Synthesis and pharmacological evaluation of new 1-[3-(4-arylpiperazin-1-yl) -2-hydroxypropyl]-pyrrolidin-2-one derivatives with anti-arrhythmic, hypotensive, and α-adrenolytic activity

Article abstract of DOI:10.1002/ardp.200700039

A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and evaluated for the binding affinity of the α₁ and α₂-adrenoceptors (AR) and for the antiarrhythmic and hypotensive activities of the compounds. The most potent and selective compound 1-[2-hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pK_i = 6.71 for α₁-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrenaline-induced arrhythmia in anaesthetized rats. Its ED₅₀ value equals 1.9 mg/kg (i.v.). Compounds with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substituents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of 5-10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in the second position of the propyl chain are critical structural features in determining the affinity of the compounds tested.

Full text of DOI:10.1002/ardp.200700039

466
Arch. Pharm. Chem. Life Sci. 2007, 340, 466–475
Full Paper
Synthesis and Pharmacological Evaluation of New 1-[3-(4-
Arylpiperazin-1-yl)-2-hydroxypropyl]-pyrrolidin-2-one
Derivatives with Anti-arrhythmic, Hypotensive, and
a-Adrenolytic Activity
Katarzyna Kulig1, Jacek Sapa2, Dorota Maciag3, Barbara Filipek2, and Barbara Malawska1
1 Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy,
Jagiellonian University Medical College, Krakꢀw, Poland
2 Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakꢀw,
Poland
3 Laboratory of Pharmacobiology, Faculty of Pharmacy, Jagiellonian University Medical College, Krakꢀw,
Poland
A series of novel arylpiperazines bearing a pyrrolidin-2-one fragment was synthesized and eval-
uated for the binding affinity of the a1- and a2-adrenoceptors (AR) and for the antiarrhythmic
and hypotensive activities of the compounds. The most potent and selective compound 1-[2-
hydroxy-3-[4-[(2-hydroxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one 8 binds with pKi = 6.71 for
a1-AR. Derivative 8 was also the most active in the prophylactic antiarrhythmic test in adrena-
line-induced arrhythmia in anaesthetized rats. Its ED50 value equals 1.9 mg/kg (i.v.). Compounds
with substituents such as a fluorine atom 4, a methyl 5, or a hydroxyl 8 group, or two substitu-
ents such as fluorine/chlorine atoms and methoxy groups in the phenyl ring, significantly
decreased the systolic and diastolic pressure in normotensive anesthetized rats at a dosages of
5–10 mg/kg (i.v.). It was found that the presence of the piperazine ring and a hydroxy group in
the second position of the propyl chain are critical structural features in determining the affin-
ity of the compounds tested.
Keywords: a-Adrenoceptor blocking activity / Antiarrhythmic / 1-[3-(4-Arylpiperazin-1-yl)-2-hydroxypropyl]-pyrrolidin-
2-one derivatives / Hypotensive activity / Molecular modeling /
Received: February 27, 2007; accepted: May 4, 2007
DOI 10.1002/ardp.200700039
nylalkylamines, piperidines, arylpiperazines, and related
Introduction
compounds [4–7]. In spite of the differences between
these classes of compounds, some common structural
elements for a1-AR have been found. According to the De-
Marinis' model [8], a typical a1-AR antagonist contains
three major features corresponding to a basic (positively
ionizable) nitrogen atom, an aromatic molecular por-
tion, and a moderately polar moiety. Two additional
sterically sensitive features have been identified within
the model defining the shape and size properties of the
ligands. Of the numerous structures that have been syn-
thesized in this field, the arylpiperazine fragment consti-
tutes one of the most versatile templates for obtaining
new molecules that show affinity for a1-AR. Recently, the
structural properties of many arylpiperazine derivatives
In the recent years, the search for novel and selective a1-
adrenoceptors (a1-ARs) antagonists has intensified,
mainly due to their therapeutic potential in the treat-
ment of hypertension and benign prostatic hyperplasia
(BPH) [1–3]. Recently, a number of a1-AR selective antago-
nists representing different structural classes of com-
pounds were disclosed. These include quinazolines, phe-
Correspondence: Dr. hab. Barbara Malawska, Department of Physico-
chemical Drug Analysis, Faculty of Pharmacy, Medical College Jagiello-
nian University, 9 Medyczna Str., 30-688 Krakꢀw, Poland.
E-mail: mfmalaws@cyf-kr.edu.pl
Fax: +48 12 657-0262
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Arch. Pharm. Chem. Life Sci. 2007, 340, 466–475
Pyrrolidin-2-one Derivatives
467
comparison of structures of the obtained compounds
and the selected a1-AR antagonist was carried out.
Taking into consideration the above presented phar-
macophore model for a1-AR antagonists, suggesting [12]
that a hydrophobic group larger than a methoxy sub-
stituent can be accommodated by a hydrophobic pocket
where the substituted phenyl ring binds to the pipera-
zine compounds with alkoxy moieties larger than a
methoxy group at the ortho-position of the phenyl ring
were obtained. The modifications in the arylpiperazinyl
moiety also included an introduction of one (2-fluoro-; 2-,
3-, or 4-hydroxy-; 2-methyl; 2-trifluoromethyl-) or two
different substituents (2,4-difluoro-; and 2-methoxy-5-
chlorophenyl-) into the phenyl ring. In order to verify the
role of the hydroxy group in the propyl chain, compound
16 with a hydroxy group blocked by a methyl group was
obtained. Finally, a more flexible analog of 1 was investi-
gated by synthesizing compound 17. The newly synthe-
sized compounds (as water-soluble hydrochlorides) were
tested for a1- and a2-ARs as well as for their antiarrhyth-
mic and hypotensive activity.
Figure 1. The pharmacophore model of a1-AR antagonists [12].
that possess affinity towards a1-ARs have been summar-
ized [9–11].
Based on these findings, a three-dimensional pharma-
cophore model for a1-AR antagonist among arylpipera-
zines was proposed [12] (Fig. 1).
