Synthesis and class III type antiarrhythmic activity of 4-Aroyl (and Aryl)-1-aralkylpiperazines

Article abstract of DOI:10.1016/S0960-894X(00)00581-3

The synthesis and in vitro Class III antiarrhythmic activity of several 4-aroyl (and aryl)-1-aralkylpiperazine and piperidine derivatives are described. Among several potent compounds identified in the series, RWJ-28810 (3), with its EC₂₀ of 3 nM, ranks as one of the most potent (in vitro) compounds reported. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0960-894X(00)00581-3

Bioorganic & Medicinal Chemistry Letters 10 (2000) 2819±2823
Synthesis and Class III Type Antiarrhythmic Activity
of 4-Aroyl (and Aryl)-1-aralkylpiperazines
Ramesh M. Kanojia,* Joseph J. Salatay and Jack Kau€man
The R. W. Johnson Pharmaceutical Research Institute, 1000 Route 202, Raritan, NJ 08869-0602, USA
Received 4 April 2000; accepted 10 October 2000
AbstractÐThe synthesis and in vitro Class III antiarrhythmic activity of several 4-aroyl (and aryl)-1-aralkylpiperazine and piper-
idine derivatives are described. Among several potent compounds identi®ed in the series, RWJ-28810 (3), with its EC20 of 3 nM,
ranks as one of the most potent (in vitro) compounds reported. # 2000 Elsevier Science Ltd. All rights reserved.
Sudden cardiac death (SCD), a primary cause of mor-
tality in patients with cardiovascular diseases, is caused
by the loss of regular cardiac rhythm resulting from
electrical instability of the cardiac muscle. These malig-
nant ventricular arrhythmias leading to the lethal event
are recognized as ventricular tachycardia (VT) and ven-
tricular ®brillation (VF).1 Although therapeutic inter-
ventions are available for VF, they are unsatisfactory
from the view point of safety and general ecacy2 Since
the ®rst observation of antiarrhythmic activity of a
cinchona alkaloid preparation in a malaria patient in
1914, the alkaloid quinidine, subsequently identi®ed as
the most potent ingredient of such natural product pre-
paration, remains an important antiarrhythmic ther-
apeutic agent.3 However, quinidine and other
conventional4 Class I antiarrhythmic agents, such as
encainide and ¯ecainide, with ionic mechanism of that
action include interference with sodium channels in the
cell membrane, are e€ective against simple ventricular,
and in some cases, supraventricular arrhythmias, but
are ine€ective for the prevention of sudden cardiac
death by VF. Moreover, the recent results of the Car-
diac Arrhythmia Suppression Trial (CAST)5 have raised
concerns about the safety of the Class I type agents
focusing attention on Class III agents. These provide
antiarrhythmic protection by selectively prolonging the
cardiac action potential and thereby increasing the
e€ective refractory period (ERP).6 d-Sotalol (35),7
Dofetilide (36),8 E-4031 (37),9 Amiodarone,10 and
Azimilide11 are a few representative examples of Class
III antiarrhythmic agents.
Herein we describe the synthesis and potent in vitro
ERP activity of a series of 4-aroyl-1-aralkylpiperazines
(Table 1), 4-aryl-1-aralkylpiperazines (Table 2), and a
few piperidine derivatives (Table 3).
Chemistry12
Various 4-aroyl-1-aralkylpiperazines I (3±11, Table 1)
were prepared according to Scheme 1. Acylation of
piperazine with 4-nitrobenzoyl chloride a€orded mono-
acylated product 2,13 separated from the diacylated
product 1 by chromatography. 4-Nitroaralkylation of 2
with the various 4-nitroaralkyl halides (or sulphonate
IIe) in re¯uxing MeCN in the presence of anhydrous
K2CO3 and NaI gave 3 (70%), 6 (94%), 9 (80%), 10
(63%), and 11 (70%). Reduction of NO2 to NH2 fol-
lowed by N-mesylation gave, respectively, 4 and 5 from
3 and a mixture of 7 and 8 from 6. Compounds 12±21
(V, Table 1) were obtained according to Scheme 2 by
®rst aralkylating mono-t-Boc protected piperazine to
give IIIa (52%) and IIIb (33%), the latter converted
sequentially to NH2 (IIIc) and NHSO2Me (IIId) fol-
lowed by deprotection to IV and then acylation to give
V
(12±21). 4-Aryl-1-aralkylpiperazines 22±30 (VII,
Table 2) were similarly prepared according to Scheme 3
by aralkylating commercially available 4-arylpiper-
azines VI to VIIa (27, 50%), VIIb [22, (80%), 23 (70%),
and 26 (80%)] and VIId,e, [28 (48%) and 31(88%),
respectively], reduction of NO2 to NH2 (VIIc, 24, 25;
VIId, 29), and then N-mesylation of 29 to 30. Three
piperidine derivatives 32±34 (IX, Table 3) were similarly
obtained according to Scheme 4.
