with the 5-HT1A receptors except for the 2-quinoline (31) and
3-quinoline (46) derivatives.
receptors are observed. Regarding the tetrahydropyridine deriva-
tives, the selectivity for 5-HT1A receptors versus D4.2 receptors
is 125, 6.3, and 1.5 times greater for the quinoxaline (16), the
2-quinoline (31), and the 3-quinoline (46) derivatives, respec-
tively, and thus superior to those found with derivatives possess-
ing a 4-phenyl-piperazine side chain.
Preliminary in vitro experiments for determining the intrin-
sic activity were done according to previously described
procedures.[26] Compounds were assessed at 10 µM for stim-
ulation of [35S]GTPγS binding to membrane fractions from
D4 receptor- and 5-HT1A receptor-expressing cells. Of the 45
compounds tested for D4 receptor agonism, only one (43) repeat-
edly exhibited more than 20% activity (baseline [35S]GTPγS
binding = 0%, [35S]GTPγS binding in the presence of 10 µM
dopamine = 100%). Several compounds exhibited less than
−20% activity, suggesting that these compounds might behave
as inverse agonists of [35S]GTPγS binding; additional studies
are necessary to confirm and characterize this. Among the 45
compounds tested for 5-HT1A agonism, five repeatedly demon-
strated more than 20% activity: 7 (74 10%), 12 (73 14%), 27
(81 8%), 37 (54 23%), and 42 (82 16%). In contrast to our
observations of activity at D4 receptors, none of the compounds
exhibited less than −20% activity at 5-HT1A receptors.
Selectivity of Serotonin 5-HT1A versus Dopamine
D4.2 Receptors
To evaluate this parameter, it is necessary to fix a limit for
compounds that present a low affinity for a receptor. In this
discussion, we have chosen a value of 500 nM for compounds
with no precisely determined affinity. In the quinoxaline series
(Table 1), it thus appears that the most selective compounds for
5-HT1A receptors possess in position 3 of the phenyl ring an
electron-withdrawing atom or group (chlorine (7) or trifluoro-
methyl (12)) or a methyl group (10). In the 2-quinoline series
(Table 2), the highest selectivity for 5-HT1A receptors, although
lower than in the quinoxaline series, is also found with com-
pounds substituted with a group in position 3 (19, 22, 25, 29) of
the distal phenyl ring. In the three series, the most selective com-
pound for 5-HT1A versus D4.2 receptors possess a CF3 group
in position 3 (12) of the distal phenyl ring. Otherwise, in these
series, some compounds (20, 23, 26) present a slight selectivity
for D4.2 receptors versus 5-HT1A receptors. In the 3-quinoline
series (Table 3), compounds substituted with a group in position
3 of the phenyl ring (37, 40, 42, 44) present a weak selectivity for
5-HT1A receptors versus D4.2 receptors in comparison with the
two other series. In this series, at least two compounds (34, 38)
being 10 times more selective for D4.2 receptors versus 5-HT1A
Conclusion
The5-HT1A versusD4selectivityissignificantlyincreasedwhen
the nitrogen-containing aromatic heterocycle replaces the naph-
thalene moiety. The presence of a quinoxaline moiety yielded
compounds not only with a high affinity for 5-HT1A receptors
but also with higher selectivity for 5-HT1A versus D4.2 recep-
tors and with a concomitant decrease in lipophilicity. In the

Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives
61
quinoline series, some derivatives possessed significant affini-
ties for D4.2 receptors whereas the affinity for 5-HT1A receptors
was reduced. The 3-CF3-substituted derivatives are the most
potent and selective compounds for 5-HT1A versus D4.2 recep-
tors. The presence of a 4-phenyl-1,2,3,6-tetrahydropyridine is
an interesting alternative to replace the phenylpiperazine moiety
without increased lipophilicity. Finally, this tetrahydropyridine
ring is also favourable in terms of affinity for α2A-adrenoceptors.
Such information will be useful for further medicinal chemistry
programs.
with a 10% aqueous K2CO3 solution (2 × 20 mL). Then the
organic layer was dried over anhydrous MgSO4, and evaporated
under reduced pressure. The residue was recrystallized in the
corresponding solvent. Overall yields are between 50 and 70%.
N-[2-(4-Phenylpiperazin-1-yl)ethyl]-2-quinoxaline
Carboxamide 2
Mp 123–124◦C. δH (500 MHz, CDCl3) 2.74 (m, 6H), 3.28 (t, J
4.9, 4H), 3.7 (q, J 6.0, 2H), 6.87 (t, J 7.3, 1H), 6.96 (d, J 8.0,
2H), 7.28 (m, 2H), 7.84 (m, 2H), 8.10 (d, J 1.1, 1H), 8.11 (d, J
1.4, 1H), 8.4 (brs, 1H), 9.69 (s, 1H). δC (500 mHz, CDCl3) (CH2)
36.28, 49.29, 53.04, 56.64;(CH)116.07, 119.81, 129.17, 129.52,
129.80, 130.76, 131.52, 143.95; (C) 140.33, 143.65, 143.89,
151.26, 163.35. νmax(KBr)/cm−1 3385, 2824, 1672, 1234, 756.
m/z [MH+] 362.4. (Calc. for C21H23N5O (361.440): C 69.78, H
6.41, N 19.38 Found: C 69.82, H 6.48, N 19.14%.)
Experimental
General
Melting points were determined on a Büchi-Tottoli capillary
melting point apparatus in open capillaries and are uncorrected.
NMR spectra were recorded on a Bruker Avance 500 spec-
trometer at 500 MHz. For 13C NMR, DEPT135 (Distortionless
Enhancement by Polarization Transfer) and APT (Attached Pro-
ton Test) experiments were used for detecting on the one hand
CH3, CH2, and CH and on the other hand C. In fluorine con-
taining derivatives, spectra are more complicated probably due
to carbon-fluorine coupling. IR spectra were performed on
a Perkin–Elmer Fourier-transform (FT)IR-1750 spectrometer
using KBr discs. Only significant bands from IR are reported.
Low resolution mass spectrometry (LRMS) was carried out
using an Ultima Triple Quadrupole instrument (Micromass,
Manchester, UK) operating under MassLynx 4.1 and config-
ured with a Z-Spray electrospray ionization source. Elemental
analyses were performed using a Carlo-Erba elemental ana-
lyzer CHNS-O model EA1108 and the results are within 0.4%
of the theoretical values. All starting materials and reagents
were obtained from Aldrich Chemical Co. and Acros Chemical
Co. and were used without further purification. When neces-
sary, separations by column chromatography were carried out
using Merck Kieselgel 60 (230–400 mesh). Concentration and
evaporation refer to removal of volatile materials under reduced
pressure (10–15 mmHg at 30–50◦C) on a Büchi-Rotavapor.
N-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 3
Mp 109–110◦C. δH (500 MHz, CDCl3) 2.76 (m, 6H), 3.19 (t, J
4.6, 4H), 3.70 (q, J 6.1, 2H), 6.92–7.09 (m, 4H), 7.85 (m, 2H),
8.13 (dd, J 1.4, 8.2, 1H), 8.19 (dd, J 1.4, 8.4, 1H), 8.40 (brs,
1H), 9.69 (s, 1H). δC (500 mHz, CDCl3) (CH2) 36.22, 50.52,
53.11, 56.71, (CH) 116.10, 116.27, 118.96, 122.53, 122.59,
124.45, 124.48, 129.53, 129.78, 130.76, 131.54, 143.94, (C)
140.01, 140.08, 140.32, 143.66, 143.87, 154.75, 156.71, 163.36.
νmax(KBr)/cm−1 3355, 2817, 1684, 1501, 1236, 748. m/z [MH+]
380.3. (Calc. for C21H22FN5O (379.431): C 66.47, H 5.84, N
18.46 Found: C 66.17, H 5.90, N 18.30%.)
N-{2-[4-(3-Fluorophenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 4
Mp 153–154◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.27 (t, J
5.0, 4H), 3.70 (q, J 6.0, 2H), 6.54 (m, 1H), 6.61 (m, 1H), 6.69
(dd, J 2.1, 8.3, 1H), 7.19 (m, 1H), 7.85 (m, 2H), 8.10 (dd, J 1.3,
8.1, 1H), 8.18 (dd, J 1.3, 8.3, 1H), 8.39 (brs, 1H), 9.68 (s, 1H).
