Synthesis and biological properties of 1,8-naphthalimidebutylamines. Serotonin 5-HT1A and 5-HT7 binding data and PASS-assisted search

Article abstract of DOI:10.1002/jhet.5570440423

(Chemical Equation Presented) Syntheses of the N-substituted butyl derivatives of 1,8-naphthalimide (1-8), containing various arylpiperazines, tetrahydroisoquinoline and methylhomopiperazine moieties attached at 4-position of the butyl chain have been described. Biological activities were evaluated in vitro for their ability to bind to serotonin 5-HT_1A and 5-HT ₇ receptors. Due to the structural similarity of derivatives 1-8 to psychotropic agents, the pharmacological properties of target compounds were predicted using PASS program.

Full text of DOI:10.1002/jhet.5570440423

Jul-Aug 2007
889
Synthesis and Biological Properties of 1,8-Naphthalimide-
butylamines. Serotonin 5-HT1A and 5-HT7 Binding Data
and PASS-Assisted Search
Piotr Kowalski*a, Teresa Kowalskaa, Andrzej J. Bojarskib, and Beata Duszyꢀskab
aCracow University of Technology, Institute of Organic Chemistry and Technology, 24 Warszawska Street, 31-
155 Kraków, Poland, e-mail: kowapi@usk.pk.edu.pl; bDepartment of Medicinal Chemistry, Institute of
Pharmacology of the Polish Academy of Sciences, 12 Smꢁtna Street, 31-343 Kraków, Poland
Received September 26, 2006
O
O
N
O
NH
O
NR2
N
NCH3
;
NAr
;
NR2
=
N
N
Syntheses of the N-substituted butyl derivatives of 1,8-naphthalimide (1–8), containing various
arylpiperazines, tetrahydroisoquinoline and methylhomopiperazine moieties attached at 4-position of the
butyl chain have been described. Biological activities were evaluated in vitro for their ability to bind to
serotonin 5-HT1A and 5-HT7 receptors. Due to the structural similarity of derivatives 1–8 to psychotropic
agents, the pharmacological properties of target compounds were predicted using PASS program.
J. Heterocyclic Chem., 44, 889 (2007).
tively, were also synthesized, and compound 8 with a cis-
2-butene spacer was obtained to explore the influence of
conformation of a butyl chain on both 5-HT1A and 5-HT7
receptor affinity. Additionally, potential biological
activity of the investigated compounds was predicted by
PASS (Prediction of Activity Spectra for Substances).
INTRODUCTION
Serotonin (5-hydroxytryptamine; 5-HT) is an important
neurotransmitter that mediates a variety of human
functions and plays a main role in many central nervous
system (CNS) disorders. Receptors activated by 5-HT are
currently categorized into seven distinct classes, several
of which are further subdivided into different subtypes [1-
5]. The 5-HT1A subtype belongs to the best studied ones,
and has been well documented to be a target for various
psychotropic drugs [6]. The last member of the serotonin
family, the 5-HT7 receptor, has recently generated interest
due to its links with depression, sleep disorders and
migraine [7,8].
O
N
N
BUSPIRONE
5-HT1A, Ki = 9-29 nM [21-25]
5-HT7, Ki = 381 nM [26]
N
O
N
N
O
N
Cl
Cl
H
ARIPIPRAZOL
Arylpiperazine derivatives are one of the most important
classes among serotonergic agents, where several drugs
(buspirone [9], ziprasidone [10], aripiprazol [11]) or comp-
ounds with a high therapeutic potential (e.g. adatanserin
[12], mazapertine [13], flesinoxan [14]) were identified.