*Corresponding author. Tel.: +1-908-704-4414; fax: +1-908-526-
6469; e-mail: rkanojia@pruis.jnj.com
yPresent address: Department of Pharmacology, Merck Research
Laboratories, West Point, PA, 19486-0004, USA.
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00581-3

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R. M. Kanojia et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2819±2823
Table 1. 4-Aroyl-1-aralkylpiperazines
#
Ar1-X
Y
Ar2
Emperical formula
Mol. Wt.
Mp ꢀ
C
Antiarrhythmic activity
EC20 mM
Tension% Á
1
2
3
4
5
6
7
8
4-O2N-PhCO±
4-O2N±PhCO±
4-O2N±PhCO±
4-O2N±PhCO±
4-MeO2SNH±PhCO±
4-O2N±PhCO±
4-MeO2SNH±PhCO±
4-MeO2SNH±PhCO±
4-O2N±PhCO±
4-O2N±PhCO±
4-O2N±PhCO±
4-O2N±PhCO±
PhCO±
CO
H
±Ph-4-NO2
Ð
±Ph-4-NO2
±Ph-4-NH2
C18H16N4O6
C11H13N3O3
C19H20N4O5/0.25H2O
C19H24N4O/0.25 H2O
384.34
235.24
384.38/388.88
324.41/333.41
>300
149±50
123±25
154±56
7
20
0.003
1.40
2.0
0.060
15
25
0.035
3.5
0.01
0.16
0.14
0.16
0.06
0.68
0.012
0.14
1
6
33
3
14
+1
0
13
14
+5
44
17
8
(CH2)2
(CH2)2
(CH2)2
(CH2)2O
(CH2)2O
(CH2)2O
CH2CONH
CH2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
±Ph-4-NHSO2Me C21H28N4O5S3/0.25H2O 480.59/485.09 130±135
±Ph-4-NO2
±Ph-4-NHSO2Me
±Ph-4-N(SO2Me)2
±Ph-4-NO2
±Ph-4-NO2
±Tha-5-NO2
±Ph
±Ph-4-NO2
±Ph-4-NHSO2Me
±Ph-4-NO2
±Ph
C19H20N4O6/0.5H2O
C21H28N4O6S2/0.5H2O
C22H30N4O8S3
400.38/404.88
496.50/505.58
674.67
160±61
107±09
212±13
192±93
211±12
137±38
101±02
138±39
186±87
170±71
155±56
101±02
91±92
9
C19H19N5O6
413.38
10
11
12
13
14
C18H18N4O5/0.25H2O
C17H18N4O5S
C19H21N3O3
C19H21N3O3
C20H24N4O5S/0.25H2O 432.48/436.96
370.36/374.86
390.41
339.38
339.38
7
4-O2N±PhCO±
+13
1
15 4-MeO2SNH±PhCO±
16 4-MeO2SNH±PhCO±
C20H24N4O5S
C20H25N3O3S
C17H18N4O5S
432.48
387.48
390.42
5
0
2
17
18
19
20
21
5-O2N-Tha±
5-O2N-Fub±
4-PyrCO±
3-O2N±PhCO±
4-O2N±PhSO2±
±Ph-4-NO2
±Ph-4-NO2
±Ph-4-NO2
±Ph-4-NO2
±Ph-4-NO2
C17H18N4O6
374.35
C18H20N4O3/0.25H2O
C19H20N4O5/0.25H2O
C18H20N4O6S
340.37/344.87
384.38/393.38
420.43
145±46
145±46
154±55
+19
7
24
0.27
1.0
aTh=Thiophene.
bFu=Furan.
Table 2. 4-Aryl-1-aralkylpiperazine
#
Ar1
Y
Ar2
Emperical formula
Mol. Wt.
