Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: Synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential

Article abstract of DOI:10.1021/jm0004289

A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation. Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue at both slow and fast pacing rates. The potential for producing polymorphic ventricular tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The S-enantiomers generally had less proarrhythmic activity than the corresponding racemates. One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was chosen for further development.

Full text of DOI:10.1021/jm0004289

J . Med. Chem. 2001, 44, 1099-1115
1099
P r ogr ess tow a r d th e Develop m en t of a Sa fe a n d Effective Agen t for Tr ea tin g
Reen tr a n t Ca r d ia c Ar r h yth m ia s: Syn th esis a n d Eva lu a tion of Ibu tilid e
An a logu es w ith En h a n ced Meta bolic Sta bility a n d Dim in ish ed P r oa r r h yth m ic
P oten tia l
J ackson B. Hester,*,‡ J ohn K. Gibson,§ Lewis V. Buchanan,§ Madeline G. Cimini,| Michael A. Clark,§
D. Edward Emmert, Michael A. Glavanovich, Rick J . Imbordino, Richelle J . LeMay,§ Moses W. McMillan,
Salvatore C. Perricone,‡ Donald M. Squires, and Rodney R. Walters†
Departments of Structural, Analytical & Medicinal Chemistry, Pharmacology, Biology II, Chemical Processing Research &
Preparation, and Pharmacokinetics & Bioanalysis Research, Pharmacia Corporation, Kalamazoo, Michigan 49007
Received October 2, 2000
A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared
and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic
potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation.
Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue
at both slow and fast pacing rates. The potential for producing polymorphic ventricular
tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The
S-enantiomers generally had less proarrhythmic activity than the corresponding racemates.
One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity
and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was
chosen for further development.
In tr od u ction
ery in 1914 that a cinchona alkaloid preparation allevi-
ated the arrhythmias of a patient that was being treated
for malaria.
Cardiac arrhythmias continue to represent a major
source of human morbidity and mortality. It has been
estimated that 2.2 million Americans have intermittent
or sustained atrial fibrillation (AF)1 which is associated
with symptoms such as palpitations and chest discom-
fort and a high incidence of stroke and heart failure.2
Results from the Framingham Heart Study have dem-
onstrated a marked increase in mortality risk associated
with this arrhythmia,3 a result that has also been
documented in the Manitoba Study.4 Atrial flutter (AFL)
