Synthesis and anticonvulsant properties of new acetamide derivatives of phthalimide, and its saturated cyclohexane and norbornene analogs

Article abstract of DOI:10.1016/j.ejmech.2011.07.043

The synthesis and anticonvulsant properties of new piperazine or morpholine acetamides derived from 2-(1,3-dioxoisoindolin-2-yl)-, 2-(1,3-dioxo-3a,4,5,6,7, 7a-hexahydroisoindol-2-yl-) and (3,5-dioxo-4-azatricyclo[5.2.1.0 ^2,6]dec-8-en-4-yl)-acetic acid were described. Initial anticonvulsant screening was performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures tests. The neurotoxicity was determined applying the minimal motor impairment rotarod test. The in vivo results revealed that numerous compounds were effective in the MES screen. The most active was 2-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}isoindoline-1,3-dione (12) that revealed protection in the electrically induced seizures at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p. administration in mice respectively. This molecule given orally in rats at a dose of 30 mg/kg was more potent than reference anticonvulsant - phenytoin.

Full text of DOI:10.1016/j.ejmech.2011.07.043

European Journal of Medicinal Chemistry 46 (2011) 4634e4641
Contents lists available at ScienceDirect
European Journal of Medicinal Chemistry
journal homepage: http://www.elsevier.com/locate/ejmech
Original article
Synthesis and anticonvulsant properties of new acetamide derivatives
of phthalimide, and its saturated cyclohexane and norbornene analogs
a
,
a
a
b
*
ꢀ
Krzysztof Kaminski , Jolanta Obniska , Beata Wiklik , Dmytro Atamanyuk
a Department of Medicinal Chemistry, Jagiellonian University, Medical College, 9 Medyczna Street, Kraków 30-688, Poland
b Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University, 69 Pekarska Street, Lviv 79-010, Ukraine
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis and anticonvulsant properties of new piperazine or morpholine acetamides derived from
2-(1,3-dioxoisoindolin-2-yl)-, 2-(1,3-dioxo-3a,4,5,6,7,7a-hexahydroisoindol-2-yl-) and (3,5-dioxo-4-
azatricyclo[5.2.1.02,6]dec-8-en-4-yl)-acetic acid were described. Initial anticonvulsant screening was
performed using maximal electroshock (MES) and subcutaneous pentylenetetrazole (scPTZ) seizures
tests. The neurotoxicity was determined applying the minimal motor impairment rotarod test. The
in vivo results revealed that numerous compounds were effective in the MES screen. The most active was
2-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}isoindoline-1,3-dione (12) that revealed protection
in the electrically induced seizures at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p.
administration in mice respectively. This molecule given orally in rats at a dose of 30 mg/kg was more
potent than reference anticonvulsant e phenytoin.
Received 5 January 2011
Received in revised form
20 May 2011
Accepted 23 July 2011
Available online 29 July 2011
Keywords:
Anticonvulsant activity
Phthalimide (isoindoline-1,3-dione)
Hexahydro-1H-isoindole-1,3(2H)-dione
4-Azatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione
In vivo studies
Ó 2011 Elsevier Masson SAS. All rights reserved.
1. Introduction
difficult to use rational methodologies of discovery. Therefore an
alternative design of new anticonvulsants is based on the different
Epilepsy, a common neurological disorder characterized by
recurrent spontaneous seizures arising from excessive electrical
activity in some portion of the brain, is a major, worldwide, public
health problem, which affects approximately 1% of the population
[1]. Despite the success of several new antiepileptic drugs, about
one third of patients with epilepsy are not seizure free on medi-
cation [2]. Therefore the ideal antiepileptic should prevent different
types of seizures without producing side effects that affect
adversely patients’ quality of life. Taking into consideration above
findings the continued search for safer, more effective and possibly
antiepileptogenic AEDs is urgently necessary. The currently used
AEDs can be classified into four categories on the basis of the main
molecular mechanisms of action, as follow: (i) modulation of
voltage-dependent Naþ and/or Ca2þ channels, (ii) enhancement of
GABA-mediated inhibition or other effect on the GABA system, (iii)
inhibition of synaptic excitation mediated by ionotropic glutamate
receptors and (iv) modulation of synaptic release [3]. The incom-
plete information on the cellular mechanism of human epilepsy
and the complex mechanism of action of majority AEDs makes it
pharmacophores that were established through the analysis of
structural characteristics of clinically effective drugs as well as
other anticonvulsant active compounds [4e11]. It is well docu-
mented that one of the important core fragments is defined by
nitrogen heteroatomic system, usually a cyclic imide, at least of one
carbonyl group and phenyl or alkyl groups attached to the
heterocyclic system [12e14]. This common template is found in the
structures of first generation, however well-established anticon-
vulsants such as ethosuximide or phenytoin, among the newest
drugs e.g. levetiracetam or compounds being currently under
clinical trials e brivaracetam and seletracetam (Fig. 1) [15e18].
Previous research in our group has identified pyrrolidine-2,5-
diones differently substituted at position-1 and -3 as targets for
new antiepileptic drugs. Many of these compounds were effective
in the maximal electroshock (MES) or/and subcutaneous pentyle-
netetrazole (scPTZ) screens [19e22]. The structureeactivity rela-
tionships studies performed in these series of derivatives have
demonstrated the potent anticonvulsant activity among the 3-
phenyl-pyrrolidine-2,5-diones containing at the imide nitrogen
atom differently substituted arylpiperazines as amine function.
Several molecules showed great protection, especially in electri-
cally induced seizures (1, Fig. 1). Furthermore, using the phthali-
mide template, Vamecq and co-workers demonstrated through
* Corresponding author. Tel.: þ48 12 620 54 59; fax: þ48 12 657 02 62.
ꢀ
E-mail address: kaminskik@cm-uj.krakow.pl (K. Kaminski).
0223-5234/$ e see front matter Ó 2011 Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.ejmech.2011.07.043

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K. Kaminski et al. / European Journal of Medicinal Chemistry 46 (2011) 4634e4641
4635
by both spectral and elemental analyses. The detailed physico-
chemical and analytical data are listed in the experimental section.
H
N
O
2.2. Anticonvulsant activity
O
N
H
O
N
H
O
The initial anticonvulsant evaluation was performed within the
Antiepileptic Drug Development (ADD) Program in Epilepsy
Branch, National Institutes of Health, National Institute of Neuro-
logical Disorders and Stroke (NIH/NINDS), Rockville, MD, USA. The
preclinical discovery and development of new chemical agents for
the treatment of epilepsy are based mainly on the use of predictable
animal models. Such models fall into two main categories, namely
models of acute seizures (non-epileptic animals induced to have
a seizure by an electrical or chemical stimulus) and models of
chronic epilepsy (animals induced to have enhanced seizure
susceptibility or spontaneous seizures). At the present time there
are three in vivo screens used routinely that include the maximal
electroshock seizure (MES), the subcutaneous pentylenetetrazole
(scPTZ) and the kindling model. From these tests the MES and scPTZ
screens are recognized as the “gold standards” in the early stages of
testing. Furthermore, the maximal electroshock (MES) and subcu-
taneous pentylenetetrazole (scPTZ) tests are claimed to detect
compounds affording protection against human generalized ton-
iceclonic seizures and generalized absence seizures, respectively
[26,27].
Phenytoin
Ethosuximide
F
F
O
O
O
N
N
N
NH2
NH2
NH2
O
H
H
H
O
O
Levetiracetam
Brivaracetam
Seletracetam
O
N
O
O
N
Cl
O
CF3
N
N
The profile of anticonvulsant activity of all the compounds was
established in the maximal electroshock (MES) and subcutaneous
pentylenetetrazole (scPTZ) tests, after intraperitoneal injection in
mice at doses of 30, 100 and 300 mg/kg. An observation was
carried out at two different time intervals, namely 0.5 h and 4 h.
