Synthesis, physicochemical and anticonvulsant properties of new N-pyridyl derivatives of 3-phenyl- and 3,3-diphenyl-succinimides

Article abstract of DOI:10.1016/S0014-827X(99)00033-6

Synthesis and physicochemical properties of new N-pyridyl derivatives of 3-phenyl and 3,3-diphenylsuccinimides (1-12) have been described. The obtained compounds were evaluated in respect of their anticonvulsant activity. The N-pyridyl derivatives of 3-ph

Full text of DOI:10.1016/S0014-827X(99)00033-6

www.elsevier.nl/locate/farmac
Il Farmaco 54 (1999) 423–429
Synthesis, physicochemical and anticonvulsant properties of new
N-pyridyl derivatives of 3-phenyl- and 3,3-diphenyl-succinimides
Jolanta Obniska a,*, Alfred Zejc a, Janina Karolak-Wojciechowska b
a Department of Medicinal Chemistry, Collegium Medicum of Jagiellonian Uni6ersity, 30-688 Medyczna 9, Krakow, Poland
b Institute of General and Ecological Chemistry, Technical Uni6ersity, Zwirki 36, 90-924 Lodz, Poland
Received 12 December 1998; accepted 9 March 1999
Abstract
Synthesis and physicochemical properties of new N-pyridyl derivatives of 3-phenyl and 3,3-diphenylsuccinimides (1–12) have
been described. The obtained compounds were evaluated in respect of their anticonvulsant activity. The N-pyridyl derivatives of
3-phenylsuccinimides (7–12) abolished the protection against MES- and scMET-induced seizures, whereas N-pyridyl derivatives
of 3,3-diphenylsuccinimides (1–6) were inactive. After molecular modelling and quantum-chemistry calculations the theoretical
activity test was applied (W. Kwiatkowski, J. Karolak-Wojciechowska, SAR and QSAR Envir. Res. 1 (1993) 233; Chem. Abstr.
120, 153001 (1994). J. Karolak-Wojciechowska, M. Blaszczyk, W. Kwiatkowski, J. Obniska, A. Zejc, J. Chem. Cryst. 27 (1997)
297; Chem. Abstr. 127, 277834k (1997)). The molecular electrostatic potential (MEP) of the active compounds differed
significantly from that of the inactive ones. © 1999 Elsevier Science S.A. All rights reserved.
Keywords: Succinimides; Pyrrolidine-2,5-dione; Anticonvulsant activity; Molecular electrostatic potential of the molecule
graphically
studied
pharmacologically
inactive
1. Introduction
molecules differs from the conformation of molecules
with a confirmed anticonvulsant activity. This differ-
ence may be regarded as a different orientation of the
pyridyl ring with respect to the five-membered succin-
imide ring (Fig. 1). The torsional angle defining the
five-member and of the pyridyl rings orientation is
equal to about 90° in the structure of active compounds
In the search for new compounds with predictable
anticonvulsant properties, our attention was drawn to a
group of phenylsuccinimides with different substituents
at the nitrogen atom. Our chemical and pharmacologi-
cal [1,2] studies with new derivatives of aryl-, arylalkyl-
and alkyl-N-substituted succinimides showed a possibil-
ity of modifying the central action of those compounds.
Wilimowski et al. [3] have demonstrated that some
N-aryl-derivatives of succinimides have a potent antide-
pressant action. Further studies with this group of
compounds led to a synthesis of new derivatives of
aryl-succinimides containing a pyridyl moiety at the
nitrogen atom. Pharmacological studies [2,4] showed an
anticonvulsant activity of some compounds of that
group.
The results of crystallographic investigations [5,6] of
new phenylsuccinimides with a pyridyl at the N atom
showed that pharmacological properties of the com-
pounds seem to be connected with the heteroaromatic
ring orientation. The conformation of some crystallo-
Fig. 1. Superimposition of the molecules for active (solid lines) and
inactive (dotted lines) samples [5,6].