In this model, the following structural properties of an
ideal a1-AR were suggested. They are a positively ioniz-
able group, corresponding to the more basic nitrogen
atom of the piperazine ring, and an ortho- or meta-substi-
tuted phenyl ring constituting the arylpiperazine sys-
tem. Moreover, a polar group able to provide a hydrogen-
bond acceptor feature incorporated or not incorporated
into the second heterocyclic terminal ring, is required at
the edge of the molecule, opposite to the arylpiperazine
moiety. Finally, a three- or four-carbon atom spacer repre-
senting the optimal polymethylene chain is used to con-
nect these two elements [12].
We have previously reported that a series of 1-[3-(4-aryl-
piperazin-1-yl)-2-hydroxy]- or 2-acetoxy]propyl-pyrrolidin-
2-one derivatives possess affinity for a1- and a2-ARs and
marked hypotensive and antiarrhythmic activities.
Among the compounds tested, the most active were 1-[2-
hydroxy-3(4-phenylpiperazin-1-yl)propyl]pyrrolidin-2-one
1 and those which contain the methoxy 2 or chloro 3 sub-
stituent in the ortho-position of the phenyl ring [13–15]. In
this context, thegoal ofour research was the development
of novel a-ARs antagonists, derivatives of arylpiperazine-
propyl-pyrrolidin-2-one. In order to better understand the
structure-activity relationship within the synthesized
compounds, amolecular study was undertaken.
Chemistry
As staring material for the synthesis of the new com-
pounds 4–17 the earlier described 1-(2,3-epoxypropyl)-
pyrrolidin-2-one was used [16]. Its aminolysis with N-sub-
stituted arylpiperazines and 1-phenylethylenediamine
yielded the relevant 1-[3-(4-arylpiperazin-1-yl)-2-hydroxy]-
propylpirolidin-2-ones 4–14 and compound 17. The
required 1-(2-hydroxyphenyl)piperazine was synthesized
according to the method described in the literature [17]
by heating 1-(2-methoxyphenyl)-piperazine in 47% HBr
(57% yield). The 1-[2-hydroxy-4-(2-isopropyloxyphenylpi-
perazin-1-yl)propyl]pyrrolidin-2-one 15 was obtained
through the reaction of compound 8 with isopropyl bro-
mide in acetone, in the presence of potassium carbonate
and potassium iodide. The 1-[2-methoxy-4-(phenylpipera-
zin-1-yl)propyl]pyrrolidin-2-one 16 was obtained through
the reaction between compound 1 and methyl iodide in
the presence of 1,4,7,10,13-pentaoxacyclopentadecane
(15-crown-5) as a catalyst [18]. Yields for these reactions
were in the range from 52 to 79%. The structures of the
new compounds were confirmed by elemental analysis
and spectral data. For the pharmacological assays, com-
pounds 4–17 were converted into their water-soluble
hydrochlorides. Synthetic routes leading to these new
compounds 4–17 are presented in Fig. 2.
In this work, we report on the synthesis and in-vitro
and in-vivo pharmacological studies of a series of new
analogues of compounds 1–2; for them, the influence of
the modifications in the arylpiperazinyl moiety on their
a1- and a2-ARs affinity and their antiarrhythmic and Pharmacology
hypotensive properties were studied. Moreover, a pre- In the presented study, several pharmacological tests
liminary molecular modeling study consisting in the were carried out to assess a1- and a2-AR affinity as well as
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K. Kulig et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 466–475
Table 1. Affinity towards different a-AR subtypes in rat cerebral
cortex.
Compound
pKi [3H]prazosin
pKi [3H]clonidine
(a1 rec.)
(a2 rec.)
1 [13]
2 [14]
3 [14]
4
5
6
7
8
9
10
11
12
13
14
15
16
17
5.72
5.89
6.57
5.80
6.00
5.70
6.15
6.71
4.63
4.95
5.36
4.07
6.14
6.45
6.25
4.17
5.41
4.54
4.39
4.79
5.89
6.15
6.68
5.96
5.64
4.31
4.81
5.21
5.64
6.11
6.00
5.85
5.27
5.80
K1 value was obtained from three experiments.
Reagents and conditions: a; 1-propanol, reflux, 12 h; b; 1-propanol, reflux, 8-12 h; c;
CH3I, NaH, 15-crown-5, toluene, 708C, 6 h; d; isopropyl bromide, KI, K2CO3, acetone,
reflux, 24 h. All compounds were isolated as hydrochloride salts using HClgas in anhy-
drous EtOH.
Table 2. The prophylactic antiarrhythmic activity in adrenaline-
induced arrhythmia in anaesthetized rats. (Route of administra-
tion: intravenously.)
Figure 2. Synthesis route of compounds 1–17.
Compound
ED50 (mg/kg)
1 [13]
2 [14]
3 [14]
4
5
6
7
8
11
13
14
15
7.6 (6.9–8.4)
12 (9.7–14.8)
2.7 (1.95–3.7)
5.2 (3.8–6.4)
8.9 (7.1–10.2)
18.2 (13.2–22.4)
3.7 (2.4–4.8)
1.9 (1.1–2.6)
7.6 (5.5–8.4)
9.8 (5.9–14.2)
12.3 (8.8–16.1)
6.2 (4.9–7.4)
3.4 (2.6–4.4)
1.05 (0.64–1.73)
antiarrhythmic and hypotensive activity of novel pyrroli-
din-2-ones.
The pharmacological profile of the new compounds
was evaluated by radioligand-binding assays (ability to
displace [3H]prazosin or [3H]clonidine from a1- and a2-ARs,
respectively) on rat cerebral cortex [19, 20]. All tested
compounds displaced [3H]prazosin from cortical binding
sites (pKi = 4.07–6.71) and [3H]clonidine (pKi = 4.31–6.68).
The obtained results are presented in Table 1.