The acute neurological toxicity (NT) was determined in the
minimal motor impairment rotorod screen. The results are shown
in Table 1.
NH2
1
2
ED50 = 9.0 mg/kg
(MES test, rats, oral administration)
ED50 = 5.7 mg/kg
(MES test, rats, oral administration)
Fig. 1. Structures of known anticonvulsants and model compounds 1 and 2.
a series of successive works the significant anticonvulsant potential
for differently N-substituted derivatives [23e25]. Several of N-
phenylphthalimides were shown to possess a phenytoin-like
profile and strong activity in the MES test (2, Fig. 1). Following
these findings, as part of our efforts to design new anticonvulsant
agents in the present studies we have synthesized a library of
compounds with the isoindoline-1,3-dione (phthalimide) system as
a core fragment (6e16). Based on results obtained previously at the
imide nitrogen atom we have introduced as an amide function
chosen piperazines or morpholine that emerged as especially
important for anticonvulsant activity. To confirm the pharmaco-
phoric role of phthalimide several saturated (17e25) and norbor-
nene analogs (26e30) have been obtained.
The in vivo studies showed activity mainly in the maximal
electroshock test. Compounds that revealed protection in the
MES test, indicative the ability of substance to prevent seizure
spread, at a dose of 100 mg/kg included 6, 7, 9, 10, 12, 13, 16, 21, 22
and 29. The other derivatives provided anti-MES protection at
a dose of 300 mg/kg (11, 17, 19). In this series only three molecules
11, 12 and 25 inhibited seizures in the scPTZ screen which iden-
tifies substances elevating seizure threshold. The majority of
these compounds showed activity at 0.5 h or/and additionally at
4 h (9, 10, 12, 13, 16, 19, 21, 29), indicating that they have rapid
onset of anticonvulsant action. The most active compound 12
showed anti-MES activity at dose of 30 mg/kg at time point 0.5 h
that was equivalent to phenytoin or carbamazepine used as
model antiepileptic drugs effective in the electrically induced
seizures. Additionally this molecule was found to be active at
dose of 300 mg/kg in the scPTZ test. It was comparable to results
obtained for ethosuximide which is recognized as reference
anticonvulsant for this screen. Thus as shown in Table 1 the
profile of anticonvulsant activity of 12 can be compared with
carbamazepine that indicates potential usefulness of this
compound in treating not only generalized toniceclonic epilepsy
but also absence seizures. In the rotorod screen (neurotoxicity),
12 that caused motor impairment at the dose of 300 mg/kg at
0.5 h and also 4 h was safer than phenytoin or carbamazepine
however more neurotoxic than ethosuximide. The other mole-
cules were neurotoxic at a dose of 30 mg/kg (20) or 300 mg/kg
(16, 23, 25 and 29). Compounds 6e11, 13e15, 17e19, 21, 22, 24,
26e28 and 30 did not show neurotoxicity at the maximum dose
administered (300 mg/kg). Among these molecules 8, 14, 15, 18,
24, 26e28 and 30 were inactive additionally. Compounds 6, 7,
9e11, 13, 17, 19, 21 and 22 emerged as anticonvulsants without
neurotoxic properties.
2. Results and discussion
2.1. Chemistry
The synthetic routes of intermediates 3e5 and final compounds
6e30 were outlined in Scheme 1. First, the condensation reaction of
commercially purchased 2-benzofuran-1,3-dione, 3a,4,5,6,7,7a-
hexahydroisobenzofuran-1,3-dione or 4-oxatricyclo[5.2.1.02,6]dec-
8-ene-3,5-dione with 2-aminoacetic acid yielded in corresponding
2-(1,3-dioxoisoindolin-2-yl)acetic
acid
(3),
2-(1,3-dioxo-
3a,4,5,6,7,7a-hexahydroisoindol-2-yl)acetic acid (4) or (3,5-dioxo-
4-azatricyclo [5.2.1.02,6]dec-8-en-4-yl)acetic acid (5). In the next
step intermediates 3e5 were converted to final compounds (6e30)
in reaction with appropriate secondary amines. The crude products
were crystallized from suitable solvent giving desired compounds
in good yields. The purities of all molecules were assessed by TLC
and gradient HPLC chromatography. The structures were confirmed

ꢀ
4636
K. Kaminski et al. / European Journal of Medicinal Chemistry 46 (2011) 4634e4641
Scheme 1. Synthetic protocols of intermediates 3e5 and target compounds 6e30.
A valuable property of a candidate anticonvulsant is its ability to
2.3. Structureeactivity relationships (SAR) analysis
inhibit convulsions when given by the oral route. This screen
discloses the time of onset, the approximate time of peak effect
(TPE) and the duration of anticonvulsant activity or neurotoxicity.
Therefore on the basis of data obtained in i.p. screens in mice and
according to Anticonvulsant Screening Project (ASP) disposition
compound 9, 12 and 21 were selected and examined for their
anticonvulsant activity in the MES screen as well as neurotoxicity
after p.o. administration in rats at a dose of 30 mg/kg. The results
obtained are presented in Table 2.
As can be seen from these data, the most active was 12 which
protected 100% (4/4) of rats at time points 2 h and 4 h, 50% (2/4) at
0.5 h and 1 h, 25% (1/4) at 0.25 h. This molecule was more active
and showed longer duration of satisfactory action than phenytoin.
The other compounds 9 and 21 were moderately effective in rat
MES oral screen and protected only 50% (2/4) of tested animals at
the time point 0.5 h (21) or 4 h (9) and 25% (1/4) at 1 h (21). All
derivatives tested were non-neurotoxic when given orally. The
in vivo data in rats confirmed absorption of compounds from
gastrointestinal tract and also their penetration to central nervous
system. The inhibition of electrically induced seizures that is
characteristic for phenytoin and phenytoin-like drugs may indicate
the influence of compounds on voltage-depended Naþ channels as
the most plausible mechanism of anticonvulsant action.
The results of the preliminary anticonvulsant screening of
compounds 6e30 revealed that the most active were the phthali-
mide derivatives (6e16). The change of the benzene ring of
phthalimide into cyclohexane (17e25) or norbornene (26e30)
moieties decreased anticonvulsant activity significantly that
confirmed the pharmacophoric role of the phthalimide system for
bioactivity. The anticonvulsant properties depended also on the
kind of the substituents at the amide function. Regardless of the
structure of imide fragment all the 4-benzylpiperazin-1-yl (14, 23,
30) and 4-(2-hydroxyethyl)-piperazin-1-yl- (15, 24) derivatives
were inactive. Taking into consideration the influence of the
substituents at the 4-phenylpiperazine it seems that the most
favorable is the presence of the highly electronegative chloro- or
fluoro- atoms at para-position (9, 12, 19, 21, 29). In general the
respective ortho-(7, 11, 28) or meta-(8, 18, 27) derivatives as well as
unsubstituted molecules (6, 17, 26) were less active or inactive.
Furthermore, introduction of the trifluoromethyl group that is well
known as one of the bioactive structural elements [28] at the meta-
position increased anticonvulsant activity especially in the series of
3a,4,5,6,7,7a-hexahydroisoindole-1,3-diones (22). It was in agree-
ment with our previous studies in which we have demonstrated
that presence of trifluoromethyl substituent was important for

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K. Kaminski et al. / European Journal of Medicinal Chemistry 46 (2011) 4634e4641
4637
Table 1
The results after i.p. administration in mice (6e30).