δC (500 mHz, CDCl3) (CH2) 36.24, 48.71, 52.82, 56.65, (CH)
102.61, 102.81, 105.88, 106.05, 111.17, 129.52, 129.77, 130.12,
130.20, 130.79, 131.56, 143.92. νmax(KBr)/cm−1 3393, 2833,
1671, 1495, 776. m/z [MH+] 380.3. (Calc. for C21H22FN5O
(379.431): C 66.47, H 5.84, N 18.46 Found: C 66.28, H 6.07, N
18.54%.)
General Method for the Preparation of Primary Amines
The corresponding N-[2-(4-phenylpiperazin-1-yl)ethyl] phtal-
imide (2.2 mmol) was refluxed in absolute EtOH (10 mL) with
an excess of hydrazine hydrate (0.22 g, 4.4 mmol) for 1 h.
After cooling and dilution with CH2Cl2 (50 mL), the sus-
pension was filtered and the resulting solution was washed
with water (10 mL), then with a saturated aqueous NaCl solu-
tion (2 × 15 mL). The organic layer was dried over anhydrous
MgSO4, andevaporatedunderreducedpressure.Theoilyresidue
was diluted in ethyl acetate (20 mL) and triethylamine (3.16 mL,
22 mmol) was added.This solution was then used without further
purification in the following step.
N-{2-[4-(4-Fluorophenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 5
Mp 132–133◦C. δH (500 MHz, CDCl3) 2.74 (m, 6H), 3.19 (t, J
4.9, 4H), 3.70 (q, J 6.2, 2H), 6.90 (m, 2H), 6.97 (m, 2H), 7.84 (m,
2H), 8.10 (m, 1H), 8.18 (dd, J 1.3, 8.2, 1H), 8.39 (brs, 1H), 9.68
(s, 1H). δC (500 mHz, CDCl3) (CH2) 36.18, 50.12, 53.02, 56.65,
(CH) 115.50, 115.68, 117.90, 117.96, 129.52, 129.78, 130.79,
131.57, 143.91, (C) 140.32, 143.60, 147.85, 156.29, 158.19,
163.41. νmax(KBr)/cm−1 3376, 2824, 1655, 1511, 1234, 818,
754. m/z [MH+] 380.3. (Calc. for C21H22FN5O (379.431): C
66.47, H 5.84, N 18.46 Found: C 66.70, H 5.72, N 18.44%.)
General Method for the Preparation of Amide
Derivatives 2–46
The appropriate carboxylic acid (2.2 mmol) was refluxed in an
excess of thionyl chloride (3.17 mL, 44 mmol) for 3 h. The solu-
tion was evaporated under reduced pressure. The residue was
solubilized in ethyl acetate (20 mL) and the resulting solution
was added dropwise to the solution of the appropriate primary
amine (see above). The mixture was stirred for 15 h. The suspen-
sion was then evaporated under reduced pressure. The residue
was stirred with a 10% aqueous K2CO3 solution (20 mL) and
CH2Cl2 (40 mL) was added. The organic layer was washed
N-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 6
Mp 119–120◦C. δH (500 MHz, CDCl3) 2.77 (m, 6H), 3.15 (brs,
4H), 3.70 (q, J 6.1, 2H), 6.98 (m, 1H), 7.08 (dd, J 1.4, 8.0, 1H),
7.23 (m, 1H), 7.37 (dd, J 1.4, 8.0, 1H), 7.86 (m, 2H), 8.13 (dd,
J 1.8, 8.3, 1H), 8.19 (dd, J 1.7, 8.2, 1H), 8.40 (brs, 1H), 9.69 (s,
1H). δC (500 mHz, CDCl3) (CH2) 36.32, 51.27, 53.22, 56.73,

62
A. Graulich et al.
(CH) 120.38, 123.76, 127.60, 129.55, 129.77, 130.72, 130.74,
131.51, 143.98, (C) 128.80, 140.34, 143.68, 143.90, 149.19,
163.37. νmax(KBr)/cm−1 3356, 2837, 2815, 1679, 1526, 772.
m/z [MH+] 396.2. (Calc. for C21H22ClN5O (395.885): C 63.71,
H 5.60, N 17.69 Found: C 63.62, H 5.74, N 17.81%.)
1.3, 8.2, 1H), 8.42 (brs, 1H), 9.68 (s, 1H). δC (500 mHz, CDCl3)
(CH3) 20.42, (CH2) 36.27, 49.83, 53.04, 56.60, (CH) 116.37,
129.49, 129.66, 129.77, 130.72, 131.47, 143.92, (C) 129.28,
140.33, 143.66, 143.88, 149.19, 163.33. νmax(KBr)/cm−1 3318,
2813, 1652, 1545, 1519, 808, 753. m/z [MH+] 376.3. (Calc.
for C22H25N5O (375.467): C 70.38, H 6.71, N 18.65 Found: C
70.67, H 6.95, N 18.68%.)
N-{2-[4-(3-Chlorophenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 7
Mp 128–129◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.27 (t,
J 5.0, 4H), 3.70 (q, J 6.1, 2H), 6.81 (m, 2H), 6.90 (t, J 2.1,
1H), 7.17 (t, J 8.1, 1H), 7.85 (m, 2H), 8.10 (dd, J 1.4, 8.6,
1H), 8.18 (dd, J 1.2, 8.3, 1H), 8.39 (brs, 1H), 9.68 (s, 1H).
δC (500 mHz, CDCl3) (CH2) 36.25, 48.78, 52.82, 56.64, (CH)
113.96, 115.80, 119.42, 129.51, 129.75, 130.04, 130.75, 131.50,
143.92, (C) 134.97, 140.31, 143.61, 143.89, 152.30, 163.34.
νmax(KBr)/cm−1 3396, 2832, 1672, 1237, 777. m/z [MH+]
396.2. (Calc. for C21H22ClN5O (395.885): C 63.71 H, 5.60, N
17.69 Found: C 63.44, H 5.68, N 17.90%.)
N-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 12
Mp 111–112◦C. δH (500 MHz, CDCl3) 2.74 (m, 6H), 3.31 (t, J
5.0, 4H), 3.70 (q, J 6.0, 2H), 7.08 (d, J 8.1, 2H), 7.14 (s, 1H),
7.36 (t, J 8.0, 1H), 7.84 (m, 2H), 8.10 (dd, J 1.3, 8.2, 1H), 8.18
(dd, J 1.2, 8.3, 1H), 8.39 (brs, 1H), 9.69 (s, 1H). δC (500 mHz,
CDCl3)(CH2)48.33, 52.78, 56.69, (CH)119.05, 129.50, 129.68,
129.83, 130.84, 131.65, 143.84, (C) 140.37, 143.28, 143.94,
150.69, 163.91. νmax(KBr)/cm−1 3310, 2825, 1652, 1112, 754.
m/z [MH+] 430.3. (Calc. for C22H22F3N5O (429.438): C 61.53,
H 5.16, N 16.31 Found: C 61.77, H 5.18, N 16.23%.)
N-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 8
Mp 174–175◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.23 (t, J 5,
4H), 3.69 (q, J 6.0, 2H), 6.86 (m, 2H), 7.21 (m, 2H), 7.84 (m, 2H),
8.10 (dd, J 1.3, 8.2, 1H), 8.18 (dd, J 1.2, 8.3, 1H), 8.39 (brs, 1H),
9.68 (s, 1H). δC (500 mHz, CDCl3) (CH2) 36.28, 49.27, 52.86,
56.63, (CH) 117.20, 128.96, 129.52, 129.73, 130.74, 131.51,
143.92, (C) 124.57, 140.31, 143.62, 143.89, 149.88, 163.35.
