Synthesis and structural investigation of some pyrimido[5,4-c]quinolin- 4(3H)-one derivatives with a long-chain arylpiperazine moiety as potent 5-HT1A/2A and 5-HT7 receptor ligands

Article abstract of DOI:10.1016/j.ejmech.2011.04.060

A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the serotonergic activity. The majority of compounds demonst

Full text of DOI:10.1016/j.ejmech.2011.04.060

European Journal of Medicinal Chemistry 46 (2011) 3348e3361
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and structural investigation of some pyrimido[5,4-c]quinolin-4(3H)-one
derivatives with a long-chain arylpiperazine moiety as potent 5-HT1A/2A
and 5-HT7 receptor ligands
Wieslawa Lewgowd a, Andrzej J. Bojarski b, Malgorzata Szczesio c, Andrzej Olczak c, Marek L. Glowka c,
,
Stefan Mordalski b, Andrzej Stanczak a
*
a Department of Hospital Pharmacy, Faculty of Pharmacy, Medical University of Lodz, 1 Muszynski Street, 91-151Lodz, Poland
b Department of Medicinal Chemistry, Institute of Pharmacology, Polish Academy of Sciences, 12 Smetna Street, 31-343 Krakow, Poland
c Institute of General and Ecological Chemistry, Technical University of Lodz, 116 Zeromski Street, 90-924 Lodz, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of new pyrimido[5,4-c]quinolin-4(3H)-ones with variable length of the spacer between amide
and 4-arylpiperazine moiety were prepared to further explore the role of a terminal portion in the
serotonergic activity. The majority of compounds demonstrated high in vitro affinity for 5-HT1A receptor,
and moderate-to-low affinity for 5-HT2A and 5-HT7 receptors. X-ray analysis, two-dimensional NMR,
conformational studies and docking into the 5-HT1A receptor model were conducted to investigate
conformational preferences of selected 5-HT1A receptor ligands in different environments. The extended
conformation of tetramethylene derivatives was found in a solid state, in DMSO (for a protonated form)
and as a global energy minimum during conformational analysis in simulated water environment. Ligand
geometry in top-scored complexes, obtained by docking to a set of 100 receptor models, were either fully
extended or with central spacer torsion in synclinal conformation.
Received 3 January 2011
Received in revised form
26 April 2011
Accepted 26 April 2011
Available online 6 May 2011
Keywords:
Pyrimidoquinolones
Long-chain arylpiperazines
5-HT receptor ligands
Molecular modeling
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
showing diverse pharmacological properties [10]. The most
promising group of 5-HT1A receptor ligands are Long-Chain Aryl-
5-Hydroxytryptamine (5-HT, serotonin) is one of the major
neurotransmitters in central nervous system (CNS) [1,2]. A plethora
of studies shows its involvement in many physiological processes
such as the regulation of mood, appetite, sleep, muscle contraction,
thermoregulation, cardiovascular function, and some cognitive
functions including learning and memory. Malfunctioning sero-
tonin system has been linked to various psychiatric diseases,
including anxiety, depression, alcoholism and others [3e5]. There
are fourteen known serotonin receptor subtypes (divided into
seven subfamilies) based on amino acid sequence, signal trans-
duction mechanism, and pharmacological function [6,7]. Thirteen
of them (5-HT3 receptor is a ligand-gated cation channel) belong to
G-protein-coupled receptor (GPCR) superfamily. 5-HT1A subtype is
one of the most extensively studied because of its early discovery
and postulated involvement in anxiety and depression [8,9]. There
are numerous potent 5-HT1A receptor ligands, which can be
subdivided into different chemical classes: aminotetralines, aryl-
piperazines, ergolines, indolylalkylamines, aporphines and more,
Piperazines (LCAPs) with several successfully developed drugs
(buspirone, tandospirone, aripiprazole) or pharmacological tools
(NAN-190, flexinoxan, WAY 1000135, WAY 1000635). This
undoubtedly high prodrug potential of LCAPs resulted in various
SAR studies focusing on all three main structural parts: the aryl
group at N1 of the piperazine ring, the aliphatic chain at N4 posi-
tion, and terminal fragment (the most often having amide or imide
moiety). Although the influence of the aryl substituent types, as
well as the length of the alkyl spacer, on 5-HT1A affinity is relatively
well established, the function of the terminal amide/imide moiety
is less clear [11]. It is postulated that this part of the ligand is located
in a large pocket formed by helices IVeVI, but the limit of hydro-
phobic pocket capacity has not been determined [12]. Therefore,
many research groups have been interested in designing of LACPs
with different terminal fragment, as 5-HT1A/2A receptor ligands.
Due to highly flexible linker (usually 2e4 methylene units)
various attempts, using diverse experimental and modeling tech-
niques, were conducted to determine the bioactive conformation of
LCAPs. Assuming that active conformations of LCAPs are closely
related to those in solutions or in solid state, two-dimensional NMR
[13e16] and crystallographic methods [13,17e24] were often
* Corresponding author. Tel./fax: þ48 42 677 92 52.
E-mail address: andrzej.stanczak@umed.lodz.pl (A. Stanczak).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.04.060

W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
3349
applied. The 2D NMR studies indicated that compounds with tet-
ramethylene spacer can adopt extended, bent or folded confor-
mations [13,15,16]. On the other hand, analysis of Cambridge
Structural Database showed that linear geometries predominated
(Table 1; see Supplementary Materials). Also molecular modeling
studies (conformational analysis, docking, dynamics), provided
with structural investigations or conducted separately, gave
equivocal results suggesting the possibility of different bioactive
conformations of LCAPs.
Looking at the structureeaffinity relationships of quinazolin-
4(3H)-ones [25], we decided to apply all the above mentioned
techniques to investigate a new series of LCAP derivatives with
a terminal heterocyclic fragment of pyrimido[5,4-c]quinolone and
variable length of the spacer as serotonin receptors ligands.
Diversified structural approaches along with thorough analysis of
existing data allowed us to formulate some general conclusions.
Fig. 1. Significant ROSY signals of 35 (as hydrochloride) in deuterated dimethylsulf-
oxide solution at 300 K. Also shown is numbering system used in NMR and X-ray
analysis.
2. Chemistry
3. Pharmacology
All compounds investigated in this research were obtained
through the synthetic pathway given in Scheme 1. The starting
pyrimido[5,4-c]quinolin-4(3H)-ones were prepared by published
procedures [26,27]. Their N-alkylation with 1-bromo-2-chloro-
ethane, 1-bromo-3-chloropropane or 1-bromo-4-chlorobutane in
tert-butanol in presence of potassium fluoride/aluminium oxide
In order to determine activity for 5-HT1A and 5-HT2A receptors,
all compounds were assayed in vitro radioligand binding experi-
ments according to previously published procedures [29].
At first, the whole set of synthesized derivatives were pre-
screened at 1 mM concentration, and those inhibited min. 85% of
radioligand binding were further examined in full competition
experiments to determine Ki value. Since a long-chain arylpiper-
azines (LCAPs) are also recognized by 5-HT7 receptor, a set of
derivatives with tetramethylene spacer was also examined at this
target (Table 1,2).
carried to respective 3-(
u-chloroalkyl)pyrimido[5,4-c]quinolin-
4(3H)-one [28]. The reaction temperature was kept at 75 ꢀC and its
progress was monitored by the TLC. The final products were ob-
tained by condensation of the appropriate 1-arylpiperazine with
above-described chloroalkyl derivatives in acetonitrile at reflux for
24 h, in the presence of potassium carbonate and potassium iodide.
The structure of the synthesized compounds was confirmed by
physical constants, elemental analysis and NMR spectroscopy. The
correlation study COSY 1He1H and HETCOR 1He13C allowed
the identification and assignment of all protonated carbons. The
remainder was deduced from an HSQC experiment. For biological
experiments, free bases (10e67) were converted into hydrochlo-
ride salts, and their molecular formulas and molecular weights
were established on the basis of an elemental analysis.
4. Molecular modeling
Six compounds with different spacer length were selected for
detailed molecular modeling studies 11, 14, 23, 35, 38 and 42. For
each molecule conformational analysis was performed using
Systematic Search module of Tripos SYBYL 8.0 package with the
step of 120ꢀ for each rotatable bond. Due to sterical clashes total
number of returned conformers has been reduced to 48 for 23, 19
for 11 and 14 and 114 for 35, 38 and 42. For each set of structures
geometry optimization with OpenMopac 2007 was performed.
Speed and accuracy of calculations decided on picking semi-
empirical methods for all the computations. PM6 Hamiltonian was
used and jobs were run for both vacuum and solvent (COSMO
algorithm) models. In parallel, flexible docking to hundred 5-HT1A
receptor models was performed to predict bioactive conformations
of investigated compounds. BioSolveIT FlexX 2.0.3 software was
used for docking, and results were scored with CScore module of
SYBYL 8.0.
The structural investigation of representative LCAPs were con-
ducted in a solid state (X-ray analysis) and in solutions (2D NMR
experiments) to get more information about conformational pref-
erences of studied compounds. Crystals of hydrochlorides of 14, 23,
38 and 42, suitable for X-ray studies, were crystallized from
ethanol/methanol mixture (or DMF for 42) by slow evaporation of
respective solvent. Appropriate crystal data are summarized in
Supplementary Materials (Table 2), while final coordinates and
details of measurements, solutions and refinements have been
deposited with Cambridge Crystallographic Data Center No.
794185e794188.
Results of geometry optimizations show that extended confor-
mations are preferred for solvent simulations, whereas in vacuum
bent geometries dominated. Results for 35 are presented in
Supplementary Materials (Fig. 2a,b). To approximate spacer angu-
lation a distance between nitrogen atoms at both ends of the linker
The ROESY experiments of tetramethylene derivatives 35, 38
and 42 (both free bases and hydrochlorides) were curried out in
DMSO and CDCl3 solutions and their results were presented on
Fig. 1 in this manuscript and in Supplementary Materials (Fig. 1).
Scheme 1. Reagents and conditions: (a) alkyldihalides, tert-butanol, KF/Al2O3; (b) arylpiperazines, CH3CN, K2CO3, KI.

3350
W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
Table 1
Table 2
5-HT1A, 5-HT2A and 5-HT7 binding data for compounds 10e45.
5-HT1A and 5-HT2A binding data for methyl derivatives 46e67.
O
O
(CH2)n
(CH2)n
N
N
N
N
N
N
R
R
N
N
N
N
R1
R2
No
R
n
5-HT1A
5-HT2A
5-HT7
% Inhiba
Ki [nM]b
% Inhiba
Ki [nM]b
No
R
R1
R2
n
5-HT1A
5-HT2A
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
H
2-Cl
3-Cl
4-Cl
2-OMe
3-OMe
4-OMe
2-F
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
4
4
66
90
93
11
93
82
6
47
40
84
89
10
95
87
91
42
97
89
0
92
85
81
85
92
93
92
96
54
97
90
11
96
75
96
89
82
e
26
17
22
4
e
% Inhiba
Ki [nM]b
% Inhiba
78
55
e
e
e
46
48
50
52
54
56
58
60
62
64
66
47
49
51
53
55
57
59
61
63
65
67
2-OMe
4-OMe
3-CF3
H
3-Cl
2-OMe
4-F
3-Cl
2-OMe
2-F
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2
2
2
3
3
3
3
4
4
4
4
2
2
2
3
3
3
3
4
4
4
4
96
9
14
e
19
9
8
e
42
e
36
11
28
25
14
34
36
29
66
41
63
67
8
26
23
27
73
32
44
0
76
72
84
79
64
76
48
79
82
82
61
17
e
88
86
73
92
68
85
99
90
60
88
5
82
86
77
93
67
91
99
94
72
241
125
e
e
44
40
18
45
62
43
45
57
11
4
e
e
e
e
31
e
4-F
e
e
2-Me
3-CF3
4-Py
H
2-Cl
3-Cl
514
160
e
e
172
20
83
e
e
H
H
H
e
47
93
80
e
e
4-F
e
2-OMe
4-OMe
3-CF3
H
3-Cl
2-OMe
4-F
3-Cl
2-OMe
2-F
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
82
e
e
4-Cl
e
e
8
2-OMe
3-OMe
4-OMe
2-F
20
120
e
e
128
e
28
44
5
39
57
48
34
56
e
e
26
e
55
129
e
e
4-F
e
67
8
97
e
2-Me
3-CF3
4-Py
H
2-Cl
3-Cl
e
243
48
28
17
34
e
e
H
H
e
4-F
612
153
184
328
276
484
>10 000
739
404
296
418
5800
a
% of Inhibition at 10ꢁ6 M.
Values are means of three experiments run in triplicate, SEM ꢂ 19%.
b
4-Cl
2-OMe
3-OMe
4-OMe
2-F
6
31
e
As expected, the combination of arylpiperazine pharmacophore,
standard alkylene linkers and pyrimido[5,4-c]quinolone as
a terminal fragment, resulted in a set of 5-HT1A receptor ligands with
well defined SAR. The results of binding experiments, expressed as Ki
values varied from 6 nM for 38 to 514 nM for 19 (Table 1) and showed
classical LCAPs affinity pattern for 5-HT1A receptors. Generally,
63
e
4-F
2-Me
3-CF3
4-Py
52
127
e
a
% of Inhibition at 10ꢁ6 M.
Values are means of three experiments run in triplicate, SEM ꢂ 21%.
b
was used. All compounds were bound into receptor models in
a way similar to that described previously [30]. Phenyl substituent
interacted with phenylalanine buried deep in binding pocket
(Phe6.51, Phe6.52), protonated piperazine nitrogen was anchored
by aspartic acid (Asp3.32) and terminal part was in contact with
phenylalanine and/or tyrosine (Tyr2.64, Phe3.28, Tyr7.43) residues.
Top scored poses of all investigated ligands are presented on Fig. 2.
5. Results and discussion
New derivatives of pyrimido[5,4-c]quinolin-4(3H)-one 10e67
with 2e4 methylene spacer between amide and 4-arylpiperazine
moiety as quinazolidin-4-one analogous [25] were prepared.
Compounds 46e67 were characterizedbythepresence of the methyl
group located attheC8orC9positionof thepyrimido[5,4-c]quinolin-
4(3H)-one system, whereas compounds 10e45 had no additional
substituent in the terminal fragment. At first, the whole set of
synthesized derivatives were pre-screened at 1 mM concentration,
and those inhibited min. 85% of radioligand binding were further
examined in full competition experiments to determine Ki value.
Fig. 2. Top scored poses of investigated compounds docked into binding pocket of 5-
HT1A receptor model. Aminoacids in red were used as pharmacophore constraints.
Green color indicates residues interacting with ligands. Hydrogen bond between
protonated piperazine nitrogen and aspartic acid 3.32 visualized with yellow dashed
line. (For interpretation of the references to color in this figure legend, the reader is
referred to the web version of this article.)

