New p-methylsulfonamido phenylethylamine analogues as class III antiarrhythmic agents: Design, synthesis, biological assay, and 3D-QSAR analysis

Article abstract of DOI:10.1021/jm010574u

Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and increase the transmembrance action potential duration (APD). Using dofetilide (2) as a template of class III antiarrhythmic agents, we designed and synthesized 16 methylsulfonamido phenylethylamine analogues (4a-d and 5a-1). Pharmacological assay indicated that all of these compounds showed activity for increasing the ERP in isolated animal atrium; among them, the effective concentration of compound 4a is 1.6 × 10^-8 mol/L in increasing ERP by 10 ms, slightly less potent than that of 2, 1.1 × 10^-8 mol/L. Compound 4a also produced a slightly lower change in ERP at 10^-5 M, ΔERP% = 17.5% (ΔERP% = 24.0% for dofetilide). On the basis of this bioassay result, these 16 compounds together with dofetilide were investigated by the three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques of comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis (CoMSIA), and the hologram QSAR (HQSAR). The 3D-QSAR models were tested with another 11 compounds (4e-h and 5m-s) that we synthesized later. Results revealed that the CoMFA, CoMSIA, and HQSAR predicted activities for the 11 newly synthesized compounds that have a good correlation with their experimental value, r² = 0.943, 0.891, and 0.809 for the three QSAR models, respectively. This indicates that the 3D-QSAR models proved a good predictive ability and could describe the steric, electrostatic, and hydrophobic requirements for recognition forces of the receptor site. On the basis of these results, we designed and synthesized another eight new analogues of methanesulfonamido phenylethyamine (6a-h) according to the clues provided by the 3D-QSAR analyses. Pharmacological assay indicated that the effective concentrations of delaying the ERP by 10 ms of these newly designed compounds correlated well with the 3D-QSAR predicted values. It is remarkable that the percent change of delaying ERP at 10^-5 M compound 6c is much higher than that of dofetilide; the effective concentration of compound 6c is 5.0 × 10^-8mol/L in increasing the ERP by 10 ms, which is slightly lower than that of 2. The results showed that the 3D-QSAR models are reliable and can be extended to design new antiarrhythmic agents.

Full text of DOI:10.1021/jm010574u

J . Med. Chem. 2002, 45, 2953-2969
2953
New p-Meth ylsu lfon a m id o P h en yleth yla m in e An a logu es a s Cla ss III
An tia r r h yth m ic Agen ts: Design , Syn th esis, Biologica l Assa y, a n d 3D-QSAR
An a lysis
Hong Liu,† Ming J i,‡ Xiaomin Luo,† J ianhua Shen,† Xiaoqin Huang,† Weiyi Hua,*,‡ Hualiang J iang,*,† and
Kaixian Chen†
Center for Drug Discovery and Design, The State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica,
Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, People’s Republic of China,
and Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, China
Received December 19, 2001
Class III antiarrhythmic agents selectively delay the effective refractory period (ERP) and
increase the transmembrance action potential duration (APD). Using dofetilide (2) as a template
of class III antiarrhythmic agents, we designed and synthesized 16 methylsulfonamido
phenylethylamine analogues (4a -d and 5a -l). Pharmacological assay indicated that all of
these compounds showed activity for increasing the ERP in isolated animal atrium; among
them, the effective concentration of compound 4a is 1.6 × 10-8 mol/L in increasing ERP by 10
ms, slightly less potent than that of 2, 1.1 × 10-8 mol/L. Compound 4a also produced a slightly
lower change in ERP at 10-5 M, ∆ERP% ) 17.5% (∆ERP% ) 24.0% for dofetilide). On the
basis of this bioassay result, these 16 compounds together with dofetilide were investigated by
the three-dimensional quantitative structure-activity relationship (3D-QSAR) techniques of
comparative molecular field analysis (CoMFA), comparative molecular similarity index analysis
(CoMSIA), and the hologram QSAR (HQSAR). The 3D-QSAR models were tested with another
11 compounds (4e-h and 5m -s) that we synthesized later. Results revealed that the CoMFA,
CoMSIA, and HQSAR predicted activities for the 11 newly synthesized compounds that have
a good correlation with their experimental value, r2 ) 0.943, 0.891, and 0.809 for the three
QSAR models, respectively. This indicates that the 3D-QSAR models proved a good predictive
ability and could describe the steric, electrostatic, and hydrophobic requirements for recognition
forces of the receptor site. On the basis of these results, we designed and synthesized another
eight new analogues of methanesulfonamido phenylethyamine (6a -h ) according to the clues
provided by the 3D-QSAR analyses. Pharmacological assay indicated that the effective
concentrations of delaying the ERP by 10 ms of these newly designed compounds correlated
well with the 3D-QSAR predicted values. It is remarkable that the percent change of delaying
ERP at 10-5 M compound 6c is much higher than that of dofetilide; the effective concentration
of compound 6c is 5.0 × 10-8mol/L in increasing the ERP by 10 ms, which is slightly lower
than that of 2. The results showed that the 3D-QSAR models are reliable and can be extended
to design new antiarrhythmic agents.
In tr od u ction
these agents inhibit the impulse conduction and con-
tractility in the myocardium; class II agents are â
blockers; and class III agents act through delaying
repolarization of cardiac myocytes. The consequence of
delayed repolarization is a lengthening of the action
potential duration (APD) of the cell and a concomitant
increase in the effective refractory period (ERP).7 The
cardiac arrhythmia suppression trial (CAST) demon-
strated that conventional antiarrhythmic treatment
with certain class I agents actually increased mortality
as compared with placebo.8,9 Since the outcome of CAST,
a perception has emerged that class I agents may be
limited in their therapeutic application; therefore, there
has been an increasing interest in compounds that exert
their antiarrhythmic effects by means other than the
sodium channel blockade.10,11 Because of this, develop-
ment of new antiarrhythmic drugs has focused upon the
potassium ion (K+) channel blockers designed to prolong
ventricular refractoriness and prevent the development
of lethal tachyarrhythmias.
The high incidence of sudden cardiac death (SCD) is
of continuing medical concern.1,2 The primary mecha-
nism of SCD is the degeneration of a normal cardiac
rhythm into ventricular tachycardia followed by ven-
tricular fibrillation. The cause underlying these rhythm
disturbances in most cases is coronary artery disease,
which has resulted in prior ischemic damage to the
heart.3,4 Therefore, it has been accepted that arrhyth-
mias such as sustained tachycardia (VT) and fibrillation
(VF) are the major origins in these deaths.5 A number
of therapeutic approaches are available for the treat-
ment of arrhythmias. According to the classification of
Vaughn Williams,6 the antiarrhythmic action can be
defined by several major classes: class I consists of
antiarrhythmic agents that block sodium channels, and
* To whom correspondence should be addressed. Tel.: +86-21-
64311833 ext. 222. Fax: +86-21-64370269. E-mail: hljiang@mail.shcnc.
ac.cn, jiang@iris3.simm.ac.cn.
† Chinese Academy of Sciences.
‡ China Pharmaceutical University.
10.1021/jm010574u CCC: $22.00 © 2002 American Chemical Society
Published on Web 06/12/2002

2954 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Liu et al.
Ch a r t 1
for recognition forces of the receptor site. Finally, we
designed and synthesized another eight new analogues
(6a -h ) of methanesulfonamido phenylethyamine ac-
cording to the clues provided by the 3D-QSAR analyses
(Table 2). Pharmacological assay indicated that the
effective concentrations in delaying the ERP by 10 ms
of these newly designed compounds have a good cor-
relation with the 3D-QSAR-predicted values. It is
remarkable that compound 6c is more active than
dofetilide in prolonging ERP at 10-5 M and its ∆ERP%
is 58% (∆ERP% ) 24.0% for dofetilide). The effective
concentration of compound 6c is 5.0 × 10-8 mol/L in
increasing the ERP by 10 ms, slightly lower than that
of 2, which is 1.1 × 10-8 mol/L.
Ch em istr y a n d Bioa ssa y
1. Design of Meth a n esu lfon a m id o P h en yleth yl-
a m in e An a logu es. Compound 2 is a class III antiar-
rhythmic agent, launched into the market by Pfizer as
a new antiarrhythmic drug in 1999.20-28 The delayed
APD and ERP of dofetilide are distinctly superior to
other class III antiarrhythmic drugs.20-28 The activity
of this new drug is about 100-1000 times higher than
that of D-sotalol (1), which can selectively block IKr
without an effect on cardiac conduction and, in addition,
lacks a negative inotropic action.20-28 Dofetilide is
therefore a suitable lead compound for designing new
antiarrhythmic agents. Accordingly, on the basis of the
structural and pharmacological features of dofetilide, 16
new methanesulfonamido phenylethylamine analogues
(4a -d and 5a -l) (Table 1) were designed and synthe-
sized for the first round. Keeping the key groups of
dofetilidesthe two aromatic rings, alkylamine ether,
and two methanesulfonamide groupsswe used various
setric, electronic, and hydrophobic groups to substitute
the N-methyl group in dofetilide and obtained four
dofetilide analogues 4a -d . On the basis of the struc-
tural features of other class III antiarrhythmic agents,
for example, D-sotalol (1) and MK-499 (3), we designed
compounds 5a -l, maintained the methylsulfonamido
phenethylamine moiety, and replaced the methylsul-
fonamido phenoxyethyl moiety with an alkyl or aromatic
alkyl. To test our 3D-QSAR models, we designed an
additional 11 new analogues; among them, four are
compound 4 analogues (4e-h ) and seven are compound
5 analogues (5m -s). According to the clues suggested
by CoMFA, CoMSIA, and HQSAR models, we designed
another eight new analogues and represented them as
6a -h (Table 2).
2. Ch em istr y. Dofetilide was synthesized using N-
methyl-p-nitrophenethylamine as the starting raw ma-
terial in Pfizer’s patents.20 This synthetic approach is
not suitable for structural modification on the N-methyl
moiety. Therefore, we used p-nitrophenethylamine (8)
as the starting material to synthesize the target com-
pounds 4a -h . Scheme 1 depicts the sequence of reac-
tions that led to the preparation of the target molecules.
In general, 2-(4-nitrophenoxy)-1-bromo ethane (7) was
prepared by p-nitrophenol reacting with 1,2-dibromo-
ethane in ethanol. Compound 7 was substituted by
using p-nitrophenethylamine hydrobromide (8), giving
the key intermediate 9. Compounds 10a ,b,d -h were
synthesized by the following steps. N-Alkylation of 9
with benzyl chloride, acetic anhydride, p-chlorobenzyl
The outward delayed rectifier potassium current, IK,
that contributes to repolarization consists of two kineti-
cally distinct and identifiable currents, i.e., a rapidly
activating, IKr, and a slowly activating, IKs, compo-
nent.12,13 Selective blockading of either IKr or IKs would
lead to a prolongation of the refractory period; therefore,
K+ channel blockers can be categorized into class III
antiarrhythmic agents.14-19 Most selective class III
antiarrhythmic agents, notably D-sotalol (1),19 dofetilide
(2),20-28 and MK-499 (3)16 (Chart 1), pharmacologically
23
function to selectively block IKr
.
To discover more potent class III antiarrhythmic
agents, we have designed and synthesized a series of
new methylsulfonamido phenylethylamine analogues
based on the structure and pharmacophore of dofetilide.
Pharmacological screening indicates that all of these
analogues exert significant class III activity in vitro
(Table 1). Some of the results have been reported in
preliminary form.29 In this paper, we describe in detail
the design, synthesis, biological activity, and three-
dimensional quantitative structure-activity relation-
ship (3D-QSAR) analyses of dofetilide (2) and 35 related
novel methylsulfonamido phenylethylamine analogues
(4a -h , 5a -s, and 6a -h ). Briefly, we designed and
synthesized 17 methylsulfonamido phenylethylamine
analogues (2, 4a -d , and 5a -l) in the first cycle.
Pharmacological assay indicated that all of these com-
pounds show the activity in increasing the ERP of
isolated animal atrium. Second, on the basis of the
bioassay results, these 17 methylsulfonamido phenyl-
ethylamine analogues were analyzed by using the 3D-
QSAR techniques of comparative molecular field analy-
sis (CoMFA),30 comparative molecular similarity index
analysis (CoMSIA),31 and the newly developed QSAR
method hologram QSAR (HQSAR).32 Then, we synthe-
sized 11 new analogues (4e-h and 5m -s) for testing
the 3D-QSAR models. Results indicated that the CoM-
FA-, CoMSIA-, and HQSAR-predicted activities for the
11 newly synthesized compounds had a good correlation
with their experimental value (r2 ) 0.943, 0.891, and
0.809, respectively). This indicated that the 3D-QSAR
models proved a good predictive ability and described
the steric, electrostatic, and hydrophobic requirements