νmax(KBr)/cm−1 3314, 2821, 1652, 1544, 1495, 812. m/z [MH+]
396.2. (Calc. for C21H22ClN5O (395.885): C 63.71, H 5.60, N
17.69 Found: C 63.95, H, 5.87, N 17.71%.)
N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 13
Mp 123–124◦C. δH (500 MHz, CDCl3) 2.76 (m, 6H), 3.17 (brs,
4H), 3.70 (q, J 6.1, 2H), 3.88 (s, 3H), 6.88 (dd, J 1.2, 8.0,
1H), 6.92–7.03 (m, 3H), 7.85 (m, 2H), 8.12 (m, 1H), 8.18 (dd,
J 1.4, 8.2, 1H), 8.42 (brs, 1H), 9.69 (s, 1H). δC (500 mHz,
CDCl3) (CH3) 55.39, (CH2) 36.32, 50.79, 53.25, 56.70, (CH)
111.28, 118.37, 121.05, 123.35, 129.47, 129.90, 130.79, 131.59,
143.85, (C) 140.35, 141.31, 143.72, 143.88, 152.30, 163.34.
νmax(KBr)/cm−1 3313, 2814, 1651, 1500, 1242, 748. m/z [MH+]
392.3. (Calc. forC22H25N5O2 (391.466): C 67.50, H 6.44, N
17.89 Found: C 67.24, H 6.66, N 17.53%.)
N-{2-[4-(2-Methylphenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 9
Mp 98–99◦C. δH (500 MHz, CDCl3) 2.32 (s, 3H), 2.76 (m, 6H),
3.01 (t, J 4.7, 4H), 3.70 (q, J 5.2, 2H), 7.00 (m, 1H), 7.06 (d, J 7.7,
1H), 7.18 (t, J 7.5, 2H), 7.86 (m, 2H), 8.14 (m, 1H), 8.19 (m, 1H),
8.42 (brs, 1H), 9.69 (s, 1H). δC (500 mHz, CDCl3) (CH3) 17.91,
(CH2) 36.36, 51.85, 53.55, 56.74, (CH) 118.92, 123.16, 126.55,
129.52, 129.77, 130.72, 131.11, 131.47, 143.96, (C) 132.61,
140.35, 143.71, 143.89, 151.45, 163.35. νmax(KBr)/cm−1 3350,
2836, 1676, 1526, 776. m/z [MH+] 376.3. (Calc. for C22H25N5O
(375.467): C 70.38, H 6.71, N 18.65 Found: C 70.00, H 6.76, N
18.55%.)
N-{2-[4-(3-Methoxyphenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 14
Mp 91–92◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.27 (t, J
4.9, 4H), 3.69 (q, J 6.1, 2H), 3.80 (s, 3H), 6.43 (dd, J 2.1,
8.1, 1H), 6.50 (t, J 2.2, 1H), 6.57 (d, J 2.1, 8.2, 1H), 7.19 (t,
J 8.2, 1H), 7.85 (m, 2H), 8.10 (m, 1H), 8.18 (dd, J 1.3, 8.2, 1H),
8.42 (brs,1H), 9.68 (s, 1H). δC (500 mHz, CDCl3) (CH3) 55.21,
(CH2) 36.09, 48.96, 52.95, 56.65, (CH) 102.66, 104.68, 108.96,
129.49, 129.83, 129.87, 130.78, 131.56, 143.91, (C) 140.32,
143.65, 143.88, 152.67, 160.62, 163.33. νmax(KBr)/cm−1 3374,
2816, 1677, 1534, 1202, 774. m/z [MH+] 392.3. (Calc. for
C22H25N5O2 (391.466): C 67.50, H 6.44, N 17.89 Found: C
67.37, H 6.80, N 17.89%.)
N-{2-[4-(3-Methylphenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 10
Mp 114–115◦C. δH (500 MHz, CDCl3) 2.33 (s, 3H), 2.73 (m,
6H), 3.26 (t, J 4.9, 4H), 3.70 (q, J 6.1, 2H), 6.69 (d, J 8.4, 1H),
6.76 (m, 2H), 7.17, (t, J 7.7, 1H), 7.84 (m, 2H), 8.10 (dd, J 1.4,
8.2, 1H), 8.18, (dd, J 1.3, 8.3, 1H), 8.42 (brs, 1H), 9.68 (s, 1H).
δC (500 mHz, CDCl3) (CH3) 21.78, (CH2) 36.16, 49.21, 53.04,
56.63, (CH) 113.27, 117.00, 120.84, 129.01, 129.49, 129.81,
130.76, 131.54, 143.89, (C) 138.80, 140.31, 143.62, 143.86,
151.28, 163.37. νmax(KBr)/cm−1 3363, 2819, 1678, 1531, 778.
m/z [MH+] 376.3. (Calc. for C22H25N5O (375.467): C 70.38, H
6.71, N 18.65 Found: C 70.78, H 6.76, N 18.82%.)
N-{2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 15
Mp 143–144◦C. δH (500 MHz, CDCl3) 2.74 (m, 6H), 3.17 (t, J
4.8, 4H), 3.69 (q, J 6.1, 2H), 3.78 (s, 3H), 6.85 (m, 2H), 6.92
(m, 2H), 7.84 (m, 2H), 8.10 (dd, J 1.8, 7.7, 1H), 8.18 (dd, J 1.3,
8.3, 1H), 8.41 (brs, 1H), 9.68 (s, 1H). δC (500 mHz, CDCl3)
(CH3) 55.58, (CH2) 36.28, 50.72, 53.13, 56.62, (CH) 114.48,
118.16, 129.51, 129.77, 130.74, 131.51, 143.93, (C) 140.33,
143.67, 143.89, 145.68, 153.84, 163.34. νmax(KBr)/cm−1 3316,
2818, 1654, 1514, 1252, 817. m/z [MH+] 392.3. (Calc. for
C22H25N5O2 (391.466): C 67.50, H 6.44, N 17.89 Found: C
67.40, H 6.72, N 17.72%.)
N-{2-[4-(4-Methylphenyl)piperazin-1-yl]ethyl}-
2-quinoxaline Carboxamide 11
Mp 151–152◦C. δH (500 MHz, CDCl3) 2.28 (s, 3H), 2.74 (m,
6H), 3.22(t, J4.9, 4H), 3.69(q, J6.1, 2H), 6.87(d, J8.4, 2H), 7.08
(d, J 8.4, 2H), 7.84 (m, 2H), 8.10 (dd, J 1.3, 8.2, 1H), 8.18 (dd, J

Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives
63
N-[2-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)ethyl]-
2-quinoxaline Carboxamide 16
νmax(KBr)/cm−1 3388, 2834, 1668, 1517, 1236, 811. m/z [MH+]
379.3. (Calc. for C22H23FN4O (378.443): C 69.82, H 6.13, N
14.80 Found: C 70.09, H 5.91, N 14.90%.)
Mp 102–104◦C. δH (500 MHz, CDCl3) 2.64 (m, 2H), 2.83 (m,
4H), 3.30 (q, J 2.7, 2H), 3.74 (q, J 6.2, 2H), 6.12 (m, 1H), 7.25 (m,
1H), 7.34 (m, 2H), 7.42 (m, 2H), 7.81 (m, 1H), 7.85 (m, 1H), 8.11
(m, 1H), 8.17 (dd, J 1.2, J 8.4, 1H), 8.37 (brs, 1H), 9.68 (s, 1H).
δC (500 mHz, CDCl3) (CH2) 27.99, 36.80, 50.34, 53.20, 56.70,
(CH) 121.53, 124.87, 127.11, 128.36, 129.49, 129.79, 130.72,
131.48, 143.96, (C) 135.05, 140.34, 140.64, 143.67, 143.86,
163.48. νmax(KBr)/cm−1 3404, 3390, 2823, 1670, 1527, 750.
m/z [MH+] 359.3. (Calc. for C22H22N4O (358.436): C 73.72, H
6.19, N 15.63 Found: C 73.63, H 6.44, N 15.56%.)
N-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 21
Mp 106–107◦C. δH (500 MHz, CDCl3) 2.77 (m, 6H), 3.16 (brs,
4H), 3.70 (q, J 6.2, 2H), 6.98 (m, 1H), 7.08 (dd, J 1.4, 8.0, 1H),
7.23 (m, 1H), 7.36 (dd, J 1.4, 8.0, 1H), 7.62 (m, 1H), 7.77 (m,
1H), 7.88 (dd, J 0.5, 8.2, 1H), 8.12 (d, J 8.5, 1H), 8.32 (s, 2H),
8.62 (brs, 1H). δC (500 mHz, CDCl3) (CH2) 36.48, 51.34, 53.25,
56.94, (CH) 118.93, 120.40, 123.69, 127.59, 127.78, 128.87,
129.80, 130.06, 130.70, 137.46, (C) 128.80, 129.30, 146.55,
149.31, 150.01, 164.56. νmax(KBr)/cm−1 3364, 2817, 1678, 781.
m/z [MH+] 395.3. (Calc. for C22H23ClN4O (394.897): C 66.91,
H 5.87, N 14.19. Found: C 66.84, H 6.15, N 14.26%.)