W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
3351
ortho- substituted phenylpiperazine derivatives displayed the high-
est Ki values and the methoxy group was the most favorable.
Unsubstituted phenylpiperazines and meta-substituted ones were
slightly less active, whereas compounds with substituents in para-
position as well as pyrimidineepiperazine analogs always presented
the lowest affinity.
Elongation of the spacer also had predictable influence on 5-
HT1A activity since, besides some derivatives with two unit spacer
(i.e. 12, 14) which showed comparable Ki values to tetramethylene
analogs 34e45, the latter compounds were more active than cor-
responding “shorter” analogs.
The analysis of the influence of substituent at the non-
pharmacophore portion on Ki values revelated that introduction
of a methyl group into a complex terminal amide system has no
importance for 5-HT1A affinity. All derivatives 46e67 showed
moderate-to-high Ki values (from 8 nM to 241 for 63 and 50,
respectively) which generally followed structureeactivity rela-
tionships described above (Table 2).
As regards 5-HT2A receptors, none of the examined compounds
displaced more than 85% of radioligand binding from the rat cortex
homogenate, and the highest activities were observed for deriva-
tives with tetramethylene linker and unsubstituted terminal amide.
With the exception of para-substituted phenylpiperazines, all
compounds were usually less active at 5-HT2A than 5-HT1A recep-
tors (Table 1,2).
The methyl group substitution at the terminal amide (46e67),
decreased 5-HT2A binding and even usually active meta-Cl-phenyl
derivatives presented moderate-to-low activity which indicates
that compounds with complex terminal amide are not optimally
accommodated within 5-HT2A binding site.
As it comes from the affinity data for 5-HT7 receptors, addi-
tionally obtained for the subset of tetramethylene derivatives
34e45, examined compounds displayed moderate-to-low activity
(Ki ¼ 153e>10 000 nM). Like in the case of 5-HT1A binding, the
most active ligands were ortho- substituted phenylpiperazines,
whereas para-methoxyphenyl derivative was practically inactive at
5-HT7 receptors.
groups) structures of 14 and 23 are important to confirm that only
antiperiplanar configuration of chain torsional angles are
observed. In the case of butyl derivatives 38 and 42, they fit to the
most populated, fully extended conformation (8 structures),
characterized by an average NþeN distance of 6.25 Å. The second
cluster, with synclinal conformation of a central C20eC30 bond
(which shorten an average NþeN distance to 5.76 Å), consists of 5
structures. There are only 2 (out of 16) folded conformations, as
indicated by visibly smaller NþeN distances: 5.4 and 5.00 Å for
two and three synclinal torsions, respectively. More thorough
analysis of Table 1 (Supplementary Materials) resulted in further
observations: e conformation along C30eC40 is always anti-
periplanar; C40eNþ e synclinal (one exception), C10eC20 e anti-
periplanar (two exceptions).
The packing of molecules in the studied crystals (14, 23, 38 and
42) was determined by two important types of intermolecular
interactions. The first one was hydrogen bonds network,
comprising in all cases NeH/Clꢁ/HeOeH hydrogen bonds with
inclusion of at least one water molecule from used solvents. The
other important interaction was stacking (except for 42), observed
only for planar pyrimido[5,4-c]quinolin-4(3H)-one systems which
may also play a role in binding to the studied receptors.
While the inspection of CSD proved strong preferences of
extended conformations of LCAPs in a solid state, our 2D NMR
studies in solutions revealed significant influence of a solvent and
protonation state.
Since the chemical shift and multiplicity of two methylene
groups (20 and 30) in the tetramethylene bridging units can provide
information about the conformational preferences of tested
compounds, at first 1H NMR studies for 3-[4-(4-arylpiperazin-1-
ylo)butyl]pyrimido[5,4-c]quinolin-4(3H)-ones (both free bases and
hydrochlorides) were performed. In general, the 1H NMR spectra of
compounds 38, 42 (as free bases), analyzed both in DMSO and
CDCl3 solutions, were characterized by two multiple peaks sepa-
rated by 0.27/0.26 ppm respectively, assigned to the two central
methylene groups (20 and 30) of the butyl chain. It might suggest the
bent conformation advantage, which is in agreement with previous
observations [13].
In the next step of our investigation, several selected agents
were used for extensive structural studies to predict their poten-
tially bioactive conformation. Special attention was focused on
tetramethylene derivatives due to their significant flexibility and
similarity to compounds with therapeutic potential. The four new
crystallographic structures obtained (14, 23, 38 and 42) are very
close to protonated analogoues of alkylarylpiperazines deposited in
the Cambridge Structural Database (Table 1; see Supplementary
Materials). In crystal structures 14, 23, 42 (as monohydrochlorides)
and 38 (as dihydrochloride) the proton essential for binding with
receptor Asp3.32 residue was localized at the piperazine nitrogen
linked to the alkyl chain. The piperazine ring was in a common
chair conformation (with the two N-substituents in equatorial
positions) as indicated by deviations of nitrogen atoms in opposite
directions from the plane defined by the ring carbons. Resulting
distances were 0.69 and 0.67 Å for 14, 0.72 and 0.64 Å for 23, 0.69
and 0.68 Å for 38, and 0.63 and 0.69 Å for 42, respectively, with the
second values referring to the protonated piperazine nitrogen,
substituted equatorially by the alkyl linker. The two aromatic
systems, both phenyl from arylpiperazine and pyrimido[5,4-c]qui-
nolin-4(3H)-one as terminal fragment, were essentially planar with
atomic deviation from their least-squares planes no greater than
0.2 Å. In all investigated structures, the alkyl chain (dimethylene in
14, trimethylene in 23 and tetramethylene in 38, 42) was in an
antiperiplanar conformation as indicated by the values of appro-
priate torsion angles (Table 2; see Supplementary Materials).
Due to a limited number of compounds with shorter linkers
(only one structure with dimethylene and two with trimethylene
The 1H NMR spectra analysis (in DMSO) of tetramethylene
derivatives with the protonated N1 piperazine nitrogen showed
a broad cluster, probably associated with the domination of an
extended conformation, whereas in CDCl3 solution, two close
connected multiplets separated only by 0.08 ppm were present. It
suggested that the extended conformation of the structures were in
equilibrium with the bent conformation. The above assignments
were confirmed by the Overhauser effect. This experimental
evidence for the conformations in solution of compounds 35, 38, 42
(as free bases and as hydrochlorides) were given by the ROESY
experiments which were conducted both in DMSO and CDCl3. In
DMSO spectra for protonated form the characteristic cross-peaks
from the methylene protons of alkyl chain were assigned for
extended conformation (Fig. 1). The lack of interactions between
the aromatic protons of the terminal portion and the phenyl-
piperazine protons or the methylene protons of the alkyl chain
excluded the folded geometry of tested compound. The results of
the ROESY experiment conducted in a non-polar solvent (CDCl3)
were significantly different. The appearance of the weak interac-
00
00
tions between H5eHb, and H5eHNH protons, H5eH5 , H5eH6 ,
besides well-defined cross-peaks from the methylene protons of
0
0
0
alkyl chain and H2eH1 , H3 eHa, H4 eHa, indicated the possibility of
equilibrium both the bent and the extended conformation.
However, the lack of interactions between the aromatic terminal
portion (H7,8,9,10) and the phenyl protons (from arylpiperazine)
definitely excluded the folded conformation of compounds and
stacking interaction (Fig. 1; see Supplementary Materials).

3352
W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
The tetramethylene derivatives of free bases were characterized
by the bent geometry. The results of the ROESY experiment for 35,
38, 42 conducted both in DMSO and CDCl3 showed interactions
The conformational studies (X-ray analysis, 2D NMR experi-
ments) of the polimethylene, especially tetramethylene chain of
LCAPs, were discussed. Representative LCAPs 14, 23, 38 and 42
demonstrated preferences for extended conformations in a solid
state whereas in solutions spatial arrangement of derivatives 35, 38,
42 revealed significant influence of a solvent and protonation state.
The above observations were compatible with molecular
modeling study performed for 11, 14, 23, 35, 38 and 42. Results of
geometry optimizations indicated preference for extended confor-
mations in the aqueous medium, whereas bent geometries were
dominating in vacuum. The data constituted the basis for molecular
modeling and prediction of the ligands binding orientation to
a receptor binding site.
00 00
0
0
between H5eHb, H5eHNH, H5eH5 ,6 , H5eH3 ,4 protons. The lack of
0
0
interactions between H2eH1 ,2 protons also confirmed the bent
conformation.
The above results are generally in agreement with those
described by Norman et al. [13], but interestingly, they are not fully
consistent with those of Lopez-Rodriguez et al. [15], who observed
NOE signals between diphenylmethylene-2,5-pyrrolidinedione
terminal and piperazine hydrogens for protonated tetramethylene
compound in DMSO. Moreover, Nishimura et al. [14] found more
folded conformations of tandospirone in aqueous solution than in
CDCl3. It thus seems that apart from solvent polarity and proton-
ation the structure of terminal part may also influence the
conformational behavior of LCAPs in solution.
Docking analysis of tested compounds showed that all LCAPs
were consequently docked in their fully extended conformations or
with synclinal C20-C30 torsion and bind to 5-HT1A receptor in
a similar way.
The results of in silico conformation analysis are in line with our
2D NMR studies. The distance between nitrogen atoms at both ends
of a linker represented simplified spacer geometry. Calculations run
in vacuum (more similar to non-polar solvent) for 11, 14, 23, 35, 38
and 42 clearly showed the advantage of bent conformations (with
the amide carbonyl oxygen pointing toward the protonated
nitrogen atom), whereas in simulated water solution (COSMO
algorithm) the lowest energy geometries were fully extended and
corresponded with conformation in a solid state. Similar results
were obtained by Siracusa et al. [16], though for a free base of orto-
methoxyphenylpiperazine with thiopropyl linker and benzoxazole
terminal. In previous reports [13,15] showing bent or folded
conformations as global energy minima, calculations were carried
out in a vacuum. Obtained results showing relation between spacer
angulation (represented by NeN distance) and relative energy for
geometry optimization of 35 run in solvent and in vacuum were
presented in Fig. 2a,b (in the Supplementary Materials section).
To complete our studies on the conformational preferences of
investigated derivatives 11, 14, 23, 35, 38 and 42, flexible docking to
hundred 5-HT1A receptor models was performed. Taking into
consideration docking results, in top-scored complexes the crucial
arylpiperazine moiety was located deep inside the receptor,
between TMHs 3, 5, and 6, and the terminal imide was oriented
toward TMHs 1, 2 and the extracellular side (Fig. 2a,b; Supple-
mentary Materials). An alternative binding orientation (i.e. oppo-
site, suggested by others) was seldom found, and in lower-ranked
complexes only. It has to be stressed that ligands were conse-
quently docked in their fully extended conformations or with
synclinal C20eC30 torsion which further support our hypothesis
about bioactive linear geometries of LCAPs.
Our structural investigations organize the knowledge in this
topic and show that potentially bioactive conformations can be
predicted by X-ray spectrometry and calculating using appropriate
solvent simulated semiempirical methods.
7. Experimental protocols
7.1. Chemistry
Reagents and solvents were purchased from common commer-
cial suppliers. The purity of the products were routinely confirmed
by the TLC on Marck plates (Kieselgel 60 F254); the appropriate
solvents were used, and spots were visualized under the UV light.
The catalyst (KF/Al2O3) was prepared according to Yamawaki et al.
[31]. The melting points were measured on an electrothermal
apparatus in open capillaries and are uncorrected. Elemental anal-
yses were carried out with a PerkineElmer series II. CHNS/O
Analyzer 2400 and were within ꢃ0.4% of the theoretical values. IR
spectra were recorded in KBr using a Mattson Infinity Series FT-IR
spectrophotometer. 1H NMR and 13C NMR spectra were recorded
on a Varian Mercury (300 MHz) spectrophotometer in CDCl3/
DMSO-d6 solutions with TMS as an internal standard. The spectra
data of new compounds refer to their free bases. Chemical shifts
were expressed in
d (ppm) and the coupling constants J in hertz
(Hz). The following abbreviations are used to describe peak patterns
when appropriate: s (single), d (doublet), t (triplet), m (multiplet).
Two-dimensional NMR COSY, ROESY experiments were performed
on a Bruker Avance II Plus 700 MHz spectrometer in DMSO at 298 K.
The pulse sequences, acquisition, and processing parameters were
taken from the standard Bruker software library.
6. Conclusions
X-ray data were collected on a Bruker SMART diffractometer with
CCD area detector APEX for 14 and 38 structure and Kuma4CCD k-
The present paper has reported the preparation, pharmacolog-
ical results and conformational studies of new pyrimido[5,4-c]
quinolin-4(3H)-ones 10e67 with variable length of the spacer
between amide and 4-arylpiperazine moiety. Three different
linkers and various substituted arylpiperazines have been
employed for this study. Generally, Ki values showed that, most
compounds (especially with four methylene spacer) had nano-
molar in vitro affinity for 5-HT1A receptor and much lower affinity
for 5-HT2A and 5-HT7 receptors. It indicated that compounds with
pyrimido[5,4-c]quinolin-4(3H)-one as terminal system were not
optimally accommodated within 5-HT2A,7 binding site.
In addition, the analysis of the effect of substituent at the
terminal amide system on 5-HT1A/2A binding activity showed that
the introduction of a methyl group into a complex terminal amide
system has no importance for 5-HT1A affinity but decreased 5-HT2A
binding.
axis diffractometer for 23, using the graphite monochromated MoK
radiation. Data reductions were performed by means of Bruker
package of programs [32] and CrysAlis RED [33]. Structures were
solved by direct methods using SHELXTL [34] and refinement by
full-matrix least squares [35]. Final coordinates and details of
measurements, solutions and refinements have been deposited with
Cambridge Crystallographic Data Center (No. 794185e794188). All
detailes of the crystal data may be obtained free of charge via www.
ccdc.cam.ac.uk/conts/retrieving.html or from Cambridge Crystallo-
graphic Data Center, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: þ44 1223 336033; or deposit@ccdc.cam.ac.uk.
7.1.1. General procedure for the preparation of compounds 1e9
A mixture of appropriate pyrimido[5,4-c]quinolin-4(3H)-one
(1 mmol), 1-bromo-2-chloroethane, 1-bromo-3-chloropropane or
1-bromo-4-chlorobutane (2.5 mmol),KF/Al2O3 catalyst (ca.