It is known that a1-AR play many roles in the myocar-
dium ranging from positive inotropic and chronotropic
effects, through ischemic preconditioning to arrhythmo-
genesis and cardiac hypertrophy [21, 22]. For example,
the nonselective and selective a-adrenoceptor antagonist
(phentolamine and prazosin) abanoquil, a highly selec-
tive a1A-receptor blocker, prevented arrhythmias induced
by adrenaline or cocaine infusions [24, 24]. Many studies
also implicate adrenoceptors in the formation of arrhyth-
mia during myocardial ischemia and reperfusion in the
isolated heart [25]. It was also shown that a1-blocking
drugs such as prazosin and phentolamine are also effec-
tive against ischemia-induced arrhythmias in a variety of
animal models [26, 27]. Taking the above into considera-
tion, the prophylactic antiarrhythmic activity of com-
pounds 4–17 was determined using a model of adrena-
line-induced arrhythmia in rats [28]. Intravenous injec-
Tolazoline
Propranolol
tions of adrenaline at a dose of 20 lg/kg caused reflex bra-
dycardia (100%), supraventricular and ventricular extra-
systoles (100%), bigeminy, and ventricular tachycardia
(50%) in rats, which led to the death of approx. 50% of ani-
mals within 10 l 5 min. Compounds 4–8, 11, and 13–15
injected intravenously 15 min before the adrenaline
administration diminished the occurrence of extrasys-
toles and reduced mortality. The ED50 value is presented
in Table 2. These data show that compound 8 was the
most active one; its ED50 value is equal to 1.9 mg/kg.
The hypotensive activity of compounds 4–17 was
determined after i.v. administration to normotensive
anaesthetized rats in doses of 5–10 mg/kg. The results
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Pyrrolidin-2-one Derivatives
469
Table 3. The hypotensive activity of tested compounds in anaesthetized normotensive rats following i.v. administration.
Compound Dose (mg/kg) Blood pres-
Time of observation (min)
sure (mmHg
l S.E.M)
0
5
10
20
30
60
4
5
10
10
5
systolic
diastolic
systolic
diastolic
systolic
diastolic
systolic
diastolic
systolic
diastolic
148 l 9.9
123 l 11
140 l 10
120 l 11
142 l 9.5
118 l 19**
100 l 19**
110 l 8***
101 l 10***
113 l 15.5**
128 l 19*
115 l 17
111 l 13** 129 l 10*
110 l 9*
121 l 13*
111 l 11.5* 111 l 14*
122.5 l 3.5* 129 l 8.5
111 l 1.5* 117 l 2.5
120 l 8.9** 129 l 9*
102.4 l 8.2* 105 l 4*
127 l 15*
115 l 17
139 l 16
120 l 10
129 l 7*
112 l 11
129 l 17
118 l 13
128.5 l 4
116 l 4
139 l 18
122 l 17
134 l 11
114 l 8
129 l 16
116 l 14
128 l 1
116.5 l 1
135 l 6
114.7 l 5
115 l 8
124 l 18*
8
129 l 11.5 104 l 13**
13
14
10
10
132 l 3.5
118 l 4.5
145 l 6
123 l 2*
103 l 5*
121 l 5.5**
101 l 6.9*
136 l 4
115 l 6.2
116.5 l 3
* p a 0.05; ** p a 0.02; *** p a 0.01.
Figure 3. The effect of compound 5 on the blood pressure
response to epinephrine, norepinephrine, methoxamine, and tyr-
amine.
Figure 5. The effect of compound 8 on the blood pressure
response to epinephrine, norepinephrine, methoxamine, and tyr-
amine.
Figure 4. The effect of compound (7) on the blood pressure
response to epinephrine, norepinephrine, methoxamine and tyr-
amine.
Figure 6. The effect of compound (13) on the blood pressure
response to epinephrine, norepinephrine, methoxamine and tyr-
amine.
are presented in Table 3. It was found that only com-
pounds 4, 5, 8, 13, and 14 significantly decreased systolic
and diastolic pressure. The observed effect persisted for
about 20 min.
In order to examine the mechanism of the hypotensive
effects of these compounds, their influence on the
pressor responses to epinephrine, norepinephrine,
methoxamine, and tyramine were studied. These com-
pounds administered intravenously to rats in the follow-
ing doses: epinephrine 2 lg/kg, norepinephrine 2 lg/kg,
methoxamine 150 lg/kg, tyramine 200 lg/kg caused a
pressor response. Compounds 5, 7, 8, 13, and 14 adminis-
tered intravenously in doses of 5 mg/kg antagonized the
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470
K. Kulig et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 466–475
affinity, compound 15 (1-[2-hydroxy-3-[4[(2-iso-propyloxy-
phenyl)piperazin-1-yl]propyl]pyrrolidin-2-one) had affin-
ity four times higher than that of the reference compound
1.
Among the compounds tested, higher affinity for a1-AR
was displayed by compound 8, pKi = 6.71, bearing the
hydroxy substituent in the ortho-position in the phenylpi-
perazine moiety. Higher affinity for a2-adrenoceptors was
exhibited by compound 6 (1-[2-hydroxy-3-[4[(3-triflouro-
methylphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one) pKi
= 6.68. It is interesting to note that compound 8 was the
sole compound characterized by selectivity for a1-AR
with respect to a2-AR, (a2/a1 ratio 12). Among the isomers
with a methoxy substituent in the phenyl ring (11, 12,
and 2), affinity for a1-AR increased in the order: para-,
meta-, ortho-. The addition of a second substituent in the
phenyl ring 13, 14 caused (in comparison with the parent
compounds 4 and 2) further increase in the a1-AR binding
affinity. The effect of protecting the hydroxy group in the
second position of the propyl chain of compound 1 was
observed as a decrease in the affinity of compound 16 for
a1-AR and an increase for a2-AR, respectively. A similar
effect was observed when the piperazine ring of com-
pound 1 was substituted by ethyldiamine 17.
Figure 7. The effect of compound 14 on the blood pressure
response to epinephrine, norepinephrine, methoxamine, and tyr-
amine.