Our own investigations with arylpiperazines were
mainly concerned with identification of their activity at 5-
HT1A binding sites; in consequence, many derivatives of
benzoxazinone, benzoxazolinone, quinazolinone, phthal-
azinedione, pyridazinedione, benzoxazolindione, etc, have
been found [15-20]. Since ligands of this type can also
bind at 5-HT7 receptors (Figure 1), in this paper we
present the synthesis of a new series of arylpiperazine
derivatives of 1,8-naphthalimide (1–5) and their affinities
for 5-HT1A and 5-HT7 receptor sites. Two other analogues
6 and 7 with isosteric amines, i.e. 1,2,3,4-tetrahydroiso-
quinoline (THIQ) and methylhomopiperazine, respec-
5-HT1A
,
= 5.6 nM [27]
Ki
O
N
N
5-HT ,
10.3 nM [27]
Ki =
7
CH3
O
N
O
O
NAN 190
5-HT1A, Ki = 0.6 nM [28]
5-HT7, Ki = 87 nM [20]
N
N
N
N
N
NCH3
Br
5-HT7, Ki = 85 nM [30]
5-HT7, Ki = 31 nM [29]
Figure 1. Selected long-chain arylpiperazine derivatives and their
binding data on 5-HT1A and 5-HT7 serotonin receptor [20-28], as well as
examples of THIQ and homopiperazine derivatives as 5-HT7 serotonin
receptor ligands [29,30].

890
P. Kowalski, T. Kowalska, A. J. Bojarski and B. Duszyꢀska
Vol 44
1
RESULTS AND DISCUSSION
The structure of bases 1–8 was confirmed by H NMR
spectra. For biological experiments, bases 1–8 were
converted into hydrochloride salts. The physicochemical
data of 1–8 are collected in Table 1.
Synthesis. The synthesis of compounds 1–7 was
conducted by a two-step procedure according to the
synthesis routes outlined in Scheme 1. The starting 1,8-
naphthalimide (9) was prepared from naphthalene-1,8-
dicarboxylic acid [31]. Alkylation of 9 with 1,4-
dibromobutane in the presence of K2CO3 in acetonitrile
led to the formation of bromo intermediate 10.
Condensation of 10 with 1-(2-pyrimidyl)piperazine (a), 1-
phenylpiperazine (b), 1-(2-methoxyphenyl)piperazine (c),
1-(3-chlorophenyl)piperazine (d), 1-(2,3-dichlorophenyl)-
piperazine (e), 1,2,3,4-tetrahydroisoquinoline (f), and 1-
methylhomopiperazine (g) afforded the target compounds
1–7, respectively. Due to the high toxicity of cis-1,4-
dichloro-2-butene, compound 8 was obtained from 9 in a
one-pot reaction (Scheme 1) according to the previously
published procedure [32].
Receptor Binding Assays. Radioligand studies with
native 5-HT1A and 5-HT7 receptors were conducted
according to the methods previously described by us
[33,34]. Briefly, in 5-HT1A assays rat hippocampal
membranes and [3H]-8-OH-DPAT (170 Ci/mmol, NEN
Chemicals) were used, whereas in 5-HT7 assays rat
hypothalamic membranes and [3H]-5-CT (102.0 Ci/mmol,
Amersham) were employed; in both experiments,
serotonin (10 μM) was used for a nonspecific binding.
In line with our earlier studies, the piperazine
derivatives 1–5 displayed high 5-HT1A receptor affinity
(Ki = 9.6–46 nM). The cis-2-butene derivative 8 was
about 13 times less active than its fully flexible analogue
4 (Ki = 160 and 12 nM, respectively). The replacement of
Scheme 1
O
O
N
O
O
Br
Br
HNR2 (a-g)
NH
O
Br
N
O
NR2
K2CO3 / CH3CN
10
1-7
9
Cl
Cl
NR2
N
N
K2CO3 / CH3CN
N
N
N
N
N
N
1;
3;
2
;
HNR2 (d)
Cl
N
O
N
4
;
N
Cl
N
O
N
H3CO
5;
7;
N
N
6
;
8
N
Cl
CH3
Cl
N
N
Table 1
Physical properties of 1,8-naphthalimidebutylamines 1–8 and their binding affinities to 5-HT1A and 5-HT7 receptors.