* Corresponding author.
0014-827X/99/$ - see front matter © 1999 Elsevier Science S.A. All rights reserved.
PII: S0014-827X(99)00033-6

424
J. Obniska et al. / Il Farmaco 54 (1999) 423–429
Fig. 2. The distribution of MEP for 1 in the plane of a five-membered ring [12].
2. Chemistry
while in inactive ones it is about 120°. Therefore, the
compounds with anticonvulsant properties are charac-
terized by an anticlinal arrangement of the pyridyl ring
in relation to the five-membered imide ring. This posi-
tion can be achieved though by the ortho substitution of
a methyl group within the pyridyl ring which, in turn,
facilitates the formation of hydrogen bonds with the
appropriate receptor. The active and inactive com-
pounds also differ slightly in the slope of the 3-phenyl
ring towards the succinimides moiety (Fig. 1).
The N-pyridyl 3,3-diphenylsuccinimides (1–6) were
synthesized according to the procedures shown in
Scheme 1.
Starting with diphenylacetonitrile and ethyl chlorac-
etate (pyridine solution) in the presence of NaOH and
TEBA, 3-cyano-3,3-diphenylpropionic acid, which was
hydrolyzed with 25% H2SO4 to yield 3,3-diphenylsuc-
cinic acid, was obtained [8,9]. 3-(4-Fluorophenyl)-,
The structure–activity relationship (SAR) studies in
the groups of N-pyridyl-3-aryl succinimides were con-
ducted by one of us [7] applying molecular electrostatic
potentials (MEP) distribution around the molecule.
This research has shown that MEP maps provide a
signature which permits the distinction between active
and inactive compounds. The active compounds could
be distinguished from inactive ones on the basis of the
differences between the minima of the MEP close to
both carbonyl oxygens V(O1) and V(O4) of the imide
five-membered ring (see Fig. 2 for the MEP distribution
example). The difference DV=V(O1)−V(O4) is nega-
tive for inactive and positive for active compounds.
Therefore when V(O1) is plotted against V(O4), two
separated regression lines are formed (see Fig. 3), one
for active and the other for inactive species. To proceed
with our research into the SARs in the five-membered
heterocyclic anticonvulsants, we have presently synthe-
sized two series of new N-pyridyl 3-phenyl and -3,3-
diphenylsuccinimides.
Fig. 3. Two clusters of V(O1) plotted vs. V(O4) for (ꢀ) inactive
3,3-diphenylsuccinimides (1–6) and (") active 3-phenylsuccinimides
(7–12).

J. Obniska et al. / Il Farmaco 54 (1999) 423–429
425
Scheme 1.
Scheme 2.
3-(3-fluorophenyl)-, 3-(2-chlorophenyl)-, 3-(2-methoxy-
phenyl)- and (3-(3-methoxyphenyl)-succinic acids, ob-
tained by the method of Miller and Long [8], as
modified by Lange and Lapszewicz [9], were used as
starting materials for compounds 7–12 (Scheme 2).
The acids were cyclized to N-substituted imides of
succinic acids (1–12) by heating them at ca. 200–220°C
for 1.5–2 h with the appropriate 2-aminomethyl-
pyridines.
examination of their IR, UV and 1H NMR spectra, and
by elemental analyses.
3. Experimental
3.1. Chemistry
Analytical results for C, H, N of compounds 1–12
were within 90.4% of their theoretical values. Melting
points are uncorrected. Spectra were recorded on a
Specord UV (Carl Zeiss, Jena) in 10−4 M/l ethanolic
The purity of the obtained compounds was checked
by TLC. The structures of 1–12 were confirmed by

426
J. Obniska et al. / Il Farmaco 54 (1999) 423–429
solutions. IR spectra were recorded on a Specord M 80
(Carl Zeiss, Jena) spectrometer using KBr discs. 1H
NMR spectra (Bruker VM 250 MHz NMR spectrome-
ter) were determined in CDCl3 solution with TMS as
internal standard. All chemical shifts are quoted in l
values. The chromatography was performed with
Merck Silica Gel GF254 precoated TLC sheets using the
following developing systems: A, chloroform:acetone
(9:1); B, chloroform:methanol:acetic acid (60:10:5); and
C, methanol:acetate ethyl:n-hexane (1:1:1). Spots were
detected by their absorption under UV light and visual-
ization with 0.05 mol I2 in 10% HCl.