In order to better define the structure-activity relation-
ship within the investigated compounds, a molecular
modeling study was undertaken. The aim of this
approach was the identification of a pharmacophore,
which is a template derived from the structure of these
compounds, and represents the geometry of the receptor
Figure 8. The effect of compound 15 on the blood pressure
response to epinephrine, norepinephrine, methoxamine, and tyr-
amine.
pressor response elicited by epinephrine, norepinephr- site as a collection of functional groups in 3D space. This
ine, and methoxamine (Figs. 3–7) statistically signifi- work was based on the above presented pharmacophore
cantly. Only compound 15 administered intravenously model for a1-AR, which includes three features: an aro-
in a dose of 5 mg/kg decreased the systolic pressor matic region, a positively ionizable group, and a hydro-
response evoked by epinephrine statistically significant gen-bond acceptor (Fig. 9). The compounds obtained
(Fig. 8). Compounds 4, 6, 11 had no statistically signifi- were modeled and minimized using the PM5 (MOPAC)
cant influence on the systolic pressor response generated method of the CAChe program [29]. Conformational anal-
by epinephrine, norepinephrine, methoxamine, and tyr- ysis has been performed by randomly changing five tor-
amine.
sion angles common to all molecules. Although this
approach explores only a part of all possible conforma-
tions, the results gave an estimation of the range of
energy in the geometry of isolated molecules. Finally, the
geometry of calculated conformers was optimized. The
Results and discussion
All the newly synthesized compounds 4–17 were found to obtained values are presented in Table 4.
possess an affinity toward a1- and a2-ARs that was compa-
The distances and angle between pharmacophoric fea-
rable to or higher than the affinity of the earlier reported tures measured for the tested compounds (Fig. 10) fall in
compounds 1–3. As expected, replacing the ortho- the range: a: 5.958–9.176 ꢀ, b: 3.728–4.903 ꢀ, c: 2.940–
methoxy substituent in the phenylpiperazine moiety of 5.728 ꢀ, and ABC: 126.20–170.758. It was found that pro-
compound 2 with larger alkoxy groups enhanced the tecting the hydroxy group with a methyl moiety 16 in
affinity. In fact, while compound 7 (1-[2-hydroxy-3-[4[(2- the second position of the propyl chain of compound 1
ethoxyphenyl)piperazin-1-yl]propyl]pyrrolidin-2-one) ex- had in particular influence on the contraction of the dis-
hibited an approximately threefold improvement in tance between the protonable nitrogen atom and hydro-
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Arch. Pharm. Chem. Life Sci. 2007, 340, 466–475
Pyrrolidin-2-one Derivatives
471
Figure 9. The pharmacophore model of a1-AR antagonists pro-
posed for arylpiperazynepropylpyrrolidin-2-one derivatives.
Figure 10. Superimposition of compounds 8 and 12, which dis-
played the highest and lowest a1-AR affinity.
Table 4. The angle (8) and distances (ꢁ) between pharmaco-
phore features for compounds 1–17.
Compound a (ꢀ)
b (ꢀ)
c (ꢀ)
ABC (8)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
9.117
9.176
8.912
7.755
8.932
8.967
8.883
8.884
8.704
8.702
8.383
8.657
8.841
8.697
8.755
5.958
9.877
4.273
4.043
3.880
4.035
4.244
4.135
4.107
4.111
3.885
3.882
4.127
3.876
3.989
4.034
4.065
3.728
4.903
5.183
5.196
5.728
5.035
4.875
5.046
5.035
5.044
4.973
4.975
5.103
4.970
4.980
4.979
5.032
2.940
4.986
148.13
166.50
135.23
117.10
156.59
149.73
149.37
132.48
158.45
158.38
130.21
156.06
160.49
161.50
140.83
126.20
170.75
Figure 11. Superimposition of compounds 6 and 9, which dis-
played the highest and lowest a2-AR affinity.
gen-bond acceptor (c = 2.940 ꢀ). The introduction of an
alkoxy substituent in the second position of the phenyl
ring caused a decrease of the angle ABC in the following
order: methyl 2, ethyl 7, and iso-propyl 15. It is also worth
noting that among the three isomers with the hydroxyl
group in the phenyl ring, the angle between the pharma-
cophoric features for meta 9 and para 10 isomers which
displayed lower affinity for a-AR was higher (ABC =
158.458 9, ABC = 158.388 10) than that of the ortho-one 8
(ABC = 132.458). The importance of the presence the phe-
nylpiperazine fragment in the tested series was also con-
firmed in molecular modeling studies. In the case of the
To obtain additional information concerning the
shape of the investigated molecules, the compounds
which displayed the highest and lowest affinity for a1
and a2-ARs were chosen for superimposition. The atoms
(except hydrogen atoms) common to these molecules
were selected for the fitting procedure. Their similarity
was calculated as a RMS fit. The RMS routine provided
estimates of how closely molecules fit to each other. The
lower the RMS value, the better the similarity. The RMS
deviations for each group are as follows: 0.7773 ꢀ (com-
pounds 8 and 12, a1-AR; Fig. 10) and 0.8681 ꢀ (compounds
6 and 9, a2-AR; Fig. 11). Comparison of the above com-
pounds showed similarity in the orientation of the pyrro-
lidin-2-one ring and the propyl chain, while the phenylpi-
perazine fragment possessed different orientation. These
results confirm that the phenylpiperazine group is an
important structural unit for their activity.
1-phenylethyldiamine derivative 17,
a
significant
increase of the angle between the pharmacophoric fea-
tures was observed (ABC = 170.758). The obtained results
have shown that the character of the substituent in the
second position of the phenyl ring could be essential for
their a1-AR affinity.
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Compounds: [3H]Clonidine (Amersham), epinephrine (adrena-
linum hydrochloricum, Polfa, Warschaw, Poland), norepinephr-
ine (Levonor, Polfa), methoxamine (Sigma, Aldrich Chem-
ie GmbH, Mꢁnchen, Germany), [3H]prazosin (Amersham), tyr-
amine (Sigma/Aldrich), sodium heparin (Polfa), thiopental
sodium (Biochemie GmbH, Vienna, Austria). Reference com-
pounds: compound 1 was used as a reference.
Conclusion
In summary, the synthesis of several new 1-[3-(4-arylpiper-
azin-1-yl)propyl]pyrrolidin-2-one derivatives is described.