Class III Antiarrhythmic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2955
Ta ble 1. Chemical Structures of the Methanesulfonamido Phenylethylamine Compounds 2, 4, and 5 and Their Activities
compd
R1
R2
R3
na
Cb
∆ERPc
∆HRd
∆FCe
2
-CH3
-CH2CH2OC6H4NHSO2CH3-p
-CH2CH2OC6H4NHSO2CH3-p
-CH2CH2OC6H4NHSO2CH3-p
-CH2CH2OC6H4NHSO2CH3-p
-CH2CH2OC6H4NHSO2CH3-p
H
H
H
H
H
H
5
4
3
3
2
2
0.011 ( 0.001 24.0 ( 1.0
0.016 ( 0.001 17.5 ( 0.8
0.021 ( 0.001 16.9 ( 0.8
-30.0 ( 1.6
-32.0 ( 1.5
-20.6 ( 0.9
17.1 ( 0.8
24.8 ( 1.0
17.5 ( 0.8
33.7 ( 1.7
20.0 ( 1.0
20.0 ( 1.0
4a
4b
4c
4d
4e
-CH2C6H5
-COCH3
-H
0.023 ( 0.001
0.037 ( 0.002
9.39 ( 0.50 -23.8 ( 1.0
9.29 ( 0.50 -40.6 ( 2.0
-CH2C6H4Cl-p
-CH2CH2OC6H4N- -CH2CH2OC6H4NHSO2CH3-p
HSO2CH3-p
-SO2CH3
-CH2-CHdCH2
-COC6H5
-CH3
-CH3
-CH3
0.383 ( 0.020 13.5 ( 0.7
-26.7 ( 2.0
4f
-CH2CH2OC6H4NHSO2CH3-p
-CH2CH2OC6H4NHSO2CH3-p
-CH2CH2OC6H4NHSO2CH3-p
-CH2C6H5
-CH2C6H4CH3-p
-CH2C6H4Cl-p
-CH2C6H4OCH3-p
-C6H11
-CH2C6H3OCH2O-3,4
-CH2C6H4OCH3-o
-CH2C6H5
H
H
H
H
2
2
3
2
2
2
2
2
2
2
2
2
2
2
2
2
3
2
2
2
2
2
Nf
Nf
-18.8 ( 0.8
-5.26 ( 0.25
-28.4 ( 1.2
-20.0 ( 0.9
-15.4 ( 0.8
16.7 ( 0.7
Nf
4g
4h
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
5r
0.267 ( 0.010 12.4 ( 0.6
0.039 ( 0.002 19.0 ( 0.9
0.372 ( 0.020 12.2 ( 0.6
0.953 ( 0.050 12.6 ( 0.7
25.0 ( 1.2
16.7 ( 0.8
-11.8 ( 0.7
8.33 ( 0.40
25.0 ( 1.2
8.33 ( 0.50
17.2 ( 0.6
-14.3 ( 0.6
Nf
-SO2CH3
-H
-SO2CH3
-H
-H
-H
-H
-SO2CH3
-H
-SO2CH3
-SO2CH3
-H
-H
-H
2.24 ( 0.130
1.17 ( 0.060
4.79 ( 0.300
0.890 ( 0.050
7.06 ( 0.30 -14.5 ( 0.7
8.70 ( 0.40 -19.2 ( 0.8
-CH3
-CH3
-CH3
6.45 ( 0.30
-8.00 ( 0.50
6.16 ( 0.20 -15.3 ( 0.6
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5
-CH2C6H5Cl-p
-CH3
-COCH3
-COC6H5
-CH3
-CH2C6H5
-CH2C6H4OCH3-p
0.141 ( 0.007 10.9 ( 0.6
0.270 ( 0.010 16.1 ( 0.6
-28.2 ( 1.0
-25.0 ( 1.2
16.0 ( 0.7
16.0 ( 0.8
-CH2C6H4CH3-p
-CH2C6H4Cl-p
0.620 ( 0.030
1.05 ( 0.050
0.790 ( 0.050
0.380 ( 0.030
5.71 ( 0.20
14.5 ( 0.6
9.09 ( 0.40 -27.3 ( 1.2
9.46 ( 0.40 -18.3 ( 0.7
25.0 ( 1.2
25.0 ( 1.2
-20.0 ( 1.0
-20.0 ( 1.0
15.0 ( 0.6
38.3 ( 2.0
14.3 ( 0.6
33.3 ( 2.0
Nf
-CH2C6H4OCH3-p
-CH2C6H3OCH2O-3,4
-CH2C6H4OCH3-p
-CH2C6H4OCH3-o
-CH2C6H4OCH3-p
-CH2C6H4OCH3-p
-C6H11
0.068 ( 0.003 19.3 ( 0.9
0.155 ( 0.005 15.6 ( 0.6
-9.09 ( 0.50
-26.7 ( 1.7
-18.2 ( 0.7
-3.70 ( 0.20
-8.36 ( 0.50
Nf
Nf
-H
6.18 ( 0.300
4.39 ( 0.200
0.653 ( 0.040
0.21 ( 0.010
6.33 ( 0.30
-SO2CH3
-SO2CH3
H
6.24 ( 0.30
-CH2C6H5
-CH2CH2OC6H4NHSO2CH3-p
9.56 ( 0.40 -16.0 ( 0.7
12.1 ( 0.6 -25.8 ( 1.7
Nf
5s
14.3 ( 0.6
a
b
n, the sample number. C, the effective concentration of delaying ERP 10 ms (µM). c ∆ERP, the percent change of delaying ERP at
10-5 M (%). ∆HR, the percent change of heart rate at 10-5 M (%). e ∆FC, the percent change of force of constriction at 10-5 M (%). f N,
d
no effect at 10-5 M.
Ta ble 2. Chemical Structures of Compound 6 and Its Activities
compd
R1
R2
na
Cb
∆ERPc
∆HRd
∆FCe
6a
6b
6c
6d
6e
6f
-CH3
-CH2C6H5
-COCH3
-CH2CHdCH2
-CH2CHdCH2
-COC6H5
-CH2C6H5
-CH3
-H
-H
-H
-H
-SO2CH3
-H
3
3
3
2
2
2
2
2
0.293 ( 0.010
Nf
0.05 ( 0.01
0.315 ( 0.010
Nf
20.2 ( 1.2
Nf
58.4 ( 2.0
9.77 ( 0.50
Nf
-28.5 ( 1.5
-31.8 ( 2.0
-46.2 ( 2.0
-15.2 ( 0.6
-8.33 ( 0.40
-20.0 ( 1.0
-17.9 ( 0.9
-20.7 ( 1.0
20.3 ( 1.0
25.0 ( 1.2
-37.9 ( 2.0
16.7 ( 0.6
16.7 ( 0.6
33.3 ( 2.0
25 ( 1
8.67 ( 0.40
5.33 ( 0.20
6g
6h
-SO2CH3
-SO2CH3
Nf
Nf
0.203 ( 0.010
12.0 ( 0.6
Nf
a
b
n, the sample number. C, the effective concentration of delaying ERP 10 ms (µM). c ∆ERP, the percent change of delaying ERP at
10-5 M (%). ∆HR, the percent change of heart rate at 10-5 M (%). e ∆FC, the percent change of force of constriction at 10-5 M (%). f N,
d
no effect at 10-5 M.
chloride, allyl bromide, and benzoyl chloride was con-
ducted by refluxing with K2CO3 in acetone, which
afforded compounds 10a ,b,d -h , respectively, which
were then reduced by Fe in hydrochloric acid. Finally,
the analogues of compound 4 were furnished by meth-
ylsulfonation in triethylamine. Compound 4 is thermally
unstable and should be handled in an ice bath. Com-
pound 4a was reduced with Pd-C in hydrogen at one
atmosphere pressure, affording compound 4c. Com-
pound 5 was synthesized through the route outlined in
Scheme 2. Phenylaldehydes (12) react with p-nitrophen-
ylethylamine (8), forming Schiff base 13, which was
reduced with KBH4 to produce compound 14; then,
when steps c-e of Scheme 1 were employed, the target
compounds 5a -s were obtained. Compounds 6a -h were
synthesized through the route outlined in Scheme 3.
They were synthesized by using the same approach as
analogues of compound 4, except p-nitrophenol was
replaced by R-naphthol (17). N-Methylation of com-
pound 20a was performed with satisfactory yields in
formate after the N atom of the amine of compound 19
was generated with formaldehyde, giving compound
20a .
3. Biologica l Assa y. Guinea pigs of either sex (250-
350 g) were stunned for quick heart excision. The
dissected left atria were attached to small platinum-
iridium punctuated electrodes for local depolarization.
They were suspended together with the spontaneously
beating right atria in an organ bath containing 100 mL
of oxygenated Tyrode’s solution of the following compo-
sition (in mM): NaCl, 147; KCl, 5.4; CaCl2, 1.8; MgCl2,
1.05; Tris 10, and Gluscose 11. The solution was

2956 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Liu et al.
Sch em e 1a
a
Reagents and conditions: (a) TBA, EtOH, 46.8%. (b) K2CO3, CH3CN, reflux, 81.5%. (c) (i) HCHO, HCOOH, reflux, 87.2%; (ii) R1X,
CH3CN, reflux, 61%; (iii) Ac2O, CH3CN, room temperature, 91%. (d) Fe, HCl, EtOH, reflux, 75%. (e) CH3SO2Cl, Et3N, CH2Cl2, 0 °C,
92.3%. (f) CH3COOH, H2/Pd-C, air pressure, 41.8%.
Sch em e 2a
during a 1 h equilibration period. In 15 min intervals,
drug was droplet from a concentrated stock solution to
the tissue bath in a cumulative manner so that the final
concentration increased geometrically. Inotropic and
chronotropic effects as well as the refractory period were
determined 10 min after drug addition.
Com p u ta tion a l Deta ils
Molecular modeling and QSAR analyses were per-
formed using the program Sybyl 6.735 on a Silicon
Graphics IRIS Indigo XZ R4000 workstation. All energy
calculations were performed employing Minimix routine
of Sybyl 6.735 based on the Tripos force field36 and
Gasteiger-Hu¨ckel charge.36 Geometric optimizations
were carried out using Powell first and then conjugate
gradient (CG) procedures with a 0.001 kcal/(mol Å)
energy gradient convergence criterion and a distance-
dependent dielectric constant.
1. Con for m ation al Sear ch an d Align m en t. Dofetil-
ide and all of our designed and synthesized molecules
are very flexible, so it is very difficult to obtain their
probable bioactive (binding) conformations for the align-
ment of 3D-QSAR analyses. Fortunately, J ohnson et
al.34 have designed and synthesized benzodiazepines
derivatives of dofetilide as class III antiarrhythmic
agents, which contain much less flexible bonds. Com-
pound 22 is the most potent compound among these
benzodiazepines, and its bioactivity is equivalent to that
of dofetilide. We assumed that compound 22 and dofetil-
ide share the same binding site because of their struc-
tural similarity and similar bioactivity. Accordingly, we
selected this compound as the template for the confor-
mational search and for the alignment of the methane-
sulfonamido phenylethylamine analogues. A systematic
search was performed on compound 22 employing the
conformational search functionality of Sybyl.35 The
a
Reagents and conditions: (a) Benzene or EtOH, reflux. (b)
KBH4, HCl, 86%. (c) (i) HCHO, HCOOH, reflux, 87.2%; (ii) R1X,
CH3CN, reflux, 61%. (d) Fe, HCl, EtOH, reflux, 75%. (e) CH3SO2Cl,
Et3N, CH2Cl2, 0 °C, 92.3%.
continuously bubbled with a mixture of 95% O2 and 5%
CO2. The temperature was kept constant at 37 ( 5 °C,
and the pH was maintained between 7.2 and 7.4. The
atria were connected to a statham strain gauge UC3,
preloaded with 10 mN, and isometric contractions were
recorded on a polygraph. The left atria were stimulated
with a basic frequency of 1 s-1 by square-wave pulses
of 3 min duration and twice-threshold voltage with a
type SEN-7103 stimulator (Nihon Kohden corporation).
The ERP was measured according to the method of
Erich:33 after every third stimulus, a second test stimu-
lus identical to the first was delivered with increasing
delays until it caused an extrasystole that could be
identified by postextrasystolic potentiation in response
to the following regular stimulus.
The contraction of the spontaneously beating right
atria was recorded at the same time to assess the
spontoneous beating rate. Measurements were obtained
every 15 min after washout with fresh Tyrode’s solution

Class III Antiarrhythmic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2957
Sch em e 3a
a
Reagents and conditions: (a) TBA, EtOH, 47.4%. (b) K2CO3, CH3CN, reflux, 81.5%. (c) (i) HCHO, HCOOH, reflux, 87.2%; (ii) R1X,
CH3CN, reflux, 61%; (iii) Ac2O, CH3CN, room temperature, 91%. (d). Fe, HCl, EtOH, reflux, 75%. (e) CH3SO2Cl, Et3N, CH2Cl2, 0 °C,
92.3%.
(Figure 2a): d1 ) 2.958 Å, d2 ) 3.793 Å, and d3 ) 4.344
Å, which were considered in the conformational search
for other methanesulfonamido phenylethylamine ana-
logues. In this way, the lowest energy conformation for
each methanesulfonamido phenylethylamine analogue
under the restriction of the dofetilide pharmacophore
was isolated as its probable bioactive conformation.
After structural optimization, conformational alignment
was carried out by taking the pharmacophore of dofetil-
ide mentioned above as the atomic pairs, which were
submitted to the following CoMFA,30 CoMSIA,31 and
HQSAR32 analyses.
2. CoMF A. For the CoMFA calculation, steric and
electronic field energies were calculated using an sp3
carbon as the steric probe atom and a +1 charge for the
electrostatic probe. Steric and electrostatic interactions
were calculated using the Tripos force field with a
distance-dependent dielectric constant at all intersec-
tions of a regularly spaced (0.2 nm) grid. The cutoff was
set to 30 kcal/mol. All models were investigated using
a full cross-validated partial least-squares (PLS)37,38
method (leave-one-out) with CoMFA standard options
F igu r e 1. Superposition of the proposed bioactive conforma-
for scaling of variables. Minimum σ (column filtering)
was set to 2.0 kcal/mol to improve the signal-to-noise
ratio by omitting those lattice points whose energy
variation was below this threshold. The optimal number
of components was five. The final model (non-cross-
validated conventional analysis) was developed and
yielded the highest non-cross-validated r2 value with
tion of dofetilide with the lowest energy conformation of
compound 22. This picture was rendered in the POV-Ray
program.42
global minimum energy conformation of this molecule
was subsequently reoptimized using the Tripos force
field36 including the electrostatic term calculated from
Gasteiger-Hu¨ckel charges.36 Superposed dofetilide (2)
with 22 (Figure 1), the dihedral angles in the methyl-
sulfonamido phenoxyethyl moiety (right part) of dofetil-
ide (divided by N atom of 9), τ4-τ6 (Figure 2), can be
restricted at 53.4, 55, and 35.2°, respectively. The
conformation of the methylsulfonamido phenylethyl-
amine moiety (left part) can be obtained in the following
way: taking the distance between C1 and N9 as a
restriction, a systematic search was performed about
bonds C6-C7, C7-C8, and C8-N9; the lowest energy
conformation of dofetilide under the distance constrain,
after further geometry optimization with the same
method mentioned above, was taken as the possible
bioactive conformation. Thus, the geometric parameters
of the 3D pharmacophore of dofetilide were obtained
the optimum number of components equal to that
2
yielding the highest rcv
.
3. CoMSIA. The alignment of the CoMFA also served
to compute similarity index fields for CoMSIA analysis.
In this study, three physicochemical properties, steric,
electrostatic, and hydrophobic fields, have been evalu-
ated. The steric contribution was reflected by the third
power of the atomic radii of the atoms. Electrostatic
properties were introduced as atomic charges. An atom-
based hydrophobicity was assigned according to the
parametrization developed by Viswanadhan et al.39 The
lattice dimensions were selected with a sufficiently large
margin (>4 Å) to enclose all aligned molecules. For
CoMSIA fields, any singularities were avoided at atomic