N-[2-(4-Phenylpiperazin-1-yl)ethyl]-2-quinoline
Carboxamide 17
Mp 158–159◦C. δH (500 MHz, CDCl3) 2.75 (m, 6H), 3.28 (t, J
4.9, 4H), 3.70 (q, J 6, 2H), 6.87 (t, J 7.3, 1H), 6.96 (d, J 7.9, 2H),
7.28 (m, 2H), 7.61 (m, 1H), 7.75 (m, 1H), 7.87 (dd, J 0.5, 8.2,
1H), 8.09(d, J8.4, 1H), 8.31(s, 2H), 8.64(brs, 1H). δC (500 mHz,
CDCl3) (CH2) 36.41, 49.28, 53.08, 56.87, (CH) 116.07, 118.88,
119.74, 127.74, 127.87, 129.15, 129.85, 130.06, 137.43, (C)
129.29, 146.54, 149.95, 151.32, 164.58. νmax(KBr)/cm−1 3386,
2834, 1668, 1497, 774. m/z [MH+] 361.3. (Calc. for C22H24N4O
(360.452): C 73.31, H 6.71, N 15.54 Found: C 73.15, H 7.06, N
15.69%.)
N-{2-[4-(3-Chlorophenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 22
Mp 160–161◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.27 (t,
J 5, 4H), 3.69 (q, J 6.2, 2H), 6.81 (m, 2H), 6.90 (t, J 2.1,
1H), 7.17 (t, J 8.1, 1H), 7.61 (m, 1H), 7.76 (m, 1H), 7.87 (dd,
J 0.6, 8.2, 1H), 8.09 (d, J 8.4, 1H), 8.31 (s, 2H), 8.62 (brs,
1H). δC (500 mHz, CDCl3) (CH2) 36.39, 48.82, 52.88, 56.86,
(CH) 113.93, 115.78, 118.88, 119.33, 127.76, 127.90, 129.82,
130.05, 130.09, 137.47, (C) 129.32, 135.00, 146.55, 149.92,
152.36, 164.61. νmax(KBr)/cm−1 3381, 2839, 1667, 1496, 778.
m/z [MH+] 395.3. (Calc. for C22H23ClN4O (394.897): C 66.91,
H 5.87, N 14.19 Found: C 66.72, H 5.45, N 14.36%.)
N-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 18
Mp 84–85◦C. δH (500 MHz, CDCl3) 2.76 (m, 6H), 3.19 (t,
J 4.7, 4H), 3.70 (q, J 6.3, 2H), 6.93–7.09 (m, 4H), 7.62 (m,
1H), 7.76 (m, 1H), 7.88 (dd, J 0.5, 8.2, 1H), 8.10 (d, J 8.5,
1H), 8.32 (s, 2H), 8.63 (brs, 1H). δC (500 mHz, CDCl3) (CH2)
36.42, 50.67, 53.14, 56.91, (CH) 116.06, 116.23, 118.90, 118.93,
122.41, 124.44, 127.75, 127.86, 129.80, 130.04, 137.44, (C)
129.32, 140.13, 140.19, 146.56, 149.99, 154.79, 156.75, 164.60.
νmax(KBr)/cm−1 3355, 2822, 1682, 1501, 1243, 780. m/z [MH+]
379.3. (Calc. for C22H23FN4O (378.443): C 69.82, H 6.13, N
14.80 Found: C 69.69, H 6.30, N 14.82%.)
N-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 23
Mp 161–162◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.23 (t,
J 5, 4H), 3.69 (q, J 6.2, 2H), 6.86 (m, 2H), 7.22 (m, 2H), 7.61
(m, 1H), 7.75 (m, 1H), 7.87 (dd, J 0.7, 8.2, 1H), 8.08 (d, J 8.5,
1H), 8.31 (s, 2H), 8.61 (brs, 1H). δC (500 mHz, CDCl3) (CH2)
36.40, 49.27, 52.92, 56.86, (CH) 117.25, 118.88, 127.76, 127.90,
128.98, 129.79, 130.09, 137.47, (C) 124.54, 129.32, 146.55,
149.95, 164.61. νmax(KBr)/cm−1 778, 1497, 1666, 2837, 3385.
m/z [MH+] 395.3. (Calc. for C22H23ClN4O (394.897): C 66.91,
H 5.87, N 14.19 Found: C 66.91, H 5.85, N 13.99%.)
N-{2-[4-(3-Fluorophenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 19
Mp 153–154◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.28 (t, J
5.0, 4H), 3.69 (q, J 6.2, 2H), 6.53 (m, 1H), 6.61 (m, 1H), 6.69
(dd, J 2.1, 8.3, 1H), 7.19 (dd, J 8.2, 15.3, 1H), 7.61 (m, 1H),
7.76 (m, 1H), 7.88 (d, J 8.2, 1H), 8.09 (d, J 8.5, 1H), 8.31 (s,
2H), 8.62 (brs, 1H). δC (500 mHz, CDCl3) (CH2) 36.41, 48.77,
52.87, 56.87, (CH) 102.56, 102.76, 105.76, 105.93, 111.13,
118.88, 127.76, 127.90, 129.81, 130.09, 130.17, 137.47, (C)
129.32, 146.55, 149.93, 152.93, 153.01, 162.93, 164.61, 164.86.
νmax(KBr)/cm−1 3384, 2839, 1667, 1497, 777. m/z [MH+]
379.3. (Calc. for C22H23FN4O (378.443): C 69.82, H 6.13, N
14.80 Found: C 69.56, H 6.56, N 14.88%.)
N-{2-[4-(2-Methylphenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 24
Mp 69–70◦C. δH (500 MHz, CDCl3) 2.32 (s, 3H), 2.76 (m, 6H),
3.01 (t, J 4.6, 4H), 3.70 (q, J 6.3, 2H), 6.99 (m, 1H), 7.06 (d, J
7.4, 1H), 7.18 (t, J 7.2, 2H), 7.62 (m, 1H), 7.77 (m, 1H), 7.88
(dd, J 0.8, 8.2, 1H), 8.12 (d, J 8.5, 1H), 8.32 (s, 2H), 8.64 (brs,
1H). δC (500 mHz, CDCl3) (CH3) 17.94, (CH2) 36.51, 51.86,
53.61, 57.00, (CH) 118.92, 118.98, 123.14, 126.57, 127.76,
127.87, 129.83, 130.07, 131.11, 137.45, (C) 129.32, 132.63,
146.58, 150.02, 151.53, 164.62. νmax(KBr)/cm−1 3263, 2824,
1650, 1494, 1145, 769. m/z [MH+] 375.3. (Calc. for C23H26N4O
(374.479): C 73.77 H 7.00, N 14.96 Found: C 73.79, H 7.13, N
14.81%.)
N-{2-[4-(4-Fluorophenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 20
Mp 163–164◦C. δH (500 MHz, CDCl3) 2.74 (m, 6H), 3.19 (t,
J 4.9, 4H), 3.69 (q, J 6.2, 2H), 6.90 (m, 2H), 6.97 (m, 2H),
7.61 (m, 1H), 7.75 (m, 1H), 7.87 (dd, J 0.6, 8.2, 1H), 8.09 (d,
J 8.09, 1H), 8.31 (s, 2H), 8.62 (brs, 1H). δC (500 mHz, CDCl3)
(CH2) 36.40, 50.25, 53.07, 56.86, (CH) 115.46, 115.63, 117.81,
117.87, 118.89, 127.76, 127.90, 129.80, 130.08, 137.47, (C)
129.29, 146.53, 147.98, 147.99, 149.94, 156.20, 158.10, 164.57.