W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
3353
5 mmol kF) and catalytic amount of KI in tert-butanole (20 mL) was
stirred at 75 ꢀC, monitored progress of reaction by the TLC. Then the
inorganic precipitate was filtered off, solvent was evaporated under
reduced pressure to one-half volume and left to crystallization. The
crude product was pure by analytical standards. The following
products were synthesized using this procedure:
147.37, 146.98, 137.06, 133.54, 128.60, 122.75, 122.72, 112.43, 44.45,
42.53, 31.08, 21.31 ppm. Anal. (C15H14ClN3O) C, H, N.
7.1.1.7. 3-(4-Chlorobutyl)pyrimido[5,4-c]quinolin-ꢁ41(3H)-one
(7). Yield: 76%, m.p. 160.5e161.9 ꢀC; IR (KBr, cm
) n: 1688 (C]O),
1600e1559 (C]N, C]C); 1H NMR (CDCl3) dH: 1.86e1.9 (m, 2H,
C-20H2), 1.99e2.17 (m, 2H, C-30H2), 3.62 (t, J ¼ 7.2 Hz, 2H, C-40H2),
4.14 (t, J ¼ 7.2 Hz, 2H, C-10H2), 7.72 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H,
C-9H), 7.90 (ddd, J ¼ 8.4, 7.0, 1.5 Hz,1H, C-8H), 8.19 (d, J ¼ 8.4 Hz,1H,
C-7H), 8.37 (s, 1H, C-2H), 8.82 (dd, J ¼ 8.2, 1.5 Hz, 1H, C-10H), 9.64
(s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.22, 152.13, 150.66,
149.95, 148.94, 132.18, 129.58, 127.65, 124.44, 123.65, 113.04, 46.74,
44.32, 29.65, 27.16 ppm. Anal. (C15H14ClN3O) C, H, N.
7.1.1.1. 3-(2-Chloroethyl)pyrimido[5,4-c]quinolin-4(3H)-one
(1). Yield: 64%, m.p. 223.7e224.1 ꢀC; IR (KBr, cmꢁ1
) n: 1682 (C]O),
1613e1506 (C]N, C]C); 1H NMR (DMSO-d6) dH: 4.04 (t, J ¼ 6.0 Hz,
2H, C-20H2), 4.43 (t, J ¼ 6.0 Hz, 2H, C-10H2), 7.80 (ddd, J ¼ 8.2, 7.0,
1.2 Hz, 1H, C-9H), 7.96 (ddd, J ¼ 8.4, 7.0, 1.5 Hz, 1H, C-8H), 8.13 (d,
J ¼ 8.4, 1.1 Hz, 1H, C-7H), 8.78 (dd, J ¼ 8.2, 1.1 Hz, 1H, C-10H), 8.85 (s,
1H, C-2H), 9.43 (s, 1H, C-5H) ppm. 13C NMR (DMSO-d6) dC: 159.32,
153.11, 151.32, 149.06, 148.05, 132.13, 129.00, 127.65, 123.97, 122.89,
112.40, 47.91, 41.94 ppm. Anal (C13H10ClN3O) C, H, N.
7.1.1.8. 3-(4-Chlorobutyl)-8-methylpyrimido[5,4-c]quꢁin1olin-4(3H)-
) n: 1671 (C]
one (8). Yield: 78%, m.p. 146.3e147.7 ꢀC; IR (KBr, cm
O), 1600e1559 (C]N, C]C); 1H NMR (CDCl3) dH: 1.84e1.95 (m, 2H,
C-20H2), 1.97e2.07 (m, 2H, C-30H2), 2.61 (s, 3H, CH3), 3.60
(t, J ¼ 6.5 Hz, 2H, C-40H2), 4.14 (t, J ¼ 76.5 Hz, 2H, C-10H2), 7.51 (dd,
J ¼ 8.4, 1.5 Hz, 1H, C-9H), 7.93 (s, 1H, C-7H), 8.33 (s, 1H, C-2H), 8.63
(d, J ¼ 8.4 Hz, 1H, C-10H), 9.56 (s, 1H, C-5H) ppm. 13C NMR (CDCl3)
dC: 160.14, 151.84, 150.52, 150.03, 148.85, 142.91, 129.59, 128.75,
123.99, 121.30, 112.40, 46.57, 44.25, 29.56, 27.06, 22.20 ppm. Anal.
(C16H16ClN3O) C, H, N.
7.1.1.2. 3-(2-Chloroethyl)-8-methylpyrimido[5,4-c]quinoliꢁn1-4(3H)-
one (2). Yield: 66%, m.p. 203.8e205.3 ꢀC; IR (KBr, cm
) n: 1674
(C]O), 1599e1557 (C]N, C]C); 1H NMR (DMSO-d6) dH: 2.62 (s,
3H, CH3), 4.03 (t, J ¼ 5.7 Hz, 2H, C-20H2), 4.41 (t, J ¼ 5.6 Hz, 2H, C-
10H2), 7.62 (dd, J ¼ 8.4, 1.6 Hz, 1H, C-9H), 7.92 (s, 1H, C-7H), 8.65 (d,
J ¼ 8.4 Hz, 1H, C-10H), 8.80 (s, 1H, C-2H), 9.39 (s, 1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.22, 152.20, 151.06, 150.31, 148.77, 143.24,
129.80, 128.90, 124.23, 121.44, 112.39, 49.46, 42.04, 22.32 ppm. Anal
(C14H12ClN3O) C, H, N.
7.1.1.9. 3-(4-Chlorobutyl)-9-methylpyrimido[5,4-c]quꢁin1olin-4(3H)-
) n: 1678 (C]
one (9). Yield: 82%, m.p. 161.3e162.9 ꢀC; IR (KBr, cm
7.1.1.3. 3-(2-Chloroethyl)-9-methylpyrimido[5,4-c]quꢁin1olin-4(3H)-
) n: 1678 (C]
O), 1600e1553 (C]N, C]C); 1H NMR (CDCl3) dH: 1.86e1.95 (m, 2H,
C-20H2),1.97e2.17 (m, 2H, C-30H2), 2.61 (s, 3H, CH3), 3.61 (t, J ¼ 6.6 Hz,
2H, C-40H2), 4.13 (t, J ¼ 6.5 Hz, 2H, C-10H2), 7.71 (dd, J ¼ 8.5,1.5 Hz,1H,
C-8H), 8.06 (d, J ¼ 8.5 Hz, 1H, C-7H), 8.36 (s, 1H, C-2H), 8.54 (s, 1H,
C-10H), 9.56 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.21, 151.51,
150.37, 148.37, 147.86, 137.87, 134,14, 129.22, 123.39, 123.33, 113.00,
46.47, 44.28, 29.60, 27.10, 22.02 ppm. Anal. (C16H16ClN3O) C, H, N.
one (3). Yield: 68%, m.p. 201.6 (dec) ꢀC; IR (KBr, cm
O), 1601e1555 (C]N, C]C); 1H NMR (CDCl3) dH: 2.53 (s, 3H, CH3),
3.88 (t, J ¼ 5.7 Hz, 2H, C-20H2), 4.30 (t, J ¼ 5.6 Hz, 2H, C-10H2), 7.61
(dd, J ¼ 8.5, 1.9 Hz, 1H, C-8H), 7.97 (d, J ¼ 8.5 Hz, 1H, C-7H), 8.30 (s,
1H, C-2H), 8.44 (s, 1H, C-10H), 9.43 (s, 1H, C-5H) ppm. 13C NMR
(CDCl3) dC: 159.99, 151.82, 151.05, 150.82, 147.94, 147.36, 138.08,
134.38, 128.85, 123.43, 112.80, 49.38, 41.98, 22.00 ppm. Anal
(C14H12ClN3O) C, H, N.
7.1.2. General procedure for the preparation of compounds 10e67
A mixture of the appropriate 1-arylpiperazine (1.2 mmol) and
chloroalkyl derivative of (1e9) (1 mmol) in acetonitrile (25 mL) was
refluxed on stirring for about 24 h, in presence of anhydrous K2CO3
(1.5 mmol) and catalytic amount of KI. The completion time of
reaction was assigned chromatographically (TLC). Then the reaction
mixture was filtered off, and the solvent was evaporated to give
a crude product, which was purified by crystallization.
Free bases 10e67 were converted into hydrochlorides by dis-
solving the corresponding base in chloroform and treating with
diethyl ether saturated with HCl. The precipitate was filtered off
and purified by crystallization.
7.1.1.4. 3-(3-Chloropropyl)pyrimido[5,4-c]quinolin-4(3H)-one
(4). Yield: 79%, m.p. 155.4e156.1 ꢀC; IR (KBr, cmꢁ1
) n: 1678 (C]O),
1600e1506 (C]N, C]C); 1H NMR (CDCl3) dH: 2.33e2.41(m, 2H, C-
20H2), 3.62 (t, J ¼ 6.5 Hz, 2H, C-30H2), 4.29 (t, J ¼ 6.5 Hz, 2H, C-10H2),
7.74 (ddd, J ¼ 8.3, 7.09, 1.3 Hz, 1H, C-9H), 7.91 (ddd, J ¼ 8.4, 7.0,
1.5 Hz, 1H, C-8H), 8.20 (d, J ¼ 8.4 Hz, 1H, C-7H), 8.44 (s, 1H, C-2H),
8.84 (dd, J ¼ 8.3, 1.2 Hz, 1H, C-10H), 9.65 (s, 1H, C-5H) ppm. 13C NMR
(DMSO-d6) dC: 159.46, 152.91, 151.23, 148.93, 148.13, 131.88, 128.93,
127.46, 123.89, 122.95, 112.55, 44.52, 42.54, 31.09 ppm. Anal.
(C14H12ClN3O) C, H, N.
7.1.1.5. 3-(3-Chloropropyl)-8-methylpyrimido[5,4-c]qꢁu1inolin-4(3H)-
7.1.2.1. [2-(4-Phenylpiperazin-1-yl)ethyl]pyrimido[5,4-c]quinoliꢁn1-
1675 (C]O), 1598e1503 (C]N, C]C); 1H NMR (CDCl3) dH
one (5). Yield: 72%, m.p. 155.5e157.2 ꢀC; IR (KBr, cm
)
n
: 1680 (C]
4(3H)-one (10). Yield: 64%, m.p. 194.6e195.8 ꢀC; IR (KBr, cm
)
n
:
:
O), 1621e1556 (C]N, C]C); 1H NMR (DMSO-d6) dH: 2.19e2.28
(m, 2H, C-20H2), 2.58 (s, 3H, CH3), 3.74 (t, J ¼ 6.5 Hz, 2H, C-30H2), 4.18
(t, J ¼ 6.6 Hz, 2H, C-10H2), 7.63 (dd, J ¼ 8.4, 1.6 Hz, 1H, C-9H), 7.92
(s, 1H, C-7H), 8.65 (d, J ¼ 8.4 Hz, 1H, C-10H), 8.77 (s, 1H, C-2H), 9.39
(s, 1H, C-5H) ppm. 13C NMR (DMSO-d6) dC: 159.40, 152.69, 151.05,
149.15, 148.08, 142.14, 129.24, 128.08, 123.57, 120.71, 111.97, 44.41,
42.50, 31.08, 21.41ppm. Anal. (C15H14ClN3O) C, H, N.
2.57e2.70 (m, 4H, piperazine 2CH2), 2.76 (t, J ¼ 5.4 Hz, 2H, C-20H2),
3.07e3.16 (m, 4H, piperazine 2CH2), 4.13 (t, J ¼ 5.5 Hz, 2H, C-10H2),
6.71e6.86 (cluster, 3H, C-200H, C-400H, C-600H), 7.13e7.22 (cluster, 2H,
C-300H, C-500H), 7.62 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.80 (ddd,
J ¼ 8.4, 6.9, 1.5 Hz, 1H, C-8H), 8.10 (d, J ¼ 8.4 Hz, 1H, C-7H), 8.32 (s,
1H, C-2H), 8.74 (dd, J ¼ 8.3, 1.0 Hz, 1H, C-10H), 9.56 (s, 1H, C-5H)
ppm. 13C NMR (CDCl3) dC: 160.27, 152.27, 151.52, 151.04, 149.93,
149.00, 132.14, 129.57, 129.18, 127.58, 124.53, 123.74, 120.03, 116.23,
113.04, 56.42, 53.46, 49.30, 44.09 ppm. 10 $ 2HCl $ 1.5H2O: Anal
(C23H23N5O $ 2HCl $ 1.5H2O) C, H, N.
7.1.1.6. 3-(3-Chloropropyl)-9-methylpyrimido[5,4-c]qꢁu1inolin-4(3H)-
) n: 1672 (C]
one (6). Yield: 69%, m.p. 149.1e150.6 ꢀC; IR (KBr, cm
O), 1598e1555 (C]N, C]C); 1H NMR (DMSO-d6) dH: 2.17e2.29
(m, 2H, C-20H2), 2.58 (s, 3H, CH3), 3.75 (t, J ¼ 6.6 Hz, 2H, C-30H2), 4.19
(t, J ¼ 6.6 Hz, 2H, C-10H2), 7.78 (dd, J ¼ 8.5, 1.8 Hz, 1H, C-8H), 8.01
(d, J ¼ 8.5 Hz, 1H, C-7H), 8.54 (s, 1H, C-2H), 8.79 (s, 1H, C-10H), 9.35
(s, 1H, C-5H) ppm. 13C NMR (DMSO-d6) dC: 159.39, 152.41, 150.61,
7.1.2.2. 3-{2-[4-(2-Chlorophenyl)piperazin-1-yl]ethyl}pyrimido[5,4-
c]quinolin-4(3H)-one (11). Yield: 58%, m.p. 184.5e185.9 ꢀC; IR (KBr,
cmꢁ1 : 1691 (C]O), 1596e1557 (C]N, C]C); 1H NMR (CDCl3) dH
) n :

3354
W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
2.64e2.70 (m, 4H, piperazine 2CH2), 2.77 (t, J ¼ 5.6 Hz, 2H, C-20H2),
2.92e3.04 (m, 4H, piperazine 2CH2), 4.14 (t, J ¼ 5.6 Hz, 2H, C-10H2),
6.82e6.97 (cluster, 2H, C-400H, C-600H), 7.12 (ddd, J ¼ 8.2, 7.8, 1.5 Hz,
1H, C-500H), 7.26 (dd, J ¼ 7.9,1.5 Hz,1H, C-300H), 7.64 (ddd, J ¼ 8.2, 7.0,
1.2 Hz, 1H, C-9H), 7.81 (ddd, J ¼ 8.4, 6.9, 1.5 Hz, 1H, C-8H), 8.11 (d,
J ¼ 8.4 Hz, 1H, C-7H), 8.35 (s, 1H, C-2H), 8.75 (dd, J ¼ 8.2, 1.0 Hz, 1H,
C-10H), 9.57 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.25, 152.25,
151.58, 149.93, 149.06, 148.99, 132.12, 130.69, 129.59, 128.80, 127.64,
127.56, 124.50, 123.88, 123.74, 120.49, 113.07, 56.51, 53.63, 51.32,
44.05 ppm. 11 $ 2HCl $ 1.5H2O: Anal (C23H22ClN5O $ 2HCl $ 1.5H2O)
C, H, N.
104.71, 102.66, 56.45, 55.37, 53.42, 49.27, 44.14 ppm. 15 $ 2HCl $
1.25H2O: Anal. (C24H25N5O2 $ 2HCl $ 1.25H2O) C, H, N.
7.1.2.7. 3-{2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethyl}pyrimido
[5,4-c]quinolin-4(3H)-one (16). Yield: 53%, m.p. 185.7e186.1 ꢀC; IR
(KBr, cmꢁ1
) n: 1681 (C]O), 1602e1509 (C]N, C]C), 1239 (OCH3);
1H NMR (CDCl3) dH: 2.62e2.72 (m, 4H, piperazine 2CH2), 2.79
(t, J ¼ 5.4 Hz, 2H, C-20H2), 2.97e3.07 (m, 4H, piperazine 2CH2), 3.73
(s, 3H, OCH3), 4.15 (t, J ¼ 5.5 Hz, 2H, C-10H2), 6.68e6.86 (cluster, 4H,
C-200H, C-200H, C-500H, C-600H), 7.63 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H,
C-9H), 7.81 (ddd, J ¼ 8.4, 6.9,1.5 Hz,1H, C-8H), 8.11 (d, J ¼ 8.2 Hz,1H,
C-7H), 8.35 (s, 1H, C-2H), 8.74 (dd, J ¼ 8.3, 1.2 Hz, 1H, C-10H), 9.57
(s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.28, 154.00, 152.26,
151.54, 149.89, 148.99, 145.25, 132.17, 129.55, 127.61, 124.51, 123.71,
118.42, 114.49, 113.02, 56.35, 55.73, 53.52, 50.72, 43.99 ppm. 16 $
2HCl $ 3H2O: Anal. (C24H25N5O2 $ 2HCl $ 3H2O) C, H, N.
7.1.2.3. 3-{2-[4-(3-Chlorophenyl)piperazin-1-yl]ethyl}pyrimido[5,4-
c]quinolin-4(3H)-one (12). Yield: 52%, m.p. 199.9e200.7 ꢀC; IR (KBr,
cmꢁ1 : 1685 (C]O), 1600e1561 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
2.57e2.65 (m, 4H, piperazine 2CH2), 2.76 (t, J ¼ 5.6 Hz, 2H, C-20H2),
3.06e3.14 (m, 4H, piperazine 2CH2), 4.13 (t, J ¼ 5.6 Hz, 2H, C-10H2),
6.65e6.82 (cluster, 3H, C-200H, C-400H, C-600H), 7.06 (t, J ¼ 8.1 Hz, 1H,
C-500H), 7.60e7.67 (m, 1H, C-9H), 7.73e7.89 (m, 1H, C-8H), 8.11
(d, J ¼ 8.3 Hz, 1H, C-7H), 8.32 (s, 1H, C-2H), 8.74 (dd, J ¼ 8.3, 0.9 Hz,
1H, C-10H), 9.57 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.26,
152.26, 152.07, 151.46, 149,92, 148.98, 134.97, 132.17, 130.10, 129.56,
127.61, 124.52, 123.72, 119.60, 115.94, 114.06, 113.03, 56.37, 53.25,
48.84, 44.10 ppm. 12 $ 2HCl $ H2O: Anal. (C23H22ClN5O $ 2HCl $ H2O)
C, H, N.
7.1.2.8. 3-{2-[4-(2-Fluorophenyl)piperazin-1-yl]ethyl}pyrimido[5,4-
c]quinolin-4(3H)-one (17). Yield: 61%, m.p. 173.5e173.9 ꢀC; IR (KBr,
cmꢁ1 : 1690 (C]O), 1597e1499 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
2.70e2.78 (m, 4H, piperazine 2CH2), 2.84 (t, J ¼ 5.6 Hz, 2H, C-20H2),
3.04e3.15 (m, 4H, piperazine 2CH2), 4.21 (t, J ¼ 5.6 Hz, 2H, C-10H2),
6.88e7.09 (cluster 4H, C-300H, C-400H, C-500H, C-600H), 7.72 (ddd,
J ¼ 8.2, 6.9, 1.2 Hz,1H, C-9H), 7.90 (ddd, J ¼ 8.4, 6.9, 1.5 Hz,1H, C-8H),
8.19 (d, J ¼ 7.9 Hz, 1H, C-7H), 8.42 (s, 1H, C-2H), 8.84 (dd, J ¼ 8.2,
1.2 Hz, 1H, C-10H), 9.66 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC
:
7.1.2.4. 3-{2-[4-(4-Chlorophenyl)piperazin-1-yl]ethyl}pyrimido[5,4-
160.28,155.91 (157.31, 154.05 JCeF ¼ 245.6 Hz),152.27, 151.57, 149.94,
149.06, 139.86 (139.91, 139.80 JCeF ¼ 8.6 Hz), 132.15, 129.60, 129.78,
127.59, 124.53 (124.55, 124.51 JCeF ¼ 3.4 Hz), 123.75, 122.70 (122.75,
122.65 JCeF ¼ 8.0 Hz), 119.03 (119.05, 119.01 JCeF ¼ 3.2 Hz), 116.21
(116.35,116.08 JCeF ¼ 20.6 Hz),113.08, 56.50, 53.55, 50.66, 44.05 ppm.
17 $ 2HCl $ 0.5H2O: Anal. (C23H22FN5O $ 2HCl $ 0.5H2O) C, H, N.
c]quinolin-4(3H)-one (13). Yield: 56%, m.p. 212.5e213.0 ꢀC; IR (KBr,
cmꢁ1 : 1670 (C]O), 1598e1510 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
2.61e2.72 (m, 4H, piperazine 2CH2), 2.80 (t, J ¼ 5.5 Hz, 2H, C-20H2),
3.03e3.15 (m, 4H, piperazine 2CH2), 4.17 (t, J ¼ 5.6 Hz, 2H, C-10H2),
6.67e6.78 (cluster, 2H, C-200H, C-600H), 7.06e7.14 (cluster, 2H, C-300H,
C-500), 7.63 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.81 (ddd, J ¼ 8.4, 6.9,
1.5 Hz, 1H, C-8H), 8.11 (d, J ¼ 8.0 Hz, 1H, C-7H), 8.35 (s, 1H, C-2H),
8.74 (dd, J ¼ 8.3, 1.0 Hz, 1H, C-10H), 9.56 (s, 1H, C-5H) ppm. 13C NMR
(CDCl3) dC: 160.29, 152.28, 151.45, 149.94, 149.57, 148.96, 132.21,
129.58, 129.05, 127.64, 124.95, 124.53, 123.72, 117.47, 113.01, 56.32,
53.30, 49.21, 44.02 ppm. 13 $ 2HCl $ 1.5H2O: Anal. (C23H22ClN5O $
2HCl $ 1.5H2O) C, H, N.
7.1.2.9. 3-{2-[4-(4-Fluorophenyl)piperazin-1-yl]ethyl}pyrimido[5,4-
c]quinolin-4(3H)-one (18). Yield: 52%, m.p. 190.8e191.8 ꢀC; IR (KBr,
cmꢁ1 : 1676 (C]O), 1598e1509 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
2.63e2,73 (m, 4H, piperazine 2CH2), 2.81 (t, J ¼ 5.6 Hz, 2H, C-20H2),
3.05e3.12 (m, 4H, piperazine 2CH2), 4.18 (t, J ¼ 5.6 Hz, 2H, C-10H2),
6.76e7.02 (cluster, 4H, C-200H, C-300H, C-500H, C-600H), 7.70 (ddd,
J ¼ 8.2, 7.0, 1.2 Hz,1H, C-9H), 7.88 (ddd, J ¼ 8.4, 7.0, 1.5 Hz, 1H, C-8H),
8.17 (d, J ¼ 8.4 Hz, 1H, C-7H), 8.38 (s, 1H, C-2H), 8.81 (dd, J ¼ 8.2,
7.1.2.5. 3-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}pyrimido
[5,4-c]quinolin-4(3H)-one (14). Yield: 60%, m.p. 161.6e162.0 ꢀC; IR
1.2 Hz, 1H, C-10H), 9.64 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC
:
(KBr, cmꢁ1
)
n
: 1676 (C]O), 1596e1498 (C]N, C]C); 1H NMR
160.26, 157.22 (158.80, 155.64 JCeF ¼ 238.5 Hz), 152.26, 151.54,
149.93, 149.04, 147.76, 132.16, 129.58, 127.60, 124.51, 123.74, 117.94
(117.99, 117.89 JCeF ¼ 7.7 Hz), 115.60 (115.75, 115.46 JCeF ¼ 22.0 Hz),
113.06, 56.42, 53.48, 50.35, 44.14 ppm. 18 $ 2HCl $ 1.5H2O: Anal.
(C23H22FN5O $ 2HCl $ 1.5H2O) C, H, N.
(CDCl3) dH: 2.63e2.71 (m, 4H, piperazine 2CH2), 2.77 (t, J ¼ 5.6 Hz,
2H, C-20H2), 2.94e3.06 (m, 4H, piperazine 2CH2), 3.71 (s, 3H, OCH3),
4.13 (t, J ¼ 5.7 Hz, 2H, C-10H2), 6.69e6.98 (cluster, 4H, C-300H, C-400H,
C-500H, C-600H), 7.62 (ddd, J ¼ 8.2, 6.9, 1.2 Hz, 1H, C-9H), 7.80 (ddd,
J ¼ 8.4, 6.9, 1.5 Hz, 1H, C-8H), 8.10 (d, J ¼ 8.3 Hz, 1H, C-7H), 8.35
(s, 1H, C-2H), 8.74 (dd, J ¼ 8.1, 1.1 Hz, 1H, C-10H), 9.56 (s, 1H, C-5H)
ppm. 13C NMR (CDCl3) dC: 160.22, 152.21, 152.16, 151.57, 149.86,
148.99, 140.92, 132.07, 129.51, 127.51, 124.47, 123.69, 123.14, 121.00,
118.27, 113.01, 111.26, 56.49, 55.53, 53.66, 50.65, 43.94 ppm. 14 $ HCl
$ 2.5H2O: Anal. (C24H25N5O2 $ HCl $ 2.5H2O) C, H, N.
7.1.2.10. 3-{2-[4-(2-Methylphenyl)piperazin-1-yl]ethyl}pyrimido
[5,4-c]quinolin-4(3H)-one (19). Yield: 82%, m.p. 188.3e189.6 ꢀC; IR
(KBr, cmꢁ1 : 1692 (C]O), 1597e1494 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 2.20 (s, 3H, CH3), 2.60e2.68 (m, 4H, piperazine 2CH2),
2.77 (t, J ¼ 5.6 Hz, 2H, C-20H2), 2,81e2.88 (m, 4H, piperazine 2CH2),
4.13 (t, J ¼ 5.6 Hz, 2H, C-10H2), 6.83e6.96 (cluster, 2H, C-400H, C-600H),
7.03e7.12 (cluster, 2H, C-300H, C-500H), 7.63 (ddd, J ¼ 8.2, 7.0, 1.2 Hz,
1H, C-9H), 7.80 (ddd, J ¼ 8.4, 7.0,1.5 Hz,1H, C-8H), 8.10 (d, J ¼ 8.3 Hz,
1H, C-7H), 8.34 (s,1H, C-2H), 8.76 (dd, J ¼ 8.2,1.1 Hz,1H, C-10H), 9.57
(s,1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.26,152.26,151.20,151.13,
149.90, 149.02, 132.59, 132.11, 131.11, 129.56, 127.56, 126.62, 124.51,
123.73, 123.35, 119.10, 113.04, 56.54, 53.99, 51.76, 44.04, 18.11 ppm.
19 $ 2HCl $ H2O: Anal. (C24H25N5O $ 2HCl $ H2O) C, H, N.
7.1.2.6. 3-{2-[4-(3-Methoxyphenyl)piperazin-1-yl]ethyl}pyrimido
[5,4-c]quinolin-4(3H)-one (15). Yield: 55%, m.p. 143.8e144.6 ꢀC; IR
(KBr, cmꢁ1 : 1686 (C]O), 1613e1555 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 2.53e2.66 (m, 4H, piperazine 2CH2), 2.73 (t, J ¼ 5.6 Hz,
2H, C-20H2), 3.02e3.20 (m, 4H, piperazine 2CH2), 3.69 (s, 3H, OCH3),
4.11 (t, J ¼ 5.6 Hz, 2H, C-10H2), 6.25e6.37 (cluster, 3H, C-200H, C-400H,
C-600H), 7.07 (t, J ¼ 7.9 Hz, 1H, C-500H), 7.56e7.69 (m, 1H, C-9H),
7.74e7.88 (m, 1H, C-8H), 8.10 (d, J ¼ 8.3 Hz, 1H, C-7H), 8.31 (s, 1H,
C-2H), 8.74 (d, J ¼ 8.3, 1.0 Hz, 1H, C-10H), 9.56 (s, 1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.55, 160.26, 152.48, 152.27, 151.55, 149.91,
149.02, 132.13, 129.85, 129.55, 127.58, 124.52, 123.74, 113.05, 108.95,
7.1.2.11. 3-(2-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyr-
imido[5,4-c]equinolin-4(3H)-one (20). Yield: 52%, m.p. 155.3e155.8 ꢀC;
IR (KBr, cmꢁ1 : 1682 (C]O), 1613e1507 (C]N, C]C); 1H NMR
) n