2958 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Liu et al.
F igu r e 2. Energetic and geometric parameters of the probable binding (bioactive) conformations (a), corresponding local energy
minimum conformations (b), and global energy minimum conformations (c) of dofetilide. Panel d is the probable bioactive
conformation of dofetilide superposing with a local energy minimum conformation derived from systematic search. τ0: C1-C6-
C7-C8; τ1: C6-C7-C8-N9; τ2: C7-C8-N9-C11; τ3: C8-N9-C11-C12; τ4: N9-C11-C12-O13; τ5: C11-C12-O13-C14; and τ6: C12-C13
-
C14-C19. This picture was rendered in POV-Ray software.42
positions because a Gaussian type distance dependence
of the physicochemical properties was adopted; thus, no
arbitrary cutoffs were required. In general, similarity
indices AF,k between the compounds of interest and a
probe atom placed at the intersections of the lattice
could be calculated with eq 1
analysis; typically, a PLS QSAR model was constructed.
The optimal HQSAR model was derived from screening
through the 12 default HL values, which were a set of
prime numbers ranging from 53 to 401.
Resu lts a n d Discu ssion
1. Ch em istr y a n d Biology. The chemical formulas
of the initially synthesized 17 compounds, denoted with
2, 4a -d , and 5a -l, are listed in Table 1. They were
synthesized through the routes outlined in Schemes 1
and 2, and the detailed synthetic procedures and the
structural characterizations were described in the fol-
lowing Experimental Section. The effective concentra-
tions of these 17 methanesulfonamido phenylethylamine
analogues upon increasing ERP of isolated animal
atrium were evaluated utilizing a pair-electric stimulus
technique (Table 1). The results show that all of the
compounds exhibit antiarrhythmic activity. The effec-
tive concentration of compound 4a is 1.6 × 10-8 mol/L
in increasing ERP by 10 ms, slightly less potent than
that of 2, which is 1.1 × 10-8 mol/L, and it produces a
slightly lower change in ERP at 10-5 M, ∆ERP% )
17.5% (∆ERP% ) 24.0% for dofetilide) (Figure 3a).
Later, we synthesized another 11 compounds (4e-h and
5m -s) through the routes outlined in Schemes 1 and
2, and the detailed synthetic procedures and the struc-
tural characterizations were also described in the
Experimental Section. Among these 11 compounds
(4e-h and 5m -s), compounds 4h and 5m are the most
interesting. They are 4-6-fold less potent than dofetilide
in the concentration needed to prolong ERP by 10 ms,
but they are only slightly less potent than dofetilide in
the prolongation of ERP at 10-5 M; the ∆ERP% values
for these two compounds are, respectively, 19.0 and
19.3% (Table 1). Moreover, compounds 4a ,h and 5m
n
2
AF,k (j) ) -
w
wike-ar
(1)
q
iq
∑
probe,k
i)1
where q represents a grid point; i is the summation
index over all atoms of the molecule j under computa-
tion; wik is the actual value of the physicochemical
property k of atom i; and wprobe,k is the value of the probe
atom. In the present study, similarity indices were
computed using a probe atom (wprobe,k) with charge +1,
radius 1 Å, hydrophobicity +1, and attenuation factor
R 0.3 for the Gaussian type distance. The statistical
evaluation for the CoMSIA analyses was performed in
the same way as described in CoMFA.
4. HQSAR. The construction of a molecular hologram
containing the HQSAR descriptors was carried out by
the following procedure. First, the molecule was hashed
to a molecular fingerprint that encoded the frequency
of occurrence of various molecular fragment types using
a predefined set of rules. This molecular fingerprint was
cut into strings at a fixed interval as specified by a
hologram length (HL) parameter. All generated strings
were then hashed into a fixed length array to produce
the molecular hologram. The Sybyl line notation (SLN)
for each string generated was mapped to a unique
integer in the range of 0 to 239 using a cyclic redundancy
check (CRC) algorithm. The numerical representation
of molecules was exploited by a subsequent correlation

Class III Antiarrhythmic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2959
prolong ERP, reduce the heart rate, and strengthen
cardiac muscle constriction (Table 1 and Figure 3). The
curves of quantity-effect are similar to dofetilide (Fig-
ure 3).
2. 3D P h a r m a cop h or e of Dofetilid e An a logu es.
The two methylsulfonamido groups are very important
pharmacophoric elements for the dofetilide ana-
logues.20-28 Because these two methylsulfonamido groups
are separated respectively by two aromatic rings from
the middle part of dofetilide (alkylamine ether moiety),
the conformations of these two parts actually do not
influence each other and also do not influence the
conformation of the alkylamine ether moiety, especially
once the compound binds to the receptor. Therefore, the
systematic search for the two methylsulfonamido group
“ends” of the dofetilide was carried out separately to
save computational time, and the lowest energy confor-
mations of these two ends were adopted in the probable
bioactive conformation for the dofetilide analogues. In
the following, we just pay attention to the conformation
of the alkylamine ether moiety of the compounds in this
study.
Besides the double methylsulfonamido groups, one or
two hydrophobic aromatic groups (the centroids are
denoted as C1 and C2, respectively), a nitrogen atom
and an oxygen atom (labeled as N9 and O13 in Figure
2), are the basic pharmacophoric elements. Therefore,
the distances between N9 and O13 (d1), N9 and C1 (d2),
and N9 and C2 (d3) play an important role for the
dofetilide analogues interacting with their receptor.
Under the restrictions of d2 and torsion angles τ4-τ6
derived from the lowest energy conformation of 22, a
probable bioactive conformation of dofetilide was ob-
tained by using the systematic search, which is pre-
sented in Figure 2a. The pharmacophoric distances d1-
d3 are 2.958, 3.793, and 4.344 Å, respectively.
Typically, the conformation representing the phar-
macophore is not always the global energy minimum;
however, it may be at or near a local energy minimum
conformation. We therefore performed a systematic
conformational search for dofetilide considering the
flexibility of the torsion angles of all of the single bonds.
Different from the proposed bioactive conformation, the
global energy minimum conformation of dofetilide adopts
a more “crooked” conformation, and its total energy is
-5.6 kcal/mol (Figure 2c). As compared with all of the
conformations obtained in the systematic search, we
found that the proposed bioactive conformation is close
to a local energy minimum conformation. The energy
of this local energy minimum is about -3.8 kcal/mol,
which is very close to that of the proposed bioactive
conformation, -3.7 kcal/mol (Figure 2b). The superposi-
tion between these two conformations is shown in
Figure 2d, and the RMSD is only 0.148 Å. All of these
indicate the reasonability of the proposed bioactive
conformation of dofetilide.
Obtaining the probable bioactive conformation and
the 3D pharmacophore (d1-d3), a systematic search was
performed for each of the other 16 methylsulfonamido
phenylethylamine analogues taking the 3D pharma-
cophore as the geometric restriction. The lowest energy
conformations under the geometric restriction were
adopted in the conformation alignment for 3D-QSAR
analyses; during this process, the 3D pharmacophore
F igu r e 3. Curves of quantity-effect of compounds 2, 4a ,h ,
5m , and 6c bioactivities measured in isolated animal atrium
(dark blue diamond, compound 2; pink square, compound 4a ;
blue circle, compound 4h ; green square, compound 5m ; red
triangle, compound 6c). (a) The ERP curves of quantity-effect
of five compounds. (b) The FC curves of quantity-effect of five
compounds. (c) The HR curves of quantity-effect of five
compounds.

2960 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Liu et al.
Ta ble 3. Statistical Indexes of CoMFA, CoMSIA, and HQSAR
Models of 17 Methanesulfonamido Phenylethylamine
Compounds
cross-validated
conventional
2
rcross
opt compnt
r2
s
F6,18
144
96.8
353 (BL)a
CoMFA
CoMSIA
HQSAR
0.695
0.700
0.810
5
4
4
0.985
0.970
0.921
0.125
0.169
0.255
Field Contributions (%)
electrostatic
steric
hydrophobic
CoMFA
CoMSIA
44.9
46.5
55.1
27.1
-
26.4
a
The best length in the HQSAR model.
Ta ble 4. Predicted Activities (PA) vs Experimental Activities
(EA, -logIC50) and Residues (δ) by CoMFA, CoMSIA, and
HQSAR
CoMFA
CoMSIA
HQSAR
F igu r e 4. Superposition of the 17 methanesulfonamido
phenylethylamine compounds (2, 4a -d , and 4a -l in Table 1)
for 3D-QSAR model construction. This picture was reproduced
by the POV-Ray program.42
compd
EA
PA
7.87
δ
PA
7.83
δ
PA
7.75
δ
2
4a
4b
4c
7.92
7.80
7.67
7.63
7.44
6.41
Na
6.57
7.96
6.34
6.02
5.65
5.93
5.32
6.15
6.85
6.57
6.21
5.98
6.10
6.41
7.17
6.81
Na
0.05
0.09
0.17
7.89 -0.09 8.02 -0.22 7.86 -0.06
7.65
7.60
0.02
0.03
7.68 -0.01 7.65
7.63 0.00 7.57
0.02
0.06
was taken as the alignment pairs. The conformational
alignment is shown in Figure 4.
4d
7.47 -0.03 7.52 -0.08 7.87 -0.43
5.92 0.49 6.57 -0.16 6.79 -0.38
3. 3D-QSAR Mod els. 3.1. CoMF A. Although CoMFA
is not able to appropriately describe all of the binding
force, because it is based principally on standard steric
and electrostatic molecular fields to model ligand-
enzyme interactions, it is still a widely used tool for the
study of QSAR at the 3D level. The major objective of
CoMFA analysis about methylsulfonamido phenylethyl-
amine analogues is to find the best predictive model of
these analogues. For our initially synthesized 17 com-
pounds (2, 4a -d , and 5a -l), PLS37,38 was used in
conjunction with leave-one-out to obtain the optimal
number of components for the subsequent analysis.
PLS37,38 analysis based on least-squares fit gave a
correlation with a cross-validated r2 of 0.695 with the
maximum number of components of five. The non-cross-
validated PLS analysis was repeated with the optimum
number of components, as determined by the cross-
validated analysis, to give an r2 value of 0.985, F ) 144,
and the estimated standard error is 0.125. These values
indicated a good conventional statistical correlation, and
the CoMFA model has a fair predictive ability. The
steric field descriptors (1320 variables) explain 55.1%
of the variance, while the electrostatic descriptors
explain 44.9% showing a balance between both effects.
These statistical parameters and the non-cross-vali-
dated predictions are listed in Tables 3 and 4 and shown
in Figures 5 and 6.
The CoMFA steric and electrostatic fields for the
analysis based on alignments of the proposed bioactive
conformations are presented as contour plots in Figure
5. To aid in visualization, the lead compound dofetilide
(2) is displayed in maps. In general, the colored poly-
hedra in the map surrounded all lattice points where
the QSAR strongly associated changes in the com-
pounds’ field values with changes in biological potency.
Green polyhedra surrounded regions where more bulk
is “good” for increasing potency, while yellow polyhedra
surrounded regions where less bulk is “good”. In Figure
5, a big region of green contour near the phenyl moiety
of phenoxyethane suggests that more potent analogues-
may be obtained by introducing bulky substitutes to this
4e*
4f*
4g*
4h *
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m *
5n *
5o*
5p *
5q*
5r *
5s*
6a **
6b**
6c**
6d **
6e**
6f**
6g**
6h **
6.84 -0.27 6.28
0.29
0.44
0.22
6.13
7.63
6.11
0.44
0.33
0.23
0.20
7.85
6.31
0.11
0.03
7.52
6.12
6.16 -0.14 6.09 -0.07 5.82
5.76 -0.11 5.77 -0.12 5.92 -0.27
5.79 0.14
6.03 -0.10 5.98 -0.05
5.33 -0.01 5.25
6.16 -0.01 6.14
6.88 -0.03 6.41
0.07
0.01
0.44
0.25
0.03
5.51 -0.19
6.29 -0.14
6.61
0.24
6.41
6.12
0.16
0.09
6.32
6.18
6.61 -0.04
6.25 -0.04
6.10 -0.12 6.16 -0.18 5.98 -0.00
6.08
0.02
6.18 -0.08 6.17 -0.07
0.12 6.45 -0.04
7.45 -0.28 7.36 -0.19
6.39 0.42 6.61 0.20
6.42 -0.01 6.29
6.98
6.60
0.19
0.21
5.21
5.36
6.19
6.68
6.79
Na
7.33
6.50
Na
5.05
5.24
0.16
0.12
5.45 -0.24 5.61 -0.40
5.57 -0.21 5.48 -0.12
6.23 -0.04 6.23 -0.04 5.68
6.72 -0.05 6.42 0.26
0.51
7.09 -0.41
6.67
7.31
0.12
0.02
7.05 -0.26 6.99 -0.20
7.45 -0.12 7.48 -0.15
6.53 -0.03 6.46
0.04
6.43
0.07
5.06
6.69
6.64
5.28 -0.21 5.47 -0.41 5.59 -0.53
6.50
6.66
0.19
0.19
6.54
6.45
0.15
0.19
7.19 -0.50
7.23 -0.59
* Compounds that were not included in the construction of the
QSAR models. ** Newly designed compounds according to the
CoMFA and CoMSIA models. N, no effect at 10-5 M.
a
region of dofetilide. Red and blue contours show regions
of desirable negative and positive electrostatic interac-
tions, respectively. Two red polyhedra near the sulfonyl
of methanesulfonamido phenoxyethylamine and O atom
of the phenoxyethyl moiety indicate that electron rich
groups are beneficial to the activity. Two blue contours
near the methyl group of methanesulfonamido phenyl-
ethylamine suggest that positively charged substituents
are favorable to increase the activity.
3.2. CoMSIA. Similar results were obtained using
CoMSIA. To estimate the hydrophobic contributions to

Class III Antiarrhythmic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2961
F igu r e 5. Contour maps from the final CoMFA analysis with
2 Å grid spacing in combination with dofetilide. (a) Steric
std*coeff contour map. Green contours (>80% contribution)
refer to sterically favored regions; yellow contours (>20%
contribution) indicate disfavored areas. (b) Electrostatic std*coeff
contour map. Blue contours (>80% contribution) refer to
regions where negatively charged substituents are disfavored;
red contours (>20% contribution) indicate regions where
negatively charged substituents are favored.
these antiarrhythmic compounds, hydrophobic similar-
ity index fields were constructed by use of CoMSIA,
which cannot be completely treated by Lennard-J ones
and Coulombic fields encoded in CoMFA. The CoMSIA
analysis was performed employing the standard options
of Sybyl.39-41 The results of CoMSIA are shown in Table
3 and Figure 7. Using steric, electrostatic, and hydro-
phobic descriptors, a CoMSIA model with an r2 value
of 0.700 for four components and a conventional r2 of
0.970 was obtained. The CoMSIA-derived QSAR of the
methanesulfonamido phenylethylamine analogues ex-
hibited a good cross-validated correlation, indicating
that it is also highly predictive; the predicted inhibitory
activities of these compounds are also listed in Table 4
and graphically shown in Figure 6. The steric field
descriptors (1320 variables) explain 27.1% of the vari-
ance while the proportion of hydrophobic descriptor
remains in the range of 26.4%. Now the additional
electrostatic field explains the remaining 46.5% of the
variance. Thus, the CoMFA steric field can be seen as
a comprehensive contribution of the pure steric and
hydrophobic effects because the steric contribution of
F igu r e 6. Correlation between predicted activities (PA) by
CoMFA (a), CoMSIA (b), and HQSAR (c) models and the
experimental activities (-logC50). [, compounds of the training
set (r2 ) 0.989, 0.959, and 0.953 for the three QSAR models,
respectively); 9, compounds of the testing set (r2 ) 0.943, 0.891,
and 0.809 for the three QSAR models, respectively); 2, newly
designed compound 6 according to CoMFA and CoMSIA clues
(r2 ) 0.980, 0.909, and 0.882 for the three QSAR models,
respectively).
CoMFA is 55.1%, which is approximately equal to the
summation of the steric and hydrophobic contributions
of CoMSIA (53.5%).