N-{2-[4-(3-Methylphenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 25
Mp 145–147◦C. δH (500 MHz, CDCl3) 2.33 (s, 3H), 2.73 (m,
6H), 3.27(t, J4.9, 4H), 3.69(q, J6.2, 2H), 6.69(d, J7.4, 1H), 6.77
(m, 2H), 7.17 (t, J 7.7, 1H), 7.61 (m, 1H), 7.75 (m, 1H), 7.87 (dd,
J 0.6, 8.2, 1H), 8.09 (d, J 8.4, 1H), 8.31 (s, 2H), 8.65 (brs, 1H).

64
A. Graulich et al.
δC (500 mHz, CDCl3) (CH3) 21.79, (CH2) 36.39, 49.36, 53.10,
56.85, (CH) 113.19, 116.91, 118.87, 120.64, 127.72, 127.85,
128.97, 129.82, 130.04, 137.42, (C) 129.29, 138.80, 146.54,
149.95, 151.39, 164.57. νmax(KBr)/cm−1 3383, 2835, 1668,
1497, 772. m/z [MH+] 375.3. (Calc. for C23H26N4O (374.479):
C 73.77 H 7.00, N 14.96 Found: C 73.83, H 7.37, N 14.80%.)
N-{2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 30
Mp 138–139◦C. δH (500 MHz, CDCl3) 2.74 (m, 6H), 3.17 (t,
J 4.9, 4H), 3.69 (q, J 6.3, 2H), 3.78 (s, 3H), 6.85 (m, 2H),
6.93 (m, 2H), 7.61 (m, 1H), 7.75 (m, 1H), 7.87 (dd, J 0.6,
8.2, 1H), 8.09 (d, J 8.5, 1H), 8.31 (s, 2H), 8.63 (brs, 1H). δC
(500 mHz, CDCl3) (CH3) 55.58, (CH2) 36.34, 50.63, 53.17,
56.83, (CH) 114.48, 118.23, 118.86, 127.72, 127.87, 129.83,
130.06, 137.43, (C) 129.31, 145.57, 146.55, 149.87, 153.93,
164.67. νmax(KBr)/cm−1 3405, 2824, 1678, 1514, 1253, 777.
m/z [MH+] 391.3. (Calc. for C23H26N4O2 (390.478): C 70.75,
H 6.71, N 14.35 Found: C 70.78, H 6.61, N 14.53%.)
N-{2-[4-(4-Methylphenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 26
Mp 157–159◦C. δH (500 MHz, CDCl3) 2.28 (s, 3H), 2.74 (m,
6H), 3.23 (t, J 4.9, 4H), 3.69 (q, J 6.2, 2H), 6.87 (d, J 8.5, 2H),
7.09 (d, J 8.5, 2H), 7.61 (m, 1H), 7.75 (m, 1H), 7.87 (dd, J
0.6, 8.1, 1H), 8.08, (d, J 8.5, 1H), 8.31 (s, 2H), 8.65 (brs, 1H).
δC (500 mHz, CDCl3) (CH3) 20.42, (CH2) 36.39, 49.83, 53.09,
56.85, (CH) 116.39, 118.86, 127.71, 127.85, 129.65, 129.82,
130.04, 137.41, (C) 129.14, 129.23, 146.49, 149.21, 149.93,
164.52. νmax(KBr)/cm−1 3384, 2836, 1668, 1521, 1498, 800.
m/z [MH+] 375.3. (Calc. for C23H26N4O (374.479): C 73.77 H
7.00, N 14.96 Found: C 73.69, H 6.68, N 15.31%.)
N-[2-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)ethyl]-
2-quinoline Carboxamide 31
Mp 139–140◦C. δH (500 MHz, CDCl3) 2.64 (m, 2H), 2.84 (m,
4H), 3.30 (q, J 2.8, 2H), 3.74 (q, J 6.4, 2H), 6.11 (m, 1H), 7.23 (m,
1H), 7.33 (m, 2H), 7.42 (m, 2H), 7.61 (m, 1H), 7.74 (m, 1H), 7.87
(dd, J 0.8, 8.2, 1H), 8.10 (d, J 8.5, 1H), 8.31 (m, 2H), 8.58 (brs,
1H). δC (500 mHz, CDCl3) (CH2) 28.06, 36.96, 50.41, 53.24,
56.93, (CH) 118.90, 121.68, 124.91, 127.04, 127.71, 127.83,
128.32, 129.82, 130.02, 137.41, (C) 129.30, 135.06, 140.78,
146.55, 149.97, 164.69. νmax(KBr)/cm−1 3402, 2803, 1668,
1498, 745. m/z [MH+] 358.3. (Calc. for C23H23N3O (357.448):
C 77.28, H 6.49, N 11.76 Found: C 77.70, H 6.69, N 11.77%.)
N-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 27
Mp 128–129◦C. δH (500 MHz, CDCl3) 2.75 (m, 6H), 3.32 (t, J
5.0, 4H), 3.70 (q, J 6.2, 2H), 7.08 (dd, J 1.5, 7.9, 2H), 7.14 (s, 1H),
7.36 (t, J 8.0, 1H), 7.61 (m, 1H), 7.75 (m, 1H), 7.87 (d, J 8.2, 1H),
8.09 (d, J 8.5, 1H), 8.31 (s, 2H), 8.62 (brs, 1H). δC (500 mHz,
CDCl3) (CH2) 36.38, 48.76, 52.86, 56.85, (CH) 112.19, 115.91,
118.78, 118.87, 127.76, 127.91, 129.57, 129.80, 130.09, 137.48,
(C) 129.33, 146.56, 149.86, 151.34, 164.68. νmax(KBr)/cm−1
3382, 2841, 1668, 1498, 1170, 1112, 780. m/z [MH+] 429.3.
(Calc. for C23H23F3N4O (428.450): C 64.48, H 5.41, N 13.08
Found: C 64.01, H 5.50, N 13.09%.)
N-[2-(4-Phenylpiperazin-1-yl)ethyl]-3-quinoline
Carboxamide 32
Mp 165–166◦C. δH (500 MHz, CDCl3) 2.72 (m, 6H), 3.24 (t,
J 4.9, 4H), 3.67 (q, J 5.5, 2H), 6.87 (t, J 7.3, 1H), 6.94 (d, J
8.0, 2H), 7.03 (brs, 1H), 7.28 (m, 2H), 7.62 (m, 1H), 7.81 (m,
1H), 7.92 (d, J 8.1, 1H), 8.15 (d, J 8.4, 1H), 8.61 (d, J 2.0, 1H),
9.26 (d, J 2.2, 1H). δC (500 mHz, CDCl3) (CH2) 36.45, 49.34,
52.93, 56.25, (CH) 116.19, 119.98, 127.53, 128.82, 129.17,
129.43, 131.22, 135.71, 148.08, (C) 127.00, 127.17, 149.25,
151.14, 165.50. νmax(KBr)/cm−1 3299, 2824, 1636, 1541, 754.
m/z [MH+] 361.3. (Calc. for C22H24N4O (360.452): C 73.31, H
6.71, N 15.54 Found: C 72.92, H 6.75, N 15.34%.)
N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 28
Mp 136–137◦C. δH (500 MHz, CDCl3) 2.76 (m, 6H), 3.17 (brs,
4H), 3.69 (q, J 6.2, 2H), 3.88 (s, 3H), 6.87 (dd, J 1.3, 7.9, 1H),
6.92–7.03 (m, 3H), 7.61 (m, 1H), 7.76 (m, 1H), 7.87 (dd, J 0.7,
8.2, 1H), 8.11 (d, J 8.5, 1H), 8.31 (s, 2H), 8.64 (brs, 1H). δC
(500 mHz, CDCl3) (CH3) 55.38, (CH2) 36.44, 50.80, 53.30,
56.94, (CH) 111.24, 118.21, 118.89, 120.99, 122.92, 127.73,
127.83, 129.82, 130.03, 137.40, (C) 129.29, 141.37, 146.55,
150.01, 152.30, 164.57. νmax(KBr)/cm−1 3375, 2821, 1671,
1497, 1238, 754. m/z [MH+] 391.3. (Calc. for C23H26N4O2
(390.478): C 70.75, H 6.71, N 14.35 Found: C 70.76, H 7.12, N
14.41%.)