The following starting materials: 3-(4-fluorophenyl)-,
3-(3-fluorophenyl)-3-(2-chlorophenyl)-, 3-(2-methoxy-
phenyl)-, and 3-(3-methoxyphenyl)-succinic acids were
prepared according to Refs. [8,9]. N-(3-Methyl-pyrid-2-
yl)-imide of 3-(3-bromophenyl)-succinic acid (10) was
synthesized by a previously published procedure [4].
3.2.5. 3,3-(Diphenyl)-1-(5-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (4)
M.p. 94–96°C, yield (58%). Anal. (C22H18N2O2) C,
H, N. TLC: Rf=0.77 (A), 0.94 (B). NMR (CDCl3):
2.37 (3H, s, CH3), 3.64 (2H, s, CH2 imide), 7.12–7.66
(12H, m, arom), 8.48 (1H, d, pyrid). IR (cm−1): CꢀO,
1776, 1716. UV u (nm): 221, log m 4.27; u (nm): 264,
log m 3.81.
3.2.6. 3,3-(Diphenyl)-1-(6-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (5)
M.p. 61–63°C, yield (65%). Anal. (C22H18N2O2) C,
H, N. TLC: Rf=0.76 (A), 0.92 (B). NMR (CDCl3):
2.79 (3H, s, CH3), 3.66 (2H, s, CH2 imide), 6.99–7.43
(12H, m, arom), 7.67–7.75 (1H, t, pyrid). IR (cm−1):
CꢀO 1768, 1712. UV u (nm): 220, log m 4.26; u (nm):
263, log m 4.00.
3.2.7. 3,3-(Diphenyl)-1-(4,6-dimethyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (6)
3.2. Procedures for the preparation of the imides
M.p. 98–100°C, yield (73%). Anal. (C23H20N2O2) C,
H, N. TLC: Rf=0.90 (A), 0.93 (B). NMR (CDCl3):
2.33 (3H, s, CH3), 2.55 (3H, s, CH3), 3.64 (2H, s, CH2
imide), 6.81–7.42 (12H, m, arom). IR (cm−1): CꢀO
1780, 1712. UV u (nm): 219, log m 4.18; u (nm): 262,
log m 4.83.
3.2.1. General procedure
A total of 0.02 mol of the appropriate 2-aminopy-
ridine was dissolved in 20 ml of water, and 0.02 mol of
the appropriate 3-substituted succinic acid was gradu-
ally added. The mixture was heated in an oil bath with
simultaneous distillation of water. After complete re-
moval of the water, the temperature of the reaction
mixture was raised up to 180°C and maintained for 1.5
h. The crude products were recrystallized from ethanol.
3.2.8. 3-(4-Fluorophenyl)-1-(3-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (7)
M.p. 115–107°C, yield (75%). Anal. (C16H13N2O2F)
C, H, N. TLC: Rf=0.42 (A), 0.47 (B). NMR (CDCl3):
2.10, 2.55 (3H, 2s, CH3), 2.75–2.84 (1H, 2dd, CH2
imide), 3.32–3.42 (1H, dd, CH2 imide), 4.15, 4.21 (1H,
dt, CH imide), 7.10–7.45 (5H, m, arom), 7.70–7.95
(1H, d, pyrid), 8.59–8.69 (1H, d, pyrid). IR (cm−1):
CꢀO 1776, 1702. UV u (nm): 205, log m 4.24; u (nm):
261, log m 3.81.