As a result, each compound was found to possess affinity
for a1-AR comparable or higher than the affinity of the
reference compound 1. Some structural features of these
derivatives have been demonstrated as important for the
affinity for a1-ARs. The hydroxyl group at the ortho-posi-
tion of the phenylpiperazine moiety 8 led to the best a1-
AR affinity and selectivity profile. It was also shown that
the ortho-position could play a crucial role in the
improvement of the a1-AR antagonist properties in terms
of affinity and selectivity. The presence of a piperazine
ring and a hydroxy group in the second position of the
propyl chain is a critical structural feature in determin-
ing the affinity of compounds 4–17. In fact, as demon-
strated by binding and molecular modeling studies,
blocking the hydroxy group in the second position of the
propyl chain by a methyl group or replacing the pipera-
zine ring with ethylenediamine led to compounds with
lower affinity for a1-AR than their parent compounds.
Our results indicate that compounds 4-8 and 11–15 pre-
vented the cardiac arrhythmia caused by administration
of adrenaline and that this effect was more potent than
its hypotensive action. The pharmacological results and
binding studies suggested that the antiarrhythmic and/
or hypotensive effects of these compounds were related
to their adrenolytic properties. More extensive structure-
activity relationship studies are in progress and will be
reported in due course.
General procedure for the synthesis of 1-(2-hydroxy-3-
substituted aminopropyl)pyrrolidin-2-one 4–14 and 17
A solution of 1.4 g (10 mmol) of 1-(2,3-epoxypropyl)pyrrolidin-2-
one and 10 mmol of the corresponding amine in n-propanol
(20 mL) was heated under reflux for 12 h. The progress of the
reaction was monitored by TLC. After evaporating the solvent,
the oily residue was dissolved in anhydrous EtOH and then EtOH
saturated with HCl gas was added until the mixture became
acidic. The obtained precipitate was crystallized from EtOH.
1-{3-[4-(2-Fluorophenyl)piperazin-1-yl]-2-hydroxypropyl}-
pyrrolidin-2-one dihydrochloride 4
Yield: 65.4%. Anal. Calc. for C17H24FN3O262HCl; Mr 394.40; mp.
185.0–186.68C; TLC Rf = S1(0.43), S2(0.32); MS (70 eV), m/z (%) 321
(5.23) [M+], 303 (12.4), 194 (100), 179 (5.6), 98 (8.2), 70 (32.8); 1H-
NMR ([d6]-DMSO): d = 1.94 (qw, CH2CH2CH2, 2H), 2.28–2.37 (m,
CH2CO, NCH2CH2, 4H), 2.45–2.59 (m, CH2 piper., 4H), 2.78–2.88
(m, CH2 piper., 4H), 3.20 (dd, CH2CH2N, 2H), 3.4 (s, OH, 1H), 3.51–
3.63 (m, CH2CH2N, CH, 3H), 6.84–7.00 (m, arom, 4H).
1-[2-Hydroxy-3-(4-o-tolylpiperazin-1-yl)-propyl]pyrrolidin-
2-one dihydrochloride 5
Yield: 68.9%. Anal. Calc. for C18H27N3O262HCl; Mr 390.40; mp.
189.3–189.78C ; TLC Rf = S1(0.12), S2(0.65); MS (70 eV), m/z (%) 317
1
(2.67) [M+], 299 (8.5), 190 (100), 179 (8.1), 98 (12.2), 70 (43.7); H-
NMR ([d6]-DMSO): d = 1.98 (qw, CH2CH2CH2, 2H), 2.19–2.27 (m,
CH2CO, NCH2CH2, 4H), 2.35 (s, CH3, 3H), 2.55–2.63 (m, CH2 piper.,
4H), 2.85-2.98 (m, CH2 piper., 4H), 3.15 (dd, CH2CH2N, 2H), 3.37 (s,
OH, 1H), 3.53–3.70 (m, CH2CH2N, CH, 3H), 6.47–6.88 (m, arom,
4H).
The study was supported by the Polish Ministry of Science and
Higher Education, grant no. 3 P05 F 03622.
1-{2-Hydroxy-3-[4-(2-trifluoromethylphenyl)piperazin-1-
yl]-propyl}-pyrrolidin-2-one dihydrochloride 6
Yield: 56.3%. Anal. Calc. for C18H24F3N3O262 HCl; Mr 444.41; mp.
167.3–168.78C; TLC Rf = S1(0.71), S2(0.62); MS (70 eV), m/z (%) 371
Experimental
1
(1.43) [M+], 353 (9.2), 243 (100), 179 (5.9), 98 (23.9), 70 (41.9); H-
Chemistry
NMR ([d6]-DMSO): d = 1.96 (qw, CH2CH2CH2, 2H), 2.21–2.32 (m,
CH2CO, NCH2CH2, 4H), 2.51–2.68 (m, CH2 piper, 4H), 2.75–2.88
(m, CH2 piper, 4H), 3.21 (dd, CH2CH2N, 2H), 3.41 (s, OH, 1H), 3.59–
3.67 (m, CH2CH2N, CH, 3H), 6.34–6.71 (m, arom, 4H).
Melting points were determined in open glass capillaries on the
Bꢁchi (353 m.p.) apparatus and are uncorrected (Bꢁchi Labor-
technik, Flawil, Switzerland). Elemental analyses (C, H, N) were
carried out within 0.4% of the theoretical values. 1H-NMR spectra
were recorded on a Varian Mercury VX 300 MHz PFG instrument
(Varian Inc., Palo Alto, CA, USA) in [d6]-DMSO at ambient temper-
ature using the solvent signal as an internal standard. Mass spec-
tra were measured at 70 eV with a 95 MAT S Sigimann spectrom-
eter (Sigimann, USA). Thin layer chromatography was carried
out on Merck silica gel pre-coated F254 plates (0.2 mm; Merck,
Darmstadt, Germany) using: S1: chloroform/acetone (1:1), S2:
chloroform/methanol/acetic acid (60:10:5), and S3: methanol/
25% ammonia (98:2) as a developing system. The plates were
visualized with UV light or iodine solution (0.05 M in 10% HCl).