N-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 33
Mp 163–164◦C. δH (500 MHz, CDCl3) 2.74 (m, 6H), 3.15 (t,
J 4.6, 4H), 3.67 (q, J 6.1, 2H), 6.92–7.09 (m, 5H), 7.62 (m,
1H), 7.81 (m, 1H), 7.93 (d, J 8.1, 1H), 8.14 (d, J 8.4, 1H),
8.64 (d, J 1.9, 1H), 9.27 (d, J 2.2, 1H). δC (500 mHz, CDCl3)
(CH2) 36.42, 50.64, 52.98, 56.29, (CH) 116.09, 116.26, 118.99,
122.63, 124.51, 127.52, 128.85, 131.23, 135.87, 148.03, (C)
127.07, 127.2, 139.86, 149.24, 154.78, 165.49. νmax(KBr)/cm−1
3304, 2817, 1631, 1540, 1241, 752. m/z [MH+] 379.3. (Calc.
for C22H23FN4O (378.443): C 69.82, H 6.13, N 14.80 Found: C
69.36, H 6.35, H 14.80%.)
N-{2-[4-(3-Methoxyphenyl)piperazin-1-yl]ethyl}-
2-quinoline Carboxamide 29
Mp 131–132◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.27 (t,
J 4.9, 4H), 3.69 (q, J 6.2, 2H), 3.80 (s, 3H), 6.42 (dd, J 2.1,
8.2, 1H), 6.50 (t, J 2.3, 1H), 6.57 (dd, J 2.1, 8.2, 1H), 7.18 (t, J
8.2, 1H), 7.61 (m, 1H), 7.75 (m, 1H), 7.87 (dd, J 0.7, 8.2, 1H),
8.08 (d, J 8.5, 1H), 8.31 (s, 2H), 8.64 (brs, 1H). δC (500 mHz,
CDCl3) (CH3) 55.19, (CH2) 36.39, 49.20, 53.02, 56.85, (CH)
102.48, 104.46, 108.86, 118.86, 127.72, 127.86, 129.80, 129.83,
130.06, 137.42, (C) 129.29, 146.54, 149.94, 152.72, 160.61,
164.58. νmax(KBr)/cm−1 3344, 2830, 1651, 1502, 1214, 777.
m/z [MH+] 391.3. (Calc. for C23H26N4O2 (390.478): C 70.75,
H 6.71, N 14.35 Found: C 70.63, H 6.66, N 14.48%.)
N-{2-[4-(3-Fluorophenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 34
Mp 158–159◦C. δH (500 MHz, CDCl3) 2.72 (m, 6H), 3.24 (t,
J 4.9, 4H), 3.67 (q, J 5.6, 2H), 6.54 (m, 1H), 6.59 (m, 1H),
6.67 (dd, J 2.1, 8.3, 1H), 7.01 (brs, 1H), 7.19 (m, 1H), 7.62 (m,
1H), 7.81 (m, 1H), 7.92 (d, J 8.2, 1H), 8.14 (d, J 8.4, 1H), 8.62
(d, J 1.8, 1H), 9.26 (d, J 2.2, 1H). δC (500 mHz, CDCl3) (CH2)
36.43, 48.76, 52.72, 56.31, (CH) 102.71, 102.91, 106.05, 106.22,
111.22, 127.55, 128.83, 129.42, 130.15, 130.23, 131.25, 135.77,
148.05, (C) 127.02, 127.17, 149.26, 152.74, 152.81, 162.90,

Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives
65
164.84, 165.60. νmax(KBr)/cm−1 3314, 2827, 1630, 1543, 1494,
764. m/z [MH+] 379.3. (Calc. for C22H23FN4O (378.443): C
69.82, H 6.13, N 14.80 Found: C 69.48, H 6.52, N 14.85%.)
(m, 1H), 7.93 (d, J 8.1, 1H), 8.15 (d, J 8.5, 1H), 8.65 (d, J 1.8, 1H),
9.28 (d, J 2.1, 1H). δC (500 mHz, CDCl3) (CH3) 17.88, (CH2)
36.46, 51.83, 53.43, 56.34, (CH) 119.03, 123.32, 126.62, 127.52,
128.86, 129.40, 131.12, 131.22, 135.88, 148.08, (C) 127.08,
127.23, 132.64, 149.25, 151.26, 165.50. νmax(KBr)/cm−1 3290,
2820, 1632, 1552, 758. m/z [MH+] 375.3. (Calc. for C23H26N4O
(374.479): C 73.77 H 7.00, N 14.96 Found: C 73.66, H 7.17, N
14.74%.)
N-{2-[4-(4-Fluorophenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 35
Mp 184–185◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.16 (t, J
4.9, 4H), 3.67 (q, J 5.6, 2H), 6.89 (m, 2H), 6.97 (m, 2H), 7.02
(brs, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.92 (d, J 8.1, 1H), 8.14 (d,
J 8.5, 1H), 8.62 (d, J 1.9, 1H), 9.25 (d, J 2.2, 1H). δC (500 mHz,
CDCl3) (CH2) 36.42, 50.28, 52.91, 56.26, (CH) 115.50, 115.68,
117.94, 118.00, 127.54, 128.84, 129.40, 131.25, 135.81, 148.04,
(C) 127.03, 127.07, 147.71, 149.25, 156.42, 158.32, 165.56.
νmax(KBr)/cm−1 3291, 2822, 1637, 1510, 1230, 816. m/z [MH+]
379.3. (Calc. for C22H23FN4O (378.443): C 69.82, H 6.13, N
14.80. Found: C 69.74, H 6.33, N 14.95%.)
N-{2-[4-(3-Methylphenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 40
Mp 143–144◦C. δH (500 MHz, CDCl3) 2.33 (s, 3H), 2.72 (m,
6H), 3.23 (t, J 4.9, 4H), 3.67 (q, J 5.6, 2H), 6.70 (d, J 7.4,
1H), 6.76 (m, 2H), 7.04 (brs, 1H), 7.16 (t, J 7.7, 1H), 7.62
(m, 1H), 7.81 (m, 1H), 7.92 (d, J 8.1, 1H), 8.14 (d, J 8.5, 1H),
8.61 (d, J 1.8, 1H), 9.26 (d, J 2.2, 1H). δC (500 mHz, CDCl3)
(CH3) 21.77, (CH2) 36.43, 49.43, 52.95, 56.26, (CH) 113.35,
117.07, 120.91, 127.50, 128.81, 128.99, 129.41, 131.20, 135.71,
148.08, (C) 127.01, 127.15, 138.84, 149.24, 151.20, 165.51.
νmax(KBr)/cm−1 3278, 2816, 1642, 1556, 1249, 748. m/z [MH+]
375.3. (Calc. for C23H26N4O (374.479): C 73.77 H 7.00, N 14.96
Found: C 73.72, H 7.19, N 14.77%.)
N-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 36
Mp 151–152◦C. δH (500 MHz, CDCl3) 2.75 (m, 6H), 3.12 (brs,
4H), 3.67 (q, J 5.5, 2H), 6.98 (m, 1H), 7.05 (dd, J 1.5, 8.0, 1H),
7.07 (brs, 1H), 7.23 (m, 1H), 7.36 (dd, J 1.5, 7.9, 1H), 7.63 (m,
1H), 7.81 (m, 1H), 7.94, (d, J 8.2, 1H), 8.15 (d, J 8.5, 1H), 8.65
(d, J 2, 1H), 9.27, (d, J 2.0, 1H). δC (500 mHz, CDCl3) (CH2)
36.43, 51.34, 53.05, 56.19, (CH) 120.42, 123.86, 127.49, 127.61,
128.81, 129.37, 130.67, 131.17, 135.85, 148.00, (C) 127.05,
127.24, 128.80, 149.06, 149.22, 165.44. νmax(KBr)/cm−1 3239,
2828, 1631, 1558. m/z [MH+] 395.3. (Calc. for C22H23ClN4O
(394.897): C 66.91, H 5.87, N 14.19 Found: C 67.16, H 6.23, N
14.29%.)