Cmpd
A
R
Intraperitoneal administration in micea
MESb
scPTZc
NTd
0.5 h
4 h
0.5 h
4 h
0.5 h
4 h
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
Benzene
H
100
100
e
e
e
e
e
e
2-Cl
3-Cl
4-Cl
2,3-Cl
2-F
e
e
e
e
e
e
e
e
e
e
100
e
100
100
e
e
e
e
e
e
e
e
e
300
30
e
300
300
e
e
e
e
4-F
100
100
e
300
e
300
e
300
e
3-CF3
H (n ¼ 1)
e
Benzene
Benzene
Benzene
e
e
e
e
e
e
e
e
e
e
e
e
100
300
e
100
e
e
e
30014
e
30014
e
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Cyclohexane
Norbornene
Norbornene
Norbornene
Norbornene
Norbornene
H
e
e
3-Cl
4-Cl
2,3-Cl
4-F
3-CF3
H (n ¼ 1)
e
e
e
e
e
e
e
300
e
e
e
e
e
20
e
e
e
3033
e
e
21g
300
100
e
300
e
e
e
e
22
23
24
25
26
27
28
29
e
e
e
e
e
e
e
300
e
e
e
e
e
e
e
e
e
e
e
300
e
300
e
e
H
3-Cl
2-F
4-F
H (n ¼ 1)
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
100
e
100
e
e
e
300
e
30014
e
30
e
e
Carbamazepinee
Phenytoine
Ethosuximidef
30
30
e
100
30
e
100
e
300
e
100
100
e
300
100
e
100
300
Response comments: 14unable to grasp rotarod, 33tremors.
a
Doses of 30, 100, and 300 mg/kg were administered. The data indicate the minimum dose whereby bioactivity was demonstrated. The animals were examined at 0.5 and
4.0 h. A dash indicates the absence of anticonvulsant activity and neurotoxicity at the maximum dose administered (300 mg/kg).
b
Maximal electroshock test.
Subcutaneous pentylenetetrazole test.
Neurotoxicity screening using rotorod test.
Reference drugs, data for carbamazepine and phenytoin Ref. [7].
Reference drug, data for ethosuximide Ref. [11].
Anti-MES activity at a dose of 100 mg/kg at 0.25 h.
c
d
e
f
g
Table 2
fluorophenyl)- piperazin-1-yl]-2-oxoethyl}isoindoline-1,3-dione
(12) that revealed protection in the electrically induced seizures
at a dose of 30 mg/kg and 100 mg/kg 0.5 h and 4 h after i.p.
administration respectively. This molecule provided also protection
in the pentylenetetrazole seizures (scPTZ) at a dose of 300 mg/kg in
both time intervals. Compound 12 given orally to rats at a dose of
30 mg/kg was more potent than phenytoin as reference
anticonvulsant.
Anticonvulsant activity of selected compounds administrated orally in rats (MES
screen).
Cmpd
Oral administration in ratsa
0.25 h
0.5 h
1 h
2 h
4 h
9
12
21
0/4
1/4
0/4
1/4
0/4
2/4
2/4
4/4
0/4
2/4
1/4
3/4
0/4
4/4
0/4
3/4
2/4
4/4
0/4
3/4
Phenytoinb
a
MES screen, dose of 30 mg/kg was administrated. The data indicate: number of
rats protected/number of rats tested.
4. Experimental protocols
b
Reference drug, data for phenytoin Ref. [11].
4.1. Chemistry
4.1.1. General remarks
anticonvulsant properties in different series of pyrrolidine-2,5-
diones [29].
All the chemicals and solvents were purchased from Merck
(Darmstadt, Germany) and were used without further purifica-
tion. Melting points (mp.) were determined in open capillaries on
Büchi 353 melting point apparatus (Büchi Labortechnik, Flawil,
Switzerland) and are uncorrected. The purity and homogeneity of
the compounds were assessed by TLC and gradient HPLC chro-
matography. The thin-layer chromatography (TLC) was performed
on Merck silica gel 60 F254 aluminum sheets (Merck; Darmstadt,
Germany), using developing system consisted of: S1 e dichlor-
omethane:methanol (9:1; v/v), S2 e n-butanol:acetic acid:water
(5:4:1; v/v/v). Spots were detected by their absorption under UV
3. Conclusion
The results obtained revealed that number of new piperazine or
morpholine acetamides derived from 2-(1,3-dioxoisoindolin-2-yl)-,
2-(1,3-dioxo-3a,4,5,6,7,7a-hexahydroisoindol-2-yl)-
and
acid
(3,5-
were
dioxo-4-azatricyclo[5.2.1.02,6]dec-8-en-4-yl)-acetic
effective in the MES or/and scPTZ screens recognized as the most
widely employed seizure models for early identification of candi-
date anticonvulsants. The most active was 2-{2-[4-(4-
light (
l
¼ 254 nm). HPLC analyses were run on an HPLC WatersÒ

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K. Kaminski et al. / European Journal of Medicinal Chemistry 46 (2011) 4634e4641
4638
2695 Separation Module equipped with photodiode array
detector (WatersÒ 2998). A Chromolith RP-18 SpeedROD column
(4.6 ꢀ 50 mm) was used. Conditions applied were as follow:
eluent A (water/0.1% TFA), eluent B (acetonitrile/0.1% TFA); flow
rate of 5 ml/min, gradient of 0e100% B over 3 min were used,
4.1.3. General procedure for the synthesis of compounds 6e30
The corresponding intermediates 3, 4 or 5 (0.01 mol) were
dissolved in 20 ml of dry DMF and N,N-carbonyldiimidazole
(0.01 mol) was added. The mixture was stirred for 0.5 h at a room
temperature. Afterward, the appropriate secondary amine
(0.01 mol) in 10 ml of dry DMF was added. The reaction mixture
was stirred for 24 h at room temperature and then poured out into
ice. The precipitated product was filtrated and purified by recrys-
tallization from isopropanol. Due to oily form 23 and 24 were
converted into hydrochloride salts in anhydrous ethanol saturated
with HCl gas. These compounds were crystallized from anhydrous
ethanol.
injection volume was 10 mL. Standard solutions (1 mg/ml) of each
compound were prepared in analytical grade acetonitrile and
analyzed at wavelengths 214 nm and 254. Retention times (tR) are
given in minutes. Elemental analysis for C, H, and N were carried
out by a micro method using the elemental Vario EI III Elemental
analyzer (Hanau, Germany). The results of elemental analyses
were within ꢁ0.4% of the theoretical values. 1H NMR and 13C NMR
spectra were obtained in a Varian Mercury spectrometer (Varian
Inc., Palo Alto, CA, USA), in CDCl3 or DMSO, operating at 300 MHz
4.1.3.1. 2-[2-Oxo-2-(4-phenylpiperazin-1-yl)ethyl]isoindoline-1,3-
dione (6). White powdery crystals. Yield: 73%; TLC: Rf ¼ 0.45 (S1);
HPLC (tR 1.087 min); mp. 189.3e190.0 ꢂC; 1H NMR (300 MHz,
and 75 MHz, respectively. Chemical shifts are reported in
d values
(ppm) relative to TMS
d
¼ 0 (1H), as internal standard. The J values
are expressed in Hertz (Hz). Signal multiplicities are represented
by the following abbreviations: s (singlet), brs (broad singlet),
d (doublet), t (triplet), dt (double triplet), m (multiplet). ESIþ mass
spectra were obtained on the LCeMS system consisting of API
2000 Applied Biosystem/MDS-SCIEX (MDS Inc., Foster City, CA,
USA) with Agilent HPLCs (Agilent Technologies, Inc., Santa Clara,
CA, USA).