Base,
yield, %
Molecular formula of
hydrochloride
Hydrochloride m.p.,
°C
Ki (nM)
Compound
Base, m.p., °C Recryst. solvent
5-HT1A
5-HT7
1
2
3
4
5
6
7
8
79
86
70
88
87
67
56
52
172–175
138–139.5
133–135 [a]
159–161
165–167
114–117 [a]
oil
butan-1-ol
butan-1-ol
ethanol
butan-1-ol
butan-1-ol
methanol
–
C24H25N5O2·2HCl
C26H27N3O2·2HCl
C27H29N3O3·HCl
246–248
250–253
270–272 [c]
249–252
256–259
250–251 [d]
263–266
279–281
33
10
46 [e]
12
9.6
620 [f]
22 000
160
12 [g]
–
1470
168
45
4600
6430
130
11 000
1470
–
C26H26N3O2Cl·HCl
C26H25Cl2N3O3 HCl·H2O
C25H24N2O2·HCl
C22H27N3O2·2HCl·0.5H2O
C26H24N3O2Cl·HCl
138–140 [b]
butan-1-ol
buspirone
methiothepin
23 [h]
[a] ref. 19 oil. [b] ref. 32 m.p. 138–140 °C. [c] ref. 19 for C27H29N3O3·2HCl m.p. 280–281 °C. [d] ref. 19 for C25H24N2O2·HCl·0.5H2O m.p. 265–267
°C. [e] ref. 19, Ki (5-HT2A) = 86 nM. [f] ref. 19, Ki (5-HT2A) = 1230 nM. [g] ref. 21-25, Ki = 9–29 nM. [h] ref. 35, Ki = 45.7 nM.

Jul-Aug 2007
Synthesis and Biological Properties of 1,8-Naphthalimidebutylamines
891
an arylpiperazine pharmacophore with THIQ yielded
a compound of moderate affinity (6; Ki = 620 nM),
whereas the methylhomopiperazine derivative 7 was
practically inactive.
Regarding 5-HT7 receptors, only three relatively active
compounds were found (3, 6 and 2; Ki = 45 and 130 and
168 nM, respectively). The o-OMe-phenylpiperazine
derivative (3) displayed the highest 5-HT7 activity in the
series (similar to that at 5-HT1A sites), while
methylhomopiperazine was again inactive.[35]
of being psychotropic agents is shown by long-chain
arylpiperazines 1 and 5, since both of them are structural
analogues of the approved drugs buspirone [9] and
aripiprazole [41], respectively. The PASS program has
also shown compounds 6 and 7 to be active psychotropic
agents, despite the fact that they do not belong to the
group of arylpiperazines. Moreover, THIQ and the
homopiperazine derivatives of 1,8-naphthalimide, 6 and 7,
seem to have good chance – better than the remaining
compounds
– to be active in the treatment of
PASS Assisted Search for Biological Activity.
Computer software PASS simultaneously predicts several
hundred biological activities depending upon the chemical
structure of compounds [36-40]. This software classifies
the predicted activity spectrum of a compound as
probable activity (Pa) and probable inactivity (Pi). Based
on the analysis of structure-activity relationships of a
training set consisting of about 46000 drugs, drug
candidates and lead compounds, the PASS program
currently predicts 2468 pharmacological effects,
mechanisms of action, mutagenicity, carcinogenicity,
teratogenicity and embryotoxicity. The high value of Pa
(Pa>0.7) offers a good chance for a compound showing a
predicted activity in real experiments. On the other hand,
the low value of Pi is an indicator that a molecule is likely
to be inactive in the predicted type of biological activity.
The most probable biological activities (Pa) of
compounds 1–8, predicted by PASS, are collected in
Table 2. Predicted Pi values for all the activities shown in
Table 2 are below 8%.
psychosexual dysfunctions.
The PASS program also permits prediction of the
molecular mechanism of compounds indicating their
potential activity at a given receptor type. Table 3 shows
the molecular effect (Pa >0.5) of compounds 1–8 on 5-
HT1A receptors (5-HT7 subtype is not yet included in
PASS algorithm) and two other targets for which high Pa
values were obtained. As regards 5-HT1A receptors,
compounds 1–7 were predicted as active agents, and those
results, except for 7, were generally in line with our
experimental binding data. The highest agonistic activity
was assigned to pyrimidylpiperazine derivative 1 – a close
analogue of buspirone, whose anxiolytic effects are
mediated by activation of 5-HT1A sites. On the other hand,
the most significant antagonism at 5-HT1A receptors was
predicted for compound 3, which contains 2-methoxy-
phenylpiperazine moiety, a well known pharmacophoric
fragment responsible for the blockade of this binding site.
The PASS program also showed that potential
psychotropic effects of the investigated compounds may
come from the interaction with dopamine and sigma
receptors, which are, besides serotonin ones, important
targets for many CNS drugs [42-45].