3.2.2. 3,3-(Diphenyl)-1-(pyrid-2-yl)-pyrrolidin-2,5-dione
(1)
M.p. 110–112°C, yield (62%). Anal. (C21H16N2O2) C,
H, N. TLC: Rf=0.76 (A), 0.92 (B). NMR (CDCl3):
3.78 (2H, s, CH2 imide), 7.32–7.70 (13H, m, arom),
8.83 (1H, d, pyrid). IR (cm −1): CꢀO 1778, 1712. UV u
(nm): 220, log m 4.23; u (nm): 258, log m 3.86.
3.2.9. 3-(3-Fluorophenyl)-1-(3-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (8)
3.2.3. 3,3-(Diphenyl)-1-(3-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (2)
M.p. 130–132°C, yield (58%). Anal. (C16H13N2O2F)
C, H, N. TLC: Rf=0.55 (A), 0.82 (B). NMR (CDCl3):
2.12, 2.19 (3H, 2s, CH3), 2.90–2.99 (1H, 2dd, CH2
imide), 3.12–3,24 (1H, dd, CH2 imide), 4.18–4.28 (1H,
d, t, CH imide), 7.18–7.39 (5H, m, arom), 7.62–7.72
(1H, d, pyrid), 8.42–8.58 (1H, d, pyrid). IR (cm−1):
CꢀO 1778, 1708. UV u (nm): 205, log m 4.18; u (nm):
260, log m 3.60.
M.p. 87–89°C, yield (58%). Anal. (C22H18N2O2) C,
H, N. TLC: Rf=0.70 (A), 0.87 (B). NMR (CDCl3):
1.99 (3H, s, CH3), 3.51–3,88 (2H, q, CH2 imide),
7.25–7.48 (11H, m, arom), 7.60–7,65 (1H, d, pyrid),
8.47–8.50 (1H, dd, pyrid). IR (cm−1): CꢀO 1776, 1716.
UV u (nm): 218, log m 4.13; u (nm): 254, log m 3.92.
3.2.4. 3,3-(Diphenyl)-1-(4-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (3)
3.2.10. 3-(2-Chlorophenyl)-1-(3-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (9)
M.p. 106–108°C, yield (60%). Anal. (C16H12N2O2Cl)
C, H, N. TLC: Rf=0.69 (A), 0.44 (C). NMR (CDCl3):
2.26, 2.32 (3H, 2s, CH3), 2.91–3.14 (1H, 2d, t, CH2
imide), 3.34–3.55 (1H, 2q, CH2 imide), 4.50–4.67 (1H,
2q, CH imide), 7.30–7.46 (4H, m, arom), 7.69–7.73
M.p. 114–116°C, yield (58%). Anal. (C22H18N2O2) C,
H, N. TLC: Rf=0.73 (A), 0.90 (B). NMR (CDCl3):
2.49 (3H, s, CH3), 2.67 (2H, s, CH2 imide), 7.08–7.48
(12H, m, arom), 8.51 (1H, d, pyrid). IR (cm−1): CꢀO
1766, 1712. UV u (nm): 220, log m 4.20; u (nm): 254,
log m 3.78.

J. Obniska et al. / Il Farmaco 54 (1999) 423–429
427
(1H, d, pyrid), 8.48–8.53 (1H, t, pyrid). IR (cm−1):
CꢀO 1774, 1712. UV u (nm): 202, log m 3.62; u (nm):
261 log m 3.09.
Disorders and Stroke (NINCDS), by testing procedures
which have been described earlier [10]. Phase I studies
of the investigated compounds involved three tests:
maximal electroshock seizure (MES), subcutaneous
pentetrazol (scMET), and neurological toxicity (TOX).