CDCl3):
d
3.24 (dt, 4H, J ¼ 5.64 Hz, J ¼ 28.21 Hz), 3.75 (dt, 4H,
piperazine, J ¼ 5.39 Hz, J ¼ 20.52 Hz), 4.55 (s, 2H, NeCH2eCOe),
6.91e6.96 (m, 3H, ArH), 7.26e7.33 (m, 2H, ArH), 7.72e7.76 (m, 2H,
ArH), 7.87e7.90 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3)
d 39.08,
42.19, 44.75, 116.87, 120.82, 123.57, 129.31, 132.24, 134.10, 150.81,
163.98, 168.06. Anal calcd for C20H19N3O3 (349.38): C, 68.75; H,
5.48; N, 12.03; found: C, 68.80; H, 5.46; N, 12.13. ESI-MS [M þ H]þ
found 350.1.
4.1.2. General procedure for the preparation of the 2-(1,3-dioxoisoin-
dolin-2-yl)acetic acid (3), 2-(1,3-dioxo-3a,4,5,6,7,7a-hexahydroiso-
indol-2-yl)acetic acid (4) and (3,5-dioxo-4-azatricyclo [5.2.1.02,6]dec-
8-en-4-yl)acetic acid (5)
0.1 mol of 2-benzofuran-1,3-dione, 3a,4,5,6,7,7a-hexahy-
droisobenzofuran-1,3-dione or 4-oxatricyclo[5.2.1.02,6]dec-8-ene-
3,5-dione were suspended in 20 ml of water and 2-aminoacetic
acid (0.1 mol) was gradually added. The mixture was heated in
term-regulated sand bath (ST 72 Roth, Karlsruhe, Germany), with
simultaneous distillation of water. After the water was completely
removed, the temperature of the reaction raised up to 180 ꢂC and
was maintained 1 h. The crude products were recrystallized from
toluene.
4.1.3.2. 2-{2-[4-(2-Chlorophenyl)piperazin-1-yl]-2-oxoethyl}isoindo-
line-1,3-dione (7). White powdery crystals. Yield: 65%; TLC:
Rf ¼ 0.73 (S1); HPLC (tR 1.540 min); mp. 172.7e173.9 ꢂC; 1H NMR
(300 MHz, CDCl3):
d
3.10 (dt, 4H, piperazine, J ¼ 4.87 Hz,
J ¼ 27.70 Hz), 3.77 (dt, 4H, piperazine, J ¼ 4.62 Hz, J ¼ 22.82 Hz),
4.55 (s, 2H, NeCH2eCOe), 7.00e7.05 (m, 2H, ArH), 7.23e7.28 (m,
1H, ArH), 7.38e7.41 (m, 1H, ArH), 7.72e7.75 (m, 2H, ArH), 7.88e7.90
(m, 2H, ArH); 13C NMR (75 MHz, CDCl3)
d 39.10, 42.11, 44.90, 116.08,
119.12, 122.96, 124.60, 130.41, 132.07, 134.05, 139.30, 154.0, 163.90,
168.95. Anal calcd for C20H18ClN3O3 (383.83): C, 62.58; H, 4.73; N,
10.95; found: C, 62.60; H, 4.70; N, 10.86. ESI-MS [M þ H]þ found
384.4.
4.1.2.1. 2-(1,3-Dioxoisoindolin-2-yl)acetic acid (3). White powdery
crystals. Yield 70%; mp 193.2e194.1 ꢂC; TLC: Rf ¼ 0.71 (S2); 1H NMR
4.1.3.3. 2-{2-[4-(3-Chlorophenyl)piperazin-1-yl]-2-oxoethyl}isoindo-
line-1,3-dione (8). White powdery crystals. Yield: 67%; TLC:
Rf ¼ 0.73 (S1); HPLC (tR 1.542 min); mp. 172.7e173.9 ꢂC; 1H NMR
(300 MHz, DMSO)
d 4.30 (s, 2H, NeCH2eCOe), 7.86e7.94 (m, 4H,
ArH), 13.25 (brs, 1H, eCOOH); 13C NMR (75 MHz, DMSO)
d
45.22,
(300 MHz, CDCl3):
d
3.10 (dt, 4H, piperazine, J ¼ 4.87 Hz,
129.11, 132.04, 134.15, 164.12, 170.11. Anal calcd for C10H7NO4
(205.17): C, 58.54; H, 3.44; N, 6.83; found: C, 58.50; H, 3.48; N, 6.86.
ESI-MS [M þ H]þ found 206.1.
J ¼ 27.70 Hz), 3.77 (dt, 4H, piperazine, J ¼ 4.62 Hz, J ¼ 22.82 Hz),
4.55 (s, 2H, NeCH2eCOe), 7.00e7.05 (m, 2H, ArH), 7.23e7.28 (m,
1H, ArH), 7.38e7.41 (m, 1H, ArH), 7.72e7.75 (m, 2H, ArH), 7.88e7.90
(m, 2H, ArH); 13C NMR (75 MHz, CDCl3)
d 39.05, 41.97, 44.54, 114.55,
4.1.2.2. 2-(1,3-Dioxo-3a,4,5,6,7,7a-hexahydroisoindol-2-yl)acetic acid
116.55, 120.36, 123.56, 130.22, 132.22, 134.12, 135.08, 151.80, 164.06,
168.01. Anal calcd for C20H18ClN3O3 (383.83): C, 62.58; H, 4.73; N,
10.95; found: C, 62.56 H, 4.75; N, 10.91. ESI-MS [M þ H]þ found
384.3.
(4). White powdery crystals. Yield 63%; mp 89.0e90.0 ꢂC; TLC:
Rf ¼ 0.58 (S2); 1H NMR (300 MHz, DMSO)
d 1.44e1.48 (m, 4H,
cyclohexane), 1.84e1.85 (m, 4H, cyclohexane), 2.91e2.99 (m, 2H,
H3a, H7a), 4.28 (s, 2H, NeCH2eCOe), 7.39 (brs, 1H, COOH); 13C NMR
(75 MHz, DMSO)
d
21.57, 23.46, 39.09, 45.23, 168.96, 179.28. Anal
4.1.3.4. 2-{2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-oxoethyl}isoindo-
line-1,3-dione (9). White powdery crystals. Yield: 70%; TLC:
Rf ¼ 0.88 (S1); HPLC (tR 1.456 min); mp. 197.6e197.4 ꢂC; 1H NMR
calcd for C10H13NO4 (211.21): C, 56.86; H, 6.20; N, 6.63; found: C,
56.80; H, 6.25; N, 6.64. ESI-MS [M þ H]þ found 212.1.