W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
3355
(CDCl3) dH: 2.64e2.70 (m, 4H, piperazine 2CH2), 2.83 (t, J ¼ 5.6 Hz, 2H,
C-20H2), 3.18e3.26 (m, 4H, piperazine 2CH2), 4.20 (t, J ¼ 5.6 Hz, 2H,
C-10H2), 6.98e7.12 (cluster, 3H, C-200H, C-400H, C-600H), 7.33 (dt, J ¼ 8.3,
8.2, 0.7 Hz, 1H, C-500H), 7.66 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.89
(ddd, J ¼ 8.4, 7.0, 1.5 Hz, 1H, C-8H), 8.19 (d, J ¼ 8.4 Hz, 1H, C-7H), 8.39
(s,1H, C-2H), 8.82 (dd, J ¼ 8.2,1.3 Hz,1H, C-10H), 9.66 (s,1H, C-5H) ppm.
13C NMR (CDCl3) dC: 160.28, 152.28, 151.49, 151.22, 149.94, 149.02,
132.18, 131.44 (131.65, 131.23 JCeF ¼ 31.8 Hz), 129.63, 129.58, 127.62,
124.36 (126.16, 122.56 JCeF ¼ 272.0 Hz), 124.53, 123.74, 118.91, 116.12
149,88, 148.89, 134.95, 132.16, 130.10, 129.55, 127.62, 124.45, 123.66,
119.66, 115.97, 114.09, 113.07, 54.44, 52.82, 48.64, 45.70, 25.11 ppm.
24 $ 2HCl $ 1.75H2O: Anal. (C24H24ClN5O $ 2HCl $ 1.75H2O) C, H, N.
7.1.2.16. 3-{3-[4-(4-Chlorophenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (25). Yield: 69%, m.p. 175.3e176.3 ꢀC; IR
(KBr, cmꢁ1 : 1680 (C]O), 1597e1497 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 1.96e2.14 (m, 2H, C-20H2), 2.42 (t, J ¼ 6.5 Hz, 2H, C-30H2),
2.50e2.56 (m, 4H, piperazine 2CH2), 3.02e3.10 (4H, piperazine
2CH2), 4.12 (t, J ¼ 6.6 Hz, 2H, C-10H2), 6.64e6.76 (cluster, 2H, C-200H,
C-600H), 7.05e7.12 (cluster, 2H, C-300H, C-500), 7.62 (ddd, J ¼ 8.2, 7.0,
1.2 Hz, 1H, C-9H), 7.80 (ddd, J ¼ 8.4, 6.9, 1.5 Hz, 1H, C-8H), 8.10 (d,
J ¼ 8.0 Hz,1H, C-7H), 8.39 (s,1H, C-2H), 8.72 (dd, J ¼ 8.3,1.0 Hz,1H, C-
10H), 9.56 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.39, 152.23,
151.57, 149.92, 149.72, 148.94, 132.14, 129.58, 128.99, 127.61, 124.75,
124.46, 123.69, 117.36, 113.12, 54.48, 52.93, 45.80, 44.96, 25.20 ppm.
25 $ 2HCl $ H2O: Anal. (C24H24ClN5O $ 2HCl $ H2O) C, H, N.
(116.14, 116.09 JCeF
¼
4.0 Hz), 113.05, 112.30 (112.32, 112.27
JCeF ¼ 4.0 Hz), 56.41, 53.27, 48.92, 44.17 ppm. 20 $ 2HCl $ 1.5H2O: Anal.
(C24H22F3N5O $ 2HCl $ 1.5H2O) C, H, N.
7.1.2.12. 3-[2-(4-Pyrimidin-2-ylpiperazin-1-yl)ethyl]pyrimido[5,4-c]
quinolin-4(3H)-one (21). Yield: 64%, m.p. 192.3e192.9 ꢀC; IR (KBr,
cmꢁ1 : 1672 (C]O), 1588e1487 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
2.57e2.65 (m, 4H, piperazine 2CH2), 2.82 (t, J ¼ 5.6 Hz, 2H, C-20H2),
3.78e3.86 (m, 4H, piperazine 2CH2), 4.22 (t, J ¼ 5.6 Hz, 2H, C-10H2),
6.49 (t, J ¼ 4.7 Hz,1H, C-600H), 7.73 (ddd, J ¼ 8.2, 5.1,1.2 Hz,1H, C-9H),
7.90 (ddd, J ¼ 8.4, 5.1,1.5 Hz,1H, C-8H), 8.20 (d, J ¼ 8.3 Hz,1H, C-7H),
8.30 (d, J ¼ 4.7 Hz, 2H, C-300H, C-500H), 8.45 (s, 1H, C-2H), 8.85 (dd,
J ¼ 8.2, 1.3 Hz, 1H, C-10H), 9.66 (s, 1H, C-5H) ppm. 13C NMR (CDCl3)
dC: 161.61, 160.23, 157.74, 152.33, 151.58, 149.96, 149.06, 132.19,
129.60, 127.64, 124.54, 123.78, 113.11, 110.18, 56.63, 53.39, 44.18,
43.89 ppm. 21 $2HCl $ 4H2O: Anal (C21H21N7O $ 2HCl $ 4H2O) C, H, N.
7.1.2.17. 3-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (26). Yield: 62%, m.p. 154.6e156.0 ꢀC; IR
(KBr, cmꢁ1 : 1686 (C]O), 1596e1498 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 2.02e2.16 (m, 2H, C-20H2), 2.49 (t, J ¼ 6.5 Hz, 2H,
C-30H2), 2.59e2.68 (m, 4H, piperazine 2CH2), 3.02e3.11 (4H,
piperazine 2CH2), 3.86 (s, 3H, OCH3), 4.22 (t, J ¼ 6.5 Hz, 2H, C-10H2),
6.81e7.07 (cluster, 4H, C-300H, C-400H, C-500H, C-600H), 7.72 (ddd,
J ¼ 8.2, 6.9,1.2 Hz,1H, C-9H), 7.90 (ddd, J ¼ 8.2, 6.8,1.4 Hz,1H, C-8H),
8.20 (d, J ¼ 8.2 Hz, 1H, C-7H), 8.52 (s, 1H, C-2H), 8.85 (dd, J ¼ 8.1,
7.1.2.13. 3-[3-(4-Phenylpiperazin-1-yl)propyl]pyrimido[5,4-c]quino-
lin-4(3H)-one (22). Yield: 78%, m.p. 128.2e129.5 ꢀC; IR (KBr, cmꢁ1
n
)
:
1.1 Hz, 1H, C-10H), 9.67 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC
:
: 1685 (C]O), 1597e1505 (C]N, C]C); 1H NMR (CDCl3) dH
160.38, 152.22, 152.18, 151.75, 149.83, 148.96, 140.96, 132.08, 129.52,
127.55, 124.44, 123.69, 123.04, 120.97, 118.17, 113.13, 111.27, 55.50,
54.44, 53.28, 50.81, 45.83, 25.13 ppm. 26 $ 2HCl $ 2.5H2O: Anal.
(C25H27N5O2 $ 2HCl $ 2.5H2O) C, H, N.
2.04e2.18 (m, 2H, C-20H2), 2.47 (t, J ¼ 6.5 Hz, 2H, C-30H2), 2.53e2.60
(m, 4H, piperazine 2CH2), 3.15e3.25 (4H, piperazine 2CH2), 4.22 (t,
J ¼ 6.6 Hz, 2H, C-10H2), 6.78e6.97 (cluster, 3H, C-200H, C-400H,
C-600H), 7.18e7.26 (cluster, 2H, C-300H, C-500H), 7.65e7.76 (m, 1H,
C-9H), 7.90 (ddd, J ¼ 8.4, 7.0,1.5 Hz,1H, C-8H), 8.20 (d, J ¼ 8.3 Hz,1H,
C-7H), 8.49 (s, 1H, C-2H), 8.84 (dd, J ¼ 8.3, 1.0 Hz, 1H, C-10H), 9.67
(s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.32, 152.18, 151.61, 151.16,
149.86, 148.92, 132.05, 129.53, 129.11, 127.53, 124.45, 123.68, 119.83,
116.11, 113.09, 54.37, 53.08, 49.35, 45.74, 25.22 ppm. 22 $ 2HCl $
2H2O: Anal. (C24H25N5O $ 2HCl $ 2H2O) C, H, N.
7.1.2.18. 3-{3-[4-(3-Methoxyphenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (27). Yield: 57%, m.p. 91.2e92.3 ꢀC; IR
(KBr, cmꢁ1 : 1670 (C]O), 1599e1556 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 1.93e2.07 (m, 2H, C-20H2), 2.38 (t, J ¼ 6.5 Hz, 2H, C-
30H2), 2.47e2.54 (m, 4H, piperazine 2CH2), 3.16e3.23 (4H, pipera-
zine 2CH2), 3.70 (s, 3H, OCH3), 4.12 (t, J ¼ 6.5 Hz, 2H, C-10H2),
6.30e6.48 (cluster, 3H, C-200H, C-400H, C-600H), 7.09 (dt, J ¼ 8.3, 8.4,
4.8 Hz, 1H, C-500H), 7.64 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.81
(ddd, J ¼ 8.4, 7.0,1.5 Hz,1H, C-8H), 8.11 (d, J ¼ 8.4 Hz,1H, C-7H), 8.41
(s, 1H, C-2H), 8.75 (dd, J ¼ 8.3, 1.1 Hz, 1H, C-10H), 9.57 (s, 1H, C-5H)
ppm. 13C NMR (CDCl3) dC: 160.54, 160.49, 152.52, 152.41, 151.66,
149.82, 149.02, 132.13, 129.94, 129.81, 127.60, 124.45, 123.68, 113.10,
108.90, 104.62, 103.01, 55.39, 54.33, 53.04, 49.17, 45.27, 25.20 ppm.
27 $ 2HCl $ 2.5H2O: Anal. (C25H27N5O2 $ 2HCl $ 2.5H2O) C, H, N.
7.1.2.14. 3-{3-[4-(2-Chlorophenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (23). Yield: 68%, m.p. 150.6e151.2 ꢀC; IR
(KBr, cmꢁ1 : 1689 (C]O), 1599e1555 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 2.03e2.14 (m, 2H, C-20H2), 2.53 (t, J ¼ 6.5 Hz, 2H,
C-30H2), 2.61e2.71 (m, 4H, piperazine 2CH2), 2.93e3.10 (4H,
piperazine 2CH2), 4.21 (t, J ¼ 6.6 Hz, 2H, C-10H2), 6.81e6.92 (cluster,
2H, C-400H, C-600H), 7.10 (dd, J ¼ 8.2, 1.5 Hz, 1H, C-500H), 7.26 (dd,
J ¼ 7.8, 1.4 Hz, 1H, C-300H), 7.63 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H),
7.82 (ddd, J ¼ 8.4, 6.9,1.5 Hz,1H, C-8H), 8.11 (d, J ¼ 8.4 Hz,1H, C-7H),
8.45 (s, 1H, C-2H), 8.75 (dd, J ¼ 8.2, 1.0 Hz, 1H, C-10H), 9.57 (s, 1H,
C-5H) ppm. 13C NMR (CDCl3) dC: 160.46, 152.28, 151.62, 149.93,
148.97, 148.82, 132.16, 130.68, 129.60, 128.85, 127.69, 127.63, 124.50,
124.05,123.73,120.48,113.14, 54.64, 53.24, 50.94, 45.82, 25.05 ppm.
23 $ HCl $ 0.25H2O: Anal. (C24H24ClN5O $ HCl $ 0.25H2O) C, H, N.
7.1.2.19. 3-{3-[4-(4-Methoxyphenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (28). Yield: 65%, m.p. 156.4e157.5 ꢀC; IR
(KBr, cmꢁ1 : 1682 (C]O),1599e1503 (C]N, C]C); 1H NMR (CDCl3)
) n
dH: 2.03e2.14 (m, 2H, C-20H2), 2.50 (t, J ¼ 6.4 Hz, 2H, C-30H2),
2.59e2.67 (m, 4H, piperazine 2CH2), 3.00e3.11 (4H, piperazine 2CH2),
3.68 (s, 3H, OCH3), 4.15 (t, J ¼ 6.5 Hz, 2H, C-10H2), 6.69e6.84 (cluster,
4H, C-200H, C-200H, C-500H, C-600H), 7.63 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-
9H), 7.81 (ddd, J ¼ 8.4, 6.9,1.5 Hz, 1H, C-8H), 8.11 (d, J ¼ 8.2 Hz,1H, C-
7H), 8.44 (s,1H, C-2H), 8.74 (dd, J ¼ 8.3,1.2 Hz,1H, C-10H), 9.56 (s,1H,
C-5H) ppm.13C NMR (CDCl3) dC: 160.43,154.06,152.24,151.57,149.90,
148.92, 145.24, 132.15, 129.57, 127.62, 124.48, 123.69, 118.53, 114.50,
113.09, 55.74, 54.43, 53.14, 50.53, 45.67, 25.07 ppm. 28 $ HCl $
1.75H2O: Anal. (C25H27N5O2 $ HCl $ 1.75H2O) C, H, N.
7.1.2.15. 3-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (24). Yield: 67%, m.p. 122.4e123.7; IR
(KBr, cmꢁ1 : 1670 (C]O), 1596e1559 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 2.01e2.13 (m, 2H, C-20H2), 2.46 (t, J ¼ 6.5 Hz, 2H,
C-30H2), 2.53e2.63 (m, 4H, piperazine 2CH2), 3.05e3.20 (4H,
piperazine 2CH2), 4.13 (t, J ¼ 6.6 Hz, 2H, C-10H2), 6.61e6.79 (cluster,
3H, C-200H, C-400H, C-600H), 7.06 (t, J ¼ 8.1 Hz, 1H, C-500H), 7.60e7.62
(m,1H, C-9H), 7.77e7.86 (m,1H, C-8H), 8.10 (d, J ¼ 8.2 Hz,1H, C-7H),
8.41 (s, 1H, C-2H), 8.72 (dd, J ¼ 8.3, 1.2 Hz, 1H, C-10H), 9.55 (s, 1H,
C-5H) ppm. 13C NMR (CDCl3) dC: 160.36, 152.21, 151.98, 151.50,
7.1.2.20. 3-{3-[4-(2-Fluorophenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (29). Yield: 61%, m.p. 115.9e116.9 ꢀC; IR
(KBr, cmꢁ1 : 1688 (C]O),1599e1499 (C]N, C]C); 1H NMR (CDCl3)
) n