is a related arrhythmia that is often associated with or
preceded by AF.5 Ventricular tachyarrhythmias, which
are often a consequence of structural heart disease, are
a major risk factor for ventricular fibrillation and
sudden cardiac death (SCD). It has been estimated that
SCD can account for more than 300 000 deaths annually
in the United States.6 All of these arrhythmias appear
to result from the reentry of an activation wave front
into newly excitable tissue in a suitable reentrant
circuit.7 Such a circuit can occur when the myocardium
manifests unidirectional conduction block and the wave-
length (product of the conduction velocity of the circu-
lating wave front and the effective refractory period
(ERP) of the reentrant circuit) is shorter than the length
of the circuit pathway.7 From a historical standpoint,
therapy for cardiac arrhythmias began with the discov-
Quinidine, the active component of this mixture, was
subsequently introduced for the treatment of cardiac
arrhythmias in 1918.8 In the 1950s the development of
techniques for evaluating electrophysiologic parameters
in vivo led to the recognition that a significant property
of antiarrhythmic agents was the ability to prolong the
ERP of relevant cardiac tissues.9 It was also established
that quinidine prolonged the ERP in ventricular myo-
cardium, and it became accepted that this was a
consequence of its primary effect: the ability to slow
conduction by depressing the maximal rate of rise of the
cardiac action potential.9 In the Vaughan Williams
classification,10 this sodium channel-mediated activity
became known as the class I mechanism for anti-
arrhythmic activity. Class I antiarrhythmic agents such
as procainamide, lidocaine, and disopyramide were
found to markedly suppress premature ventricular
contractions (PVCs) which were believed to be a risk
factor for SCD after a myocardial infarction (MI), and
research during the next two decades was devoted to
optimizing this activity.9 This research culminated in
the development of encainide, flecainide, and moricizine
which, in 1989, were evaluated for their ability to reduce
the rate of death from arrhythmia in patients with
asymptomatic or mildly symptomatic ventricular ar-
rhythmias after a MI. Although these class I agents
effectively controlled the PVCs in this patient popula-
tion, this pivotal Cardiac Arrhythmia Suppression Trial
(CAST) was terminated prematurely when it was found
that the death rate in the treated group exceeded that
* To whom correspondence should be addressed. Phone: (616) 833-
7769. Fax: (616) 833-1559. E-mail: jackson.b.hester@pharmacia.com.
‡ Department of Structural, Analytical & Medicinal Chemistry.
§ Department of Pharmacology.
| Department of Biology II.
Department of Chemical Processing Research & Preparation.
† Department of Pharmacokinetics & Bioanalysis Research.
10.1021/jm0004289 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/06/2001

1100 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Hester et al.
in the control group.11,12 Subsequent analysis has sug-
gested that class I antiarrhythmic agents predispose
patients with acute myocardial ischemia to lethal ar-
rhythmias. This appears to explain the increased mor-
tality observed in the CAST study.13 As a result, the
use of class I agents for treating cardiac arrhythmias
appears to be diminishing.14
Ch a r t 1
Early studies with sotalol15 and amiodarone16 estab-
lished that prolongation of the action potential duration,
reflected in a prolongation of the QTc interval in the
electrocardiogram, was a second method for increasing
the ERP of cardiac tissue. Compounds with this mech-
anism of antiarrhythmic action became known as class
III agents.10 Since this time a number of compounds
with relatively pure class III antiarrhythmic activity
have been investigated.17 Many of these have excellent
activity for treating reentrant arrhythmias in both atrial
and ventricular tissues.17-19 Unfortunately, class III
antiarrhythmic activity is associated with the precipita-
tion of a potentially serious polymorphic ventricular
tachyarrhythmia (PVT), known as torsade de pointes,
in a small but significant percentage of treated pa-
tients.20 This was perhaps anticipated by the discoveries
of the J ervell and Lange-Nielsen (J LN) and Romano-
Ward syndromes which are characterized by a marked
prolongation of the QT interval and are often associated
with syncope, seizures, or sudden death due to torsade
de pointes.21,22 In recent years these syndromes, col-
lectively known as the congenital long-QT syndrome
(LQTS), have been the subject of a series of revolution-
ary clinical discoveries. It is now known that LQTS is
the result of inherited mutations that have been identi-
fied both in the fast sodium channel: INa (LQT3, SCN5A)
and in the repolarizing potassium channels: IKr (LQT2,
HERG), IKs (LQT1, KVLQT1), and the IKs â-subunit, min
K (LQT5, KCNE1). Mutations in SCN5A can block the
complete deactivation of INa thus providing a slow
depolarizing sodium current, while mutations of the
delayed rectifier potassium channels can slow repolar-
ization of the action potential.22 Historically it had been
assumed that these mutations were nearly all expressed
in the ECG (high penetrance) as a prolonged QTc
interval which is a criterion for the clinical diagnosis of