(300 MHz, CDCl3):
d
3.20 (dt, 4H, piperazine, J ¼ 5.13 Hz,
4.1.2.3. (3,5-Dioxo-4-azatricyclo [5.2.1.02,6]dec-8-en-4-yl)acetic acid
J ¼ 28.98 Hz), 3.73 (dt, 4H, piperazine, J ¼ 4.87 Hz, J ¼ 19.49 Hz),
4.54 (s, 2H, NeCH2eCOe), 6.83e6.89 (m, 2H, ArH), 7.22e7.27 (m,
2H, ArH), 7.71e7.77 (m, 2H, ArH), 7.86e7.90 (m, 2H, ArH); 13C NMR
(5). White powdery crystals. Yield 73%; mp 151.0e151.5 ꢂC; TLC:
Rf ¼ 0.65 (S2); 1H NMR (300 MHz, DMSO)
d 1.59 (d, 1H, H10a, nor-
bornene, J ¼ 9.08 Hz), 1.68 (d, 1H, H10a, norbornene, J ¼ 8.80 Hz),
3.31e3.40 (m, 4H, 4H, H1, H2, H6, H7, norbornene), 6.08 (d, 2H, 4H,
H8, H9, norbornene, J ¼ 1.65 Hz), 4.28 (s, 2H, NeCH2eCOe), 8.40
(75 MHz, CDCl3) d 39.06, 42.25, 44.81, 115.63, 115.92, 118.79, 118.90,
123.57, 132.24, 134.10, 163.97, 168.04. Anal calcd for C20H18ClN3O3
(383.83): C, 62.58; H, 4.73; N, 10.95; found: C, 62.62; H, 4.74; N,
10.93. ESI-MS [M þ H]þ found 384.2.
(brs, 1H, COOH); 13C NMR (75 MHz, DMSO)
d 39.09, 44.74, 45.89,
52.17, 134.76, 168.50, 177.09. Anal calcd for C11H11NO4 (221.21): C,
59.73; H, 5.01; N, 6.33; found: C, 59.83; H, 4.98; N, 6.36. ESI-MS
[M þ H]þ found 222.1.
4.1.3.5. 2-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]-2-oxoethyl}iso-
indoline-1,3-dione (10). White powdery crystals. Yield: 51%; TLC:

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K. Kaminski et al. / European Journal of Medicinal Chemistry 46 (2011) 4634e4641
4639
Rf ¼ 0.90 (S2); HPLC (tR 1.646 min); mp. 225.0e226.0 ꢂC; 1H NMR
ArH), 7.84e7.90 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3)
d
39.12,
(300 MHz, CDCl3):
d
3.09 (dt, 4H, piperazine, J ¼ 4.87 Hz,
42.18, 44.68, 52.12, 61.87, 129.11, 132.20, 134.17, 164.07, 168.03. Anal
calcd for C16H19N3O4 (317.34): C, 60.56; H, 6.03; N, 13.24; found: C,
60.60; H, 6.05; N, 13.20. ESI-MS [M þ H]þ found 318.1.
J ¼ 27.44 Hz), 3.77 (dt, 4H, piperazine, J ¼ 4.87 Hz, J ¼ 21.29 Hz), 4.55
(s, 2H, NeCH2eCOe), 6.94e6.97 (m, 1H, ArH), 7.15e7.26 (m, 2H,
ArH), 7.72e7.76 (m, 2H, ArH), 7.86e7.90 (m, 2H, ArH); 13C NMR
(75 MHz, CDCl3)
d
39.10, 42.50, 45.06, 118.85, 123.55, 125.38, 127.63,
4.1.3.11. 2-[2-(Morpholin-4-yl)-2-oxoethyl]isoindoline-1,3-dione(16).
White powdery crystals. Yield: 80%; TLC: Rf ¼ 0.73 (S1); HPLC (tR
1.053 min); mp. 175.4e176.2 ꢂC; 1H NMR (300 MHz, CDCl3):
127.79, 132.24, 134.10, 134.22, 150.42, 164.10, 168.05. Anal calcd for
C20H17Cl2N3O3 (418.27): C, 57.43; H, 4.10; N, 10.05; found: C, 57.40;
H, 4.15; N, 9.98. ESI-MS [M þ H]þ found 418.2.
d
1.57e1.68 (m, 4H, morpholine), 3.50 (dt, 4H, piperazine, J ¼ 5.64 Hz,
J ¼ 23.85 Hz), 4.48 (s, 2H, NeCH2eCOe), 7.68e7.74 (m, 2H, ArH),
7.83e7.90 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3)
39.90, 43.44,
4.1.3.6. 2-{2-[4-(2-Fluorophenyl)piperazin-1-yl]-2-oxoethyl}isoindo-
line-1,3-dione (11). White powdery crystals. Yield: 62%; TLC:
Rf ¼ 0.74 (S1); HPLC (tR 1.348 min); mp. 180.1e180.8 ꢂC; 1H NMR
d
44.76, 129.22, 132.18, 134.28, 163.20, 179.58. Anal calcd for
C14H14N2O4 (274.27): C, 61.31; H, 5.14; N, 10.21; found: C, 61.36; H,
5.20; N, 10.40. ESI-MS [M þ H]þ found 275.1.
(300 MHz, CDCl3):
d
3.14 (dt, 4H, piperazine, J ¼ 5.13 Hz,
J ¼ 29.75 Hz), 3.76 (dt, 4H, piperazine, J ¼ 4.88 Hz, J ¼ 22.82 Hz),
4.55 (s, 2H, NeCH2eCOe), 6.92e7.12 (m, 4H, ArH), 7.71e7.76 (m, 2H,
4.1.3.12. 2-[2-Oxo-2-(4-phenylpiperazin-1-yl)ethyl]-3a,4,5,6,7,7a-he-
xahydroisoindole-1,3-dione (17). White powdery crystals. Yield: 70%;
TLC: Rf ¼ 0.74 (S1); HPLC (tR 1.004 min); mp.131.9e132.8 ꢂC; 1H NMR
ArH), 7.86e7.91 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3)
d 39.07,
42.37, 44.96, 116.16, 119.27, 123.29, 124.63, 132.26, 134.08, 139.36,
139.47, 154.13, 163.97, 168.06. Anal calcd for C20H18FN3O3 (367.37):
C, 65.39; H, 4.94; N, 11.44; found: C, 65.44; H, 4.99; N, 11.40. ESI-MS
[M þ H]þ found 368.2.
(300 MHz, CDCl3):
d 1.44e1.55 (m, 4H, cyclohexane), 1.89e1.94 (m,
4H, cyclohexane), 2.92e3.00 (m, 2H, H3a, H7a), 3.21 (dt, 4H, pipera-
zine, J ¼ 5.13 Hz, J ¼ 21.29 Hz), 3.70 (dt, 4H, piperazine, J ¼ 4.87 Hz,
J ¼ 34.88 Hz), 4.33 (s, 2H, NeCH2eCOe), 6.90e6.94 (m, 3H, ArH),
4.1.3.7. 2-{2-[4-(4-Fluorophenyl)piperazin-1-yl]-2-oxoethyl}isoindo-
line-1,3-dione (12). White powdery crystals. Yield: 65%; TLC:
Rf ¼ 0.50 (S1); HPLC (tR 1.183 min); mp. 180.7e181.3 ꢂC; 1H NMR
7.26e7.32 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3)
d 21.75, 23.75,
39.08, 40.01, 42.14, 44.66, 116.87, 120.83, 129.29, 150.80, 163.69,
179.49. Anal calcd for C20H25N3O3 (355.43): C, 67.58; H, 7.09; N,11.82;
found: C, 67.62; H, 7.11; N, 11.79. ESI-MS [M þ H]þ found 356.2.
(300 MHz, CDCl3):
d
3.15 (dt, 4H, piperazine, J ¼ 5.13 Hz,
J ¼ 28.72 Hz), 3.74 (dt, 4H, piperazine, J ¼ 4.87 Hz, J ¼ 20.26 Hz),
4.55 (s, 2H, NeCH2eCOe), 6.88e7.03 (m, 4H, ArH), 7.72e7.76 (m,
4.1.3.13. 2-{2-[4-(3-Chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3a,4,5,
6,7,7a-hexahydroisoindole-1,3-dione (18). White powdery crystals.
Yield: 84%; TLC: Rf ¼ 0.60 (S1); HPLC (tR 1.442 min); mp.