2962 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Liu et al.
The inspection of CoMSIA steric Std* coeff contour
maps shows a high correspondence to the CoMFA
results except for the small green contour near the
methyl of the N-methyl moiety (see Figures 5a and 7a).
In general, CoMSIA contours are scattered at the edge
of the ligand surface, thus highlighting complementary
features at the receptor site. CoMSIA fields can also be
represented by color contour plots. In general, yellow
polyhedra indicate that hydrophobic substituents are
“good” for increasing the potency, while hydrophilic
substituents are beneficial to the activity at the regions
of white contours. In Figure 7c, large yellow polyhedra
around the phenyl of phenoxyethane indicate that
enhanced hydrophobic substituents in this region are
favorable. A white contour near the methyl of the
N-methyl moiety suggests that hydrophilic substituents
in this position may increase the antiarrhythmic activ-
ity.
3.3. HQSAR. The major objective of our HQSAR
study is the accurate prediction of the inhibitory activi-
ties of the 17 methanesulfonamido phenylethylamine
compounds; Table 4 also shows a summary of the results
of the HQSAR calculation. These data show that the
least standard error occurs at a cross-validated r2 (q2)
of 0.810 with four optimal components, and the holo-
gram that gives the lowest standard error has a length
of 353. The PLS analysis yields a conventional r2 of
0.921 for the studied compounds. The predicted inhibi-
tory activities of these compounds are also listed in
Table 5, and their correlation is shown graphically in
Figure 6c. It is important to have a QSAR technique
that offers not only a consistent and reproducible
prediction but also a fast and convenient procedure. The
HQSAR model in our study appears well-suited for such
application.
4. Va lid a tion of th e QSAR Mod els. To test the
stability and predictive ability of the QSAR models
derived from the 17 methanesulfonamido phenylethyl-
amine compounds so that they can be employed in new
analogue designs, 11 new analogues (4e-h and 5m -s)
were synthesized (Schemes 1 and 2, Table 1) as a set of
testing for validation. The predicted results are simul-
taneously shown in Table 4 and Figure 6 (in square
pattern-labeled symbols). The predicted values are
consistent with the experimental data in a statistically
tolerable error range, r2 ) 0.943, 0.891, and 0.809 for
CoMFA, CoMSIA, and HQSAR models, respectively.
The testing results for these 11 analogues indicate that
all of the three QSAR models, CoMFA, CoMSIA, and
HQSAR, are reliable and can be used in predicting
newly designed compounds.
5. New An a logu e Design , Syn th esis, a n d Bioa s-
sa y. Satisfied by the stability and predictive ability of
the QSAR models, we intended to design new analogues
based on the clues of CoMFA and CoMSIA. According
to CoMFA and CoMSIA analyses (Figures 5 and 7), we
can see that adding bulky and hydrophobic groups to
the phenyl moiety of phenoxyethane of dofetilide may
increase the bioactivity. Following these indications, we
designed eight new analogues, denoted as 6a -h (Table
2). They were synthesized through the route outlined
in Scheme 3, and the detailed synthetic procedures and
the structural characterizations were described in the
Experimental Section. With completion of the synthesis,
F igu r e 7. Contour maps from the final CoMSIA analysis with
2 Å grid spacing in combination with dofetilide. (a) Steric
std*coeff contour map. Green contours (>80% contribution)
refer to sterically favored regions; yellow contours (>20%
contribution) indicate disfavored areas. (b) Electrostatic std*coeff
contour map. Blue contours (>80% contribution) refer to
regions where negatively charged substituents are disfavored;
red contours (>20% contribution) indicate regions where
negatively charged substituents are favored. (c) Hydrophobic
std*coeff contour map. White contours (>80% contribution)
refer to regions where hydrophilic substituents are favored;
yellow contours (>20% contribution) indicate regions where
hydrophobic substituents are favored.

Class III Antiarrhythmic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2963
in vitro K+ channel inhibitory activity of these eight
target compounds as compared with dofetilide was
measured. According to the method of Wettwer et al.,27
the effective concentration of these eight methane-
sulfonamido phenylethylamine analogues upon increas-
ing ERP in isolated animal atrium was evaluated
utilizing a pair-electric stimulus technique. The results
are summarized in Table 2; the bioassay result of
compound 6c is shown in Figure 3. It is remarkable that
the percent change of delaying ERP at 10-5 M of
compound 6c is 58%, which is higher than that of
dofetilide, of which the ∆ERP% is 24.02%. The effective
concentration of compound 6c is 5 × 10-8 mol/L in
increasing ERP by 10 ms, slightly lower than that of
dofetilide, which is 1.1 × 10-8 mol/L. Figure 3 shows
that compound 6c prolongs ERP and reduces heart rate
and cardiac muscle constriction. The level of prolonging
ERP of compound 6c is much higher than that of
dofetilide at 10-5 M. Reduction in the cardiac muscle
constriction of compound 6c indicates that this com-
pound may block complex K+/Ca2+ channels.44
the experimental data of our design compounds, espe-
cially compound 6c, showed its better prolongation of
ERP than dofetilide, indicating that these compounds
are worth further study.
Exp er im en ta l Section
Reactions were run in flame-dried round-bottomed flasks
under a N2 atmosphere. The reagents (chemicals) were pur-
chased from Shanghai Chemical Reagent Company and used
without further purification. Analytical thin-layer chromatog-
raphy (TLC) was conducted with silica gel 60 F254 plates (250
µm thickness, Qindao Ocean Chemical Company, China).
Yields were not optimized. Melting points were measured in
capillary tube and were uncorrected. Infrared (IR) spectra were
given using a Perkin-Elmer 983 IR spectrometer and Bruker
IFS-48 FT-IR IR spectrometer, and the resonance of both
instruments was reported in wavenumbers (cm-1), windows
material using potassium bromide (KBr) powder. Nuclear
magnetic resonance (NMR) spectra were given on a J EOLF*90
Q FT-NMR and/or ACF* 300Q Buker NMR (IS as TMS).
Chemical shifts were reported in parts per million (ppm, δ)
downfield from tetramethylsilane. Splitting patterns were
described as singlet (s), doublet (d), triplet (t), quartet (q),
multiplet (m), and broad (br). Low- and high-resolution mass
spectra (LRMS and HRMS) were given with electric or
chemical inoization (EI or CI) produced by Nicolet 2000 model
FT-MS spectrometer.
Con clu sion
In summary, we designed and synthesized 16 meth-
ylsulfonamido phenylethylamine analogues (4a -d and
5a -l) using 2 as the leading compound. The pharma-
cological assay indicated that all of these compounds
show the activity for increasing the ERP in isolated
animal atrium. 3D-QSAR analyses were then performed
on dofetilide and the 16 methylsulfonamido phenylethyl-
amine analogues by means of CoMFA, CoMSIA, and
HQSAR methods. The 3D-QSAR models proved good
predictive abilities in predicting the activity of new
compounds. The QSAR models were tested by 11 newly
synthesized compounds (4e-h and 5m -s). Results
revealed that the CoMFA, CoMSIA, and HQSAR pre-
dicted activities for these 11 new analogues had a good
correlation with their experimental value, r2 ) 0.943,
0.891, and 0.809 for these three QSAR models, respec-
tively. This indicated that the 3D-QSAR models proved
good predictive ability and could describe the steric,
electrostatic, and hydrophobic requirements for recogni-
tion forces of the receptor site. According to the clues
provided by 3D-QSAR analyses, we designed and syn-
thesized a series of new analogues of methanesulfona-
mido phenylethylamine (6a -h ). The pharmacological
assay indicated that the effective concentration of
delaying ERP by 10 ms of these new compounds had a
good correlation with the 3D-QSAR predicted data. It
was remarkable that the percent change of delaying
ERP at 10-5 M of compound 6c was much higher than
that of dofetilide.
The pharmacological assay for our synthesized com-
pounds was not comprehensive, for we did not deter-
mine the APD and ERP on ventricular tissue. However,
in this paper, we have shown a comprehensive cycle of
active compound design, i.e., construct predictive 3D-
QSAR models based on synthesized compounds and
their bioactivities; have verified the QSAR models with
newly synthesized compounds; have designed and syn-
thesized new active compounds according to the predic-
tion of the QSAR models; and finally have tested the
new compounds’ activities by using a pharmacological
method. The consistency between the predicted data and
Gen er a l P r oced u r es for P r ep a r a tion s of 4 Ar e De-
scr ib ed a s Th ose for 4a . N-Ben zyl-N-[2-(p -m et h a n e-
su lfon am ido ph en oxy)eth yl]-p-m eth an esu lfon am ido P h en -
eth yla m in e (4a ). The mixture of methanesulfo chloride (28
mL, 0.361 mol), compound 11a (35 g, 0.0985 mol), and (Et)3N
(84 mL) in CH2Cl2 (280 mL) was stirred overnight, filtered,
and condensed. Flash chromatography was performed with
acetate-methanol (10:1,v/v), and compound 4a was given (40
g); yield 78.4%. IR (KBr): 1600, 1500 cm-1. 1H NMR (DMSO):
δ 2.53 (s, 6H), 2.61 (s, 4H), 2.82 (t, 2H), 3.71 (s, 2H), 3.90 (t,
2H), 6.60∼6.80 (m, 8H), 7.28 (s, 5H). MS (SCI) data calcd
C
25H31N3S2O5 m/z (M+), 518.1846; found, 518.1818. Anal.
(C25H31N3S2O5) C, H, N.
N-Acetyl-N-[2-(p-m eth an esu lfon am ido ph en oxy)eth yl]-
p-m eth a n esu lfon a m id o P h en eth yla m in e (4b). IR (KBr):
1640, 1520 cm-1 .1H NMR (DMSO): δ 1.858, 2.054 (d, 3H),
2.852 (s, 3H), 2.871 (s, 3H), 3.626 (m, 6H), 4.046 (t, 2H), 6.828,
6.931 (d, 2H), 7.122, 7.193 (d, 6H). MS (SCI) data calcd
C
20H29N3O6S2 m/z (M+), 470.4315; found, 470.4362. Anal.
(C20H29N3O6S2) C, H, N.
N-[2-(p-Meth a n esu lfon a m id o p h en oxy)eth yl]-p-m eth -
a n esu lfon a m id o P h en eth yl-a m in e (4c). The mixture of
palladium carbon, compound 4a (1.5 g, 0.0028 mol), and acetic
acid (40 mL) at 30 °C and 15 kg atm was stirred and bubbled
by the hydrogen for 8 h, filtered, and neutralized to neutron
using alkali and then extracted with acetyl ether; the white
compound 4c (0.5 g) was given; mp 149∼151 °C. IR (KBr):
1600, 1510 cm-1 1H NMR (CD3COCD3): δ 2.811-2.830 (m,
.
4H), 2.904 (s, 3H), 2.950 (s, 3H), 2.997 (t, 2H), 4.091 (t, 2H),
6.921 (d, 2H), 7.277 (m, 6H). HRMS (SCI) m/z calcd for M+,
428.128; found, 428.131. Anal. (C18H25N3S2O5) C, H, N.
N-(p-Ch lor oben zyl)-N-[2-(p-m eth an esu lfon am idoph en -
oxy)eth yl]-p-m eth yl-su lfon a m id o P h en eth yla m in e (4d ).
IR (KBr): 1600, 1520 cm-1. 1H NMR (DMSO): δ 2.914, 2.9675
(2s, 6H), 3.13, 3.36 (2t, 4H), 3.624 (s, 2H), 4.362 (s, 2H), 4.552
(s, 2H), 7.0 (d, 2H), 7.23 (m, 6H), 7.56∼7.70 (dd, 4H). HRMS
(SCI) m/z calcd for M+, 552.136; found, 552.139. Anal.
(C25H30N3S2O5Cl) C, H, N.
N-[2-(p-Meth a n esu lfon a m id o p h en oxy)eth yl]-N-[2-(p-
m eth a n esu lfon a m id o p h en oxy)eth yl]-p-m eth a n esu lfon a -
m id o P h en eth yla m in e (4e). mp 130-133 °C. IR (KBr):
1
1620, 1520 cm-1. H NMR (DMSO-d6): δ 2.847 (s, 9H), 2.863
(t, 8H), 3.095 (m, 4H), 3.99 (t, 4H), 6.773, 6.882 (d, 4H), 7.141,
7.281 (d, 8H). MS (SCI) m/z 640 (M+). Anal. (C27H36O8S3N4)
C, H, N.
N-(Meth a n esu lfon a m id o)-N-[2-(p-m eth a n esu lfon a m i-
d op h en oxy)eth yl]-p-m eth a n esu lfon a m id o P h en eth yla m -