The data shown in Table 2 indicate that all the
compounds studied exhibit high (Pa 81–89%) likelihood
of general psychotropic activity. The highest probability
Table 2
The activity (Pa) of compounds 1–8 evaluated by the PASS program.
Compound
Activity Type
1 [a]
2
3 [b]
4
5
6
7
8
Psychotropic
Antipsychotic
Anxiolytic
Antidepressant
Nootropic
0.880
0.781
0.823
0.624
0.660
–
0.870
0.785
0.743
0.634
0.551
0.519
0.596
0.822
0.716
0.726
0.653
0.533
–
0.854
0.751
0.744
0.614
–
0.896
0.845
0.745
0.721
0.680
0.570
0.509
0.839
0.719
0.628
0.656
0.703
0.596
0.770
0.845
0.718
0.660
0.644
0.686
–
0.791
0.675
0.687
0.528
–
Antiepileptic
Psychosexual dysfunction treatment
0.610
0.564
0.604
–
–
0.591
0.769
[a] vasodilator, peripheral 0.714. [b] vasodilator, renal 0.540
Table 3
The molecular effect (Pa) of compounds 1–8 evaluated by the PASS program.
Compound
Effect Type
1
2
3
4
5
6
7
8
5-Hydroxytryptamine 1A agonist
5-Hydroxytryptamine 1A antagonist
Dopamine antagonist
0.893
–
0.620
–
0.648
0.535
0.658
0.739
0.640
0.672
0.560
0.708
0.530
–
0.661
0.679
0.580
–
0.779
0.632
0.564
–
0.587
0.598
0.530
–
–
–
–
0.591
0.750
Sigma receptor agonist
0.599

892
P. Kowalski, T. Kowalska, A. J. Bojarski and B. Duszyꢀska
Vol 44
their molecular formulae were established on the basis of
elemental analysis.
N-{4-[4-(pyrimidin-2-yl)piperazin-1-yl]butyl}-1,8-naph-
Acknowledgement. The authors wish to thank the Research
Group from the Institute of Biomedicinal Chemistry of the
Russian Academy of Medicinal Sciences (www.ibmc.msk.ru/
PASS/) for access to the PASS computer program applied to the
research presented in this paper.
1
thalimide (1). Base; H nmr: ꢀ 1.67-1.86 (m, 4H, -CH2CH2-),
2.45 (t, 2H, CH2-N-pip), 2.43-2.60 (m, 4H, 2CH2-pip), 3.70-3.91
(m, 4H, 2CH2-pip), 4.23 (t, 2H, CH2-N-imide), 6.47 (t, 1H, H5-
pyr), 7.74 (t, 2H, H3,6-imide), 8.22 (d, 2H, H4,5-imide), 8.30 (d,
2H, H4,6-pyr), 8.60 ppm (d, 2H, H2,7-imide). Anal. Calcd. for
C24H25N5O2·2HCl (488.41): C, 59.02; H, 5.57; N, 14.34. Found:
C, 59.21; H, 5.67; N, 14.15.
EXPERIMENTAL
Melting points were determined on a Böetius melting point
apparatus and are uncorrected. Elemental analyses were
performed on a Perkin-Elmer 2400 analyzer located in the
Regional Laboratory of Jagiellonian University, and the results
are within ±0.4% of the calculated values. 1H NMR spectra were
taken on a Tesla 487C (80MHz) spectrometer in CDCl3 solution,
using TMS as an internal standard; the chemical shifts are given
in ppm (ꢀ); and, the coupling constants are taken from the
expanded spectra. Mass spectra (EI) were recorded with
a Varian – MAT 112 spectrometer at 70 eV. The reactions and
the product purification were monitored by TLC on silica-gel
plates (Merck 60F254) using chloroform/methanol (95:5) mixture
as eluent. For column chromatography, silica gel (Merck) was
used. Starting materials, solvents, and reagents were purchased
from commercial sources (Sigma-Aldrich and Merck) and were
used without further purification, except for DMF, which was
purified by distillation shortly before use.
N-[4-(4-phenylpiperazin-1-yl)butyl]-1,8-naphthalimide (2).