3356
W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
dH: 2.03e2.15 (m, 2H, C-20H2), 2.49 (t, J ¼ 6.4 Hz, 2H, C-30H2),
2.59e2.66 (m, 4H, piperazine 2CH2), 3.04e3.11 (4H, piperazine
2CH2), 4.22 (t, J ¼ 6.5 Hz, 2H, C-10H2), 6.82e7.09 (cluster 4H, C-300H, C-
400H, C-500H, C-600H), 7.70e7.79 (m, 1H, C-9H), 7.88e7.96 (m, 1H, C-
8H), 8.20 (d, J ¼ 7.9 Hz, 1H, C-7H), 8.51 (s, 1H, C-2H), 8.84 (dd, J ¼ 8.2,
1.2 Hz,1H, C-10H), 9.70 (s,1H, C-5H) ppm.13C NMR (CDCl3) dC: 160.42,
155.72 (157.35, 154.10 JCeF ¼ 245.6 Hz), 152.27, 151.69, 149.92, 149.01,
140.01 (140.06, 139.95 JCeF ¼ 8.6 Hz), 132.13, 129.60, 129.78, 127.60,
124.52 (124.54, 124.49 JCeF ¼ 4.0 Hz), 123.73, 122.62 (122.67, 122.57
JCeF ¼ 8.0 Hz), 118.97 (118.99, 118.95 JCeF ¼ 3.2 Hz), 116.18 (116.32,
116.05 JCeF ¼ 20.9 Hz), 113.20, 54.50, 53.18, 50.73, 45.88, 25.19 ppm.
29 $ 2HCl $ 2H2O: Anal. (C24H24FN5O $ 2HCl $ 2H2O) C, H, N.
piperazine 2CH2), 3.78e3.83 (4H, piperazine 2CH2), 4.21
(t, J ¼ 6.6 Hz, 2H, C-10H2), 6.47 (t, J ¼ 4.7 Hz, 1H, C-600H), 7.71 (ddd,
J ¼ 8.2, 5.1, 1.2 Hz, 1H, C-9H), 7.88 (ddd, J ¼ 8.4, 5.1, 1.5 Hz, 1H, C-8H),
8.18 (d, J ¼ 8.2 Hz, 1H, C-7H), 8.28 (d, J ¼ 4.8, 2H, C-300H, C-500H), 8.49
(s, 1H, C-2H), 8.82 (dd, J ¼ 8.2, 1.3 Hz, 1H, C-10H), 9.65 (s, 1H, C-5H)
ppm. 13C NMR (CDCl3) dC: 161.57, 160.42, 157.72, 152.25, 151.63,
149.94, 148.99, 132.13, 129.62, 127.61, 124.50, 123.72, 113.14, 110.04,
54.62, 53.06, 45.85, 43.86, 25.25 ppm. 33 $ 2HCl $ 2H2O: Anal
(C22H23N7O $ 2HCl $ 2H2O) C, H, N.
7.1.2.25. 3-[4-(4-Phenylpiperazin-1-yl)butyl]pyrimido[5,4-c]quinoꢁ-1
: 1680 (C]O), 1600e1560 (C]N, C]C); 1H NMR (CDCl3) dH
:
lin-4(3H)-one (34). Yield: 77%, m.p. 174.4e175.5 ꢀC; IR (KBr, cm
)
n
1.57e1.71 (m, 2H, C-20H2). 1.83e1.99 (m, 2H, C-30H2), 2.46 (t,
J ¼ 7.2 Hz, 2H, C-40H2), 2.52e2.65 (m, 4H, piperazine 2CH2),
3.09e3.24 (4H, piperazine 2CH2), 4.13 (t, J ¼ 7.3 Hz, 2H, C-10H2),
6.78e6.95 (cluster, 3H, C-200H, C-400H, C-600H), 7.19e7.26 (cluster, 2H,
C-300H, C-500H), 7.65e7.76 (m, 1H, C-9H), 7.89 (ddd, J ¼ 8.4, 7.0,
1.5 Hz, 1H, C-8H), 8.19 (d, J ¼ 8.2 Hz, 1H, C-7H), 8.38 (s, 1H, C-2H),
8.82 (dd, J ¼ 8.2, 1.3 Hz, 1H, C-10H), 9.65 (s, 1H, C-5H) ppm. 13C NMR
(CDCl3) dC: 160.20, 152.12, 151.21, 150.82, 149.87, 148.98, 132.13,
129.55, 129.12, 127.61, 124.40, 123.64, 119.75, 116.06, 113.09, 57.96,
53.45, 49.29, 47.43, 27.67, 24.18 ppm. 34 $ 2HCl $ 2H2O: Anal.
(C25H27N5O $ 2HCl $ 2H2O) C, H, N.
7.1.2.21. 3-{3-[4-(4-Fluorophenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (30). Yield: 52%, m.p. 137.9e139.0 ꢀC; IR
(KBr, cmꢁ1 : 1681 (C]O), 1599e1510 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 2.00e2.13 (m, 2H, C-20H2), 2.46 (t, J ¼ 6.4 Hz, 2H, C-
30H2), 2.61e2.65 (m, 4H, piperazine 2CH2), 3.04e3.12 (4H, pipera-
zine 2CH2), 4.20 (t, J ¼ 6.5 Hz, 2H, C-10H2), 6.74e7.05 (cluster, 4H, C-
200H, C-300H, C-500H, C-600H), 7.70e7.79 (m, 1H, C-9H), 7.86e7.92 (m,
1H, C-8H), 8.20 (d, J ¼ 8.4 Hz, 1H, C-7H), 8.45 (s, 1H, C-2H), 8.82 (dd,
J ¼ 8.2, 1.2 Hz, 1H, C-10H), 9.66 (s, 1H, C-5H) ppm. 13C NMR (CDCl3)
dC: 160.25, 157.22 (158.78, 155.66 JCeF ¼ 238.5 Hz), 152.27, 151.53,
149.92, 149.06, 147.76, 132.15, 129.60, 127.61, 124.53, 123.74, 117.96
(117.99, 117.93 JCeF ¼ 7.7 Hz), 115.61 (115.76, 115.46 JCeF ¼ 22.0 Hz),
113.08, 54.52, 53.20, 50.74, 45.86, 25.20 ppm. 30 $ 2HCl $ 3.5H2O:
Anal. (C24H24FN5O $ 2HCl $ 3.5H2O) C, H, N.
7.1.2.26. 3-{4-[4-(2-Chlorophenylpiperazin-1-yl)butyl]pyrimido[5,4-
c]quinolin-4(3H)-one (35). Yield: 72%, m.p. 151.4e151.9 ꢀC; IR (KBr,
cmꢁ1 : 1686 (C]O), 1595e1555 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
1.60e1.72 (m, 2H, C-20H2), 1.85e1.99 (m, 2H, C-30H2), 2.49
(t, J ¼ 7.2 Hz, 2H, C-40H2), 2.55e2.72 (m, 4H, piperazine 2CH2),
2.96e3.16 (4H, piperazine 2CH2), 4.14 (t, J ¼ 7.3 Hz, 2H, C-10H2),
6.89e7.06 (cluster, 2H, C-400H, C-600H), 7.20 (t, J ¼ 7.7 Hz, 1H, C-500H),
7.34 (d, J ¼ 7.8 Hz, 1H, C-300H), 7.72 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-
9H), 7.90 (ddd, J ¼ 8.4, 6.9, 1.5 Hz, 1H, C-8H), 8.19 (d, J ¼ 8.4 Hz, 1H,
C-7H), 8.39 (s, 1H, C-2H), 8.82 (dd, J ¼ 8.2, 1.0 Hz, 1H, C-10H), 9.65
(s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.21, 152.12, 150.84,
149.86, 149.15, 148.99, 148.819, 132.13, 130.63, 129.55, 128.73,
127.62, 124.40, 123.72, 123.64, 120.38, 113.09, 57.96, 53.56, 51.33,
47.48, 27.67, 24.19 ppm. 35 $ 2HCl $ 0.75H2O: Anal. (C25H26ClN5O $
2HCl $ 0.75H2O) C, H, N.
7.1.2.22. 3-{3-[4-(2-Methylphenyl)piperazin-1-yl]propyl}pyrimido
[5,4-c]quinolin-4(3H)-one (31). Yield: 72%, m.p. 135.7e136.7 ꢀC; IR
(KBr, cmꢁ1 : 1680 (C]O), 1598e1505 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 2.02e2.15 (m, 2H, C-20H2), 2.27 (s, 3H, CH3), 2.48
(t, J ¼ 6.4 Hz, 2H, C-30H2), 2.54e2.61 (m, 4H, piperazine 2CH2),
2.81e2.92 (4H, piperazine 2CH2), 4.21 (t, J ¼ 6.5 Hz, 2H, C-10H2),
6.83e7.02 (cluster, 2H, C-400H, C-600H), 7.07e7.20 (cluster, 2H, C-300H,
C-500H), 7.67 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.86 (ddd, J ¼ 8.4,
7.0, 1.5 Hz, 1H, C-8H), 8.19 (d, J ¼ 8.3 Hz, 1H, C-7H), 8.51 (s, 1H, C-
2H), 8.84 (dd, J ¼ 8.2, 1.1 Hz, 1H, C-10H), 9.66 (s, 1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.46, 152.29, 151.79, 151.31, 149.91, 149.03,
132.65, 132.12, 131.08, 129.61, 127.60, 126.60, 124.49, 123.75, 123.25,
118.99,113.20, 54.57, 53.61, 51.91, 45.93, 25.11.18.11 ppm. 31 $ 2HCl $
3.25H2O: Anal. (C25H27N5O $ 2HCl $ 3.25H2O) C, H, N.
7.1.2.27. 3-{4-[4-(3-Chlorophenylpiperazin-1-yl)butyl]pyrimido[5,4-
c]quinolin-4(3H)-one (36). Yield: 75%, m.p. 159.5e160.3 ꢀC; IR (KBr,
cmꢁ1 : 1676 (C]O), 1595e1559 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
1.55e1.75 (m, 2H, C-20H2). 1.84e1.98 (m, 2H, C-30H2), 2.46
(t, J ¼ 7.2 Hz, 2H, C-40H2), 2.53e2.65 (m, 4H, piperazine 2CH2),
3.07e3.28 (4H, piperazine 2CH2), 4.13 (t, J ¼ 7.3 Hz, 2H, C-10H2),
6.71e6.80 (cluster, 3H, C-200H, C-400H, C-600H), 7.14 (t, J ¼ 8.1 Hz, 1H,
C-500H), 7.66e7.77 (m, 1H, C-9H), 7.83e7.85 (m, 1H, C-8H), 8.19 (d,
J ¼ 8.2 Hz, 1H, C-7H), 8.38 (s, 1H, C-2H), 8.82 (dd, J ¼ 8.2, 1.2 Hz, 1H,
C-10H), 9.65 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.20, 152.21,
151.11, 150.81, 149,87, 148.97, 134.90, 132.15, 130.04, 129.56, 127.63,
124.40, 123.64, 119.28, 115.72, 113.87, 113.08, 57.88, 53.20, 48.76,
47.40, 27.64, 24.13 ppm. 36 $ 2HCl $ H2O: Anal. (C25H26ClN5O $ 2HCl
$ H2O) C, H, N.
7.1.2.23. 3-(3-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}propyl)
pyrimido[5,4-c]quinolin-4(3Hꢁ)-1one
(32). Yield:
) n: 1686 (C]O), 1598e1507 (C]N,
51%,
m.p.
221.0e223.4 ꢀC; IR (KBr, cm
C]C); 1H NMR (CDCl3) dH: 2.02e2.13 (m, 2H, C-20H2), 2.47 (t,
J ¼ 6.4 Hz, 2H, C-30H2), 2.61e2.66 (m, 4H, piperazine 2CH2),
3.06e3.11 (4H, piperazine 2CH2), 4.20 (t, J ¼ 6.5 Hz, 2H, C-10H2),
6.96e7.12 (cluster, 3H, C-200H, C-400H, C-600H), 7.35 (dt, J ¼ 8.3, 8.2,
0.7 Hz, 1H, C-500H), 7.67 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.88
(ddd, J ¼ 8.4, 7.0,1.5 Hz,1H, C-8H), 8.19 (d, J ¼ 8.4 Hz,1H, C-7H), 8.39
(s, 1H, C-2H), 8.81 (dd, J ¼ 8.2, 1.3 Hz, 1H, C-10H), 9.65 (s, 1H, C-5H)
ppm. 13C NMR (CDCl3) dC: 160.26, 152.25, 151.46, 151.12, 149.89,
149.04, 132.20, 131.42 129.42, 129.58, 127.57, 124.37 (126.17, 122.57
JCeF ¼ 272.0 Hz), 124.53, 123.74, 118.90, 116.01 (116.04, 115.98
JCeF ¼ 4.0 Hz), 113.06, 112.29 (112.31, 112.27 JCeF ¼ 4.0 Hz), 54.55,
7.1.2.28. 3-{4-[4-(4-Chlorophenylpiperazin-1-yl)butyl]pyrimido[5,4-
c]quinolin-4(3H)-one (37). Yield: 68%, m.p. 175.8e177.0 ꢀC; IR (KBr,
cmꢁ1 : 1681 (C]O), 1597e1499 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
53.59, 51.86, 45.90, 25.10 ppm. 32
$ 2HCl $ 3H2O: Anal.
1.65e1.72 (m, 2H, C-20H2). 1.89e1.98 (m, 2H, C-30H2), 2.47
(t, J ¼ 7.2 Hz, 2H, C-40H2), 2.57e2.66 (m, 4H, piperazine 2CH2),
3.04e3.28 (4H, piperazine 2CH2), 4.14 (t, J ¼ 7.3 Hz, 2H, C-10H2),
6.62e6.77 (cluster, 2H, C-200H, C-600H), 7.01e7.13 (cluster, 2H, C-300H,
C-500), 7.68 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.86 (ddd, J ¼ 8.4, 6.9,
1.5 Hz, 1H, C-8H), 8.16 (d, J ¼ 8.0 Hz, 1H, C-7H), 8.37 (s, 1H, C-2H),
(C25H24F3N5O $ 2HCl $ 3H2O) C, H, N.
7.1.2.24. 3-[3-(4-Pyrimidin-2-ylpiperazin-1-yl)propyl]pyrimido[5,4-
c]quinolin-4(3H)-one (33). Yield: 67%, m.p. 184.4e185.4 ꢀC; IR (KBr,
cmꢁ1 : 1674 (C]O), 1588e1497 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
2.03e2.14 (m, 2H, C-20H2), 2.41e2.51 (cluster, 2H, C-30H2 þ 4H,