2H, ArH), 7.86e7.90 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3)
d 39.12,
42.20, 44.08, 115.60, 115.95, 118.81, 118.90, 123.63, 132.31, 134.16,
163.96, 168.07. Anal calcd for C20H18FN3O3 (367.37): C, 65.39; H,
4.94; N, 11.44; found: C, 65.41; H, 4.90; N, 11.42. ESI-MS [M þ H]þ
found 368.2.
155.7e156.4 ꢂC; 1H NMR (300 MHz, CDCl3):
d 1.44e1.60 (m, 4H,
cyclohexane), 1.91e1.93 (m, 4H, cyclohexane), 2.92e3.00 (m, 2H,
H3a, H7a), 3.22 (dt, 4H, piperazine, J ¼ 5.13 Hz, J ¼ 21.29 Hz), 3.69
(dt, 4H, piperazine, J ¼ 5.13 Hz, J ¼ 33.08 Hz), 4.32 (s, 2H,
NeCH2eCOe), 6.76e6.80 (m, 1H, ArH), 6.85e6.89 (m, 2H, ArH),
4.1.3.8. 2-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-2-oxoethyl}
isoindoline-1,3-dione (13). White powdery crystals. Yield: 59%; TLC:
Rf ¼ 0.87 (S1); HPLC (tR 1.594 min); mp. 204.0e206.0 ꢂC; 1H NMR
7.16e7.22 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3)
d 21.70, 23.71,
39.18, 40.08, 42.16, 44.71, 112.80, 113.02, 119.40, 129.78, 132.11,
150.79, 164.10, 179.33. Anal calcd for C20H24ClN3O3 (389.88): C,
61.61; H, 6.20; N, 10.78; found: C, 61.59; H, 6.25; N, 10.81. ESI-MS
[M þ H]þ found 390.2.
(300 MHz, CDCl3):
d
3.30 (dt, 4H, piperazine, J ¼ 5.39 Hz,
J ¼ 28.72 Hz), 3.76 (dt, 4H, piperazine, J ¼ 5.13 Hz, J ¼ 18.47 Hz), 4.55
(s, 2H, NeCH2eCOe), 7.07e7.16 (m, 3H, ArH), 7.39 (t, 1H, ArH,
J ¼ 7.95 Hz), 7.71e7.77 (m, 2H, ArH), 7.86e7.91 (m, 2H, ArH); 13C NMR
(75 MHz, CDCl3)
d
39.05, 41.98, 44.54, 112.97, 116.95, 119.45, 123.57,
4.1.3.14. 2-{2-[4-(4-Chlorophenyl)piperazin-1-yl]-2-oxoethyl}-3a,4,5,
124.11, 129.79, 132.21, 134.14, 150.91, 164.07, 168.03. Anal calcd for
C21H18F3N3O3 (417.38): C, 60.43; H, 4.35; N,10.07; found: C, 60.40; H,
4.38; N, 10.02. ESI-MS [M þ H]þ found 418.1.
6,7,7a-hexahydroisoindole-1,3-dione (19). White powdery crystals.
Yield: 78%; TLC: Rf
¼
0.61 (S1); HPLC (tR 1.385 min); mp.
1.44e1.54 (m, 4H,
146.1e147.9 ꢂC; 1H NMR (300 MHz, CDCl3):
d
cyclohexane), 1.89e1.93 (m, 4H, cyclohexane), 2.92e3.00 (m, 2H,
H3a, H7a), 3.17 (dt, 4H, piperazine, J ¼ 5.13 Hz, J ¼ 22.05 Hz), 3.69 (dt,
4H, piperazine, J ¼ 5.13 Hz, J ¼ 34.12 Hz), 4.32 (s, 2H, NeCH2eCOe),
6.82e6.87 (m, 2H, ArH), 7.21e7.26 (m, 2H, ArH); 13C NMR (75 MHz,
4.1.3.9. 2-{2-[4-(Benzylphenyl)piperazin-1-yl]-2-oxoethyl}isoindo-
line-1,3-dione (14). White powdery crystals. Yield: 74%; TLC:
Rf ¼ 0.58 (S1); HPLC (tR 0.879 min); mp. 151.3e151.9 ꢂC; 1H NMR
(300 MHz, CDCl3):
d
2.49 (dt, 4H, piperazine, J ¼ 5.13 Hz,
CDCl3) d 21.73, 23.73, 39.06, 40.00, 42.19, 44.71, 115.60, 118.77,
J ¼ 21.80 Hz), 3.52e3.55 (m, 4H; 2H, eCH2- benzyl; 2H, piperazine),
3.62 (t, 2H, piperazine, J ¼ 5.13 Hz), 4.48 (s, 2H, NeCH2eCOe),
7.26e7.34 (m, 5H, ArH), 7.69e7.75 (m, 2H, ArH), 7.88e7.90 (m, 2H,
124.42, 134.18, 163.69, 179.47. Anal calcd for C20H24ClN3O3 (389.88):
C, 61.61; H, 6.20; N, 10.78; found: C, 61.57; H, 6.22; N, 10.80. ESI-MS
[M þ H]þ found 390.1.
ArH); 13C NMR (75 MHz, CDCl3)
d 39.10, 42.15, 44.63, 55.16, 116.80,
120.81, 123.52, 129.28, 132.23, 134.07, 150.80, 163.88, 168.11. Anal
calcd for C21H21N3O3 (363.41): C, 69.41; H, 5.82; N, 11.56; found: C,
69.50; H, 5.88; N, 11.51. ESI-MS [M þ H]þ found 364.2.
4.1.3.15. 2-{2-[4-(2,3-Dichlorophenyl)piperazin-1-yl]-2-oxoethyl}-3a,
4,5,6,7,7a-hexahydroisoindole-1,3-dione (20). White powdery crys-
tals. Yield: 71%; TLC: Rf ¼ 0.78 (S1); HPLC (tR 1.446 min); mp.
181.0e182.0 ꢂC; 1H NMR (300 MHz, CDCl3):
d 1.43e1.46 (m, 4H,
4.1.3.10. 2-{2-[4-(2-Hydroxyethyl)piperazin-1-yl]-2-oxoethyl}isoindo-
line-1,3-dione (15). White powdery crystals. Yield: 66%; TLC:
Rf ¼ 0.36 (S1); HPLC (tR 0.589 min); mp. 159.3e159.9 ꢂC; 1H NMR
cyclohexane), 1.84e1.86 (m, 4H, cyclohexane), 2.85e2.93 (m, 2H,
H3a, H7a), 3.21e3.22 (m, 8H, piperazine), 4.08 (s, 2H, NeCH2eCOe),
7.06e7.10 (m, 1H, ArH), 7.16e7.26 (m, 2H, ArH); 13C NMR (75 MHz,
(300 MHz, CDCl3):
d
2.52 (t, 2H, piperazine, J ¼ 5.13 Hz), 2.58e2.63
CDCl3) d 21.73, 23.78, 39.12, 40.11, 42.15, 44.67,118.86,123.49,127.60,
(m, 4H; 2H, piperazine; 2H NeCH2eCH2eO), 3.56 (t, 2H, piperazine,
J ¼ 4.87 Hz), 3.62e3.67 (m, 4H, 2H, piperazine; 2H, NeCH2eCH2eO),
4.49 (s, 2H, NeCH2eCOe), 5.34 (brs, 1H, eOH), 7.69e7.75 (m, 2H,
134.11, 134.21, 150.42, 163.97, 180.06. Anal calcd for C20H23Cl2N3O3
(424.32): C, 56.61; H, 5.46; N, 9.90; found: C, 56.55; H, 5.40; N, 10.12.