Base; 1H nmr: ꢀ 1.67-1.84 (m, 4H, -CH2CH2-), 2.48 (t, 2H, CH2-
N-pip), 2.53-2.68 (m, 4H, 2CH2-pip), 3.13-3.27 (m, 4H, 2CH2-
pip), 4.23 (t, 2H, CH2-N-imide), 6.75-7.36 (m, 5H, ArH), 7.74 (t,
2H, H3,6-imide), 8.20 (d, 2H, H4,5-imide), 8.59 ppm (d, 2H, H2,7
-
imide). Anal. Calcd. for C26H27N3O2·2HCl (486.43): C, 64.20; H,
6.01; N, 8.64. Found: C, 64.42; H, 6.06; N, 8.59.
N-{4-[4-(2-methoxyphenyl)piperazin-1-yl]butyl}-1,8-naph-
1
thalimide (3). Base; H nmr: ꢀ 1.65-1.82 (m, 4H, -CH2CH2-),
2.44 (t, 2H, CH2-N-pip), 2.60-2.71 (m, 4H, 2CH2-pip), 3.03-3.12
(m, 4H, 2CH2-pip), 3.85 (s, 3H, OCH3), 4.24 (t, 2H, CH2-N-
imide), 6.86-7.04 (m, 4H, ArH), 7.75 (t, 2H, H3,6-imide), 8.21 (d,
2H, H4,5-imide), 8.59 ppm (d, 2H, H2,7-imide). Anal. Calcd. for
C27H29N3O3·HCl (480.00): C, 67.56; H, 6.30; N, 8.75. Found: C,
67.29; H, 6.32; N, 8.68.
N-{4-[4-(3-chlorophenyl)piperazin-1-yl]butyl}-1,8-naph-
1
thalimide (4). Base; H nmr: ꢀ 1.60-1.83 (m, 4H, -CH2CH2-),
Synthesis of N-(4-bromobutyl)-1,8-naphthalimide (10).
A mixture of 9.86 g (0.05 mol) of 1,8-naphthalimide (9), 15.11 g
(0.07 mol) of 1,4-dibromobutane, 10.35 g (0.075 mol) of
anhydrous potassium carbonate, and a few crystals (~0.01 g) of
potassium iodide in 80 mL of acetonitrile was stirred and
refluxed for 40 hours. After cooling down inorganic precipitate
was filtered off, and excess 1,4-dibromobutane was evaporated.
The semisolid raw material was recrystallized from acetone to
yield 7.5 g (45%) of N-(4-bromobutyl)-1,8-naphthalimide (10)
2.45 (t, 2H, CH2-N-pip), 2.52-2.64 (m, 4H, 2CH2-pip), 3.12-3.25
(m, 4H, 2CH2-pip), 4.23 (t, 2H, CH2-N-imide), 6.73-7.15 (m,
4H, ArH), 7.76 (t, 2H, H3,6-imide), 8.21 (d, 2H, H4,5-imide), 8.60
ppm (d, 2H, H2,7-imide). Anal. Calcd. for C26H26ClN3O2·HCl
(484.42): C, 64.47; H, 5.62; N, 8.67. Found: C, 64.21; H, 5.92;
N, 8.68.
N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}-1,8-naph-
1
thalimide (5). Base; H nmr: ꢀ 1.76-1.89 (m, 4H, -CH2CH2-),
2.54 (t, 2H, CH2-N-pip), 2.63-2.76 (m, 4H, 2CH2-pip), 3.01-
3.3.17 (m, 4H, 2CH2-pip), 4.24 (t, 2H, CH2-N-imide), 6.90-7.18
(m, 3H, ArH), 7.76 (t, 2H, H3,6-imide), 8.22 (d, 2H, H4,5-imide),
o
1
with m.p. 117–119 C, H nmr: ꢀ 1.91-2.01 (m, 4H, -CH2CH2-),
3.48 (t, 2H, CH2-Br, J = 6.3 Hz), 4.22 (t, 2H, CH2-N-imide, J =
6.9 Hz), 7.73 (t, 2H, H3,6-imide, J = 8.3 Hz), 8.20 (d, 2H, H4,5
-
8.60 ppm (d, 2H,
H2,7-imide). Anal. Calcd. for
imide, J = 8.3 Hz), 8.59 ppm (d, 2H, H2,7-imide, J = 7.3 Hz); ms:
m/z (%) 331 (M, 52), 333 (M+2, 51).