2964 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
in e (4f). Compound 4f was given simultaneously in preparing
Liu et al.
N-Ben zyl-N-(p-m eth ylben zyl)-p-d im eth a n esu lfon a m i-
d o P h en eth yla m in e (5i). mp 112-116 °C. IR (KBr): 1504,
1368 cm-1. 1H NMR (CDCl3 + DMSO-d6): δ 2.35 (s, 3H), 2.80-
2.85 (m, 4H), 3.35 (s, 6H), 4.15 (s, 2H), 4.30 (s, 2H), 7.20-7.55
(m, 13H). HRMS (SCI) m/z calcd for M+, 487.2410; found,
487.2470. Anal. (C24H28N2SO2) C, H, N.
1
compound 4e. IR (KBr): 1600, 1510 cm-1. H NMR (CDCl3 +
DMSO-d6): δ 2.858-2.945 (m, 11H), 3.44-3.49 (t, 2H), 3.57-
3.66 (t, 2H), 4.03-4.08 (t, 2H), 6.817-6.869 (d, 2H), 7.151-
+
7.219 (m, 6H), 9.318, 9.557 (2s, 2H). MS (SCI) m/z 544 (M
)
(base peak). Anal. (C19H27N3S3O7) C, H, N.
N-Allyl-N-[2-(p-m eth a n esu lfon a m id o p h en oxy)eth yl]-
p-m eth a n esu lfon a m id o P h en eth yla m in e (4g). IR (KBr):
N-Ben zyl-N-(p-ch lor oben zyl)-p -m et h a n esu lfon a m id o
P h en eth yla m in e (5j). mp 152-154 °C. IR (KBr): 1616, 1364
1
1611, 1509 cm-1. H NMR (CDCl3): δ 2.716 (s, 4H), 2.863 (m,
cm-1 1H NMR (CDCl3 + DMSO-d6): δ 2.70 (s, 4H), 3.30 (s,
.
8H), 3.186 (t, 2H), 3.999-4.06 (t, 2H), 5.05-5.20 (m, 2H), 5.80-
5.92 (m, 1H), 6.70-6.784 (m, 2H), 7.062-7.281 (m, 6H). HRMS
(SCI) m/z calcd for M+, 468.1621; found, 468.1578. Anal.
(C21H29N3S2O5) C, H, N.
3H), 3.60 (s, 4H), 7.10-7.40 (m, 13H). HRMS (SCI) m/z calcd
for M+, 428.9810; found, 428.9890. Anal. (C23H25N2SO2Cl) C,
H, N.
N-Ben zyl-N-(p -m et h oxyb en zyl)-p -d im et h a n esu lfon a -
m id o P h en eth yla m in e (5k ). mp 102-106 °C. IR (KBr):
N-Ben zoyl-N-[2-(p-m eth a n esu lfon a m id o p h en oxy)eth -
yl]-p -m et h a n esu lfon a m id o P h en et h yla m in e (4h ). IR
1672, 1284 cm-1 1H NMR (CDCl3 + DMSO-d6): δ 2.85 (m,
.
(KBr): 1612, 1510 cm-1 1H NMR (CDCl3): δ 2.65-2.85 (m,
.
4H), 3.30 (s, 6H), 3.60 (s, 2H), 3.70 (s, 2H), 3.82 (s, 3H), 6.85
(d, 2H), 7.15-7.30 (m, 11H). HRMS (SCI) m/z calcd for M+,
503.5600; found, 503.5620. Anal. (C25H30N2S2O5) C, H, N.
7H), 3.5-3.67 (m, 2H), 4.2-4.35 (m, 2H), 6.55-6.6 (m, 2H),
7.18-7.40 (m, 11H). MS (SCI) m/z calcd for M+, 454.1795;
found, 454.1832. Anal. (C24H27N3SO4) C, H, N.
N-Ben zyl-N-(3,4-m eth ylen ed ioxyben zyl)-p-d im eth a n e-
su lfon a m id o P h en eth yla m in e (5l). mp 122-125 °C. IR
(KBr): 1490, 1368 cm-1. 1H NMR (CDCl3 + DMSO-d6): δ 2.85
(m, 4H), 3.35 (s, 6H), 3.55 (s, 2H), 3.60 (s, 2H), 6.05 (s, 2H),
7.20-7.55 (m, 12H). HRMS (SCI) m/z calcd for M+, 517.1500;
found, 517.1590. Anal. (C25H28N2S2O6) C, H, N.
Gen er a l P r oced u r es for P r ep a r a tion s of 5 Ar e De-
scr ibed a s Th ose for 5a . N-Meth yl-N-ben zyl-p-m eth a n e-
su lfon a m id o P h en eth yla m in e (5a ). The mixture of meth-
anesulfochloride (0.6 mL, 0.0075 mol), compound 16a (1.7 g,
0.0071 mol), and (Et)3N (2 mL) in CH2Cl2 (5 mL) was stirred
overnight, filtered, and condensed. Flash chromatography was
performed with acetate-methanol (10:1,v/v), and compound
5a was given (1.75 g); yield 77.6%; mp 97-99 °C. IR (KBr):
1620, 1368 cm-1. 1H NMR (CDCl3 + DMSO-d6): δ 2.30 (s, 3H),
2.85 (m, 4H), 3.40 (s, 3H), 3.60 (s, 2H), 7.20-7.30 (m, 9H).
HRMS (SCI) m/z calcd for M+, 319.4420; found, 319.4611. Anal.
(C17H22N2SO2) C, H, N.
N-(p-Ch lor oben zyl)-N-(p-m eth oxyben zyl)-p-m eth a n e-
su lfon a m id o P h en eth yla m in e (5m ). IR (KBr): 1610, 1510
cm-1 1H NMR (CDCl3): δ 2.65 (s, 4H), 2.95 (s, 3H), 3.50 (s,
.
4H), 3.75 (s, 3H), 6.75-6.85 (d, 2H), 6.95-7.20 (m, 10H).
HRMS (SCI) m/z calcd for M+, 459.1503; found, 459.1525. Anal.
(C24H27N2SO3Cl) C, H, N.
N-Meth yl-N-(o-m eth oxyben zyl)-p-m eth a n esu lfon a m i-
d o P h en eth yla m in e (5n ). In the same manner as described
for 5a , 5n was prepared from 16n ; mp 96-98 °C. IR (KBr):
2913, 1522 cm-1. 1H NMR (CDCl3 + DMSO-d6): δ 2.30 (s, 3H),
2.95-3.02 (m, 4H), 3.30 (s, 3H), 3.80 (s, 3H), 3.95 (s, 2H), 7.30-
7.85 (m, 8H). HRMS (SCI) m/z calcd for M+, 349.1583; found,
349.1595. Anal. (C24H28N2SO3) C, H, N.
N-Meth yl-N-(p-m eth ylben zyl)-p-d im eth a n esu lfon a m i-
d o P h en eth yla m in e (5b). In the same manner as described
for 5a , 5b was prepared from 16b; mp 102-104 °C. IR (KBr):
1515, 1368 cm-1. 1H NMR (CDCl3 + DMSO-d6): δ 2.25 (s, 3H),
2.30 (s, 3H), 2.60-2.90 (m, 4H), 3.35 (s, 6H), 3.53 (s, 2H), 7.23-
7.44 (m, 8H). HRMS (SCI) m/z calcd for M+, 411.2710; found,
411.2691. Anal. (C19H26N2S2O4) C, H, N.
N-Meth yl-N-(p-ch lor oben zyl)-p-m eth a n esu lfon a m id o
P h en eth yla m in e (5c). In the same manner as described for
5a , 5c was prepared from 16c; mp 59-62 °C. IR (KBr): 1508,
1368 cm-1. 1H NMR (CDCl3 + DMSO-d6): δ 2.25 (s, 3H), 2.70-
2.75 (m, 4H), 3.35 (s, 3H), 3.50 (s, 2H), 7.10-7.40 (m, 8H).
HRMS (SCI) m/z calcd for M+, 352.8800; found, 352.8820. Anal.
(C17H21N2SO2Cl) C, H, N.
N-Met h yl-N-(p -m et h oxyb en zyl)-p -d im et h a n esu lfon a -
m id o P h en eth yla m in e (5d ). IR (KBr): 1616, 1364 cm-1. 1H
NMR (CDCl3 + DMSO-d6): δ 2.25 (s, 3H), 2.83-2.90 (m, 4H),
3.30 (s, 6H), 3.64 (s, 2H), 3.80 (s, 3H), 6.85 (d, 2H), 7.22-7.31
(m, 6H). HRMS (SCI) m/z calcd for M+, 427.1400; found,
427.1420. Anal. (C18H24N2SO3) C, H, N.
N-Acet yl-N-(p -m et h oxyb en zyl)-p -m et h a n esu lfon a m i-
d o P h en eth yla m in e (5o). Yield 29%; flash chromatography
with acetate-petroleum ether (2:1,v/v); Rf ) 0.3; mp 118-120
°C. IR (KBr): 1618, 1512 cm-1 1H NMR (CDCl3): δ 2.10-
.
2.15 (dd, 3H), 2.85-2.90 (m, 2H), 3.0 (s, 3H), 3.50 (m, 2H),
3.80 (s, 3H), 4.40 (s, 2H), 6.80-7.25 (m, 8H). HRMS (SCI) m/z
calcd for M+, 376.1451; found, 376.1445. Anal. (C19H24N2O4S)
C, H, N.
N-Ben zoyl-N-(p -m et h oxyb en zyl)-p -m et h a n esu lfon a -
m id o P h en eth yla m in e (5p ). In the same manner as de-
scribed for 5a , 5p was prepared from 16p ; yield 26%; mp 124-
126 °C; flash chromatography with acetate-petroleum ether
(1:1, v/v); Rf ) 0.4. IR (KBr): 1628, 1512 cm-1 1H NMR
.
(CDCl3): δ 2.5-2.9 (m, 5H), 3.50 (s, 2H), 3.70 (s, 3H), 4.30 (s,
2H), 6.60-7.50 (m, 13H). HRMS (SCI) m/z calcd for M+,
439.1686; found, 439.1701. Anal. (C24H26N2O4S) C, H, N.
N-Meth yl-N-cycloh exyl-p-m eth a n esu lfon a m id o P h en -
eth yla m in e (5e). mp 82-86 °C. IR (KBr): 1673, 1372 cm-1
.
1H NMR (CDCl3 + DMSO-d6): δ 1.05-1.90 (m, 11H), 2.35 (s,
3H), 2.80 (m, 4H), 3.05 (s, 3H), 7.30 (m, 4H). HRMS (SCI) m/z
calcd for M+, 311.4620; found, 311.4590. Anal. (C16H25N2SO2)
C, H, N.
N-Meth yl-N-cycloh exyl-p-dim eth an esu lfon am ido P h en -
eth yla m in e (5q). Compound 5q was given simultaneously in
preparing compound 5e. IR (KBr): 1663, 1382 cm-1. 1H NMR
(CDCl3 + DMSO-d6): δ 1.05-1.90 (m, 11H), 2.35 (s, 3H), 2.80
(m, 4H), 3.35 (s, 6H), 7.30 (m, 4H). HRMS (SCI) m/z calcd for
M+, 389.4620; found, 389.4590. Anal. (C17H28N2S2O4) C, H, N.
N-Met h yl-N-(3,4-m et h ylen ed ioxyb en zyl)-p -m et h a n e-
su lfon a m id o P h en eth yla m in e (5f). mp 115-117 °C. IR
(KBr): 1612, 1372 cm-1. 1H NMR (CDCl3 + DMSO-d6): δ 2.30
(s, 3H), 3.05 (m, 4H), 3.35 (s, 3H), 3.63 (s, 2H), 6.03 (s, 2H),
6.82-7.65 (m, 7H). HRMS (SCI) m/z calcd for M+, 363.4410;
found, 363.4390. Anal. (C18H28N2SO4) C, H, N.
N,N-Diben zyl-p-d im eth a n esu lfon a m id o P h en eth yla m -
in e (5r ). Compound 5r was given simultaneously in preparing
1
compound 5h . IR (KBr): 1615, 1368 cm-1. H NMR (CDCl3):
δ 2.85 (m, 4H), 3.35 (s, 6H), 3.65 (s, 4H), 7.25-7.40 (m, 14H).
HRMS (SCI) m/z calcd for M+, 473.5310; found, 473.5360. Anal.
(C24H28N2S2O4) C, H, N.
N-Ben zyl-N-(o-m eth oxyben zyl)-p-m eth a n esu lfon a m i-
d o P h en eth yla m in e (5g). mp 96-98 °C. IR (KBr): 2913,
1522 cm-1. 1H NMR (CDCl3 + DMSO-d6): δ 2.95-3.02 (m, 4H),
3.30 (s, 3H), 3.65 (s, 2H), 3.80 (s, 3H), 3.95 (s, 2H), 7.30-7.85
(m, 13H). HRMS (SCI) m/z calcd for M+, 424.3750; found,
424.3790. Anal. (C24H28N2SO3) C, H, N.
N-(p-Methoxybenzyl)-N-[2-(p-methanesulfonamidophen-
oxy)eth yl]-p-m eth a n esu lfon a m id o P h en eth yla m in e (5s).
In the same manner as described for 5a , 5s was prepared from
N,N-Diben zyl-p-m eth an esu lfon am ido P h en eth ylam in e
16s; mp 147-150 °C. IR (KBr): 1600, 1520 cm-1 1H NMR
.
(5h ). mp 107-111 °C. IR (KBr): 1515, 1368 cm-1
.
1H NMR
(CDCl3): δ 2.77 (s, 6H), 2.889 (s, 4H), 2.984 (t, 2H), 3.67 (s,
2H,), 3.74 (s, 3H), 4.30 (t, 2H), 6.84-6.99 (m, 5H), 7.15-7.22
(m, 7H). HRMS (SCI) m/z calcd for M+, 549.2013; found,
549.2061. Anal. (C24H29N3O2) C, H, N.
(CDCl3): δ 2.85 (m, 4H), 3.35 (s, 3H), 3.65 (s, 4H), 7.25-7.40
(m, 14H). HRMS (SCI) m/z calcd for M+, 395.5310; found,
395.5360. Anal. (C23H26N2SO2) C, H, N.