W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
3357
8.82 (dd, J ¼ 8.3, 1.0 Hz, 1H, C-10H), 9.56 (s, 1H, C-5H) ppm. 13C NMR
(CDCl3) dC: 160.28, 152.20, 151.67, 149.88, 149.76, 148.84, 132.04,
129.48, 128.91, 127.65, 124.74, 124.42, 123.63, 117.32, 113.09, 57.98,
53.37, 49.26, 47.45, 27.64, 24.16 ppm. 37 $ 2HCl $ 2H2O: Anal.
(C25H26ClN5O $ 2HCl $ 2H2O) C, H, N.
(122.55, 122.44 JCeF ¼ 8.0 Hz), 118.94 (118.96, 118.92 JCeF ¼ 3.1 Hz),
116.13 (116.27, 115.99 JCeF ¼ 20.6 Hz), 113.11, 57.98, 53.49, 50.67,
47.47, 27.67, 24.18 ppm. 41 $ 2HCl: Anal. (C25H26FN5O $ 2HCl) C, H, N.
7.1.2.33. 3-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}pyrimido[5,4-
c]quinolin-4(3H)-one (42). Yield: 53%, m.p. 179.4e180.0 ꢀC; IR (KBr,
cmꢁ1 : 1678 (C]O), 1600e1510 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
7.1.2.29. 3-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}pyrimido
[5,4-c]quinolin-4(3H)-one (38). Yield: 87%, m.p. 137.8e138.6 ꢀC; IR
1.55e1.76 (m, 2H, C-20H2). 1.82e2.05 (m, 2H, C-30H2), 2.46
(t, J ¼ 7.3 Hz, 2H, C-40H2), 2.53e2.69 (m, 4H, piperazine 2CH2),
2.99e3.19 (4H, piperazine 2CH2), 4.13 (t, J ¼ 7.2 Hz, 2H, C-10H2), 6.90
(dt, J ¼ 13.7, 9.1 Hz, 4H, C-200H, C-300H, C-500H, C-600H), 7.63e7.78
(m, 1H, C-9H), 7.84e7.99 (m, 1H, C-8H), 8.19 (d, J ¼ 8.3 Hz, 1H, C-7H),
8.38 (s, 1H, C-2H), 8.81 (d, J ¼ 8.2 Hz, 1H, C-10H), 9.65 (s, 1H, C-5H)
(KBr, cmꢁ1 : 1688 (C]O), 1599e1498 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 1.56e1.74 (m, 2H, C-20H2). 1.83e1.99 (m, 2H, C-30H2),
2.48 (t, J ¼ 7.2 Hz, 2H, C-40H2), 2.56e2.73 (m, 4H, piperazine 2CH2),
2.94e3.21 (4H, piperazine 2CH2), 3.85 (s, 3H, OCH3), 4.13 (t,
J ¼ 7.3 Hz, 2H, C-10H2), 6.79e7.04 (cluster, 4H, C-300H, C-400H, C-500H,
C-600H), 7.72 (ddd, J ¼ 8.2, 6.9, 1.2 Hz, 1H, C-9H), 7.90 (ddd, J ¼ 8.2,
6.8, 1.4 Hz, 1H, C-8H), 8.19 (d, J ¼ 8.2 Hz, 1H, C-7H), 8.39 (s, 1H, C-
2H), 8.82 (dd, J ¼ 8.1, 1.1 Hz, 1H, C-10H), 9.66 (s, 1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.20, 152.19, 152.11, 150.83, 149.87, 148.99,
141.22, 132.10, 129.55, 127.59, 124.40, 123.65, 122.96, 120.98, 118.20,
113.09, 111.15, 58.06, 55.49, 53.64, 50.80, 47.49, 27.68, 24.19 ppm. 38
$ 2HCl $ 3.5H2O: Anal. (C26H29N5O2 $ 2HCl $ 3.5H2O) C, H, N.
ppm. 13C NMR (CDCl3) dC
: 160.23, 157.12 (158.70, 155.54
JCeF ¼ 238.2 Hz), 152.14,150.84,149.88, 148.99, 147.92,132.16,129.57,
127.65, 124.42, 123.66, 117.83 (117.88, 117.78 JCeF ¼ 7.7 Hz), 115.55
(115.70, 115.41 JCeF ¼ 22.0 Hz), 113.10, 57.92, 53.44, 50.31, 47.44,
27.68, 24.19 ppm. 42 $ 2HCl: Anal. (C25H26FN5O $ 2HCl) C, H, N.
7.1.2.34. 3-{4-[4-(2-Methylphenyl)piperazin-1-yl]butyl}pyrimido
[5,4-c]quinolin-4(3H)-one (43). Yield: 72%, m.p. 132.7e133.8 ꢀC; IR
7.1.2.30. 3-{4-[4-(3-Methoxyphenyl)piperazin-1-yl]butyl}pyrimido
(KBr, cmꢁ1 : 1677 (C]O), 1595e1494 (C]N, C]C); 1H NMR
) n
[5,4-c]quinolin-4(3H)-one (39). Yield: 76%, m.p. 142.5e143.2 ꢀC; IR
(CDCl3) dH: 1.55e1.75 (m, 2H, C-20H2). 1.85e1.97 (m, 2H, C-30H2),
2.45 (s, 3H, CH3), 2.47 (t, J ¼ 7.3 Hz, 2H, C-40H2), 2.56e2.63 (m, 4H,
piperazine 2CH2), 3.08e3.04 (4H, piperazine 2CH2), 4.13 (t,
J ¼ 7.2 Hz, 2H, C-10H2), 6.75e6.96 (cluster, 4H, C-400H, C-600H, C-300H,
C-500H), 7.67 (ddd, J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.90 (ddd, J ¼ 8.4,
7.0, 1.5 Hz, 1H, C-8H), 8.19 (d, J ¼ 8.3 Hz, 1H, C-7H), 8.38 (s, 1H, C-
2H), 8.82 (dd, J ¼ 8.2, 1.0 Hz, 1H, C-10H), 9.65 (s, 1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.20, 152.13, 151.39, 150.87, 149.87, 148.99,
132.57, 132.13, 131.06, 129.55, 127.61, 126.58, 124.41, 123.66, 123.15,
118.98, 113.12, 58.07, 53.95, 51.84, 47.46, 27.70, 24.21, 18.12 ppm. 43
$ 2HCl $ H2O: Anal. (C26H29N5O $ 2HCl $ H2O) C, H, N.
(KBr, cmꢁ1
(CDCl3):
) n
: 1687 (C]O), 1597e1498 (C]N, C]C); 1H NMR
d
1.56e1.74 (m, 2H, C-20H2). 1.83e1.99 (m, 2H, C-30H2), 2.48
(t, J ¼ 7.2 Hz, 2H, C-40H2), 2.56e2.73 (m, 4H, piperazine 2CH2),
2.94e3.21 (4H, piperazine 2CH2), 3.85 (s, 3H, OCH3), 4.13 (t,
J ¼ 7.3 Hz, 2H, C-10H2), 6.33e6.57 (cluster, 3H, C-200H, C-400H, C-600H),
7.16 (t, J ¼ 8.2 Hz,1H, C-500H), 7.72 (ddd, J ¼ 8.2, 7.0,1.2 Hz,1H, C-9H),
7.90 (ddd, J ¼ 8.3, 7.0,1.5 Hz,1H, C-8H), 8.19 (d, J ¼ 8.3 Hz,1H, C-7H),
8.38 (s, 1H, C-2H), 8.82 (dd, J ¼ 8.2, 1.1 Hz, 1H, C-10H), 9.65 (s, 1H, C-
5H) ppm. 13C NMR (CDCl3) dC: 160.50, 160.22, 152.62, 152.13, 150.83,
149.88, 149.00, 132.14, 129.79, 129.57, 127.62, 124.41, 123.66, 113.10,
108.88, 104.48, 102.52, 57.96, 55.34, 53.41, 49.21, 47.44, 27.67,
24.19 ppm. 39 $ 2HCl $ 3.5H2O: Anal. (C26H29N5O2 $ 2HCl $ 3.5H2O)
C, H, N.
7.1.2.35. 3-(4-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}butyl)
pyrimido[5,4-c]quinolin-4(3Hꢁ)-1one
(44). Yield:
) n: 1682 (C]O), 1613e1560 (C]N,
55%,
m.p.
194.3e195.2 ꢀC; IR (KBr, cm
7.1.2.31. 3-{4-[4-(4-Methoxyphenyl)piperazin-1-yl]butyl}pyrimido
C]C); 1H NMR (CDCl3) dH: 1.59e1.72 (m, 2H, C-20H2). 1.86e1.97 (m,
2H, C-30H2), 2.47 (t, J ¼ 7.3 Hz, 2H, C-40H2), 2.55e2.63 (m, 4H,
piperazine 2CH2), 3.17e3.28 (4H, piperazine 2CH2), 4.14 (t,
J ¼ 7.3 Hz, 2H, C-10H2), 7.00e7.12 (cluster, 3H, C-200H, C-400H, C-600H),
7.33 (t, J ¼ 8.3 Hz, 1H, C-500H), 7.69e7.76 (m, 1H, C-9H), 7.87e7.94
(m, 1H, C-8H), 8.20 (d, J ¼ 8.4 Hz, 1H, C-7H), 8.39 (s, 1H, C-2H), 8.83
(dd, J ¼ 8.2, 1.3 Hz, 1H, C-10H), 9.66 (s, 1H, C-5H) ppm. 13C NMR
(CDCl3) dC: 160.27, 152.17, 151.32, 150.84, 149.92, 149.02, 132.20,
131.40 (131.61, 131.19 JCeF ¼ 31.5 Hz), 129.62, 129.59, 127.68, 124.39
(126.19, 122.59 JCeF ¼ 272.0 Hz), 124.43, 123.68, 118.72, 115.88
(115.91, 115.85 JCeF ¼ 4.0 Hz), 113.12, 112.18 (112.20, 112.15
JCeF ¼ 4.0 Hz), 57.90, 53.24, 48.82, 47.45, 27.68, 24.19 ppm. 44 $ HCl $
1.25H2O: Anal. (C26H26F3N5O $ HCl $ 1.25H2O) C, H, N.
[5,4-c]quinolin-4(3H)-one (40). Yield: 57%, m.p. 170.9e171.5 ꢀC; IR
(KBr, cmꢁ1 : 1686 (C]O), 1597e1513 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 1.54e1.73 (m, 2H, C-20H2). 1.83e1.99 (m, 2H, C-30H2),
2.46 (t, J ¼ 7.2 Hz, 2H, C-40H2), 2.54e2.67 (m, 4H, piperazine 2CH2),
3.00e3.17 (4H, piperazine 2CH2), 3.75 (s, 3H, OCH3), 4.12 (t,
J ¼ 7.3 Hz, 2H, C-10H2), 6.85 (q, J ¼ 9.2 Hz, 4H, C-200H, C-200H, C-500H,
C-600H), 7.71 (dd, J ¼ 8.2, 1.2 Hz, 1H, C-9H), 7.88 (dd, J ¼ 8.4, 1.5 Hz,
1H, C-8H), 8.19 (d, J ¼ 8.3 Hz, 1H, C-7H), 8.37 (s, 1H, C-2H), 8.81 (d,
J ¼ 8.3, Hz, 1H, C-10H), 9.64 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC
:
160.60, 154.15, 152.52, 151.24, 150.27, 149.39, 146.03, 132.53, 129.96,
128.01, 124.81, 124.05, 118.60, 114.86, 113.50, 58.37, 56.12, 53.96,
51.17, 47.85, 28.08, 24.60 ppm. 40 $ HCl $ 2H2O: Anal. (C26H29N5O2 $
HCl $ 2H2O) C, H, N.
7.1.2.36. 3-[4-(4-Pyrimidin-2-ylpiperazin-1-yl)butyl]pyrimido[5,4-c]
7.1.2.32. 3-{4-[4-(2-Fluorophenyl)piperazin-1-yl]butyl}pyrimido[5,4-
quinolin-4(3H)-one (45). Yield: 59%, m.p. 184.5e185.6 ꢀC; IR (KBr,
c]quinolin-4(3H)-one (41). Yield: 61%, m.p. 169.3e170.2 ꢀC; IR (KBr,
cmꢁ1 : 1695 (C]O), 1588e1490 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
cmꢁ1 : 1696 (C]O), 1600e1499 (C]N, C]C); 1H NMR (CDCl3) dH
) n :
1.57e1.76 (m, 2H, C-20H2). 1.85e1.99 (m, 2H, C-30H2), 2.33e2.61
(cluster, 2H, C-40H2 þ 4H, piperazine 2CH2), 3.78e3.87 (4H, piper-
azine 2CH2), 4.14 (t, J ¼ 7.2 Hz, 2H, C-10H2), 6.47 (t, J ¼ 4.7, 1H, C-
600H), 7.72 (ddd, J ¼ 8.3, 5.1, 1.2 Hz, 1H, C-9H), 7.90 (ddd, J ¼ 8.4, 5.1,
1.5 Hz,1H, C-8H), 8.19 (d, J ¼ 8.3 Hz,1H, C-7H), 8.30 (d, J ¼ 4.7, 2H, C-
300H, C-500H), 8.40 (s, 1H, C-2H), 8.82 (d, J ¼ 8.2 Hz, 1H, C-10H), 9.65
(s,1H, C-5H) ppm. 13C NMR (CDCl3) dC: 161.57,160.23,157.69,152.15,
150.84, 149.88, 148.99, 132.16, 129.59, 127.64, 124.42, 123.66, 113.11,
109.97, 58.07, 53.32, 45.85, 43.79, 27.67, 24.15 ppm. 45 $ 2HCl $
2.5H2O: Anal. (C23H25N7O $ 2HCl $ 2.5H2O) C, H, N.
1.55e1.75 (m, 2H, C-20H2). 1.82e2.05 (m, 2H, C-30H2), 2.55 (t,
J ¼ 7.3 Hz, 2H, C-40H2), 2.39e2.71 (m, 4H, piperazine 2CH2),
3.09e3.18 (4H, piperazine 2CH2), 4.13 (t, J ¼ 7.3 Hz, 2H, C-10H2),
6.84e7.12 (cluster, 4H, C-300H, C-400H, C-500H, C-600H), 7.72 (ddd,
J ¼ 8.2, 7.0, 1.2 Hz, 1H, C-9H), 7.90 (ddd, J ¼ 8.4, 7.0, 1.5 Hz,1H, C-8H),
8.19 (d, J ¼ 8.1 Hz, 1H, C-7H), 8.40 (s, 1H, C-2H), 8.82 (dd, J ¼ 8.3,
1.1 Hz, 1H, C-10H), 9.64 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC
:
160.22, 155.67 (157.30, 154.05 JCeF ¼ 245.3 Hz), 152.14, 150.85,
149.88, 149.00, 140.07 (140.12, 140.02 JCeF ¼ 8.3 Hz), 132.14, 129.57,
127.62, 124.50 (124.52, 124.48 JCeF ¼ 3.7 Hz), 124.42, 123.66, 122.49