Mp ꢀ
C
Antiarrhythmic activity
EC20 mM
Tension% Á
22
23
24
25
26
27
28
29
30
31
4-O2N-Ph±
4-O2N±Ph±
4-H2N±Ph±
4-H2N±Ph±
4-O2N±Ph±
Ph±
4-Pyr±
4-Pyr±
4-Pyr±
5-O2N-2-Pyr±
(CH2)2
(CH2)2O
(CH2)2
(CH2)2O
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
(CH2)2
±Ph-4-NO2
±Ph-4-NO2
±Ph-4-NH2
±Ph-4-NH2
±Ph
±Ph-4-NO2
±Ph-4-NO2
±Ph-4-NH2
C18H20N4O4
C18H20N4O5
C18H24N4/0.8H2O
C18H24N4O/0.75H2O
C18H21N3O2
C18H21N3O2/0.125H2O
C17H20N4O2/0.5H2O
C17H22N4/0.5H2O
C18H24N4O2S/0.5H2O
C17H19N5O4/0.5H2O
356.37
372.37
296.40/310.82
312.40/325.91
311.39
311.39/313.64
312.36/321.36
282.38/291.38
360.46/369.46
357.36361.86
148±49
150±51
158±59
105±06
163±64
140±41
146±48
184±85
202±03
137±38
0.03
0.35
>100
>100
0.5
+5
27
53*
43*
6
0.8
0.03
15
0.22
1.3
+10
+8
+9
+2
21
±Ph-4-NHSO2Me
±Ph-4-NO2
Table 3. 4-Aryl(or aroyl)-1-aralkylpiperidines
#
Ar1X
Y
Ar2
Emperical formula
Mol. Wt.
Mp ꢀ
C
Antiarrhythmic activity
EC20 mM
Tension% Á
32
33
34
4-O2N±Ph±
4-H2N±Ph±
4-Cl±PhCO±
(CH2)2
(CH2)2
(CH2)2
±Ph-4-NO2
±Ph-4-NH2
±Ph-4-NO2
C19H21N3O4/0.25H2O
C19H25N3/0.25H2O
C20H21ClN2O3
355.38/359.88
295.43/299.91
372.84
133±34
140±42
1501
0.3
2.0
0.3
0
+15
4

R. M. Kanojia et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2819±2823
2821
Biological Materials and Methods
pH 7.3, gassed with 5% CO2. 95% O2 at 37 ꢀC. Timolol
(0.1 mM) was added to prevent variations in tension
produced by spontaneous or stimulation-induced
release of catecholamines. Isometric force was recorded
during stimulation with constant current pulses (3 msec;
1.3Âthreshold) using platinum bipolar electrodes. The
ERP was determined using the extra stimulus technique
by applying trains of 20 basic stimuli (S1) at cycle length
of 300 msec (1 Hz), followed by application of an extra
Measurement of e€ective refractory period (ERP)
Papillary muscles were dissected from the right ventricle
of anesthetized male ferrets, secured at one end and
attached to a force transducer. Muscles were placed in a
tissue bath containing Tyrode's solution of the follow-
ing composition (mM): NaCl, 130; KCl, 4; MgCl2, 1.0;
NaHCO3, 25; KH2PO4, 1.2; CaCl2, 2; dextrose, 11;
Scheme 1. Reagents: (a) 4-O2NPhCOCl, acetone, HCl; (b) 4-O2NPh(CH2)2-Br (Cl), K2CO3, NaI, MeCN, Á; (c) Ra-Ni, H2, EtOH; (d) MeSO2Cl,
Pyr, CH2Cl2; (e) 4-O2NPhO(CH2)2Cl, K2CO3, NaI, MeCH, Á; (f) 4-O2NPhNHCOCH2Cl, K2CO3, MeCN, Á; (g) O2NPhCH2Cl, K2CO3, NaI,
MeCN, Á; (h) (Ac)2O, H2SO4; (i) HNO3, (Ac)2O, 10 ꢀC!0 ꢀC; (j) 10% H2SO4/H2O, Á; (k) MeSO2Cl, Et3N, CH2Cl2, 0ꢀC; (l) IIe, EtOH, Á.
Scheme 2. Reagents: (a) Ar2-Y-Br, K2CO3, NaI, MeCN, Á; (b) Ra-Ni, H2, EtOH; (c) MeSO2Cl, Pyr, CH2Cl2; (d) CF3CO2H; (e) Ar1-X-C, Et3N,
CH2Cl2.
Scheme 3. Reagents: (a) Ar2-Y-Cl (or Br), K2CO3, NaI, MeCN, Á; (b) Ra-Ni, H2, EtOH; (c) MeSO2Cl, Pyr.