ESI-MS [M þ H]þ found 424.1.

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4.1.3.16. 2-{2-[4-(4-Fluorophenyl)piperazin-1-yl]-2-oxoethyl}-3a,4,5,
6,7,7a-hexahydroisoindole-1,3-dione (21). White powdery crystals.
Yield: 82%; TLC: Rf ¼ 0.89 (S1); HPLC (tR 1.103 min); mp.
1H NMR (300 MHz, CDCl3):
d 1.62 (d, 1H, H10a, norbornene,
J ¼ 9.08 Hz), 1.79 (d, 1H, H10b, norbornene, J ¼ 8.80 Hz), 3.22 (dt, 4H,
piperazine, J ¼ 4.95 Hz, J ¼ 21.80 Hz), 3.31e3.40 (m, 4H, H1, H2, H6,
H7, norbornene), 3.69 (dt, 4H, piperazine, J ¼ 4.90 Hz, J ¼ 34.60 Hz),
4.22 (s, 2H, NeCH2eCOe-), 6.18 (d, 2H, H8, H9, norbornene,
J ¼ 1.65 Hz), 6.92e7.02 (m, 3H, ArH), 7.30e7.36 (m, 2H, ArH); 13C
122.3e123.1 ꢂC; 1H NMR (300 MHz, CDCl3):
d 1.43e1.54 (m, 4H,
cyclohexane), 1.89e1.93 (m, 4H, cyclohexane), 2.92e3.00 (m, 2H,
H3a, H7a), 3.11 (dt, 4H, piperazine, J ¼ 5.13 Hz, J ¼ 21.80 Hz), 3.69 (dt,
4H, piperazine, J ¼ 4.87 Hz, J ¼ 34.62 Hz), 4.32 (s, 2H, NeCH2eCOe),
6.86e6.92 (m, 2H, ArH), 6.94e7.02 (m, 2H, ArH); 13C NMR (75 MHz,
NMR (75 MHz, CDCl3)
d 39.15, 40.22, 41.80, 42.18, 44.78, 46.02,
116.91, 121.07, 129.29, 134.70, 150.32, 163.54, 179.18. Anal calcd for
C21H23N3O3 (365.42): C, 69.02; H, 6.34; N, 11.50; found: C, 69.12; H,
6.26; N, 11.34. ESI-MS [M þ H]þ found 366.2.
CDCl3)
d 21.75, 23.75, 39.08, 40.01, 42.14, 44.66, 116.10, 118.89,
124.70, 134.14, 163.21, 179.10. Anal calcd for C20H24FN3O3 (373.42):
C, 64.33; H, 6.48; N, 11.25; found: C, 64.40; H, 6.44; N, 11.20. ESI-MS
[M þ H]þ found 374.2.
4.1.3.22. 4-{2-[4-(3-Chlorophenyl)piperazin-1-yl]-2-oxoethyl}-4-aza-
tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (27). White powdery crystals.
4.1.3.17. 2-{2-[4-(3-Trifluoromethylphenyl)piperazin-1-yl]-2-oxoethyl}-
3a,4,5,6,7,7a-hexahydroisoindole-1,3-dione (22). White powdery crys-
tals. Yield: 55%; TLC: Rf ¼ 0.85 (S1); HPLC (tR 1.534 min); mp.
Yield: 77%; TLC: Rf
¼
0.80 (S1); HPLC (tR 1.440 min); mp.
1.61 (d, 1H, H10a
197.2e198.0 ꢂC; 1H NMR (300 MHz, CDCl3):
d
,
norbornene, J ¼ 8.80 Hz), 1.80 (d, 1H, H10b, norbornene, J ¼ 8.80 Hz),
3.24 (dt, 4H, piperazine, J ¼ 5.13 Hz, J ¼ 22.05 Hz), 3.42e3.45 (m, 4H,
H1, H2, H6, H7, norbornene), 3.69 (dt, 4H, piperazine, J ¼ 4.85 Hz,
J ¼ 34.22 Hz), 4.21 (s, 2H, NeCH2eCOe), 6.18 (d, 2H, H8, H9, nor-
bornene, J ¼ 1.65 Hz), 6.79e6.84 (m, 1H, ArH), 6.88e6.92 (m, 2H,
105.3e106.0 ꢂC; 1H NMR (300 MHz, CDCl3):
d 1.44e1.58 (m, 4H,
cyclohexane), 1.89e1.93 (m, 4H, cyclohexane), 2.93e3.01 (m, 2H, H3a
,
H7a), 3.27 (dt, 4H, piperazine, J ¼ 5.13 Hz, J ¼ 21.80 Hz), 3.72 (dt, 4H,
piperazine, J ¼ 4.87 Hz, J ¼ 33.08 Hz), 4.33 (s, 2H, NeCH2eCOe),
7.06e7.16 (m, 2H, ArH), 7.36e7.41 (m, 2H, ArH); 13C NMR (75 MHz,
ArH), 7.20e7.28 (m, 1H, ArH); 13C NMR (75 MHz, CDCl3)
d 39.24,
CDCl3)
d
21.75, 23.75, 39.05, 40.01, 41.93, 44.57, 112.99, 113.05, 116.98,
40.54, 41.88, 42.20, 44.81, 46.12, 112.92, 113.22, 120.05, 129.98,
132.55, 134.71, 150.32, 163.62, 179.23. Anal calcd for C21H22ClN3O3
(399.87): C, 63.08; H, 5.55; N, 10.51; found: C, 63.28; H, 5.65; N,
10.30. ESI-MS [M þ H]þ found 400.1.
119.48, 124.11, 129.78, 150.85, 163.78, 179.47. Anal calcd for
C21H24F3N3O3 (423.43): C, 59.57; H, 5.71; N, 9.92; found: C, 59.59; H,
5.67; N, 9.95. ESI-MS [M þ H]þ found 424.2.
4.1.3.18. 2-{2-[4-(Benzylphenyl)piperazin-1-yl]-2-oxoethyl}-3a,4,5,6,
7,7a-hexahydroisoindole-1,3-dione monohydrochloride (23). White
powdery crystals. Yield: 67%; TLC: Rf ¼ 0.34 (S1); HPLC (tR
0.872 min); mp. 268.0e269.0 ꢂC; 1H NMR (300 MHz, DMSO):
4.1.3.23. 4-{2-[4-(2-Fluorophenyl)piperazin-1-yl]-2-oxoethyl}-4-aza-
tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (28). White powdery crystals.
Yield: 81%; TLC: Rf
¼
0.69 (S1); HPLC (tR 1.123 min); mp.
1.60 (d, 1H, H10a
212.6e213.5 ꢂC; 1H NMR (300 MHz, CDCl3):
d
,
d
1.28e1.40 (m, 4H, cyclohexane), 1.70e1.72 (m, 4H, cyclohexane),
norbornene, J ¼ 8.80 Hz), 1.82 (d, 1H, H10b, norbornene, J ¼ 8.80 Hz),
3.12 (dt, 4H, piperazine, J ¼ 5.23 Hz, J ¼ 21.90 Hz), 3.42e3.48 (m, 4H,
H1, H2, H6, H7, norbornene), 3.65 (dt, 4H, piperazine, J ¼ 5.23 Hz,
J ¼ 34.20 Hz), 4.21 (s, 2H, NeCH2eCOe), 6.19 (d, 2H, H8, H9, nor-
bornene, J ¼ 1.38 Hz), 6.94e7.15 (m, 4H, ArH); 13C NMR (75 MHz,
2.93e3.62 (m, 8H, piperazine), 4.01e4.44 (m, 6H; 2H, H3a, H7a; 2H,
NeCH2eCOe; 2H, eCH2- benzyl), 7.44e7.58 (m, 5H, ArH),11.19 (brs,
1H, HCl); 13C NMR (75 MHz, DMSO)
d 21.70, 23.68, 39.01, 40.03,
42.08, 44.57, 55.11, 116.78, 120.65, 123.48, 150.21, 163.60, 179.41.