3358
W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
7.1.2.37. 3-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-8-methyl-
dC: 160.36, 152.16, 151.39, 151.24, 150.24, 149.09, 143.03, 131.47
(131.68, 131.26 JCeF ¼ 31.7 Hz), 129.69, 129.63, 128.92, 124.37
(126.17, 122.57 JCeF ¼ 272.0 Hz), 124.21, 121.55, 118.94, 116.13
(116.16, 116.11 JCeF ¼ 3.7 Hz), 112.57, 112.32 (112.35, 112.29
JCeF ¼ 4.0 Hz), 56.46, 53.29, 48.93, 44.14, 22.31 ppm. 50 $ 2HCl $
H2O: Anal. (C25H24F3N5O $ 2HCl $ H2O) C, H, N.
pyrimido[5,4-c]quinolin-4(3H)-one (46). Yield: 59%, m.p. 183.2e
184.1 ꢀC; IR (KBr, cmꢁ1 : 1680 (C]O), 1602e1497 (C]N, C]C); 1H
) n
NMR (CDCl3) dH: 2.62 (s, 3H, CH3), 2.71e2.77 (m, 4H, piperazine
2CH2), 2.83 (t, J ¼ 5.7 Hz, 2H, C-20H2), 3.03e3.11 (m, 4H, piperazine
2CH2), 3.85 (s, 3H, OCH3), 4.19 (t, J ¼ 5.7 Hz, 2H, C-10H2), 6.82e7.03
(cluster, 4H, C-300H, C-400H, C-500H, C-600H), 7.54 (dd, J ¼ 8.4, 1.5 Hz,
1H, C-9H), 7.96 (s, 1H, C-7H), 8.40 (s, 1H, C-2H), 8.70 (d, J ¼ 8.4, 1H,
C-10H), 9.62 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.30, 152.18,
152.11, 151.52, 150.15, 149.10, 142.88, 141.04, 129.58, 128.87, 124.15,
123.09, 121.52, 121.00, 118.26, 112.56, 111.24, 56.61, 55.53, 53.70,
7.1.2.42. 3-(2-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-9-
methylpyrimido[5,4-c]quinoliꢁn1-4(3H)-one (51). Yield: 56%, m.p.
) n: 1677 (C]O), 1600e1559 (C]N,
187.3e187.7 ꢀC; IR (KBr, cm
C]C); 1H NMR (CDCl3) dH: 2.52 (s, 3H, CH3), 2.69e2.77 (m, 4H,
piperazine 2CH2), 2.81 (t, J ¼ 5.7 Hz, 2H, C-20H2), 3.10e3.26 (m, 4H,
piperazine 2CH2), 4.16 (t, J ¼ 5.7 Hz, 2H, C-10H2), 6.90e7.03
(cluster, 3H, C-200H, C-400H, C-600H), 7.24 (t, J ¼ 7.8 Hz, 1H, C-500H),
7.62 (dd, J ¼ 8.5, 1.8 Hz, 1H, C-8H), 7.98 (d, J ¼ 8.5 Hz, 1H, C-7H),
8.33 (s, 1H, C-2H), 8.48 (s, 1H, C-10H), 9.49 (s, 1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.34, 151.76, 151.22, 151.07, 148.40, 147.92,
137.93, 134.23, 131.45 (131.66, 131.24 JCeF ¼ 31.7 Hz), 129.66,
129.26, 124.32 (126.12, 122.52 JCeF ¼ 272.0 Hz), 123.51, 123.58,
119.04, 116.04, 113.02, 112.42 (112.45, 112.40 JCeF ¼ 3.7 Hz), 56.25,
50.78, 43.97, 22.28 ppm. 46 $ 2HCl $ 0.5H2O: Anal (C25H27N5O2
2HCl $ 0.5H2O) C, H, N.
$
7.1.2.38. 3-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}-9-methyl-
pyrimido[5,4-c]quinoꢁli1n-4(3H)-one (47). Yield: 57%, m.p. 167.2e
168.3 ꢀC; IR (KBr, cm
) n
: 1678 (C]O), 1601e1500 (C]N, C]C); 1H
NMR (CDCl3) dH: 2.64 (s, 3H, CH3), 2.71e2.80 (m, 4H, piperazine
2CH2), 2.86 (t, J ¼ 5.7 Hz, 2H, C-20H2), 3.05e3.14 (m, 4H, piperazine
2CH2), 3.87 (s, 3H, OCH3), 4.23 (t, J ¼ 5.7 Hz, 2H, C-10H2), 6.81e7.08
(cluster, 4H, C-300H, C-400H, C-500H, C-600H), 7.73 (dd, J ¼ 8.5, 1.7 Hz
1H, C-8H), 8.10 (d, J ¼ 8.5 Hz 1H, C-7H), 8.44 (s, 1H, C-2H), 8.63 (s,
1H, C-10H), 9.62 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.36,
152.19, 151.74, 151.31, 148.45, 147.97, 140.73, 137.84, 134.15, 129.29,
123.54, 123.49, 123.33, 121.06, 118.37, 113.04, 111.29, 56.38, 55.58,
53.68, 50.40, 43.78, 22.05 ppm. 47 $ 2HCl $ H2O: Anal. (C25H27N5O2
$ 2HCl $ H2O) C, H, N.
53.21, 48.74, 43.98, 22.05 ppm. 51 $ 2HCl
(C25H24F3N5O $ 2HCl $ 0.5H2O) C, H, N.
$ 0.5H2O: Anal.
7.1.2.43. 3-[3-(4-Phenylpiperazin-1-yl)propyl]-8-methylpyrimido
[5,4-c]quinolin-4(3H)-one (52). Yield: 72%, m.p. 161.1e161.8 ꢀC; IR
(KBr, cmꢁ1 : 1679 (C]O), 1620e1501 (C]N, C]C); 1H NMR
) n
(CDCl3) dH: 2.04e2.12 (m, 2H, C-20H2), 2.46 (t, J ¼ 6.5 Hz, 2H, C-
30H2), 2-57-2.62 (cluster, 4H, piperazine 2CH2, 3H, CH3), 3.14e3.19
(4H, piperazine 2CH2), 4.18 (t, J ¼ 6.6 Hz, 2H, C-10H2), 6.83e6.91
(cluster, 3H, C-200H, C-400H, C-600H), 7.22e7.28 (cluster, 2H, C-300H, C-
500H), 7.53 (dd, J ¼ 8.5, 1.6 Hz, 1H, C-9H), 7.96 (s, 1H, C-7H), 8.44 (s,
1H, C-2H), 8.68 (d, J ¼ 8.5 Hz,1H, C-10H), 9.62 (s, 1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.39, 152.04, 151.49, 151.16, 150.12, 148.97,
142.83, 129.55, 129.10, 128.85, 124.12, 121.47, 119.79, 116.09, 112.59,
54.40, 53.08, 49.34, 45.66, 25.27, 22.24 ppm. 52 $ 2HCl $ 2.5H2O:
Anal. (C25H27N5O $ 2HCl $ 2.5H2O) C, H, N.
7.1.2.39. 3-{2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethyl}-8-methylpyr-
imido[5,4-c]quinolin-4(3H)-one (48). Yield: 61%, m.p. 203.7e204.2 ꢀC;
IR (KBr, cmꢁ1 : 1675 (C]O), 1597e1508 (C]N, C]C); 1H NMR
) n
(CDCl3) dH:2.61 (s, 3H, CH3), 2.66e2.72 (m, 4H, piperazine 2CH2),
2.80 (t, J ¼ 5.5 Hz, 2H, C-20H2), 3.03e3.10 (m, 4H, piperazine 2CH2),
3.75 (s, 3H, OCH3), 4.17 (t, J ¼ 5.5 Hz, 2H, C-10H2), 6.76e6.91 (cluster,
4H, C-200H, C-200H, C-500H, C-600H), 7.53 (dd, J ¼ 8.4, 1.5 Hz, 1H, C-9H),
7.95 (s, 1H, C-7H), 8.37 (s, 1H, C-2H), 8.68 (d, J ¼ 8.4 Hz, 1H, C-10H),
9.60 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.32, 153.86, 152.12,
151.48, 150.16, 149.09, 145.46, 142.17, 129.63, 128.87, 124.17, 121.52,
118.30, 114.47, 112.55, 56.49, 55.73, 53.58, 50.80, 44.04, 22.30 ppm.
48 $ 2HCl $ 2.25H2O: Anal. (C25H27N5O2 $ 2HCl $ 2.25H2O) C, H, N.
7.1.2.44. 3-[3-(4-Phenylpiperazin-1-yl)propyl]-9-methylpyrimido
[5,4-c]quinolin-4(3H)-one (53). Yield: 71%, m.p. 154.3e154.9 ꢀC; IR
(KBr, cmꢁ1 : 1685 (C]O), 1600e1505 (C]N, C]C); 1H NMR
) n
(CDCl3) dH:2.05e2.14 (m, 2H, C-20H2), 2.47 (t, J ¼ 6.5 Hz, 2H, C-30H2),
2.58e2.62 (cluster, 4H, piperazine 2CH2, 3H, CH3), 3.17e3.20 (4H,
piperazine 2CH2), 4.21 (t, J ¼ 6.6 Hz, 2H, C-10H2), 6.83e6.92 (cluster,
3H, C-200H, C-400H, C-600H), 7.22e7.29 (cluster, 2H, C-300H, C-500H),
7.71 (dd, J ¼ 8.5, 1.8 Hz, 1H, C-8H), 8.09 (d, J ¼ 8.5 Hz, 1H, C-7H), 8.47
(s, 1H, C-2H), 8.59 (s, 1H, C-10H), 9.59 (s, 1H, C-5H) ppm. 13C NMR
(CDCl3) dC: 160.40, 151.67, 151.36, 151.15, 148.39, 147.93, 137.79,
134.07, 129.26, 129.11, 123.51, 123.40, 119.85, 116.13, 113.13, 54.38,
53.08, 49.34, 45.71, 25.20, 22.01 ppm. 53 $ 2HCl $ H2O: Anal.
(C25H27N5O $ 2HCl $ H2O) C, H, N.
7.1.2.40. 3-{2-[4-(4-Methoxyphenyl)piperazin-1-yl]ethyl}-9-methyl-
pyrimido[5,4-c]quinoꢁli1n-4(3H)-one (49). Yield: 67%, m.p. 179.2e
179.9 ꢀC; IR (KBr, cm
) n
: 1678 (C]O), 1598e1511 (C]N, C]C); 1H
NMR (CDCl3) dH: 2.60 (s, 3H, CH3), 2.71e2.85 (m, 4H, piperazine
2CH2), 2.90 (t, J ¼ 5.5 Hz, 2H, C-20H2), 3.08e3.17 (m, 4H, piperazine
2CH2), 3.75 (s, 3H, OCH3), 4.25 (t, J ¼ 5.5 Hz, 2H, C-10H2), 6.73e6.93
(cluster, 4H, C-200H, C-200H, C-500H, C-600H), 7.69 (dd, J ¼ 8.5, 1.9 Hz
1H, C-8H), 8.05 (d, J ¼ 8.5 Hz 1H, C-7H), 8.42 (s, 1H, C-2H), 8.56 (s,
1H, C-10H), 9.56 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.31,
154.09, 151.70, 151.24, 148.41, 147.91, 145.08, 137.82, 134.13, 129.25,
123.50, 123.46, 118.49, 114.50, 113.00, 56.25, 55.71, 53.46, 50.60,
43.85, 22.02 ppm. 49 $ 2HCl $ 3H2O: Anal (C25H27N5O2 $ 2HCl $
3H2O) C, H, N.
7.1.2.45. 3-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl}-8-methyl-
pyrimido[5,4-c]quinoliꢁn1-4(3H)-one (54). Yield: 58%, m.p. 149.3e
150.3 ꢀC; IR (KBr, cm
) n: 1686 (C]O), 1596e1487 (C]N, C]C);
1H NMR (CDCl3) dH: 2.04e2.15 (m, 2H, C-20H2), 2.48 (t, J ¼ 6.5 Hz,
2H, C-30H2), 2.55e2.60 (m, 4H, piperazine 2CH2), 2.64 (s, 3H, CH3),
3.12e3.20 (4H, piperazine 2CH2), 4.21 (t, J ¼ 6.6 Hz, 2H, C-10H2),
6.69e6.86 (cluster, 3H, C-200H, C-400H, C-600H), 7.56 (t, J ¼ 8.1 Hz, 1H,
C-500H), 7.56 (d, J ¼ 8.5 Hz, 1H, C-9H), 7.98 (s, 1H, C-7H), 8.46 (s, 1H,
C-2H), 8.71 (d, J ¼ 8.5, 1H, C-10H), 9.63 (s, 1H, C-5H) ppm. 13C NMR
(CDCl3) dC: 160.46, 152.10, 152.05, 151.43, 150.15, 148.95, 142.99,
134.96, 130.09, 129.68, 128.87, 124.13, 121.48, 119.61, 115.94, 114.09,
112.59, 54.52, 52.84, 48.67, 45.69, 25.21, 22.28 ppm. 54 $ 2HCl $
1.5H2O: Anal. (C25H26ClN5O $ 2HCl $ 1.5H2O) C, H, N.
7.1.2.41. 3-(2-{4-[3-(Trifluoromethyl)phenyl]piperazin-1-yl}ethyl)-8-
methylpyrimido[5,4-c]quinolin-4(3H)-one (50). Yield: 60%, m.p.
183.3e184.5 ꢀC; IR (KBr, cmꢁ1
) n: 1672 (C]O), 1598e1497 (C]N,
C]C); 1H NMR (CDCl3) dH: 2.62 (s, 3H, CH3), 2.65e2.75 (m, 4H,
piperazine 2CH2), 2.83 (t, J ¼ 5.7 Hz, 2H, C-20H2), 3.17e3.27 (m, 4H,
piperazine 2CH2), 4.20 (t, J ¼ 5.7 Hz, 2H, C-10H2), 6.99e7.13 (cluster,
3H, C-200H, C-400H, C-600H), 7.33 (t, J ¼ 7.9 Hz, 1H, C-500H), 7.54 (dd,
J ¼ 8.4, 1.5 Hz, 1H, C-9H), 7.97 (s, 1H, C-7H), 8.37 (s, 1H, C-2H), 8.69
(d, J ¼ 8.4 Hz, 1H, C-10H), 9.62 (s, 1H, C-5H) ppm. 13C NMR (CDCl3)

W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
3359
7.1.2.46. 3-{3-[4-(3-Chlorophenyl)piperazin-1-yl]propyl}-9-methyl-
2CH2), 2.99e3.04 (4H, piperazine 2CH2), 4.11 (t, J ¼ 6.5 Hz, 2H, C-
10H2), 6.71e6.89 (cluster, 4H, C-200H, C-300H, C-500H, C-600H), 7.62 (dd,
J ¼ 8.5, 1.9 Hz, 1H, C-8H), 7.97 (d, J ¼ 8.5 Hz, 1H, C-7H), 8.38 (s, 1H, C-
pyrimido[5,4-c]quinolin-4(3Hꢁ)-1one
(55). Yield:
) n: 1678 (C]O), 1595e1554 (C]N,
61%,
m.p.
155.3e155.9 ꢀC; IR (KBr, cm
C]C); 1H NMR (CDCl3) dH: 2.05e2.16 (m, 2H, C-20H2), 2.53 (s, 3H,
CH3), 2.57 (t, J ¼ 6.6 Hz, 2H, C-30H2), 2.62e2.70 (m, 4H, piperazine
2CH2), 3.13e3.23 (4H, piperazine 2CH2), 4.15 (t, J ¼ 6.6 Hz, 2H, C-
10H2), 6.62e6.87 (cluster, 3H, C-200H, C-400H, C-600H), 7.07 (t,
J ¼ 8.1 Hz, 1H, C-500H), 7.62 (dd, J ¼ 8.5, 1.9 Hz, 1H, C-8H), 7.97 (d,
J ¼ 8.5 Hz, 1H, C-7H), 8.43 (s, 1H, C-2H), 8.47 (s, 1H, C-10H), 9.47 (s,
1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.49, 151.82, 151.69, 151.23,
148.39, 147.84, 137.92, 134.99, 134.20, 130.15, 129.26, 123.46, 123.41,
119.87, 116.08, 114.21, 113.06, 54.48, 52.76, 48.41, 45.58, 25.02,
22.07 ppm. 55 $ 2HCl $ 1.25H2O: Anal. (C25H26ClN5O $ 2HCl $
1.25H2O) C, H, N.
2H), 8.47 (s, 1H, C-10H), 9.47 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC
:
160.45, 157.23 (158.81, 155.65 JCeF ¼ 238.5 Hz), 151.69, 151.34,
148.41, 147.92, 147.73, 137.85, 134.13, 129.29, 123.49, 123.40, 117.99
(118.04, 117.94 JCeF ¼ 7.4 Hz), 115.57 (115.72, 115.43 JCeF ¼ 22.0 Hz),
113.13, 54.41, 53.04, 50.23, 45.72, 25.11, 22.04 ppm. 59 $ 2HCl $
1.5H2O: Anal. (C25H26FN5O $ 2HCl $ 1.5H2O) C, H, N.
7.1.2.51. 3-{4-[4-(3-Chlorophenylpiperazin-1-yl)butyl]-8-methylpyr-
imido[5,4-c]quinolin-4(3H)-one (60). Yield: 57%, m.p. 154.9e
156.0 ꢀC; IR (KBr, cmꢁ1 : 1690 (C]O),1599e1555 (C]N, C]C); 1H
) n
NMR (CDCl3) dH: 1.57e1.72 (m, 2H, C-20H2), 1.83e1.98 (m, 2H, C-
30H2), 2.48 (t, J ¼ 7.5 Hz, 2H, C-40H2), 2.62 (s, 3H, CH3), 2.53e2.65 (m,
4H, piperazine 2CH2), 3.04e3.21 (m, 4H, piperazine 2CH2), 4.14 (t,
J ¼ 7.5 Hz, 2H, C-10H2), 6.71e6.83 (cluster, 3H, C-200H, C-400H, C-600H),
7.18 (t, J ¼ 8.2 Hz, 1H, C-500H), 7.56 (dd, J ¼ 8.5, 1.6 Hz, 1H, C-9H), 7.94
(s, 1H, C-7H), 8.37 (s, 1H, C-2H), 8.65 (d, J ¼ 8.5 Hz, 1H, C-10H), 9.62
(s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.36, 152.16, 152.05,
151.37, 150.05, 148.87, 142.76, 134.93, 130.11, 129.71, 128.89, 124.12,
121.48, 119.57, 115.84, 114.13, 112.49, 57.91, 53.24, 50.28, 47.40,
27.69, 24.21, 22.28 ppm. 60 $ 2HCl $ 1.25H2O: Anal. (C26H28ClN5O $
2HCl $ 1.25H2O) C, H, N.
7.1.2.47. 3-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl}-8-meth-
ylpyrimido[5,4-c]-quinolin-4(ꢁ3H1 )-one
(56). Yield:
) n: 1677 (C]O), 1603e1499 (C]N,
59%,
m.p.
152.9e153.5 ꢀC; IR (KBr, cm
C]C); 1H NMR (CDCl3) dH: 2.01e2.15 (m, 2H, C-20H2), 2.48 (t,
6.3 Hz, 2H, C-30H2), 2.62e2.76 (cluster, 4H, piperazine
J
¼
2CH2 þ 3H, CH3), 2.94e3.16 (4H, piperazine 2CH2), 3.84 (s, 3H,
OCH3), 4.19 (t, J ¼ 6.5 Hz, 2H, C-10H2), 6.81e7.06 (cluster, 4H, C-
300H, C-400H, C-500H, C-600H), 7.53 (d, J ¼ 8.5 Hz, 1H, C-9H), 7.96 (s,
1H, C-7H), 8.47 (s, 1H, C-2H), 8.68 (d, J ¼ 8.5 Hz, 1H, C-10H), 9.61
(s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.40, 152.19, 152.06,
151.61, 150.08, 148.99, 142.83, 141.12, 129.56, 128.82, 124.10, 122.99,
121.48, 120.96, 118.17, 112.61, 111.18, 55.49, 54.47, 53.28, 50.81,
7.1.2.52. 3-{4-[4-(3-Chlorophenylpiperazin-1-yl)butyl]-9-methylpyr-
imido[5,4-c]quinolin-4(3H)-one (61). Yield: 71%, m.p. 196.1e
45,74, 25.20, 22.25 ppm. 56 $ 2HCl $ H2O: Anal. (C26H29N5O2
2HCl $ H2O) C, H, N.
$
196.73 ꢀC; IR (KBr, cmꢁ1
) n: 1674 (C]O), 1597e1554 (C]N, C]C);
1H NMR (CDCl3) dH:1.55e1.72 (m, 2H, C-20H2). 1.82e1.97 (m, 2H, C-
30H2), 2.45 (t, J ¼ 7.2 Hz, 2H, C-40H2), 2.53e2.58 (m, 4H, piperazine
2CH2), 2.62 (s, 3H, CH3), 3.10e3.22 (4H, piperazine 2CH2), 4.12 (t,
J ¼ 7.2 Hz, 2H, C-10H2), 6.68e6.89 (cluster, 3H, C-200H, C-400H, C-
600H), 7.14 (t, J ¼ 8.1 Hz, 1H, C-500H), 7.71 (d, J ¼ 8.5 Hz, 1H, C-9H),
8.08 (d, J ¼ 8.5 Hz, 1H, C-7H), 8.36 (s, 1H, C-2H), 8.57 (s, 1H, C-10H),
9.58 (s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.28, 152.25, 151.61,
150.55, 148.43, 147.99, 137.90, 134.92, 134.17, 130.05, 129.31, 123.49,
123.37, 119.30, 115.74, 113.89, 113.13, 57.91, 53.24, 48.80, 47.40,
27.66, 24.18, 22.07 ppm. 61 $ 2HCl $ 1.25H2O: Anal. (C26H28ClN5O $
2HCl $ 1.25H2O) C, H, N.
7.1.2.48. 3-{3-[4-(2-Methoxyphenyl)piperazin-1-yl]propyl}-9-meth-
ylpyrimido[5,4-c]-quinolin-4(ꢁ3H1 )-one
(57). Yield:
) n: 1686 (C]O), 1607e1501 (C]N,
63%,
m.p.
152.7e153.5 ꢀC; IR (KBr, cm
C]C); 1H NMR (CDCl3) dH: 2.10e2.19 (m, 2H, C-20H2), 2.53 (t,
J ¼ 6.5 Hz, 2H, C-30H2), 2.62 (s, 3H, CH3), 2.72e2.81 (m, 4H,
piperazine 2CH2), 3.06e3.11 (4H, piperazine 2CH2), 3.85 (s, 3H,
OCH3), 4.22 (t, J ¼ 6.5 Hz, 2H, C-10H2), 6.82e7.02 (cluster, 4H, C-
300H, C-400H, C-500H, C-600H), 7.70 (dd, J ¼ 8.5, 1.9 Hz, 1H, C-8H), 8.05
(d, J ¼ 8.5 Hz, 1H, C-7H), 8.50 (s, 1H, C-2H), 8.57 (s, 1H, C-10H), 9.57
(s, 1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.47, 152.19, 151.71,
151.38, 148.42, 147.93, 140.83, 137.82, 134.11, 129.29, 123.52, 123.43,
123.24, 121.02, 118.29, 113.12, 11.22, 55.53, 54.49, 53.25, 50.41,
7.1.2.53. 3-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-8-methyl-
pyrimido[5,4-c]quinoꢁli1n-4(3H)-one (62). Yield: 83%, m.p. 144.9e
45.67, 25.02, 22.04 ppm. 57 $ 2HCl $ 4H2O: Anal. (C26H29N5O2
2HCl $ 4H2O) C,H, N.
$
145.7 ꢀC; IR (KBr, cm
) n
: 1686 (C]O),1601e1498 (C]N, C]C); 1H
NMR (CDCl3) dH: 1.59e1.73 (m, 2H, C-20H2). 1.85e1.98 (m, 2H, C-
30H2), 2.51 (t, J ¼ 7.3 Hz, 2H, C-40H2), 2.63 (s, 3H, CH3), 2.65e2.68 (m,
4H, piperazine 2CH2), 3.04e3.17 (4H, piperazine 2CH2), 3.85 (s, 3H,
OCH3), 4.13 (t, J ¼ 7.3 Hz, 2H, C-10H2), 6.82e7.06 (cluster, 4H, C-300H,
C-400H, C-500H, C-600H), 7.56 (d, J ¼ 8.4 Hz, 1H, C-9H), 7.98 (s, 1H, C-
7H), 8.37 (s, 1H, C-2H), 8.70 (d, J ¼ 8.4 Hz, 1H, C-10H), 9.62 (s, 1H, C-
5H) ppm. 13C NMR (CDCl3) dC: 160.28, 152.20, 152.01, 150.74, 150.14,
149.05, 142.96, 141.12, 129.67, 128.87, 124.04, 123.04, 121.46, 121.00,
118.25, 112.59, 111.18, 58.01, 55.50, 53.60, 50.65, 47.38, 27.68, 24.06,
22.26 ppm. 62$ fumarate $ 2H2O: Anal. (C27H31N5O2 $ fumarate $
2H2O) C, H, N.
7.1.2.49. 3-{3-[4-(4-Fluorophenyl)piperazin-1-yl]propyl}-8-methyl-
pyrimido[5,4-c]quinolin-4(3Hꢁ)-1one
(58). Yield:
) n: 1680 (C]O), 1601e1509 (C]N,
54%,
m.p.
146.3e147.7 ꢀC; IR (KBr, cm
C]C); 1H NMR (CDCl3) dH: 2.01e2.08 (m, 2H, C-20H2), 2.42 (t,
J ¼ 6.4 Hz, 2H, C-30H2), 2.51e2.54 (cluster, 3H, CH3, 4H, piperazine
2CH2), 2.99e3.05 (4H, piperazine 2CH2), 4.11 (t, J ¼ 6.5 Hz, 2H, C-
10H2), 6.70e6.93 (cluster, 4H, C-200H, C-300H, C-500H, C-600H), 7.44 (dd,
J ¼ 8.5, 1.6 Hz, 1H, C-9H), 7.87 (s, 1H, C-7H), 8.37 (s, 1H, C-2H), 8.60
(d, J ¼ 8.5 Hz, 1H, C-10H), 9.523 (s, 1H, C-5H) ppm. 13C NMR (CDCl3)
dC: 160.45, 157.21 (158.79, 155.63 JCeF ¼ 238.5 Hz), 152.17, 151.49,
150.15, 148.99, 147.78, 142.95, 129.64, 128.87, 124.12, 121.49, 117.95
(118.00, 117.90 JCeF ¼ 7.7 Hz), 115.76 (115.83, 115.70 JCeF ¼ 22.0 Hz),
112.62, 54.47, 53.07, 50.29, 45.74, 25.23, 22.26 ppm. 58 $ 2HCl $
2H2O: Anal. (C25H26FN5O $ 2HCl $ 2H2O) C, H, N.
7.1.2.54. 3-{4-[4-(2-Methoxyphenyl)piperazin-1-yl]butyl}-9-methyl-
pyrimido[5,4-c]quinoꢁli1n-4(3H)-one (63). Yield: 84%, m.p. 159.2e
160.4 ꢀC; IR (KBr, cm
) n
: 1684 (C]O),1601e1499 (C]N, C]C); 1H
NMR (CDCl3) dH: 1.56e1.74 (m, 2H, C-20H2). 1.83e1.98 (m, 2H, C-
30H2), 2.48 (t, J ¼ 7.3 Hz, 2H, C-40H2), 2.57e2.73 (cluster, 4H,
piperazine 2CH2 þ 3H, CH3), 2.98e3.18 (4H, piperazine 2CH2), 3.85
(s, 3H, OCH3), 4.13 (t, J ¼ 7.3 Hz, 2H, C-10H2), 6.80e7.04 (cluster, 4H,
C-300H, C-400H, C-500H, C-600H), 7.71 (d, J ¼ 8.5 Hz, 1H, C-9H), 8.08 (d,
J ¼ 8.5 Hz, 1H, C-7H), 8.36 (s, 1H, C-2H), 8.58 (s, 1H, C-10H), 9.59 (s,
1H, C-5H) ppm. 13C NMR (CDCl3) dC: 160.24, 152.19, 151.58, 150.56,
7.1.2.50. 3-{3-[4-(4-Fluorophenyl)piperazin-1-yl]propyl}-9-methyl-
pyrimido[5,4-c]quinolin-4(3Hꢁ)-1one
(59). Yield:
) n: 1680 (C]O), 1601e1508 (C]N,
59%,
m.p.
153.5e154.6 ꢀC; IR (KBr, cm
C]C); 1H NMR (CDCl3) dH: 2.01e2.08 (m, 2H, C-20H2), 2.43 (t,
J ¼ 6.4 Hz, 2H, C-30H2), 2.52e2.56 (cluster, 3H, CH3, 4H, piperazine