Phase I involved i.p. administration of the com-
pounds as suspensions in 0.5% methylcellulose. Phase I
was a qualitative assay involving a small number of
mice (1–4) at dose levels of 30, 100 and 300 mg/kg.
Promising compounds from phase I underwent phase
VIa. In phase VIa, compounds were administered orally
into rats at a dose of 50 mg/kg. The details of these
procedures have been published [10,11].
3.2.11. 3-(2-Methoxyphenyl)-1-(3-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (11)
M.p. 177–179°C, yield (65%). Anal. (C17H16N2O3) C,
H, N. TLC: Rf=0.63 (A), 0.37 (C). NMR (CDCl3):
2.25, 2.32 (3H, 2s, CH3), 2.89–3.04 (1H, d, t, CH2
imide), 3.10–3.36 (1H, q, t, CH2 imide), 3.83–3.89 (3H,
2s, OCH3), 4.11–4.20 (1H, q, t, CH imide),), 6.89–7.38
(5H, m, arom), 7.65–7.71 (1H, t, pyrid), 8.46–8.52 (1H,
t, pyrid). IR (cm−1): CꢀO 1772, 1712. UV u (nm): 204,
log m 3.81; u (nm): 262, log m 3.33.
3.4. Computational procedure
3.2.12. 3-(3-Methoxyphenyl)-1-(3-methyl-pyrid-2-yl)-
pyrrolidin-2,5-dione (12)
The X-ray structure analysis of some selected com-
pounds were published separately [5–7,12,15]. The re-
sults were then used in the modeling of remaining
molecules. The optimization of the geometries in the
global minimum found by molecular mechanics (PC-
MOD 4.0 [13] was performed using MNDO-PM3 ap-
proximation from MOPAC 6.0 [14] package of programs.
The MEP calculations were performed using in-house
written VMNDO program [7] in MNDO approxima-
tion. The calculations described above were conducted
for all molecules from Schemes 1 and 2 and are col-
lected in Table 1.
M.p. 131–133°C, yield (75%). Anal. (C17H16N2O3) C,
H, N. TLC: Rf=0.63 (A), 0.35 (C). NMR (CDCl3):
2.21, 2.24 (3H, 2s, CH3), 2.98–3.10 (1H, dd, CH2
imide), 3.40–3.49 (1H, 2q, CH2 imide), 3.81 (3H, s,
OCH3), 4.18–4.26 (1H, q, CH imide), 6.84–7.36 (5H,
m, arom), 7.66–7.70 (1H, dd, pyrid), 8.47–8.50 (1H, d,
pyrid). IR (cm−1): CꢀO 1778, 1712. UV u (nm): 204,
log m 3.75; u (nm): 262, log m 3.11.
3.3. Pharmacology
Preliminary pharmacological tests of all the synthe-
sized compounds 1–12 have been provided by the
Antiepileptic Drug Development (ADD) Program,
Epilepsy Branch, Neurological Disorders Program, Na-
tional Institutes of Neurological and Communicative
4. Results and discussion
As anticipated, the synthesized N-pyridyl derivatives
of 3,3-diphenylsuccinimides (1–6) were inactive. A the-
oretical test of activity (the depth of electrostatic poten-
tial minima in the vicinity of both carbonyl oxygens)
confirmed the inactivity of the screened compounds
(Table 1, Fig. 3). The results demonstrate that the
differences between the MEP minima close to both
carbonyl oxygens of the imide ring of the discussed
group are positive [12].
Table 1
The values of MEP at minima in vicinity of O1 and O4 of succin-
imides
In contrast to the above, compounds 1–6 being the
N-pyridyl derivatives of 3-phenylsuccinimides (7–12)
showed some anticonvulsant properties in phase I of
the screening project (Table 2). Compounds 7 and 10
were advanced to phase VI and were evaluated for their
oral activity in the rat by the ADD Program. Com-
pound 7 was active in a dose of 50 mg/kg in the MES
test (2/4 animals protected, 0/4 animals toxic at 0.5 h).