LQTS; but, several recent studies have identified fami-
lies with mutations of KVLQT1 and HERG genes that
have a very low penetrance of the disease.23-25 These
mutations can, however, interact with QT prolonging
agents to provide a marked prolongation of the QT
interval, the acquired long-QT syndrome.23 The results
of these studies have major implications for the iden-
tification and treatment of individuals with these
genetic abnormalities.25 They suggest that the tradi-
tional clinical approach for identification of affected
individuals may be inadequate and that the abnormality
may be more widespread than originally thought. They
also may have implications for the use of medications
that prolong the QT interval. It might be possible, for
example, to use genetic screening to identify individuals
who might have an adverse reaction to such medica-
tions.26,27
however, these proarrhythmic events have occurred
either during or shortly after infusion of the drug, are
time-limited, and are easily controlled.28 This suggests
that initial administration of the antiarrhythmic agent
in-hospital29 might be used as an alternative method
to identify patients who might be susceptible to the
induction of torsade de pointes by these agents. This
approach appears to have been successfully employed
in the DIAMOND study of the use of dofetilide for the
treatment of patients with clinical congestive heart
failure and MI.30
Ibutilide fumarate (1E, Corvert), our first class III
antiarrhythmic agent from this series,31 was introduced
on the U.S. market in 1996 for the rapid conversion of
AF and AFL to normal sinus rhythm. Although ibutilide
is effective for the treatment of both atrial32 and
ventricular33 tachyarrhythmias, it is limited to intra-
venous administration due to rapid first-pass metabo-
lism.32 Because of this limitation, we investigated a
series of analogues designed to retain ibutilide’s useful
antiarrhythmic activity but prevent its rapid hepatic
metabolism. In humans ibutilide is metabolized prima-
rily by ω-oxidation of the heptyl side chain first to the
alcohol and then to the carboxylic acid which is further
metabolized by the â-oxidation pathway.34 We thus
concentrated our attention on modifications of the
heptyl side chain that were intended to retard or
prevent its metabolism. These included the incorpora-
tion of alkyl, cycloalkyl, hydroxy, acetoxy, and fluoro
substituents.35 Fluorine substitution yielded especially
interesting compounds that are the subject of this
report.
Ch em istr y
Most of the compounds in this series 2 (Table 1) were
prepared by alkylating an amine 3 (Chart 1) with an
appropriately substituted alkyl bromide (RBr) in re-
fluxing acetonitrile. Sodium bicarbonate was the pre-
ferred base for this reaction. Initial evaluation suggested
that stronger bases would give substantial amounts of
products resulting from alkylation of the sulfonamide
in addition to the basic nitrogen. Procedures A and B
in the Experimental Section describe this reaction.
Products from procedure B were isolated as the crystal-
Clinical studies of the intravenously administered
class III antiarrhythmic agent, ibutilide, have found an
incidence of torsade de pointes, both sustained and
nonsustained, of about 4-8%. Almost without exception,

Synthesis and Evaluation of Ibutilide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1101
Ch a r t 2
the fluorine atoms. Thus, the ethylene dithioketal 29
was prepared and treated with 1,3-dibromo-5,5-dimeth-
ylhydantoin and hydrogen fluoride-pyridine to give 30
which was reduced with LAH to give 27.
Resu lts a n d Discu ssion
Our initial evaluation of the cardiac electrophysiology
of potential antiarrhythmic agents was carried out with
rabbit heart preparations.31,41 This methodology allowed
us to evaluate the effects of test compounds on conduc-
tion velocity, refractoriness, and contractility of the
tissue at both a slow (1 Hz) and fast (3 Hz) pacing rate.
Effects on right atrial automaticity were also evaluated.
In general, compounds in this series have had little
effect on the conduction velocity or contractility of
cardiac tissue, and since we are primarily interested in
their potential class III antiarrhythmic activity for this
discussion, we have only recorded data supporting
effects on refractoriness in Table 1. We have also
documented in Table 1 the concentration-dependent
effects of these compounds on right atrial automaticity.
Metabolic stability was initially evaluated in vitro by
incubating the compounds with human liver microsomes.
The R-(+)-enantiomer 31E of ibutilide served as a
control in these experiments, and the data were nor-
malized to this compound as described in the Experi-
mental Section and recorded in Table 1. Values greater
than 1 indicate greater metabolic stability than 31E in
this evaluation.
When we began this study, it was becoming apparent
that the propensity to cause PVT would be a potential
detriment to any antiarrhythmic agent with the class
III mechanism of action.20 We, therefore, made evalu-
ation of the proarrhythmic potential of these compounds
an integral part of the program. For this purpose, we
chose the anesthetized rabbit model that had been
developed by Carlsson and co-workers42 for studying the
induction of early after depolarization (EAD) and tor-
sade de pointes by agents that prolong the QT interval.