1-{3-[4-(2-Ethoxyphenyl)piperazin-1-yl]-2-hydroxy-
propyl}-pyrrolidin-2-one dihydrochloride 7
Yield: 85.3%. Anal. Calc. for C19H29N3O362 HCl; Mr 420.38; mp.
187.5–188.78C; TLC Rf = S1(0.63), S2(0.45); MS (70 eV), m/z (%) 347
(2.13) [M+], 332 (5.9), 329 (10.5), 318 (6.78), 315 (3.8), 300 (14.2),
205 (100), 179 (4.2), 98 (31.4), 70 (52.9); 1H-NMR ([d6]-DMSO): d =
1.33 (t, CH3, J = 3.5 Hz, 3H), 1.96 (qw, CH2CH2CH2, 2H), 2.18–2.25
(m, CH2CO, NCH2CH2, 4H), 2.61–2.72 (m, CH2 piper, 4H), 2.80–
2.93 (m, CH2 piper, 4H), 3.19 (dd, CH2CH2N, 2H), 3.32 (s, OH, 1H),
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Arch. Pharm. Chem. Life Sci. 2007, 340, 466–475
Pyrrolidin-2-one Derivatives
473
3.53–3.63 (m, CH2CH2N, CH, 3H), 3.98 (qw, CH2, 2H), 6.34–6.71
(m, arom, 4H).
(1.05) [M+], 321 (8.2), 211 (100), 190 (45.4) 179 (12.5), 98 (41.7), 70
(25.1); H-NMR ([d6]-DMSO): d = 1.96 (qw, CH2CH2CH2, 2H), 2.46–
1
2.68 (m, CH2CO, NCH2CH2, 4H), 2.75–2.77 (m, CH2 piper, 4H),
2.92–3.01 (m, CH2 piper, 4H), 3.11 (dd, CH2CH2N, 2H), 3.36 (s, OH,
1H), 3.45–3.51 (m, CH2CH2N, CH, 3H), 6.39–6.52 (m, arom, 3H).
1-{2-Hydroxy-3-[4-(2-hydroxyphenyl)piperazin-1-yl]-
propyl}-pyrrolidin-2-one dihydrochloride 8
Yield: 57.5%. Anal. Calc. for C17H25N3O362 HCl; Mr 392.33; mp.
209.8–11.38C; TLC Rf = S2(0.76), S3(0.52); MS (70 eV), m/z (%) 319
1-{3-[4-(4-Chloro-2-methoxyphenyl)piperazin-1-yl]-2-
hydroxypropyl}-pyrrolidin-2-one dihydrochloride 14
1
(3.48) [M+], 301 (7.9), 191 (100), 179 (6.8), 98 (38.4), 70 (49.1); H-
NMR ([d6]-DMSO): d = 1.96 (qw, CH2CH2CH2, 2H), 2.21–2.35 (m,
CH2CO, NCH2CH2, 4H), 2.69–2.74 (m, CH2 piper, 4H), 2.85–2.99
(m, CH2 piper, 4H), 3.25 (dd, CH2CH2N, 2H), 3.26 (s, OH, 1H), 3.43–
3.58 (m, CH2CH2N, CH, 3H), 6.42–6.64 (m, arom, 4H).
Yield: 78.3%. Anal. Calc. for C18H26N3O3Cl62 HCl; Mr 440.80; mp.
145.2–146.88C; TLC Rf = S1(0.24), S2(0.65); MS (70 eV), m/z (%) 369
(0.3) [M++2] 367 (1.05) [M+], 352 (3.1), 349 (5.6), 239 (100), 190 (45.4)
1
179 (12.5), 98 (41.7), 70 (25.1); H-NMR ([d6]-DMSO): d = 1.96 (qw,
CH2CH2CH2, 2H), 2.32–2.48 (m, CH2CO, NCH2CH2, 4H), 2.65–2.79
(m, CH2 piper, 4H), 2.82–2.99 (m, CH2 piper, 4H), 3.07 (dd,
CH2CH2N, 2H), 3.43 (s, OH, 1H), 3.57–3.68 (m, CH2CH2N, CH, 3H),
3.79 (s, CH3, 3H), 6.29–6.58 (m, arom, 3H).
1-{2-Hydroxy-3-[4-(3-hydroxyphenyl)piperazin-1-yl]-
propyl}-pyrrolidin-2-one dihydrochloride 9
Yield: 78.3%. Anal. Calc. for C17H25N3O362 HCl; Mr 392.33; mp.
132,3–133,88C; TLC Rf = S1(0.45), S2(0.63); MS (70 eV), m/z (%) 319
(2.32) [M+], 301 (6.3), 191 (100), 179 (5.4), 98 (41.2), 70 (49.1); H-
1
1-[2-Hydroxy-3-(2-phenylaminoethyl)amino-
NMR ([d6]-DMSO): d = 1.96 (qw, CH2CH2CH2, 2H), 2.26–2.38 (m,
CH2CO, NCH2CH2, 4H), 2.70–2.79 (m, CH2 piper, 4H), 2.79–2.85
(m, CH2 piper, 4H), 3.13 (dd, CH2CH2N, 2H), 3.46 (s, OH, 1H), 3.58–
3.72 (m, CH2CH2N, CH, 3H), 6.06–6.15 (m, arom, 4H).
propyl]pyrrolidin-2-one dihydrochloride 1
Yield: 20.5%. Anal. Calc. for C15H23N3O262 HCl; Mr 350.29; mp.
145.3–146.28C; TLC Rf = S2(0.17), S3(0.35); MS (70 eV), m/z (%) 277
(3.05) [M+], 259 (1.7), 135 (100), 98 (32.6), 70 (36.1); 1H-NMR ([d6]-
DMSO): d = 1.91 (qw, CH2CH2CH2, 2H), 2.22–2.36 (m, CH2CO,
NCH2CH2, 4H), 2.88 (t, CH2, 2H), 3.07 (dd, CH2CH2N, 2H), 3.32 (t,
CH2, J = 4.8 Hz, 2H), 3.43 (s, OH, 1H), 3.57–3.68 (m, CH2CH2N, CH,
3H), 3.79 (s, CH3, 3H), 6.43–7.04 (m, arom, 4H).