In the scMET test, that compound was only marginally
active (1/4 animals protected at 0.25 h and 0.5 h, 0/4
animals toxic at 0.25 h). Compound 10 was active in
the MES (1/4 animals protected at 0.25 h), and less
active in the scMET tests (1/4 animals protected at 0.25
h, 2/4 at 0.5 h, Table 3).
Comp.
V(O1)
V(O4)
DV=
Ref.
V(O1)−V(O4)
1
2
3
4
5
6
7
8
−16.05
−16.09
−16.12
−16.13
−16.01
−16.18
−14.17
−14.05
−14.06
−14.27
−14.28
−14.35
−16.33
−16.50
−16.32
−16.43
−16.45
−16.61
−13.93
−13.85
−13.86
−13.99
−14.03
−14.13
0.28
0.41
0.20
0.30
0.44
[12]
[12]
[12]
[12]
[12]
[12]
this work
0.43
−0.24
−0.20
−0.20
−0.28
−0.25
−0.22
9
10
11
12

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J. Obniska et al. / Il Farmaco 54 (1999) 423–429
Table 2
Anticonvulsant screening project (ASP) phase I test result in mice
Comp.
Dose (mg/kg)
Activity
a
MES
scMET b
0.5 h
Tox c
0.5 h
ASP d
Class
2
0.5 h
4 h
4 h
4 h
1
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
30
100
300
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
0/4
0/1
0/3
0/4
0/1
0/3
0/1
0/1
0/3
0/1
0/1
3/3
1/1
0/1
1/3
1/1
1/1
3/3
1/1
0/1
3/3
1/1
0/1
1/3
1/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/3
1/1
0/1
2/3
1/1
0/1
0/3
0/1
0/1
1/3
1/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/3
0/1
0/1
0/3
0/1
0/1
0/1
0/1
0/1
0/1
0/1
3/5
5/5
1/1
0/1
0/1
0/1
0/1
0/1
1/1
0/1
3/5
5/5
0/1
0/1
4/5
1/5
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/3
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/1
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
0/4
0/4
0/8
4/4
0/4
0/8
4/4
0/4
5/8
4/4
0/4
0/8
4/4
0/4
0/8
0/4
0/4
0/8
0/4
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/2
0/2
0/2
0/2
0/4
0/2
0/4
0/2
0/2
0/4
2/2
0/2
0/4
2/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
0/2
0/4
0/2
2
2
3
3
3
3
1
1
1
1
1
2
3
4
5
6
7
8
9
10
11
12
a Maximal electroshock test (number of animals protected/number of animals tested).
b Subcutaneous pentetrazol test.
c Toxicity (number of animals exhibiting toxicity/number of animals tested).
d The classifications are as follows: 1, anticonvulsant activity at 100 mg/kg or less; 2, anticonvulsant activity at doses greater than 100 mg/kg;
and 3, compound inactive at 300 mg/kg.
Table 3
Anticonvulsant screening project (ASP) phase VIa test results in rats (dose 50 mg/kg)
Comp.
MES
scMET
0.25 h
TOX
0.25 h
0.5 h
1 h
2 h
4 h
0.5 h
1 h
2 h
4 h
0.25 h
0.5 h
1 h
2 h
7
10
0/4
1/4
2/4
2/4
2/1
0/4
1/4
0/4
1/4
0/4
1/4
1/4
1/4
0/4
0/4
0/4
0/3
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
0/4
The application of MEP for an analysis of the anti-
convulsant activity showed that the differences MEP
minima close to both carbonyl oxygens of the imide
ring for compounds 7–12 are negative (Table 1, Fig. 3).
The results of the present study show that the MEP
calculation provides a signature which permits the dis-

J. Obniska et al. / Il Farmaco 54 (1999) 423–429
429
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epileptic Drug Development Program, Epilepsy Branch,
National Institute of Neurological Disorders and
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