EADs, depolarizing processes that occur before the
action potential repolarization is complete, are associ-
ated with the initiation of PVT.42 Using a modification
of this procedure, it was found that ibutilide was less
effective than several other class III agents studied for
inducing EADs and PVT in anesthetized and methox-
amine-treated rabbits.43 That is, statistically fewer
rabbits developed EADs and PVT when treated with
ibutilide. The endpoint for this determination, therefore,
became the number of animals that developed EADs
and PVT when treated with the test compound. These
data and the EAD amplitudes are recorded in Table 2.
The maximum prolongations of the QTc and MAPD90
which are measures of the class III efficacy are also
recorded.
line fumaric acid (E) salts. Products from procedure A
were generally not crystalline, but in some cases crys-
talline salts were subsequently prepared. In all cases
the crystalline salts were hemifumarates and are des-
ignated by the E suffix. Preparation of the water-soluble
amine intermediate 4 for this alkylation was accom-
plished by lithium aluminum hydride (LAH) reduction
of the ketoamide 8. The corresponding S-alcohol 5 was
obtained by first reducing 8 with (-)-B-chlorodiiso-
pinocamphenylborane to give 10 which was obtained
optically pure by recrystallization from solvents such
as acetonitrile-tert-butyl methyl ether. Further reduc-
tion of 10 with sodium bis(2-methoxyethoxy)aluminum
hydride using a nonaqueous workup gave 5. Assignment
of the S-configuration to this compound was based on
related published work from this laboratory.36 Prepara-
tion of the R-enantiomer 6 was accomplished by sodium
bis(2-methoxyethoxy)aluminum hydride reduction of 11,
the byproduct from the preparation of 10 from the
racemate by a lipase-mediated acetylation.37 The amine
7 was prepared by LAH reduction of the corresponding
amide 51.
Fluorine was generally incorporated into the side-
chain intermediates (RBr), used in the preparations of
2, by the reaction of diethylaminosulfur trifluoride
(DAST) with the appropriately substituted alcohols or
aldehydes. For example, the reaction of 1338 (Chart 2)
with DAST gave 14 which was deprotected and con-
verted to the bromide 15 with triphenylphosphine and
N-bromosuccinimide (NBS) (procedure C). Similar prepa-
rations to give 16-20 are detailed in the Experimental
Section. Side-chain intermediate 26 was prepared by
first alkylating tert-butyl acetate with 5-bromo-1-pen-
tene to give 21 which was allowed to react with NBS
and triethylamine trihydrofluoride39 to give 22 in 75%
yield. Dehydrobromination of 22 with potassium tert-
butoxide in THF gave 23 which was resubjected to the
bromofluorination conditions to give 24. LAH reduction
of 24 gave 25 which was converted to the bromide 26
by procedure C.
It is well-known that fluorine can replace a hydrogen
without introducing major steric changes in the result-
ing molecule;44 however, because of its inductive effect,
fluorine would be expected to retard electrophilic oxida-
tion of the substituted carbon by enzymes such as
cytochrome P450.45 We, thus, expected that fluorine
substitution of the terminal carbon of ibutilide’s heptyl
side chain would give a compound with interesting
properties. This fluoro-substituted derivative had con-
centration-dependent effects on ERP1 that were very
The olefin 50E (Table 1) was prepared by dehydrating
the corresponding alcohol 36 with trifluoroacetic acid.
Assignment of the E-stereochemistry for this compound
1
was based on its H NMR. Compound 37 (Table 1) was
prepared by condensing 12 with 27 and reducing the
resulting ketoamide 9 with LAH. The amine 27 was
prepared from N-ethyl-5-acetylvaleramide (28) using the
method of Sondej and Katzenellenbogen40 to introduce

1102 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Ta ble 1. In Vitro Evaluation of Potential Efficacy and Stability
Hester et al.
electrophysiologya
no.