Anal calcd for C21H28ClN3O3 (405.92): C, 62.14; H, 6.95; N, 10.35;
found: C, 62.20; H, 6.90; N, 10.31. ESI-MS [M þ H]þ (for C21H27N3O3)
found 370.2.
CDCl3) d 39.20, 40.51, 41.84, 42.18, 44.80, 46.11, 116.19,119.32,123.33,
124.61, 134.70, 139.45, 157.06, 163.65, 179.26. Anal calcd for
C21H22FN3O3 (383.42): C, 65.78; H, 5.78; N,10.96; found: C, 65.85; H,
5.60; N, 10.79. ESI-MS [M þ H]þ found 384.2.
4.1.3.19. 2-{2-[4-(2-Hydroxyethyl)piperazin-1-yl]-2-oxoethyl}-3a,4,5,
6,7,7a-hexahydroisoindole-1,3-dione monohydrochloride (24). White
powdery crystals. Yield: 68%; TLC: Rf ¼ 0.43 (S1); HPLC (tR
0.582 min); mp. 226.5e228.5 ꢂC; 1H NMR (300 MHz, DMSO):
4.1.3.24. 4-{2-[4-(4-Fluorophenyl)piperazin-1-yl]-2-oxoethyl}-4-aza-
tricyclo[5.2.1.02,6]dec-8-ene-3,5-dione (29). White powdery crystals.
Yield: 68%; TLC: Rf
¼
0.61 (S1); HPLC (tR 1.143 min); mp.
1.63 (d, 1H, H10a,
d
1.31e1.40 (m, 4H, cyclohexane), 1.70e1.72 (m, 4H, cyclohexane),
2.87e4.04 (m, 14H; 2H, H3a H7a 8H, piperazine; 4H,
NeCH2eCH2eO), 4.34 (s, 2H, NeCH2eCOe), 5.36 (brs, 1H, eOH),
10.08 (brs, 1H, HCl); 13C NMR (75 MHz, DMSO)
21.60, 23.55, 38.76,
182.1e182.9 ꢂC; 1H NMR (300 MHz, CDCl3):
d
,
;
norbornene, J ¼ 6.05 Hz), 1.80 (d, 1H, H10b, norbornene, J ¼ 8.80 Hz),
3.11 (dt, 4H, piperazine, J ¼ 4.95 Hz, J ¼ 21.80 Hz), 3.42e3.46 (m, 4H,
H1, H2, H6, H7, norbornene), 3.63 (dt, 4H, piperazine, J ¼ 4.95 Hz,
J ¼ 34.20 Hz), 4.21 (s, 2H, NeCH2eCOe), 6.18 (d, 2H, H8, H9, nor-
bornene, J ¼ 1.65 Hz), 6.90e6.96 (m, 2H, ArH), 6.98e7.04 (m, 2H,
d
39.75, 40.88, 44.01, 52.08, 61.62, 162.50, 178.43. Anal calcd for
C16H26ClN3O4 (359.85): C, 53.40; H, 7.28; N,11.68; found: C, 53.50; H,
7.32; N, 11.61. ESI-MS [M þ H]þ (for C16H25N3O4) found 324.2.
ArH); 13C NMR (75 MHz, CDCl3)
d 39.23, 40.52, 41.82, 42.17, 44.82,
46.13, 116.34, 118.98, 124.87, 134.20, 134.72, 163.62, 179.20. Anal
calcd for C21H22FN3O3 (383.42): C, 65.78; H, 5.78; N, 10.96; found: C,
65.80; H, 5.62; N, 10.84. ESI-MS [M þ H]þ found 384.2.
4.1.3.20. 2-[2-(Morpholin-4-yl)-2-oxoethyl]-3a,4,5,6,7,7a-hexahydr-
oisoindole-1,3-dione (25). White powdery crystals. Yield: 63%; TLC:
Rf ¼ 0.53 (S1); HPLC (tR 0.959 min); mp. 138.4e138.8 ꢂC; 1H NMR
(300 MHz, CDCl3):
d
1.42e1.65 (m, 8H; 4H, cyclohexane; 4H, mor-
4.1.3.25. 4-[2-Oxo-2-(4-benzylpiperazin-1-yl)ethyl]-4-azatricyclo
[5.2.1.02,6]dec-8-ene-3,5-dione (30). White powdery crystals.
Yield: 75%; TLC: Rf ¼ 0.57 (S1); HPLC (tR 0.965 min); mp.
pholine), 1.83e1.95 (m, 4H, cyclohexane), 2.90e2.98 (m, 2H, H3a
H7a), 3.39e3.54 (m, 4H, morpholine), 4.26 (s, 2H, NeCH2eCOe); 13
NMR (75 MHz, CDCl3) 21.74, 23.72, 39.12, 39.98, 43.31, 45.71,
,
C
d
187.5e188.6 ꢂC; 1H NMR (300 MHz, CDCl3):
d
1.61 (d, 1H, H10a
,
163.28,179.52. Anal calcd for C14H20N2O4 (280.32): C, 59.99; H, 7.19;
N, 9.99; found: C, 60.11; H, 7.30; N, 9.89. ESI-MS [M þ H]þ found
281.1.
norbornene,
J
¼
8.80 Hz), 1.78 (d, 1H, H10b, norbornene,
J ¼ 8.80 Hz), 2.48 (dt, 4H, piperazine, J ¼ 4.95 Hz, J ¼ 22.10 Hz),
3.40e3.42 (m, 4H, H1, H2, H6, H7, norbornene), 3.53 (dt, 4H,
piperazine, J ¼ 4.95 Hz, J ¼ 34.12 Hz), 3.55 (s, 2H, eCH2e benzyl),
4.15 (s, 2H, NeCH2eCOe), 6.17 (d, 2H, H8, H9, norbornene,
J ¼ 1.65 Hz), 7.27e7.39 (m, 5H, ArH); 13C NMR (75 MHz, CDCl3)
4.1.3.21. 4-[2-Oxo-2-(4-phenylpiperazin-1-yl)ethyl]-4-azatricyclo
[5.2.1.02,6]dec-8-ene-3,5-dione (26). White powdery crystals. Yield:
66%; TLC: Rf ¼ 0.63 (S1); HPLC (tR 1.114 min); mp. 226.1e227.2 ꢂC;
d
39.01, 40.22, 41.79, 42.04, 44.64, 45.93, 55.12, 116.80, 121.03,

ꢀ
K. Kaminski et al. / European Journal of Medicinal Chemistry 46 (2011) 4634e4641
4641
123.60, 134.69, 150.02, 163.53, 179.18. Anal calcd for C22H25N3O3
(379.45): C, 69.64; H, 6.64; N, 11.07; found: C, 69.84; H, 6.52; N,
11.09. ESI-MS [M þ H]þ found 380.2.
support of this work by the Jagiellonian University Medical College
grant No K/ZDS/001291.
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The authors wish to thank Dr James Stables for providing them
with pharmacological data through the Antiepileptic Drug Devel-
opment Program (Epilepsy Branch, National Institute of Neurolog-
ical Disorders and Stroke, National Institutes of Health, Rockville,
MD, USA). We are pleased to acknowledge the generous financial
ꢀ
_
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