1-{2-Hydroxy-3-[4-(4-hydroxyphenyl)piperazin-1-yl]-
propyl}-pyrrolidin-2-one dihydrochloride 10
Yield: 45.3%. Anal. Calc. for C17H25N3O362 HCl; Mr 392.33; mp.
189.2–190,28C; TLC Rf = S1(0.54), S2(0.62); MS (70 eV), m/z (%) 319
1
(1.28) [M+], 301 (5.9), 191 (100), 179 (8.2), 98 (48.9), 70 (39.5); H-
1-{2-Hydroxy-3-[4-(2-isopropoxyphenyl)piperazin-1-yl]-
NMR ([d6]-DMSO): d = 1.96 (qw, CH2CH2CH2, 2H), 2.26–2.38 (m,
CH2CO, NCH2CH2, 4H), 2.70–2.79 (m, CH2 piper, 4H), 2.79–2.85
(m, CH2 piper, 4H), 3.13 (dd, CH2CH2N, 2H), 3.46 (s, OH, 1H), 3.58–
3.72 (m, CH2CH2N, CH, 3H), 6.42–6.55 (m, arom, 4H).
propyl}-pyrrolidin-2-one dihydrochloride 15
To a solution of 5.2 mmol (1.66 g) of 8 in 60 mL acetone
5.2 mmol (0.64 g) isopropylbromide and 10 mmol (1.38 g) anhy-
drous K2CO3 and 0.03 mmol (0.005 g) of dry potassium iodide
were added. The reaction mixture was stirred at room tempera-
ture for 24 h. Then, the inorganic salt was filtered, the solvent
was evaporated, and the oily residue was purified by column
chromatography using a mixture of methanol and ammonia
(98:2). After evaporating the solvent, the oily residue was dis-
solved in EtOH and then EtOH saturated with HCl gas was added
until the mixture became acidic. The obtained precipitate was
crystallized from EtOH.
1-{2-Hydroxy-3-[4-(3-methoxyphenyl)piperazin-1-yl]-
propyl}-pyrrolidin-2-one dihydrochloride 11
Yield: 76.2%. Anal. Calc. for C18H27N3O362 HCl; Mr 405.92; mp.
190.2-191.68C; TLC Rf = S1(0.21), S2(0.63); MS (70 eV), m/z (%) 333
(0.98) [M+], 318 (3.7), 315 (5.9), 205 (100), 190 (37.1) 179 (9.4), 98
1
(32.1), 70 (31.5); H-NMR ([d6]-DMSO): d = 1.96 (qw, CH2CH2CH2,
2H), 2.36–2.48 (m, CH2CO, NCH2CH2, 4H), 2.65–2.71 (m, CH2
piper, 4H), 2.82–2.97 (m, CH2 piper, 4H), 3.21 (dd, CH2CH2N, 2H),
3.46 (s, OH, 1H), 3.52–3.68 (m, CH2CH2N, CH, 3H), 3.73 (s, CH3,
3H), 5.99–6.43 (m, arom, 4H).
Yield: 61.3%. Anal. Calc. for C20H31N3O362 HCl; Mr 434.41; mp.
194.4–195.68C; TLC Rf = S2(0.53), S3(0.57); MS (70 eV), m/z (%) 361
(2.5) [M+], 343 (7.6), 233 (100), 190 (43.7) 179 (11.8), 98 (47.1), 70
(25.1); 1H-NMR ([d6]-DMSO): d = 1.38 (d, CH3, 6H), 1.96 (qw,
CH2CH2CH2, 2H), 2.32–2.48 (m, CH2CO, NCH2CH2, 4H), 2.65–2.79
(m, CH2 piper, 4H), 2.82–2.99 (m, CH2 piper, 4H), 3.07 (dd,
CH2CH2N, 2H), 3.43 (s, OH, 1H), 3.57–3.68 (m, CH2CH2N, CH, 3H),
4.04 (t, CH, J = 3.8 Hz, 1H), 6.78–7.12 (m, arom, 4H).
1-{2-Hydroxy-3-[4-(4-methoxyphenyl)piperazin-1-yl]-
propyl}-pyrrolidin-2-one dihydrochloride 12
Yield: 75.2%. Anal. Calc. for C18H27N3O362 HCl; Mr 405.92; mp.
165.2–166.98C; TLC Rf = S1(0.56), S2(0.48); MS (70 eV), m/z (%) 333
(1.05) [M+], 318 (2.1), 315 (4.1), 205 (100), 190 (42.1) 179 (11.7), 98
1-[2-Methoxy-3-(4-phenylpiperazin-1-yl)propyl]pyrrolidin-
2-one dihydrochloride 16
1
(39.5), 70 (21.8); H-NMR ([d6]-DMSO): d = 1.96 (qw, CH2CH2CH2,
2H), 2.36–2.48 (m, CH2CO, NCH2CH2, 4H), 2.65–2.71 (m, CH2
piper, 4H), 2.82–2.97 (m, CH2 piper, 4H), 3.21 (dd, CH2CH2N, 2H),
3.46 (s, OH, 1H), 3.52–3.68 (m, CH2CH2N, CH, 3H), 3.83 (s, CH3,
3H), 6.32–6.55 (m, arom, 4H).
NaH (6 mmol; 60% suspension in mineral oil) and 0.5 mmol
(0.1 mL) of 1,4,7,10,13-pentaoxacyclopentadecane (15-crown-5)
were added to a solution of 5 mmol (1.51 g) 1-[2-hydroxy-3-(4-phe-
nyl-piperazin-1-yl)-propyl]-pyrrolidin-2-one 1 in 10 mL dry tol-
uene. The reaction was stirred at room temperature for 8 h.