X
R
concnb
ERP1 (N, SEM)
ERP3 (N, SEM)
rate (N, SEM)
metabolisml
NEk
1Eh,j,m
CH(OH)CH2
(CH2)6CH3
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
10-7
10-6
10-5
1.1 (8, 3.0)
12.0e (8, 4.9)
17.9e (8, 4.1)
4.1 (6, 0.9)
3.0 (8, 1.1)
8.0 (8, 1.9)
16.0e (8, 2.1)
4.0 (6, 0.9)
6.0 (6, 2.0)
13.0e (6, 1.8)
-2.9 (6, 4.9)
4.9 (6, 1.0)
7.0 (6, 4.1)
7.3 (3, 7.5)
10.5 (3, 5.5)
21.6 (3, 7.1)
5.5 (3, 3.6)
1.6 (3, 2.9)
22.4 (3, 13.2)
0.70 (3, 5.3)
3.2 (3, 4.6)
5.3 (3, 5.4)
10.3 (3, 5.8)
17.6e (3, 11.4)
29.7e (3, 7.0)
6.0 (4, 4.6)
16.0e (4, 12.7)
18.6 (4, 11.9)
6.2 (4, 2.6)
24.0e (4, 3.0)
5.1 (3, 6.3)
6.4 (3, 3.2)
14.2 (3, 8.9)
18.1e (4, 6.5)
33.5e (4, 12.3)
26.1 (4, 21.3)
-13.4 (6, 4.6)
-7.1 (7, 5.7)
8.7 (7, 8.9)
8.2 (4, 3.1)
10.4 (4, 3.7)
15.5 (4, 5.6)
1.4 (8, 2.2)
6.5 (8, 3.2)
31.1 (8, 9.0)
9.5 (8, 3.0)
22.7e (8, 6.6)
40.3e (8, 11.7)
8.0 (9, 3.5)
10.0 (9, 2.0)
27.7e (9, 3.4)
5.1 (9, 2.2)
15.9e (9, 4.6)
40.6e (9, 7.6)
12.7e (4, 3.8)
29.2e (4, 8.5)
g
3.0 (4, 3.0)
-8.0 (4, 2.0)
-21.9 (4, 0.9)
-2.0 (3, 4.2)
-13.9e(3, 5.1)
-19.0 (3, 4.1)
-0.9 (3, 2.7)
-12.0e (3, 2.0)
-32.2e (3, 5.0)
-5.2 (2, 2.7)
-17.4 (2, 3.6)
-20.4 (2, 2.5)
-26.1 (2, 0.19)
-31.4 (2, 0.23)
-35.1 (2, 0.26)
-10.5 (2, 1.2)
-25.2 (2, 2.7)
-31.9 (2, 0.15)
-6.3 (2, 4.4)
-11.0 (2, 4.2)
-26.4 (2, 1.1)
-6.9 (2, 1.0)
-22.3 (2, 1.3)
-23.9 (2, 1.3)
-5.5 (2, 3.7)
-21.7 (2, 2.6)
0.0 (2, 0.00)
-4.0 (2, 0.96)
-28.7 (2, 2.9)
-2.4 (2, 1.4)
-5.7 (2, 9.7)
-28.3 (2, 7.6)
-1.9 (4, 1.6)
-22.6 (4, 5.5)
-38.5 (4, 6.0)
-5.6 (2, 3.2)
-14.5 (2, 9.5)
-27.1 (2, 5.6)
-13.5e (6, 2.2)
-29.8d (6, 3.5)
-36.2d (6, 4.3)
-4.6 (6, 0.78)
-23.1d (6, 2.4)
-37.3d (6, 3.1)
-3.2 (6, 0.85)
-15.3e (6, 2.0)
-35.6d (6, 3.7)
-4.7 (6, 1.1)
-19.1e (6, 3.0)
-31.6d (6, 2.6)
-9.6 (2, 1.8)
-27.7 (2, 4.1)
-43.0 (2, 4.8)
-6.0 (2, 1.1)
-22.8 (2, 3.8)
-32.5 (2, 0.26)
-0.45 (4, 1.7)
-12.1 (4, 5.8)
-23.0 (3, 0.73)
-5.6 (2, 1.2)
-14.6 (2, 1.6)
-30.2 (2, 4.6)
31Ei,j
32Ei,j
33E
34E
35E
36
(R)-CH(OH)CH2
(S)-CH(OH)CH2
CH(OH)CH2
CH(OH)CH2
CH(OH)CH2
CH(OH)CH2
CH(OH)CH2
(CH2)6CH3
1
7.1 (6, 2.0)
12.9e (6, 1.9)
-1.0 (6, 1.9)
1.9 (6, 2.0)
(CH2)6CH3
NE
4.2
g20
g20
13
9.0 (6, 2.9)