Anal. Calcd. for C16H14BrNO2 (332.19): C, 57.85; H, 4.25; N,
4.22. Found: C, 57.98; H, 4.20; N, 4.34.
C26H25Cl2N3O3·HCl·H2O (536.88): C, 58.17; H, 5.26; N, 7.83.
Found: C, 58.36; H, 5.17; N, 7.99.
N-{4-[3,4-dihydroisoquinolin-2(1H)-yl]butyl}-1,8-naph-
1
thalimide (6). Base; H nmr: ꢀ 1.70-1.85 (m, 4H, -CH2CH2-),
General procedure for the synthesis of 1,8-naphthal-
imidebutylamines (1–7). A mixture of 10 mmol of 10, 10 mmol
of the respective amine a–g, 20 mmol of anhydrous potassium
carbonate (when the hydrochoride salt of amine was used
equivalent of potassium carbonate was added additionally), and
a few crystals (~0.01 g) of potassium iodide in 50 mL of
dimethylformamide was stirred with magnetic stirrer at 60–70
oC for 40 hours. Next, the reaction mixture was poured into 100–
150 mL of water, and the precipitate was either colleted by
filtration or extracted with chloroform. The crude products 1–6
were purified by crystallization. The compound 7 was purified
by column chromatography, using chloroform:methanol (95:5)
as eluent.
Compound 8 was obtained from 9 in a one-pot reaction
according to the previously published procedure [32].
The yields and physical properties of 1–8 are collected in the
Table 1.
For biological experiments, free bases 1–8 were converted
into hydrochloride salts with ethanol saturated with HCl, and
2.58 (t, 2H, CH2-N-THIQ), 2.67-2.90 (m, 4H, 2CH2-THIQ),
3.63 (s, 2H, CH2-THIQ), 4.24 (t, 2H, CH2-N-imide), 7.01-7.13
(m, 4H, ArH), 7.72 (t, 2H, H3,6-imide), 8.18 (d, 2H, H4,5-imide),
8.57 ppm (d, 2H, H2,7-imide). Anal. Calcd. for C25H24N2O2·HCl
(420.93): C, 71.33; H, 5.99; N, 6.65. Found: C, 70.99; H, 6.01;
N, 6.57.
N-[4-(4-methyl-1,4-diazepan-1-yl)butyl]-1,8-naphthalimide (7).
1
Base; H nmr: ꢀ 1.58-1.86 (m, 6H, 3CH2), 2.34 (s, 3H, CH3),
2.45-2.79 (m, 10H, 5CH2), 4.18 (t, 2H, CH2-N-imide), 7.70 (t,
2H, H3,6-imide), 8.16 (d, 2H, H4,5-imide), 8.52 ppm (d, 2H, H2,7
-
imide). Anal. Calcd. for C22H27N3O2·2HCl·0.5H2O (447.40): C,
59.06; H, 6.76; N, 9.39. Found: C, 58.84; H, 6.59; N, 9.25.
N-{(2Z)-4-[4-(3-chlorophenyl)piperazin-1-yl]but-2-enyl}-
1,8-naphthalimide (8). Base; 1H nmr: ꢀ 2.64-2.76 (m, 4H,
2CH2-pip), 3.17-3.30 (m, 4H, 2CH2-pip), 3.39 (d, 2H, CH2-N-
pip), 4.87 (d, 2H, CH2-N-imide), 5.68-5.79 (m, 2H, CH=CH),
6.74-7.26 (m, 4H, ArH), 7.74 (t, 2H, H3,6-imide), 8.22 (d, 2H,
H4,5-imide), 8.61 ppm (d, 2H, H2,7-imide).

Jul-Aug 2007
Synthesis and Biological Properties of 1,8-Naphthalimidebutylamines
893
[20] Bojarski, A. J.; Duszyꢀska, B.; Koꢁaczkowski, M.; Kowalski,
P.; Kowalska, T. Bioorg. Med. Chem. Lett. 2004, 14, 5863.
[21] Zifa, E.; Fillion, G. Pharmacol. Rev. 1992, 44, 401.
[22] McCall, R. B.; Clement, M. E. Pharmacol. Rev. 1994, 46,
231.
Anal. Calcd. for C26H24ClN3O2·HCl (482.41): C, 64.73; H,
5.22; N, 8.71. Found: C, 64.79; H, 5.33; N, 8.48.
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