N-{2-[4-(4-Methylphenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 41
Mp 172–174◦C. δH (500 MHz, CDCl3) 2.28 (s, 3H), 2.72 (m,
6H), 3.19 (t, J 4.9, 4H), 3.66 (q, J 5.6, 2H), 6.85 (d, J 9.5,
2H), 7.03 (brs, 1H), 7.07 (d, J 9.5, 2H), 7.62 (m, 1H), 7.80
(m, 1H), 7.91 (d, J 8.0, 1H), 8.14 (d, J 8.5, 1H), 8.61 (d, J 1.9,
1H), 9.26 (d, J 2.2, 1H). δC (500 mHz, CDCl3) (CH3) 20.43,
(CH2) 36.44, 49.85, 52.95, 56.30, (CH) 116.51, 127.49, 128.81,
129.38, 129.68, 131.19, 135.71, 148.11, (C) 127.01, 127.14,
129.53, 149.01, 149.23, 165.53. νmax(KBr)/cm−1 3302, 2942,
2812, 1642, 1538, 1518, 809, 745. m/z [MH+] 375.3. (Calc. for
C23H26N4O (374.479): C 73.77 H 7.00, N 14.96 Found: C 73.89,
H 7.27, N 15.21%.)
N-{2-[4-(3-Chlorophenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 37
Mp 144–145◦C. δH (500 MHz, CDCl3) 2.70 (m, 6H), 3.24 (t, J
4.9, 4H), 3.67(q, J5.6, 2H), 6.80(m, 2H), 6.88(d, J1.8, 1H), 6.99
(brs, 1H), 7.17 (t, J 8.1, 1H), 7.62 (t, J 7.5, 1H), 7.81 (t, J 7.3, 1H),
7.92 (d, J 8.2, 1H), 8.15 (d, J 8.4, 1H), 8.61 (d, J 1.8, 1H), 9.26
(d, J 1.8, 1H). δC (500 mHz, CDCl3) (CH2) 36.43, 48.80, 52.76,
56.48, (CH) 114.03, 115.94, 119.63, 127.55, 128.84, 129.34,
130.10, 131.28, 135.83, 148.11, (C) 127.00, 127.14, 134.97,
149.25, 152.17, 165.53. νmax(KBr)/cm−1 3284, 2816, 1636, 760.
m/z [MH+] 395.3. (Calc. for C22H23ClN4O (394.897): C 66.91,
H 5.87, N 14.19 Found: C 66.79, H 5.67, N 14.39%.)
N-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 42
Mp 172–174◦C. δH (500 MHz, CDCl3) 2.73 (m, 6H), 3.28 (t, J
5.0, 4H), 3.68 (q, J 5.6, 2H), 6.99 (brs, 1H), 7.07 (m, 2H), 7.12 (s,
1H), 7.35 (t, J 8.0, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.92 (d, J 8.2,
1H), 8.14 (d, J 8.4, 1H), 8.61 (d, J 1.9, 1H), 9.26 (d, J 2.2, 1H).
δC (500 mHz, CDCl3) (CH2) 36.38, 48.79, 52.72, 56.33, (CH)
112.34, 116.22, 118.93, 127.53, 128.79, 129.40, 129.59, 131.23,
135.71, 148.03, (C) 127.01, 127.15, 131.34, 131.59, 149.26,
151.25, 165.55. νmax(KBr)/cm−1 3277, 2829, 1662, 1308, 1153,
1110. m/z [MH+] 429.3. (Calc. for C23H23F3N4O (428.450): C
64.48, H 5.41, N 13.08 Found: C 64.58, H5.49, N 13.13%.)
N-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 38
Mp 204–205◦C. δH (500 MHz, CDCl3) 2.71 (m, 6H), 3.20 (t, J
4.9, 4H), 3.66 (q, J 5.6, 2H), 6.84 (m, 2H), 7.00 (brs, 1H), 7.21
(m, 2H), 7.62 (m, 1H), 7.81 (m, 1H), 7.92 (d, J 8.1, 1H), 8.14 (d,
J 8.4, 1H), 8.62 (d, J 1.9, 1H), 9.25 (d, J 2.2, 1H). δC (500 mHz,
CDCl3) (CH2) 36.41, 49.29, 52.76, 56.28, (CH) 117.36, 127.54,
128.82, 129.01, 129.41, 131.25, 135.80, 148.01, (C) 124.86,
127.02, 127.08, 149.26, 149.70, 165.52. νmax(KBr)/cm−1 3298,
2825, 1631, 1546, 1498, 814. m/z [MH+] 395.3. (Calc. for
C22H23ClN4O (394.897): C 66.91, H 5.87, N 14.19 Found: C
66.63, H 6.10, N 14.23%.)
N-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 43
Mp 150–151◦C. δH (500 MHz, CDCl3) 2.74 (m, 6H), 3.13 (brs,
4H), 3.66 (q, J 5.6, 2H), 3.88 (s, 3H), 6.87 (dd, J 1.0, 7.8, 1H),
6.94 (m, 2H), 7.01 (m, 1H), 7.12 (brs, 1H), 7.62 (m, 1H), 7.81
(m, 1H), 7.93 (d, J 8.1, 1H), 8.15 (d, J 8.5, 1H), 8.64 (d, J 1.9, 1H),
9.27 (d, J 2.2, 1H). δC (500 mHz, CDCl3) (CH3) 55.40, (CH2)
36.41, 50.75, 53.13, 56.31, (CH) 111.26, 118.25, 121.03, 123.12,
127.49, 128.84, 129.39, 131.19, 135.89, 148.09, (C) 127.06,
127.21, 141.08, 149.24, 152.28, 165.47. νmax(KBr)/cm−1 3339,
2824, 1636, 1542, 1499, 1241, 746. m/z [MH+] 391.3. (Calc. for
N-{2-[4-(2-Methylphenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 39
Mp 126–128◦C. δH (500 MHz, CDCl3) 2.32 (s, 3H), 2.73 (m,
6H), 2.98 (t, J 4.5, 4H), 3.66 (q, J 5.6, 2H), 6.99 (m, 1H), 7.03 (d,
J 7.7, 1H), 7.10 (brs, 1H), 7.18 (t, J 7.5, 2H), 7.63 (m, 1H), 7.81

66
A. Graulich et al.
C23H26N4O2 (390.478): C 70.75, H 6.71, N 14.35 Found: C
70.76, H 7.18, N 14.41%.)
obtain a daughter solution of each compound (20 µg mL−1).
These diluted solutions (20 µL) were injected. The flow rate was
maintained at 1 mL min−1. The temperature of the column was
fixed at 25◦C, and the ultraviolet absorption wavelength was set
at 250 nm.The mobile phases were phosphate buffer (50 mM, pH
7.4) containing 10 to 60% methanol, according to the lipophilic-
ity of the compounds. The increment of methanol between two
mobile phases is 10%. All retention factors given represent the
mean of three determinations of each sample solution. Retention
N-{2-[4-(3-Methoxyphenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 44
Mp 137–139◦C. δH (500 MHz, CDCl3) 2.71 (m, 6H), 3.24 (t, J
4.9, 4H), 3.66 (q, J 5.6, 2H), 3.80 (s, 3H), 6.43 (dd, J 2.0, 8.0, 1H),
6.47 (t, J 2.2, 1H), 6.54 (dd, J 2.0, 8.2, 1H), 7.03 (brs, 1H), 7.18 (t,
J 8.2, 1H), 7.62 (m, 1H), 7.80 (m,1H), 7.91 (d, J 8.1, 1H), 8.14 (d,
J 8.5, 1H), 8.61 (d, J 1.7, 1H), 9.26 (d, J 2.2, 1H). δC (500 mHz,
CDCl3) (CH3) 55.20, (CH2) 36.43, 49.23, 52.87, 56.27, (CH)
102.63, 104.70, 108.94, 127.51, 128.81, 129.42, 129.84, 131.21,
135.69, 148.08, (C) 127.02, 127.15, 149.26, 152.52, 160.61,
165.51. νmax(KBr)/cm−1 3292, 2819, 1641, 1549, 1210, 753.
m/z [MH+] 391.3. (Calc. for C23H26N4O2 (390.478): C 70.75,
H 6.71, N 14.35 Found: C 70.70, H 6.80, N 14.49%.)
times of the test compounds were transformed into capacity fac-
(tr − t0)
tors (kꢀIAM) according to the following equation: kꢀIAM
=
,
t0
where tr and t0 are the retention time of the test compound and
the column void volume time respectively. Capacity factors were
expressed as a logarithm (log kꢀIAM). The values reported in the
text correspond to the extrapolation at 100% aqueous medium.