Class III Antiarrhythmic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2965
N -Me t h yl-N -[2-(n a p h t h -1-yl-oxy)e t h yl]-p -m e t h a n e -
su lfon a m id o P h en eth yla m in e (6a ). In the same manner
as described for 4a , 6a was prepared from 20a ; yield 60.3%;
flash chromatography CH3COOC2H5/petroleum ether (2:1, v/v);
(m, 2H). HRMS (SCI) m/z calcd for M+, 477.1486; found,
477.1511. Anal. (C23H28N2S2O5) C, H, N.
2-(4-Nitr op h en oxy)-1-br om oeth a n e (7). The mixture of
4-nitrophenol (140 g, 1.006 mol), NaOH (40 g), TBA (5 g), and
anhydrous alcohol (600 mL) was cooled to 30 °C after it was
heated and refluxed for 15 min, added dropwise to 1,2-
dibromoethane (250 mL, 2.89 mol), heated, and refluxed for
24 h. Then, the mixture was condensed, filtered, and extracted
with acetate. The organic phase was washed with water and
dried with anhydrous Na2SO4. The condensate was recrystal-
lized in anhydrous alcohol. White crystallized compound (116
g) was given; yield 46.8%; mp 62-64 °C; chromatography CH3-
COOC2H5/ petroleum ether (1:2, v/v); Rf ) 0.35.
N-Acetyl-p-n itr op h en eth yla m in e. A mechanically stirred
suspension of â-phenethylamine (100 mL, 0.796 mol) was
cooled in an ice bath and added dropwise at a rate with acetic
anhydride (76 mL, 0.804 mol). It was stirred for 2 h, and the
temperature was maintained at 40-45 °C. A stirred mixture
of concentrated sulfuric acid (150 mL, 2.81 mol) and concen-
trated nitric acid (150 mL, 3.33 mol) was added dropwise to
the upper solution to the mix acid, continually reacted for 2
h, and then poured into the ice water, extracted three times
with acetate, and then combined with the organic phase, dried
with anhydrous Na2SO4, and condensed. The residue was
recrystallized using acetone-water (3:1) to afford the desired
product; white acicular crystal 76 g; yield 46.0%; mp 138-
140 °C; Merk Index p-NO2C6H4CH2CH2NHAc mp 138 °C.
p-Nitr op h en eth yla m in e Hyd r obr om id e (8). A 47% (v/
v) amount of hydrobromic acid (110 mL, 0.75 mol) was added
to N-acetyl-p-nitrophenethylamine (60 g, 0.288 mol), and the
solution was refluxed for 6 h by stirring and heating and then
cooled at room temperature, and a white powder appeared;
weight 71 g; yield 99%; mp 218 °C; Merk Index p-NO2C6H4-
CH2CH2NH2 mp 27 °C.
N-[2-(p-Nitr oph en oxy)eth yl]-p-n itr oph en eth ylam in e (9).
The mixture of compound 8 (40.0 g, 0.162 mol), compound 7
(32 g, 0.13 mol), and K2CO3 (33 g, 0.239 mol) in acetonitrile
(160 mL) was stirred at room temperature overnight. The
reaction mixture was poured into ice water and adjusted to
pH 2 with 10% HCl. The precipitated solid was recrystallized
with acetic ether/petroleum ether, and then, a yellowish
powder was given (43.5 g); yield 81.5%; chromatography CH3-
COOC2H5/petroleum ether (2:1, v/v); Rf ) 0.4; mp 58-60 °C.
Rf ) 0.17; mp 130-131 °C. IR (KBr): 1600, 1511 cm-1 1H
.
NMR (CDCl3): δ 2.45 (s,3H), 2.75-2.85 (2s,7H), 2.95 (t,2H),
4.15 (t,2H), 6.75-6.80 (q,1H), 7.0-7.4 (m, 6H), 7.55-7.70 (m,
2H), 8.0-8.2 (m, 2H). HRMS (SCI) m/z calcd for M+, 398.1516;
found, 398.1481. Anal. (C22H26N2SO3) C, H, N.
N -Be n zyl-N -[2-(n a p h t h -1-yl-oxy)e t h yl]-p -m e t h a n e -
su lfon a m id o P h en eth yla m in e (6b). In the same manner
as described for 4a , 6b was prepared from 21b; yield 40.7%;
flash chromatography CH3COOC2H5/petroleum ether (1:2, v/v);
Rf ) 0.44. IR (KBr): 1579, 1510 cm-1 1H NMR (CDCl3): δ
.
2.863 (s, 7H), 2.863-3.613 (t, 2H), 3.828 (s, 2H), 4.059-4.163
(t, 2H), 6.740-6.920 (q, 1H), 6.920-7.465 (m, 11H), 7.705 (m,
2H), 8.138-8.179 (m, 2H). HRMS (SCI) m/z calcd for M+,
475.2059; found, 475.2021. Anal. (C28H30N2SO3) C, H, N.
N -Ace t yl-N -[2-(n a p h t h -1-yl-oxy)e t h yl]-p -m e t h a n e -
su lfon a m id o P h en eth yla m in e (6c). In the same manner as
described for 4a , 6c was prepared from 21c; mp 132-134 °C;
yield 81.6%; flash chromatography CH3COOC2H5/petroleum
ether (2:1, v/v); Rf ) 0.28. IR (KBr): 1632, 1509 cm-1. 1H NMR
(CDCl3): δ 1.95, 2.05 (2s, 3H), 2.90-3.00 (m, 5H), 3.65 (t, 2H),
3.80 (t, 2H), 4.20 (t, 2H), 6.70-6.80 (q, 1H), 7.05-7.45 (m,
11H), 7.60-7.90 (m, 2H), 8.0-8.15 (m, 2H). HRMS (SCI) m/z
calcd for M+, 427.1689; found, 427.1701. Anal. (C23H26N2SO4)
C, H, N.
N-Allyl-N-[2-(n aph th -1-yl-oxy)eth yl]-p-m eth an esu lfon a-
m id o P h en eth yla m in e (6d ). In the same manner as de-
scribed for 4a , 6d was prepared from 21d ; yield 20.5%; flash
chromatography CH3COOC2H5/petroleum ether (1:2, v/v); Rf
1
) 0.22. IR (KBr): 1615, 1504 cm-1. H NMR (CDCl3): δ 2.85
(s, 4H), 2.90 (s, 3H), 3.05-3.20 (t, 2H), 3.25-3.40 (d, 2H), 4.10-
4.20 (m, 2H), 5.10-5.35 (t, 2H), 5.85 (m, 1H), 6.70-6.85 (q,
1H), 7.10-7.50 (m, 8H), 7.70-7.85 (m, 1H), 8.15-8.30 (m, 1H).
HRMS (SCI) m/z calcd for M+, 425.1893; found, 425.1870. Anal.
(C24H28N2SO3) C, H, N.
N -Allyl-N -[2-(n a p h t h -1-yl-oxy)e t h yl]-p -d im e t h a n e -
su lfon a m id o P h en eth yla m in e (6e). Compound 6e was
given simultaneously in preparing compound 6d ; yield 20%;
flash chromatography CH3COOC2H5/petroleum ether (1:2, v/v);
Rf ) 0.35. IR (KBr): 1579, 1508 cm-1 1H NMR (CDCl3): δ
.
2.90 (s, 4H), 3.10 (t, 2H), 3.40 (d+s, 8H), 4.15 (t, 2H), 5.10-
5.20 (t, 2H), 5.70-5.90 (m, 1H), 6.70-6.85 (q, 1H), 7.15-7.5
(m, 8H), 7.55-7.7 (m, 1H), 8.10-8.30 (m, 1H). HRMS (SCI)
m/zcalcd for M+,503.1663;found,503.1640.Anal.(C25H30N2S2O5)
C, H, N.
Gen er a l P r oced u r es for P r ep a r a tion s of 10 Ar e De-
scr ib ed a s Th ose for 10a . N-Ben zyl-N-[2-(p-n it r op h en -
oxy)eth yl]-p-n itr op h en eth yla m in e (10a ). The mixture of
compound 9 (10 g, 0.0302 mol) and K2CO3 (6 g, 0.044 mol) in
CH3CN (100 mL) was added to C6H5CH2Cl (3.54 g, 0.028 mol)
and stirred and refluxed for 3.5 h. The reaction mixture was
filtered and condensed. Flash chromatography with acetate-
petroleum ether was performed (4:1, v/v); Rf ) 0.7. Compound
10a was given (3.6 g); yield 61%; mp 94-96 °C. IR (KBr): 1600,
1510 cm-1. 1H NMR (CDCl3): δ 2.912 (s, 4H), 2.98 (t, 2H), 3.76
(s, 2H), 4.03 (t, 2H), 6.885 (m, 2H), 7.261-7.30 (m, 7H), 8.1-
8.2 (m, 4H). MS (SCI) m/z 422 (M+).
N-Acetyl-N-[2-(p-n itr op h en oxy)eth yl]-p-n itr op h en eth -
ylam in e (10b). Yield 91%; flash chromatography with acetate-
petroleum ether (1:1, v/v); Rf ) 0.45; mp 112-113 °C. IR
(KBr): 1600, 1520 cm-1. 1H NMR (CDCl3): δ 2.04, 2.21 (d, 3H),
3.04 (t, 2H), 3.72 (m, 4H), 4.03-4.30(m, 2H), 6.88-6.98 (m,
2H), 7.30-7.48 (m, 2H), 8.01-8.29 (m, 4H). MS (SCI) m/z 374
(M+).
N-Ben zoyl-N-[2-(n a p h t h -1-yl-oxy)et h yl]-p -m et h a n e-
su lfon a m id o P h en eth yla m in e (6f). In the same manner as
described for 4a , 6f was prepared from 21f; yield 60.5%; flash
chromatography CH3COOC2H5/petroleum ether (1:1, v/v); Rf
1
) 0.52. IR (KBr): 1634, 1506 cm-1. H NMR (CDCl3): δ 2.75
(b, 2H), 3.0 (s, 3H), 3.55 (b, 2H), 3.85 (b, 2H), 4.25 (b, 2H),
6.70 (b, 3H), 7.0-7.40 (m, 9H), 7.50-7.70 (m, 2H), 8.0-8.15
(b, 2H). HRMS (SCI) m/z calcd for M+, 488.1633; found,
488.1640. Anal. (C28H28N2SO4) C, H, N.
N-Ben zyl-N-[2-(n a p h t h -1-yl-oxy)et h yl]-p -d im et h a n e-
su lfon a m id o P h en eth yla m in e (6g). Compound 6g was
given simultaneously in preparing compound 6b. Flash chro-
matography CH3COOC2H5/petroleum ether (1:2, v/v); Rf ) 0.6.
1
IR (KBr): 1580, 1508 cm-1. H NMR (CDCl3): δ 2.85-2.90 (t,
2H), 3.05 (s, 4H), 3.55 (s, 6H), 4.05 (s, 2H), 4.35 (t, 2H), 6.70-
6.85 (q, 1H), 7.05-7.50 (m, 11H), 7.60-7.80 (m, 2H), 8.0-8.20
(m, 2H). HRMS (SCI) m/z calcd for M+, 553.1829; found,
553.1871. Anal. (C29H32N2S2O5) C, H, N.
N-(p-Ch lor oben zyl)-N-[2-(p-n itr op h en oxy)eth yl]-p-n i-
tr op h en eth yla m in e (10d ). Yield 50%; flash chromatography
with acetate-petroleum ether (1:2, v/v); Rf ) 0.70; mp 96-98
1
°C. IR (KBr): 1600, 1510 cm-1. H NMR (DMSO): δ 2.87 (s,
4H), 2.95 (t, 2H), 3.23 (s, 2H), 4.00 (t, 2H), 6.89 (d, 2H), 7.2-
N-Met h yl-N-[2-(n a p h t h -1-yl-oxy)et h yl]-p -d im et h a n e-
su lfon a m id o P h en eth yla m in e (6h ). Compound 6h was
given simultaneously in preparing compound 6a . Flash chro-
7.4 (m, 6H), 8.0-8.4 (m, 4H). MS (SCI) m/z 458 (M2+).
N-[2-(p -Nit r op h en oxy)et h yl]-N-[2-(p -n it r op h en oxy)-
eth yl]-p-n itr op h en eth yla m in e (10e). Flash chromatogra-
phy with acetate-petroleum ether (1:1, v/v), Rf ) 0.45, was
performed, and the yellow solid was given; mp 110-113 °C.
matography CH3COOC2H5/petroleum ether (2:1, v/v); Rf
)
1
0.35. IR (KBr): 1582, 1508 cm-1. H NMR (CDCl3): δ 2.55 (s,
3H), 2.90 (s, 4H), 3.10 (t, 2H), 3.45 (s, 6H), 4.20 (t, 2H), 6.75-
6.85 (q, 1H), 7.20-7.50 (m, 6H), 7.70-7.85 (m, 2H), 8.10-8.20
1
IR (KBr): 1600, 1510 cm-1. H NMR (CDCl3): δ 2.98 (s, 8H),