3360
W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
148.39, 147.98, 141.21, 137.82, 134.10, 129.27, 123.46, 123.35, 122.95,
120.98, 118.19, 113.12, 111.14, 58.05, 55.49, 53.64, 50.79, 47.45, 27.68,
24.19, 22.04 ppm. 63 $ 2HCl $ 3H2O: Anal. (C27H31N5O2 $ 2HCl $
3H2O) C, H, N.
123.35, 117.78 (117.83, 117.73 JCeF ¼ 7.7 Hz), 115.51 (115.66, 115.37
JCeF ¼ 22.0 Hz), 113.11, 57.89, 53.41, 50.28, 47.38, 27.64, 24.18,
22.03 ppm. 67 $ HCl $ H2O: Anal. (C26H28FN5O $ HCl $ H2O) C, H, N.
7.2. In vitro radioligand binding assays
7.1.2.55. 3-{4-[4-(2-Fluorophenyl)piperazin-1-yl]butyl}-8-methyl-
pyrimido[5,4-c]quinolin-4(3H)-one (64). Yield: 66%, m.p. 174.6e
Radioligand studies with native 5-HT1A and 5-HT2A receptors
were conducted according to the methods previously described.
Briefly, the following were used: for 5-HT1A assays, rat hippocampal
membranes, [3H]-8-OH-DPAT (170 Ci/mmol, PerkineElmer), and
175.8 ꢀC; IR (KBr, cmꢁ1 : 1686 (C]O),1600e1501 (C]N, C]C); 1H
) n
NMR (CDCl3) dH: 1.55e1.74 (m, 2H, C-20H2). 1.85e2.00 (m, 2H, C-
30H2), 2.47 (t, J ¼ 7.3 Hz, 2H, C-40H2), 2.56e2.65 (cluster, 4H, piper-
azine 2CH2 þ 3H, CH3), 3.04e3.14 (4H, piperazine 2CH2), 4.12 (t,
J ¼ 7.3 Hz, 2H, C-10H2), 6.85e7.09 (cluster, 4H, C-300H, C-400H, C-500H,
C-600H), 7.54 (dd, J ¼ 8.4, 1.6 Hz, 1H, C-9H), 7.96 (s, 1H, C-7H), 8.37 (s,
1H, C-2H), 8.68 (d, J ¼ 8.4 Hz,1H, C-10H), 9.61 (s,1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.28, 155.69 (157.32, 154.07 JCeF ¼ 245.3 Hz),
152.01, 150.76, 150.15, 149.06, 142.97, 140.08 (140.14, 140.03
JCeF ¼ 8.3 Hz), 129.68, 128.89, 124.51 (124.53, 124.48 JCeF ¼ 3.7 Hz),
124.09, 122.49 (122.54, 122.44 JCeF ¼ 7.7 Hz), 121.47, 118.95 (118.97,
118.93 JCeF ¼ 2.9 Hz), 116.14 (116.28, 116.00 JCeF ¼ 20.6 Hz), 112.61,
57.99, 53.49, 50.71, 47.41, 27.69, 24.19, 22.28 ppm. 64 $ 2HCl $ H2O:
Anal. (C26H28FN5O $ 2HCl $ H2O) C, H, N.
5-HT (10 m
M) for non-specific binding; [3H]-ketanserin (88.0 Ci/
mmol, PerkineElmer) and methysergide (1
mM) for non-specific
binding.
For 5-HT7 binding assay, membranes from HEK-293 cells, stably
expressing human 5-HT7b receptor and [3H]-5-CT (93.0 Ci/mmol,
Hartmann) as radioligand were used [36].
In the screening procedure one compound concentrations at
1 mM was tested, whereas in full binding experiments 7e9 sample
concentrations, each run in triplicate, were used to determine
inhibition constant (Ki).
7.3. Molecular modeling
7.1.2.56. 3-{4-[4-(2-Fluorophenyl)piperazin-1-yl]butyl}-9-methyl-
pyrimido[5,4-c]quinolin-4(3H)-one (65). Yield: 64%, m.p. 160.7e
161.6 ꢀC; IR (KBr, cmꢁ1 : 1686 (C]O),1600e1500 (C]N, C]C); 1H
) n
For each of selected molecules conformational analysis and
docking were performed. Systematic Search module from Tripos
SYBYL 8.0 suite was used for generating geometries. Step of 120ꢀ
was set for each rotatable bond within spacer, VdW General ¼ 0.5
and VdW 1e4 ¼ 0.2.
NMR (CDCl3) dH: 1.58e1.71 (m, 2H, C-20H2). 1.87e1.97 (m, 2H, C-
30H2), 2.48 (t, J ¼ 7.3 Hz, 2H, C-40H2), 2.56e2.68 (cluster, 4H,
piperazine 2CH2 þ 3H, CH3), 3.04e3.14 (4H, piperazine 2CH2), 4.13
(t, J ¼ 7.3 Hz, 2H, C-10H2), 6.86e7.01 (cluster, 4H, C-300H, C-400H, C-
500H, C-600H), 7.71 (d, J ¼ 8.5 Hz, 1H, C-9H), 8.08 (d, J ¼ 8.5 Hz, 1H, C-
7H), 8.36 (s, 1H, C-2H), 8.58 (s, 1H, C-10H), 9.58 (s, 1H, C-5H) ppm.
13C NMR (CDCl3) dC: 160.26, 155.66 (157.29, 154.04 JCeF ¼ 245.3 Hz),
151.59, 150.57, 148.39, 147.98, 140.06 (140.12, 140.01 JCeF ¼ 8.6 Hz),
137.86, 134.13, 129.27, 124.49 (124.51, 124.47 JCeF ¼ 3.4 Hz), 123.48,
123.37, 122.48 (122.53, 122.43 JCeF ¼ 7.7 Hz), 118.93 (118.95, 118.91
JCeF ¼ 2.9 Hz), 116.12 (116.26, 115.98 JCeF ¼ 20.9 Hz), 113.13, 57.91,
53.47, 50.701, 47.43, 27.65, 24.17, 22.04 ppm. 65 $ 2HCl $ 2H2O: Anal.
(C26H28FN5O $ 2HCl $ 2H2O) C, H, N.
For each so created conformer geometry optimization in
vacuum and in solvent (COSMO algorithm) using OpenMopac 2007
was run [37,38]. For all calculations with OpenMopac PM6 Hamil-
tonian was used along with dielectric constant of 78 (keyword
EPS ¼ 78), number of geometric segments equal 60 (NSPA ¼ 60)
and Van der Waals radius of solvent 1 (RSOLV ¼ 1 keyword) for
COSMO computations.
Docking (using BioSolveIT FlexX 2.0.3) was set up with 100
5-HT1A receptor models with pharmacophore restraints on
Asp3.32 and Phe6.52 as shown previously [39,40]. Results were
scored using CScore module of SYBYL 8.0.
7.1.2.57. 3-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-8-methyl-
pyrimido[5,4-c]quinoꢁli1n-4(3H)-one (66). Yield: 71%, m.p. 199.6e
200.1 ꢀC; IR (KBr, cm
) n
: 1672 (C]O),1600e1506 (C]N, C]C); 1H
Authors’ contributions
NMR (CDCl3) dH: 1.55e1.70 (m, 2H, C-20H2). 1.85e1.97 (m, 2H, C-
30H2), 2.46 (t, J ¼ 7.3 Hz, 2H, C-40H2), 2.53e2.67 (m, 4H, piperazine
2CH2), 2.60 (s, 3H, CH3), 3.04e3.14 (4H, piperazine 2CH2), 4.12 (t,
J ¼ 7.2 Hz, 2H, C-10H2), 6.78e7.02 (cluster, 4H, C-200H, C-300H, C-500H,
C-600H), 7.54 (dd, J ¼ 8.5, 1.7 Hz, 1H, C-9H), 7.96 (s, 1H, C-7H), 8.35 (s,
1H, C-2H), 8.68 (d, J ¼ 8.4 Hz,1H, C-10H), 9.61 (s,1H, C-5H) ppm. 13C
NMR (CDCl3) dC: 160.28, 157.12 (158.70, 155.54 JCeF ¼ 238.2 Hz),
152.01,150.73, 150.16,149.05, 147. 94, 142.98, 129.69,128.89, 124.09,
121.46, 117.84 (117.87, 117.77 JCeF ¼ 7.4 Hz), 115.55 (115.69, 115.40
JCeF ¼ 22.0 Hz), 112.60, 57.93, 53.44, 50.31, 47.37, 27.69, 24.20,
22.28 ppm. 66 $ HCl $ H2O: Anal. (C26H28FN5O/HCl $ H2O) C, H, N.
WL participated in the design of the study, preparing the
manuscript, and carried out the synthesis of the compounds. WL
was involved in the interpretation of spectral, analytical data and
2D NMR analysis of obtained compounds. AB took the lead on
performing biological study, data interpretation and preparing the
manuscript. MS, AO and MG participated in the structural investi-
gations of selected compounds and writing the manuscript. SM
contributed to conformational analysis and docking of selected
molecules. AS acquired funding for the project and worked on the
design of the study. All authors read and approved the final
manuscript.
7.1.2.58. 3-{4-[4-(4-Fluorophenyl)piperazin-1-yl]butyl}-9-methyl-
pyrimido[5,4-c]quinoꢁli1n-4(3H)-one (67). Yield: 77%, m.p. 175.2e
Acknowledgements
175.8 ꢀC; IR (KBr, cm
) n
: 1686 (C]O), 1597e1508 (C]N, C]C); 1H
NMR (CDCl3) dH: 1.53e1.69 (m, 2H, C-20H2). 1.82e1.97 (m, 2H, C-
30H2), 2.45 (t, J ¼ 7.3 Hz, 2H, C-40H2), 2.53e2.65 (cluster, 4H, piper-
azine 2CH2 þ 3H, CH3), 3.02e3.14 (4H, piperazine 2CH2), 4.12
(t, J ¼ 7.3 Hz, 2H, C-10H2), 6.75e7.01 (cluster, 4H, C-300H, C-400H, C-
500H, C-600H), 7.71 (dd, J ¼ 8.5,1.7 Hz,1H, C-9H), 8.07 (d, J ¼ 8.5 Hz,1H,
C-7H), 8.35 (s, 1H, C-2H), 8.56 (s, 1H, C-10H), 9.58 (s, 1H, C-5H) ppm.
13C NMR (CDCl3) dC: 160.24, 157.08 (158.66, 155.50 JCeF ¼ 238.2 Hz),
151.57, 150.53, 148.40, 147.96, 147.92, 137.85, 134.12, 129.27, 123.46,
This study was supported by Grant No. N N 405 1656 33 from
Ministry of Science and Higher Education, Poland.
Appendix. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.ejmech.2011.04.060.

W. Lewgowd et al. / European Journal of Medicinal Chemistry 46 (2011) 3348e3361
3361
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