Then, 10 mmol (1.9 g) of iodomethane was added and the mix-
ture was heated on an oil bath at 708C for 20 h. After completion
of hydrolysis, the solution was cooled and toluene was evapo-
rated. The remaining oily residue was dissolved in 20 mL of ace-
1-{3-[4-(2,4-Difluorophenyl)piperazin-1-yl]-2-
hydroxypropyl}-pyrrolidin-2-one dihydrochloride 13
Yield: 65.2%. Anal. Calc. for C17H23N3O2F262 HCl; Mr 412.31; mp.
154.3–155.88C; TLC Rf = S1(0.42), S2(0.65); MS (70 eV), m/z (%) 339
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474
K. Kulig et al.
Arch. Pharm. Chem. Life Sci. 2007, 340, 466–475
tone; 30 mL 2M HCl was added and the mixture was heated on
an oil bath at 708C for 2 h. After completion of hydrolysis, the
solution was cooled and acetone was evaporated in vacuo. Subse-
quently, 50 mL of ethyl ether was added to the residue. The
water layer was washed twice with 50 mL ethyl ether, alkalized
with Na2CO3, and twice extracted with 25 mL dichloromethane.
The combined organic layer was dried with anhydrous Na2SO4
and evaporated. The obtained oil was purified by column chro-
matography using a mixture of methanol and 25% ammonia
(98:2) as a solvent. After evaporating the solvent, the oily residue
was dissolved in EtOH and then EtOH saturated with HCl gas was
added until the mixture became acidic. The obtained precipitate
was crystallized from EtOH.
Yield: 21.3%. Anal. Calc. for C18H27N3O262 HCl; Mr 390.45; mp.
135.4–136.78C; TLC Rf = S2(0.32), S3(0.72); MS (70 eV), m/z (%) 361
(2.5) [M+], 343 (7.6), 233 (100), 190 (43.7) 179 (11.8), 98 (47.1), 70
(25.1); 1H-NMR ([d6]-DMSO): d = 1.96 (qw, CH2CH2CH2, 2H), 2.32–
2.48 (m, CH2CO, NCH2CH2, 4H), 2.65–2.79 (m, CH2 piper, 4H),
2.82–2.99 (m, CH2 piper, 4H), 3.07 (dd, CH2CH2N, 2H), 3.57–3.68
(m, CH2CH2N, CH, 3H), 3.79 (s, CH3, 3H), 6.78–7.12 (m, arom, 5H).
a-Adrenoceptor radioligand binding assay
The experiment was carried out on rat cerebral cortex. [3H]prazo-
sin (19.5 Ci/mmol, an a1-adrenergic receptor) and [3H]clonidine
(70.5 Ci/mmol, an a2-adrenergic receptor) were used. The brains
were homogenized in 20 vol of ice-cold 50 mM Tris-HCl buffer
(pH 7.6) and centrifuged at 20000 g for 20 min (0–48C). The cell
pellet was resuspended in the Tris-HCl buffer and centrifuged
again. Radioligand binding assays were performed in plates
(MultiScreen/Millipore, Billerica, MA, USA). The final incubation
mixture (final volume 300 lL) consisted of 240 lL of the mem-
brane suspension, 30 lL of [3H]prazosin (0.2 nM) or [3H]clonidine
(2 nM) solution and 30 lL of the buffer containing seven to eight
concentration (10– 11 –10– 4M) of the tested compounds. To meas-
ure the unspecific binding, 10 lM of phentolamine (in the case
of [3H]prazosin), or 10 lM of clonidine (in the case of [3H]cloni-
dine), was applied. The incubation was terminated by rapid fil-
tration over glass fibre and placed in scintillation vials with a
liquid scintillation cocktail. Radioactivity was measured in a
WALLAC 1409 DSA liquid scintillation counter (Perkin Elmer,
Norwalk, CT, USA). All assays were made in duplicate. The radio-
ligand binding were analyzed using an iterative curve-fitting
routine (GraphPAD/Prism, Version 3.0 – San Diego, CA, USA). Ki
values were calculated from the Cheng and Prusoff [20].
Pharmacology
Animals
Statistical analysis
The experiments were carried out on male Wistal rats (180–
250 g). Animals were housed in constant temperature facilities
exposed to a 12/12 h light-dark cycle, and maintained on a stand-
ard pellet diet, with tap water given ad libitum. Control and
experimental groups consisted of 8-10 animals each. All proce-
dures were done according to the Animal Care and Use Commit-
tee Guidelines and approved by the Ethical Committee of the
Jagiellonian University, Krakꢂw, Poland.
The data are expressed as mean l S.E.M. Statistical significance
was calculated using one-way ANOVA. Differences were consid-
ered significant for P a 0.05.
Molecular modelling
The conformational analysis and the measurement of minimiz-
ing energy of compounds were performed by the MM/PM5
method of the CAChe programme [29]. Conformational analysis
was carried out by changing the five torsion angles marked in
Fig. 12 as b1 –b5, common to all molecules. The adopted conver-
gence criterion was an energy gradient of 0.1 kcal/mol ꢀ.
Antiarrhythmic activity
Prophylactic antiarrhythmic activity in a model of adrenaline-
induced arrhythmia according to [28].
Arrhythmia was evoked in thiopental (60 mg/kg, i.p.)-anaes-
thetized rats by intravenous injection of adrenaline (20 lg/kg).
The tested compounds were administered intravenously 15 min
before adrenaline. The criterion of anti-arrhythmic activity was
the lack of premature beats and the inhibition of rhythm distur-
bances in comparison with the control group (ventricular brady-
cardia, atrioventicular block, ventricular tachycardia, or ventric-
ular fibrillation). The cardiac rhythm disturbances were
recorded for 15 min after adrenaline injection. ECGs were ana-
lyzed according to the guidelines of the Lambeth Convention
[30] on ventricular premature beats (VBs), bigeminy, salvos (less
than four succecive VBs), ventricular tachycardia (VT, four or
more successive VBs), and ventricular fibrillation (VF).
Figure 12. Schematic structure of 1-[3-(4-arylpiperazin-1-yl)-2-
hydroxy]-propylpyrrolidin-2-ones derivatives.
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