2966 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Liu et al.
3.08 (t, 4H), 4.06 (t, 4H), 6.80-6.87 (d, 2H), 7.30-7.37 (d, 2H),
8.00-8.17 (m, 6H). MS (SCI) m/z 497 (M+).
1H NMR (CDCl3 + DMSO-d6): δ 3.20-3.25 (m, 4H), 3.65 (s,
3H), 3.90 (s, 2H), 7.15-8.15 (m, 8H).
N-(p-Meth oxyben zyl)-p-n itr op h en eth yla m in e Hyd r o-
ch lor id e(14o). The mixture of p-nitrophenylethylamine (30
g, 0.18 mol), benzene (90 mL, 24.19 mL, 0.19 mol), and
anisaldehyde was stirred and refluxed for 4 h and then cooled,
and ethanol (120 mL) and KBH4 (9 g) were added, and it was
refluxed for 2 h. The reaction was cooled and then adjusted to
pH 3 and filtered, and the white solid was given (50 g); yield
N-Allyl-N-[2-(p-n itr op h en oxy)eth yl]-p-n itr op h en eth yl-
a m in e (10g). Flash chromatography with acetate-petroleum
ether (1:1, v/v), Rf ) 0.35, was performed, and the yellow solid
was given. IR (KBr): 1605, 1510 cm-1 1H NMR (CDCl3): δ
.
2.80 (s, 4H), 2.86 (m, 2H), 3.13 (t, 2H), 4.06 (t, 2H), 5.10 (m,
2H), 5.90 (m, 1H), 6.80-6.87 (d, 2H), 7.30-7.37 (m, 6H). MS
(SCI) m/z 371 (M+).
1
85.8%; mp 230-232 °C. IR (KBr): 1600, 1510 cm-1. H NMR
N-Ben zoyl-N-[2-(p -n it r op h en oxy)et h yl]-p -n it r op h en -
1
(CDCl3): δ 2.91 (s, 4H), 3.74 (s, 2H), 3.78 (s, 3H), 6.78-6.9
eth yla m in e (10h ). mp 82-84 °C. H NMR (CDCl3): δ 3.024
(m, 2H), 7.1-7.4 (m, 4H), 8.0-8.2 (m, 2H).
(m, 2H), 3.779, 3.849 (m, 4H), 4.220 (m, 2H), 7.086-7.454 (m,
9H), 8.075-8.247 (m, 4H).
Gen er a l P r oced u r es for P r ep a r a tion s of 15a -g,n Ar e
Descr ibed a s Th ose for 15a . N-Meth yl-N-ben zyl-p-n itr o-
p h en eth yla m in e Hyd r och lor id e (15a ). A 36% formalde-
hyde (11 mL, 0.16 mol) amount was added to compound 14a
(10 g, 0.034 mol) in formic acid 88% (6.4 mL, 0.21 mol), it was
heated and refluxed for 4 h, and then, it was adjusted to a
solution of pH 14 with 20% NaOH, extracted with acetate, and
condensed. Flash chromatography with acetate-petroleum
ether (2:1, v/v) was performed, and compound 15a was given
Gen er a l P r oced u r es for P r ep a r a tion s of 11 Ar e De-
scr ibed a s Th ose for 11a . N-Ben zyl-N-[2-(p-a m in op h en -
oxy)eth yl]-p-(a m in o)p h en eth yla m in e (11a ). The mixture
of acetone (50 mL), hydrochloric acid (1 mL), reductive iron
powder (5 g, 0.089 mol), and a little ammonium chloride was
stirred and boiled for 0.5 h and cooled to 45 °C, and then, a
solution of compound 10a (8.14 g, 0.0217 mol) in 50 mL of
acetone was added to the mixture dropwise over 3 h. The
reaction mixture was cooled and adjusted to pH 10 with 10%
NaOH, then filtered, and condensed. Flash chromatography
with acetate-petroleum ether (1:1,v/v) was performed, and
compound 11a was given (5.1 g); yield 87%. 1H NMR (CDCl3):
δ 2.8 (s, 4H), 3.0 (t, 2H), 3.73 (s, 2H), 3.87 (t, 2H), 6.9-7.0 (m,
8H), 7.27 (s, 5H). MS (SCI) m/z 362 (M+) (base peak).
N-Acetyl-N-[2-(p-am in oph en oxy)eth yl]-p-(am in o)ph en -
eth yla m in e (11b). Yield 78%; flash chromatography with
acetate-petroleum ether (1:1, v/v); Rf ) 0.33. 1H NMR
(CDCl3): δ 1.92, 2.15, (d, 3H), 2.75 (t, 2H), 3.41-3.62 (q, 4H),
4.03 (t, 2H), 6.57-6.68 (m, 6H), 6.89-7.01 (m, 2H). MS (SCI)
m/z 314 (M+).
Gen er a l P r oced u r es for P r ep a r a tion s of 14 Ar e De-
scr ib ed a s Th ose for 14a . N-Ben zyl-p -n it r op h en et h yl-
a m in e Hyd r och lor id e (14a ). The mixture of p-nitrophenyl-
ethylamine (10 g, 0.06 mol), benzaldehyde (5.8 mL, 0.06 mol),
and anhydrous ethanol (50 mL) was heated and stirred for 2
h and then cooled, and KBH4 (3 g) was added and reacted for
5 h. The reaction was cooled and filtered, and the yellow solid
was given (15.1 g); yield 86%; mp 256-258 °C. 1H NMR (CDCl3
+ DMSO-d6): δ 3.20 (s, 4H), 4.15 (dd, 2H), 7.20-7.85 (m, 7H),
8.15 (d, 2H).
N-(p -Met h ylb en zyl)-p -n it r op h en et h yla m in e H yd r o-
ch lor id e (14b). In the same manner as described for 14a , 14b
was prepared from p-methyl-benzaldehyde; mp 246-248 °C.
1H NMR (CDCl3 + DMSO-d6): δ 2.35 (s, 3H), 3.00-3.40 (m,
4H), 3.83 (s, 2H), 7.10 (d, 2H), 7.30 (d, 2H), 7.49 (d, 2H), 8.12
(d, 2H)
N-(p -Ch lor ob en zyl)-p -n it r op h en et h yla m in e H yd r o-
ch lor id e (14c). In the same manner as described for 14a , 14c
was prepared from p-chloro-benzaldehyde; mp 203-205 °C.
1H NMR (CDCl3 + DMSO-d6): δ 3.22 (m, 4H), 4.40 (s, 2H),
7.44-8.25 (m, 8H).
N-(p-Meth oxyben zyl)-p-n itr op h en eth yla m in e Hyd r o-
ch lor id e (14d ). In the same manner as described for 14a , 14d
was prepared from p-methoxyl-benzaldehyde; mp 246-248 °C.
1H NMR (CDCl3 + DMSO-d6): δ 3.45 (m, 4H), 3.85 (s, 3H),
4.10 (s, 2H), 6.90 (d, 2H), 7.20-7.40 (m, 4H), 8.15 (d, 2H).
N-(Cycloh exyl)-p -n it r op h en et h yla m in e H yd r och lo-
r id e (14e). In the same manner as described for 14a , 14e was
prepared from cyclohexanone; mp 180-182 °C. 1H NMR
(CDCl3 + DMSO-d6): δ 1.05-2.34 (m, 11H), 3.34-3.40 (m, 4H),
7.50 (d, 2H), 8.12 (d, 2H), 9.50 (bro, 1H, D2O exchangeable).
N -(3,4-Me t h y le n e d io x y b e n zy l)-p -n it r o p h e n e t h y l-
a m in e Hyd r och lor id e (14f). In the same manner as de-
scribed for 14a , 14f was prepared from 3,4-methylenedioxyl
benzaldehyde; mp 242-246 °C. 1H NMR (CDCl3 + DMSO-
d6): δ 3.20-3.40 (m, 4H), 4.05 (s, 2H), 6.10 (s, 2H), 6.80 (d,
2H), 7.10 (d, 2H), 7.28 (s, 1H), 7.52 (d, 2H), 8.15 (d, 2H).
(9.5 g); yield 92.3%; mp 218-220 °C. 1H NMR (CDCl3
+
DMSO-d6) δ 2.75 (s, 3H), 3.15 (s, 4H), 4.20 (s, 2H), 7.45-7.78
(m, 7H), 8.15 (d, 2H).
N -Me t h y l-N -(p -m e t h y lb e n zy l)-p -n it r o p h e n e t h y l-
a m in e Hyd r och lor id e (15b). In the same manner as de-
scribed for 15a , 15b was prepared from 14b; mp 185-186.5
°C. 1H NMR (CDCl3 + DMSO-d6): δ 2.30 (s, 3H), 2.65 (s, 3H),
3.35 (s, 4H), 4.40 (q, 2H), 7.20-7.60 (m, 6H), 8.12 (d, 2H).
N -M e t h y l-N -(p -c h lo r o b e n z y l)-p -n i t r o p h e n e t h y l-
a m in e Hyd r och lor id e (15c). In the same manner as de-
scribed for 15a , 15c was prepared from 14c; mp 146-150 °C.
1H NMR (CDCl3 + DMSO-d6): δ 2.80 (s, 3H), 3.35 (s, 2H), 3.40
(s, 2H), 4.40 (s, 2H), 7.30-7.85 (m, 6H), 8.12 (d, 2H).
N -Me t h yl-N -(p -m e t h oxyb e n zyl)-p -n it r op h e n e t h yl-
a m in e Hyd r och lor id e (15d ). mp 170-172 °C. 1H NMR
(CDCl3 + DMSO-d6): δ 2.70 (s, 3H), 3.25 (s, 4H), 3.75 (s, 3H),
4.30 (q, 2H), 6.95 (d, 2H), 7.54 (d, 4H), 8.15 (d, 2H).
N-Meth yl-N-cycloh exyl-p-n itr oph en eth ylam in e Hydr o-
1
ch lor id e (15e). mp 214-217 °C. H NMR (CDCl3 + DMSO-
d6): δ 1.15-2.30 (m, 11H), 2.70 (s, 3H), 3.20-3.35 (m, 4H),
7.60 (d, 2H), 8.15 (d, 2H).
N-Meth yl-N-(3,4-m eth ylen ed ioxyben zyl)-p-n itr op h en -
eth yla m in e Hyd r och lor id e (15f). mp 208-209 °C. 1H NMR
(CDCl3 + DMSO-d6): δ 2.70 (s, 3H), 3.25 (s, 2H), 3.30 (s, 2H),
4.28 (q, 2H), 6.05 (s, 2H), 6.81 (d, 1H), 7.08 (d, 1H), 7.25 (s,
1H), 7.51 (d, 2H), 8.15 (d, 2H).
N -B e n zy l-N -(o-m e t h o x y b e n zy l)-p -n it r o p h e n e t h y l-
a m in e Hyd r och lor id e (15g). mp 168-169 °C. 1H NMR
(CDCl3 + DMSO-d6): δ 3.20 (s, 4H), 3.65 (s, 2H), 3.83 (s, 3H),
4.05 (q, 2H), 7.30-8.15 (m, 13H).
Gen er a l P r oced u r es for P r ep a r a tion s of (15h -m ,o,p )
Ar e Descr ibed a s Th ose for 15h . N,N-Diben zyl-p-n itr o-
p h en eth yla m in e Hyd r och lor id e (15h ). To the mixture of
compound 14a (10 g, 0.034 mol) and K2CO3 (8.3 g, 0.06 mol)
in anhydrous ethanol (50 mL) was added C6H5CH2Br (4.5 mL,
0.03 mol), and it was stirred and refluxed for 3.5 h. The
reaction mixture was filtered and condensed. Flash chroma-
tography with acetate-petroleum ether (4:1, v/v), Rf ) 0.45,
was performed, and compound 15h was given (11.8 g); yield
91.3%; mp 186-189 °C. 1H NMR (CDCl3 + DMSO-d6): δ 3.30
(s, 2H), 3.36 (s, 2H), 4.45 (s, 4H), 7.2-8.15 (m, 14H).
N -B e n z y l-N -(p -m e t h y lb e n z y l)-p -n i t r o p h e n e t h y l-
a m in e Hyd r och lor id e (15i). In the same manner as de-
scribed for 15h , 15i was prepared from 14b; mp 212-214 °C.
1H NMR (CDCl3 + DMSO-d6): δ 2.25 (s, 3H), 3.30-3.35 (m,
4H), 4.30-4.55 (d, 4H), 7.25-8.10 (m, 13H).
N -B e n z y l-N -(p -c h lo r o b e n z y l)-p -n i t r o p h e n e t h y l-
a m in e Hyd r och lor id e (15j). In the same manner as de-
scribed for 15h , 15j was prepared from 14c; mp 168-172 °C.
1H NMR (CDCl3 + DMSO-d6): δ 3.40 (m, 4H), 4.50 (s, 4H),
7.45-8.10 (m, 13H).
N-(o-Meth oxyben zyl)-p-n itr op h en eth yla m in e Hyd r o-
ch lor id e (14g). In the same manner as described for 14a , 14g
was prepared from o-methoxyl benzaldehyde; mp 179-182 °C.
N -Be n zyl-N -(p -m e t h oxyb e n zyl)-p -n it r op h e n e t h yl-
a m in e Hyd r och lor id e (15k ). In the same manner as de-