Scheme 4. Reagents: (a) HNO3, H2SO4; (b) Ar2-(CH2)2-Br, K2CO3, NaI, MeCN, Á; (c) Pd/C, H2, EtOH.

2822
R. M. Kanojia et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2819±2823
Table 4. Class III antiarrhythmic standards
#
Antiarrhythmic activity
EC20 mM
Tension% Á
35
36
37
d-Sotalol
Dofetilide
E-4031
3.5
13
0.015
0.02
+5
+9
stimulus (S2) at decreasing coupling intervals (S1±S2) in
decrements of 2 ms until muscle activation failed. ERP
was de®ned as the shortest S1±S2 interval producing
muscle activation. Test compounds were dissolved in
dimethylsulfoxide (DMSO) at a stock concentration of
1Â10 2 M and added in appropriate amounts directly to
Tyrode's solution to achieve the ®nal concentrations.
Following duplicate control measurements, compound
concentrations were increased sequentially and ERP
measurements were taken at steady state, usually 15 min
after addition of each concentration. The mean dose
that produced a 20% increase in ERP is de®ned as EC20
and is reported in mM (1Â10 6 M), as a measure of
Class III antiarrhythmic activity.
CH group (e.g. piperidine derivative 34) as also is the
anilino nitrogen of VII, but with signi®cant loss of
potency (compare 22 with 32). For the spacer group X,
whereas CO is better than SO2 (21), it is altogether dis-
pensable (e.g. 22). For the spacer group Y, (CH2)2 (3) is
better than (CH2)2O (6) or CH2 (10). There were only
two compounds showing signi®cant decrease in tension
(24 and 25, possibly 10) and these were at high mM
concentrations where vehicle (DMSO) is known to
decrease tension. Others had little or no change in ten-
sion indicating selectivity of Class III action, since
selective block of K channels is associated with no
change or an actual increase in isometric tension in the
absence of an e€ect on Na or Ca channels.
Measurement of tension
Summary
Tension was measured as peak isometric tension during
the basic stimulus trains (S1) during control, and com-
pound induced changes in tension were expressed as a
percent of control.
We have synthesized and identi®ed a series of 4-aroyl
(andaryl)-1-aralkylpiperazine derivatives as potent Class
III Type antiarrhythmics as evidenced by in vitro ERP
prolongation.
The lead compound RWJ-28810 (3) with its EC20 of
3 nM represents one of the most potent (in vitro)
compounds reported.
Results and Discussion
SAR highlights
In in vitro tests, the most potent compound of the ser-
ies, RWJ-28810 (3), increased ERP ꢁ5 times more
potently than Dofetilide (36),8 the most potent reference
standard tested (Table 4). In the piperazine series, the
general potency order for the 4,40-substituents on the
two terminal aromatic rings, keeping NO2 constant on
one end while varying the other is, for Ar1CO (I and V):
NO2 (3) >NHSO2Me (15) >H (13); for Ar2: NO2 (3) >
H (12) >MeSO2NH (14) >NH2 (4) [3-NO2 on Ar1 (20)
is much weaker than 4-NO2 on Ar1 (3)]; for arylpiper-
azines (VII), on Ar1: NO2 (22) > H (27); on Ar2: NO2
(22) > H (26) > NH2 (24). Of the two possible regio-
isomeric mono-NO2 analogues 12 and 13 of the di-NO2
lead 3, the 4-NO2-aroyl analogue 12, although 5 times
less potent than 3, is 10 times more potent than the 4-
NO2-aralkyl isomer 13. With mixed functionality, pre-
sent on di€erent aryl moieties, the potencies are reversed
in favor of MeSO2NH-aroyl/NO2-aralkyl (15) versus
NO2-aroyl/MeSO2NH-aralkyl (14). For the aromatic
ring Ar1, potency order is: benzoyl (3) > thienoyl (17)
>> furanoyl (18) > 4-pyridoyl (19); for Ar2 potency
order is: phenyl > thienyl. The non-basic amido nitro-
gen of aroyl-piperazine core (as in I) is replaceable by a
Acknowledgements
We wish to thank Drs. S. Bell, J. Press, D. Klaubert, A.
Tobia, and R. Falotico for helpful discussions and sup-
port during the tenure of this work and M. Macielag for
his interest and encouragement during the preparation
of this manuscript.
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