N-{2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethyl}-
3-quinoline Carboxamide 45
In Vitro Binding Procedures
5-HT1A Receptor Binding Assays
Mp 172–174◦C. δH (500 MHz, CDCl3) 2.72 (m, 6H), 3.13 (t, J
4.8, 4H), 3.66 (q, J 5.6, 2H), 3.78 (s, 3H), 6.85 (m, 2H), 6.90 (m,
2H), 7.05 (brs, 1H), 7.62 (m, 1H), 7.81 (m, 1H), 7.92 (d, J 7.9,
1H), 8.14 (d, J 8.5, 1H), 8.62 (d, J 1.8, 1H), 9.26 (d, J 2.2, 1H).
δC (500 mHz, CDCl3) (CH3) 55.57, (CH2) 36.30, 50.63, 53.03,
56.35, (CH) 114.50, 118.40, 127.49, 128.86, 129.39, 131.21,
135.79, 148.15, (C) 126.99, 127.19, 145.53, 149.22, 153.92,
165.49. νmax(KBr)/cm−1 3304, 2818, 1638, 1513, 1251, 822.
m/z [MH+] 391.3. (Calc. for C23H26N4O2 (390.478): C 70.75,
H 6.71, N 14.35 Found: C 70.84, H 6.89, N 14.00%.)
CHO cells expressing recombinant human serotonin recep-
tors subtype 1A were used as membrane preparations (Perkin–
Elmer 6110501). Briefly, incubations were carried out in 50 mM
Tris-HCl buffer (pH 7.4) containing 10 mM MgSO4, 0.5 mM
EDTA, and 0.1% ascorbic acid. Binding assays were performed
in 540 µL total volume divided in 500 µL diluted membranes,
20 µL radioligand ([3H]-8-OH-DPAT at 0.25 nM) and 20 µL
buffer, unlabelled ligand, or tested drugs. After 60 min at 27◦C,
incubations were terminated by rapid filtration on Whatman
GF/C filters pre-soaked in 0.3% polyethylenimine followed by
washing two times with ice-cold 50 mM TRIS-HCl (pH 7.4).
Filters were placed in a vial containing 7.5 mL Ecoscint A.
Radioactivity remaining on the filter was evaluated by liquid
scintillation using aTRI-CARB 1600TR liquid scintillation ana-
lyzer. Non-specific binding was estimated in the presence of
10 µM WB4101.Affinities were determined at least in duplicate
with eight concentrations in duplicate. A preliminary screening
was made at 10−6 M. Compounds displacing more than 60%
specific radioactivity were further tested for Ki determinations
(Kd of the radioligand is 0.32 nM).
N-[2-(4-Phenyl-1,2,3,6-tetrahydropyridin-1-yl)ethyl]-
3-quinoline Carboxamide 46
Mp 173–175◦C. δH (500 MHz, CDCl3) 2.61 (m, 2H), 2.81 (m,
4H), 3.26 (q, J 2.9, 2H), 3.70 (q, J 5.5, 2H), 6.10 (m, 1H), 7.10
(brs, 1H), 7.24 (m, 1H), 7.33 (m, 2H), 7.40 (m, 2H), 7.60 (m, 1H),
7.79 (m, 1H), 7.90 (d, J 8.2, 1H), 8.13 (d, J 8.4, 1H), 8.60 (d, J
1.9, 1H), 9.27 (d, J 2.2, 1H). δC (500 mHz, CDCl3) (CH2) 27.92,
36.83, 50.12, 53.02, 56.21, (CH) 121.23, 124.84, 127.21, 127.42,
128.37, 128.80, 129.39, 131.13, 135.64, 148.33, (C) 126.96,
127.20, 135.09, 140.43, 149.21, 165.68. νmax(KBr)/cm−1 3299,
2920, 1638, 1540, 743. m/z [MH+] 358.3. (Calc. for C23H23N3O
(357.448): C 77.28, H 6.49, N 11.76 Found: C 77.39, H 6.71, N
11.77%.)
α
2A-Adrenoceptor Binding Assays
Sf9 cells expressing human cloned α2A-adrenoceptors were
used as membrane preparations (Perkin–Elmer 6110113).
Briefly, incubations were carried out in 50 mM Tris-HCl buffer
(pH 7.4) containing 12.5 mM MgCl2 and 2 mM EDTA. Bind-
ing assays were performed in 540 µL total volume divided in
500 µL diluted membranes, 20 µL radioligand ([3H]-MK912 at
0.7 nM), and 20 µL buffer, unlabelled ligand or tested drugs.
After 60 min at 27◦C, incubations were terminated by rapid fil-
tration on Whatman GF/C filters followed by washing two times
with ice-cold 50 mM Tris-HCl (pH 7.4). Filters were placed in a
vial containing 7.5 mL Ecoscint A. Radioactivity remaining on
the filter was evaluated by liquid scintillation using aTRI-CARB
1600TR liquid scintillation analyzer. Non-specific binding was
estimated in the presence of 10 µM metergoline. Affinities were
determined at least in duplicate with eight concentrations in
duplicate. A preliminary screening was made at 10−6 M. Com-
pounds displacing more than 60% specific radioactivity were
further tested for Ki determinations (Kd of the radioligand is
0.75 nM).
Lipophilicity Measurement (Log kIꢀAM
)
The column was an IAM.PC.DD2 HPLC column (30
length × 4.6 mm internal diameter; particle size: 12 µm; pore
diameter: 300 Å) from Regis Technologies (Morton Grove, IL,
USA). The LC system consisted in a Merck-Hitachi L-6000
Pump, a Merck-Hitachi D-2000 Chromato-Integrator and a
Rheodyne 7125 injector module equipped with a 20-µL loop
(Rohnert Park, CA, USA). The column was maintained in
a thermostatted water-bath Tectron 473–100 from Selecta
(Barcelona, Spain), and detection was carried out with a
Merck-Hitachi L-4000 UV detector. Prior to use, mobile phases
were degassed for 15 min in a Branson 5510 ultrasonic bath
(Branson Ultrasonics Corporation, Danbury, CT, USA). Buffer
was adjusted to the expected pH values with a Radiometer Ana-
lytical pH meter, model ION check 10 (Villeurbanne, France).
Each drug was dissolved in methanol (10.0 mL) at a concen-
tration of 200 µg mL−1. A 1-mL volume of this stock solution
was then diluted with methanol in a 10-mL flask in order to

Chemical Modifications on 4-Arylpiperazine-Ethyl Carboxamide Derivatives
67
D4.2 Receptor Binding Assays
alsosupportedinpartbytheNationalInstituteofMentalHealthPsychoactive
Drug Screening Program and U19MH82441 to B.L.R.
Sf9 cells expressing human cloned D4.2 receptors were used
as membrane preparations (Sigma D2439). Briefly, incubations
were carried out in 50 mM Tris-HCl buffer (pH 7.4) contain-
ing 5 mM MgCl2, 5 mM KCl, 1.5 mM CaCl2, and 5 mM EDTA.
Binding assays were performed in 540 µL total volume divided
in 500 µL diluted membranes, 20 µL radioligand ([3H]-YM-
09151–2 at 0.2 nM) and 20 µL buffer, unlabelled ligand, or
tested drugs. After 60 min at 27◦C, incubations were termi-
nated by rapid filtration on Whatman GF/C filters followed by
washing two times with ice-cold 50 mM Tris-HCl (pH 7.4).
Filters were placed in a vial containing 7.5 mL Ecoscint A.
Radioactivity remaining on the filter was evaluated by liquid
scintillation using aTRI-CARB 1600TR liquid scintillation ana-
lyzer. Non-specific binding was estimated in the presence of
10 µM clozapine.Affinities were determined at least in duplicate
with eight concentrations in duplicate. A preliminary screening
was made at 10−6 M. Compounds displacing more than 60%
specific radioactivity were further tested for Ki determinations
(Kd of the radioligand is 0.06 nM).
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Acknowledgement
The technical assistance of Y. Abrassart, P. Fraikin, S. Counerotte, and
J. Wuidart for IR spectra, 13C NMR measurements, elemental analyses,
and mass spectra respectively is gratefully acknowledged. Supported in
part by grants of the Fonds de la Recherche Scientifique FNRS (F.R.S.-
FNRS) and the Fonds Spéciaux pour la Recherche of the University of Liège
(Belgium). J.-F.L. is a Research Director of the F.R.S.-FNRS. This work was