Class III Antiarrhythmic Agents
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14 2967
scribed for 15h , 15k was prepared from 14d ; mp 166-169 °C.
1H NMR (CD3COCD3): δ 3.32-3.48 (m, 4H), 3.80 (s, 3H),
4.40-4.50 (d, 4H), 7.00 (d, 2H), 7.55-7.98 (m, 9H), 8.12 (d,
2H).
N-Met h yl-N-(3,4-m et h ylen ed ioxyb en zyl)-p -(a m in o)-
p h en eth yla m in e Hyd r och lor id e (16f). mp 258-260 °C. 1H
NMR (DMSO-d6): δ 2.65 (s, 3H), 3.20 (s, 4H), 4.15 (q, 2H),
6.10 (s, 2H), 6.90-7.40 (m, 7H).
N-Ben zyl-N-(o-m et h oxyb en zyl)-p -(a m in o)p h en et h yl-
a m in e Hyd r och lor id e (16g). mp 245-247 °C. 1H NMR
(DMSO-d6): δ 3.05-3.10 (m, 4H), 3.65 (s, 2H), 3.75 (s, 3H),
4.02 (s, 2H), 7.27-7.90 (m, 13H).
N,N-Diben zyl-p-(a m in o)p h en eth yla m in e Hyd r och lo-
r id e (16h ). mp 222-224 °C. 1H NMR (CDCl3): δ 3.14 (s, 4H),
4.40 (s, 4H), 7.08 (d, 2H), 7.22-7.80 (m, 12H).
N -Be n zyl-N -(p -m e t h ylb e n zyl)-p -(a m in o)p h e n e t h yl-
a m in e Hyd r och lor id e (16i). mp 252-256 °C. 1H NMR
(CDCl3 + DMSO-d6): δ 2.30 (s, 3H), 3.00 (s, 4H), 4.12 (s, 2H),
4.15 (s, 2H), 6.65-7.55 (m, 13H).
N -Be n zyl-N -(p -ch lor ob e n zyl)-p -(a m in o)p h e n e t h yl-
a m in e Hyd r och lor id e (16j). mp 207-209 °C. 1H NMR
(CDCl3): δ 3.25 (s, 4H), 4.35 (s, 2H), 4.43 (s, 2H), 7.20-7.85
(m, 13H).
N-Ben zyl-N-(3,4-m eth ylen ed ioxyben zyl)-p-n itr op h en -
eth yla m in e Hyd r och lor id e (15l). In the same manner as
described for 15h , 15l was prepared from 14f; mp 166-169
1
°C. H NMR (CDCl3): δ 3.20-3.25 (m, 4H), 4.20 (s, 4H), 6.05
(s, 2H), 7.0-8.0 (m, 12H).
N-(p-Ch lor oben zyl)-N-(p-m eth oxyben zyl)-p-n itr op h en -
eth yla m in e Hyd r och lor id e (15m ). In the same manner as
described for 15h , 15l was prepared from 14d ; mp 166-169
°C. 1H NMR (CDCl3): δ 2.65 (s, 4H), 3.55 (s, 4H), 3.80 (s, 3H),
6.5-6.6 (dd, 2H), 6.75-6.9 (m, 4H), 7.10-7.30 (m, 6H).
N -Me t h yl-N -(o-m e t h oxyb e n zyl)-p -n it r op h e n e t h yl-
a m in e Hyd r och lor id e (15n ). In the same manner as de-
scribed for 15a , 15n was prepared from 14g; mp 168-169 °C.
1H NMR (CDCl3 + DMSO-d6): δ 2.70 (s, 3H), 3.20 (s, 4H), 3.83
(s, 3H), 4.05 (s, 2H), 7.30-8.15 (m, 8H).
N -Ac e t y l-N -(p -m e t h o x y b e n zy l)-p -n it r o p h e n e t h y l-
a m in e (15o). In the same manner as described for 15h , 15o
was prepared from 14o (1.6 g) and acetic oxide. We were given
a yellow solid (1.6 g); yield 97%; flash chromatography with
acetate-petroleum ether (1:1, v/v); Rf ) 0.3; mp 68-70 °C. 1H
NMR (CDCl3): δ 2.05, 2.10 (d, 3H), 2.95-3.0 (m, 2H), 3.50 (m,
2H), 3.80 (s, 3H), 4.40 (s, 2H), 6.80-7.30 (m, 6H), 8.10-8.15
(m, 2H).
N-Ben zyl-N-(p -m et h oxyb en zyl)-p -(a m in o)p h en et h yl-
a m in e Hyd r och lor id e (16k ). mp 234-236 °C. 1H NMR
(CDCl3 + DMSO-d6): δ 2.95 (s, 4H), 3.70 (s, 3H), 3.90 (s, 2H),
3.95 (s, 2H), 7.55-7.88 (m, 13H).
N-Ben zyl-N-(3,4-m eth ylen edioxyben zyl)-p-(am in o)ph en -
eth yla m in e Hyd r och lor id e (16l). mp 217-219 °C. 1H NMR
(CDCl3): δ 3.10-3.15 (m, 4H), 4.35 (s, 4H), 6.05 (s, 2H), 7.0-
7.75 (m, 12H).
N -Be n zoyl-N -(p -m e t h oxyb e n zyl)-p -n it r op h e n e t h yl-
a m in e (15p ). In the same manner as described for 15h , 15p
was prepared from 14o (3 g) and benzoyl chloride, and a yellow
solid was given (1.1 g); yield 26%; flash chromatography with
acetate-petroleum ether (1:2, v/v); Rf ) 0.3; mp 100-102 °C.
1H NMR (CDCl3): δ 2.90-3.0 (s, 2H), 3.50 (s, 2H), 3.80 (s, 3H),
4.45 (s, 2H), 6.80-6.90 (d, 2H), 7.2-7.4 (m, 9H), 8.0-8.2 (d,
2H).
N-(p -Ch lor ob en zyl)-N-(p -m et h oxyb en zyl)-p -(a m in o)-
p h en eth yla m in e (16m ). In the same manner as described
for 16a , 16m was prepared from 15m . 1H NMR (CDCl3): δ
2.65 (s, 4H), 3.55 (s, 4H), 3.80 (s, 3H), 6.5-6.6 (dd, 2H), 6.75-
6.9 (m, 4H), 7.10-7.30 (m, 6H).
N-Met h yl-N-(o-m et h oxyb en zyl)-p -(a m in o)p h en et h yl-
a m in e Hyd r och lor id e (16n ). mp 245-247 °C. 1H NMR
(DMSO-d6): δ 2.55 (s, 3H), 3.05-3.10 (m, 4H), 3.75 (s, 3H),
4.02 (s, 2H), 7.27-7.90 (m, 8H).
N-(p -Met h oxyb en zyl)-N-[2-(p -n it r op h en oxy)et h yl]-p -
n itr op h en eth yla m in e Hyd r och lor id e (15s). In the same
manner as described for 10a , 15s was prepared from 14o; yield
N-Acet yl-N-(p -m et h oxyb en zyl)-p -(a m in o)p h en et h yl-
a m in e (16o). Yield 80%; flash chromatography with acetate-
petroleum ether (2:1, v/v); Rf ) 0.5.
45.7%; mp 91-93 °C. IR (KBr): 1600, 1520 cm-1 1H NMR
.
(CDCl3): δ 2.90 (s, 4H), 3.00 (t, 2H), 3.73 (s, 2H), 3.76 (s, 3H),
4.167 (t, 2H), 6.819-7.52 (m, 6H), 8.06-8.20 (m, 6H).
Gen er a l P r oced u r es for P r ep a r a tion s of 16 Ar e De-
scr ibed a s Th ose for 16a . N-Meth yl-N-ben zyl-p-(a m in o)-
p h en eth yla m in e Hyd r och lor id e (16a ). The mixture of
acetone (50 mL), hydrochloric acid (1 mL), reductive iron
powder (6 g, 0.107 mol), and a little ammonium chloride was
stirred and boiled for 0.5 h and cooled to 45 °C, and then, a
solution of compound 15a (4.0 g) in 50 mL of acetone was
added to the mixture dropwise over 3 h. The reaction mixture
was cooled and adjusted to pH 10 with 10% NaOH and then
filtered and condensed. Flash chromatography with acetate-
petroleum ether (1:1, v/v) was performed, and compound 16a
was given (3.4 g); yield 93.7%; mp 264-265 °C. 1H NMR
(DMSO-d6): δ 2.65 (s, 3H), 3.15 (s, 4H), 4.38 (s, 2H), 7.20-
7.72 (m, 9H).
N -Me t h yl-N -(p -m e t h ylb e n zyl)-p -(a m in o)p h e n e t h yl-
a m in e Hyd r och lor id e (16b). In the same manner as de-
scribed for 16a , 16b was prepared from 15b; mp 267-270 °C.
1H NMR (DMSO-d6): δ 2.30 (s, 3H), 2.65 (s, 3H), 3.10 (s, 4H),
4.33 (q, 2H), 7.20-7.58 (m, 8H).
N -Me t h yl-N -(p -ch lor ob e n zyl)-p -(a m in o)p h e n e t h yl-
a m in e Hyd r och lor id e (16c). In the same manner as de-
scribed for 16a , 16c was prepared from 15c; mp 261-263 °C.
1H NMR (DMSO-d6): δ 2.70 (s, 3H), 3.20-3.25 (m, 4H), 4.30
(s, 2H), 6.92 (d, 2H), 7.11 (d, 2H), 7.42 (d, 2H), 7.69 (d, 2H).
N-Met h yl-N-(p -m et h oxyb en zyl)-p -(a m in o)p h en et h yl-
a m in e Hyd r och lor id e (16d ). mp 257-258 °C. 1H NMR
(CDCl3 + DMSO-d6): δ 2.70 (s, 3H), 3.20-3.25 (m, 4H), 3.83
(s, 3H), 4.30 (q, 2H), 6.91 (d, 2H), 7.20-7.40 (m, 4H), 7.52 (d,
2H).
N-(p-Meth oxyben zyl)-N-[2-(p-a m in op h en oxy)eth yl]-p-
(a m in o)p h en eth yla m in e (16s). In the same manner as
described for 16a , 16s was prepared from 15s. MS (SCI) m/z
392 (M+).
1-Br om o-2-(n a p h th -1-yl-oxy)eth a n e (18). The mixture of
4-nitrophenol R-naphthol (17) (20 g, 0.1387 mol), NaOH (5.7
g), TBA (5 g), and anhydrous alcohol (85 mL) was cooled to 30
°C after it was heated and refluxed for 15 min; 1,2-dibromo-
ethane (34.5 mL, 0.398mol) was added dropwise, heated, and
refluxed for 24 h, and it was condensed, filtered, and extracted.
The organic phase was washed with water and dried (anhy-
drous Na2SO4) and recrystallized in anhydrous alcohol. White
crystallized compound (16.5 g) was given; yield 47.4%; mp 62-
64 °C. Flash chromatography CH3COOC2H5/petroleum ether
(1:4, v/v); Rf ) 0.8. MS (SCI) m/z 252 (MH+), 115 (base peak).
N-[2-(Na p h t h -1-yl-oxy)et h yl]-p -n it r op h en et h yla m in e
(19). In the same manner as described for 9, 19 was prepared
from 18. Flash chromatography CH3COOC2H5/petroleum ether
(1:4, v/v); Rf ) 0.48.
N-Met h yl-N-[2-(n a p h t h -1-yl-oxy)et h yl]-p -n it r op h en -
eth yla m in e (20a ). A 36% amount of formaldehyde (3.7 mL,
0.0448 mol) was added to compound 19 (4.42 g, 0.0132 mol)
in formic acid 88% (2.6 mL, 0.0606 mol), and it was heated
and refluxed for 4 h, then adjusted solution to pH 14 with 20%
NaOH, extracted with acetate, and condensed. Flash chroma-
tography with acetate-petroleum ether (2:1, v/v) was per-
formed, and compound 20a was given (2.2 g); yield 47.6%; flash
chromatography CH3COOC2H5/petroleum ether (1:1, v/v); Rf
) 0.45. 1H NMR (CDCl3): δ 2.5 (s, 3H), 2.95 (s, 4H), 3.0 (t,
2H), 4.20 (t, 2H), 6.70-6.80 (q, 1H), 7.20-7.45 (m, 6H), 7.70-
7.80 (m, 2H), 7.95-8.20 (m, 2H).
N-Meth yl-N-cycloh exyl-p-(a m in o)p h en eth yla m in e Hy-
N-Ben zyl-N-[2-(n a p h t h -1-yl-oxy)et h yl]-p -n it r op h en -
eth yla m in e (20b). In the same manner as described for 10a ,
20b was prepared from 19; yield 65.9%; mp 58-60 °C; flash
chromatography CH3COOC2H5/petroleum ether (2:1, v/v); Rf
d r och lor id e (16e). mp 264-266 °C. 1H NMR (CDCl3
+
DMSO-d6): δ 1.05-2.40 (m, 11H), 2.80 (s, 3H), 3.00-3.30 (m,
4H), 7.38 (q, 4H).

2968 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 14
Liu et al.
) 0.65. 1H NMR (CD3COCD3): δ 2.95 (s, 4H), 3.05 (t, 2H), 3.75
(s, 2H), 4.15 (t, 2H), 6.65-6.80 (q, 1H), 7.10-7.50 (m, 11H),
7.70-8.0 (m, 3H), 8.10-8.25 (m, 1H).
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Manno, D.; Barker, A. H.; Arensberg, D.; Baker, A.; Friedman,
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an antiarrhythmic principle. Eur. Heart J . 1985, 6 (Suppl. D),
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N-Acetyl-N-[2-(n a p h th -1-yl-oxy)eth yl]-p-n itr op h en eth -
yla m in e (20c). In the same manner as described for 10b, 20c
was prepared from 19; mp 60-62 °C; flash chromatography
1
CH3COOC2H5/petroleum ether (1:5, v/v); Rf ) 0.73. H NMR
(CD3COCD3): δ 1.95, 2.20 (2s, 3H), 3.10 (m, 2H), 3.70-3.90
(m, 4H), 4.15-4.40 (m, 2H), 6.80-6.90 (m, 1H), 7.25-7.50 (m,
6H), 7.65-7.85 (m, 1H), 7.95-8.25 (m, 3H).
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N-Allyl-N-[2-(n a p h th -1-yl-oxy)eth yl]-p-n itr op h en eth yl-
a m in e (20d ). In the same manner as described for 10b, 20d
was prepared from 19; mp 60-62 °C; flash chromatography
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dealayed rectifier K+ current. J . Gen. Physiol. 1990, 96, 195-
215.
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1
CH3COOC2H5/petroleum ether (1:5, v/v); Rf ) 0.45. H NMR
(CD3COCD3): δ 2.95 (m, 4H), 3.05-3.15 (t, 2H), 3.25-3.40 (t,
2H), 4.15-4.20 (t, 2H), 5.10-5.35 (t, 2H), 5.85 (m, 1H), 6.70-
6.85 (q, 1H), 7.10-7.50 (m, 8H), 7.70-7.85 (m, 1H), 8.15-8.30
(m, 1H).
N-Ben zoyl-N-[2-(n a p h t h -1-yl-oxy)et h yl]-p -n it r op h en -
eth yla m in e (20f). In the same manner as described for 10a ,
20f was prepared from 19; yellow oil; yield 66.2%; flash
chromatography CH3COOC2H5/petroleum ether (1:2, v/v); Rf
) 0.27. 1H NMR (CD3COCD3): δ 3.10 (s, 2H), 3.90 (b, 4H),
4.40 (b, 2H), 6.90 (b, 1H), 7.20-7.60 (m, 11H), 7.75-7.90 (m,
2H), 8.0-8.20 (m, 2H).
N-Ben zyl-N-[2-(n a p h th -1-yl-oxy)eth yl]-p-(a m in o)p h en -
eth yla m in e (21b). In the same manner as described for 11a ,
21b was prepared from 20b; yield 59%; flash chromatography
CH3COOC2H5/petroleum ether (1:4, v/v); Rf ) 0.36.
N-Ben zoyl-N-[2-(n aph th -1-yl-oxy)eth yl]-p-(am in o)ph en -
eth yla m in e (21f). In the same manner as described for 11a ,
21f was prepared from 20f; yield 50%; flash chromatography
CH3COOC2H5/petroleum ether (1:2, v/v); Rf ) 0.38. MS (SCI)
data calcd C27H26N2O2 m/z (M+), 411.2063; found, 411.2040.
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Cardiol. 1996, 78, 28-33.
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R. P.; Wohl, R. A.; Argentieri, T. M.; Sullivan M. E. Synthesis
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derivatives of the class III antiarrhythmic agent sematilide.
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(18) Selnick, H. G.; Liverton, N. J .; Baldwin, J . J .; Butcher, J . W.;
Claremon, D. A.; Elliott, J . M.; Freidinger, R. M.; King, S. A.;
Libby, B. E.; McIntyre, C. J .; Pribush, D. A.; Remy, D. C.; Smith,
G. R.; Tebben, A. J .; J urkiewicz, N. K.; Lynch, J . J .; Salata, J .
J .; Sanguinetti, M. C.; Siegl, P. K.; Slaughter, D. E.; Vyas, K.
Class III antiarrhythmic activity in vivo by selective blockade
of the slowly activating cardiac delayed rectifier potassium
current IKs by (R)-2-(2,4-trifluoromethyl)-N-[2-oxo-5-phenyl-1-
(2,2,2-trifluoroethyl)-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl]-
acetamide. J . Med. Chem. 1997, 40, 3865-3868.
Ack n ow led gm en t. We gratefully acknowledge fi-
nancial support from the National Natural Science
Foundation of China (Grants 29725203 and 20072042),
the State Key Program of Basic Research of China
(Grant 1998051115), the Life Science Foundation for
Young Scientists of CAS (Grant STZ-00-06), the Qi Ming
Xiang Foundation of Shanghai Ministry of Science and
Technology (Grant 00QB14034), and the Postdoctoral
Fellowship of Shanghai. The calculations were per-
formed on a Power challenge server at the Network
Information Center, Chinese Academy of Science, Shang-
hai Branch. We also thank Madam Frances Sue Payton
for improving the English.
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