4.3 (3, 8.0)
(CH2)6CH2F
(CH2)6CHF2
(CH2)5CHF2
(CH2)5CH(F)CH3
(CH2)5CF2CH3
14.7 (3, 9.0)
21.6 (3, 7.2)
24.0e (3, 7.8)
31.7e (3, 8.6)
40.6f (3, 10.9)
15.6 (3, 6.4)
33.1e (3, 16.8)
34.6e (3, 12.5)
35.6d (3, 7.2)
67.6d (3, 11.7)
80.8d (3, 11.7)
8.8 (4, 4.1)
37
NE
22.6f (4, 4.9)
22.8 (4, 8.7)
0.4 (4, 1.1)
16.1 (4, 5.4)
-1.0 (3, 4.7)
6.5 (3, 7.1)
38
39
CH(OH)CH2
CH(OH)CH2
(CH2)5C(CH3)2F
(CH2)4C(CH3)2F
g20
NE
18.2 (3, 11.6)
21.5 (4, 3.7)
47.6e (4, 16.4)
43.5e (4, 18.5)
0.52 (7, 7.8)
17.8 (7, 12.2)
30.7 (7, 8.2)
13.7e (4, 2.5)
33.5f (4, 3.7)
28.8e (4, 5.3)
18.6d (8, 2.6)
47.0d (8, 7.1)
51.0d (8, 7.4)
8.6e (8, 3.5)
35.6d (8, 6.5)
48.0d (8, 10.3)
2.5 (9, 1.3)
40E
41E
42E
43E
44
(S)-CH(OH)CH2
(S)-CH(OH)CH2
(S)-CH(OH)CH2
(S)-CH(OH)CH2
(S)-CH(OH)CH2
(S)-CH(OH)CH2
(R)-CH(OH)CH2
CH2CH2
(CH2)6CH2F
4
(CH2)5CH(F)CH3
(CH2)6CHF2
g20
NE
NE
NE
g20c
NE
3
(CH2)5CHF2
(CH2)5CF2CH3
(CH2)5C(CH3)2F
(CH2)5C(CH3)2F
(CH2)5CH(F)CH3
(CH2)6CH2F
45E
46E
47
14.4 (9, 3.4)
38.9d (9, 6.0)
3.8 (9, 2.2)
17.6e (9, 3.5)
27.9e (9, 5.8)
17.8f (4, 5.0)
50.1d (4, 9.4)
g
48
CH2CH2
8.1 (4, 2.8)
4.1 (4, 2.4)
14.8 (4, 4.2)
30.4 (4, 1.3)
4.9 (7, 3.9)
19.9 (7, 3.7)
50.1e (5, 11.0)
3.7 (4, 5.8)
7.7 (4, 7.9)
26.0 (4, 6.2)
1
22.0 (4, 6.7)
29.5 (4, 5.4)
8.7e (7, 3.7)
23.8d (7, 4.8)
45.5d (7, 9.8)
10.2 (4, 3.7)
22.3e (4, 6.4)
34.6e (4, 7.0)
49
CH2CH2
(CH2)5C(CH3)2F
(CH2)5CH(F)CH3
3
50E
(E)-CHdCH
3
a
Effective refractory period evaluated at 1.0 and 3.0 Hz (ERP1 and ERP3) on right ventricular papillary muscles and change in rate
of spontaneously beating right atria (rate) from isolated rabbit myocardium. Data expressed as mean percent change from baseline for
b
the number of tissues (N) ( the standard error of the mean (SEM). Molar concentration of the test compound. c Determined on the free
d
base (45). Statistically different from control (p < 0.0005). e Statistically different from control (p < 0.05). f Statistically different from
h
i
control (p < 0.005). g Tissues were too refractory to follow the primary stimulus. Ref 31. Ref 36. j Some of these data have been reported
k
l
m
in ref 41. Not evaluated. Stability relative to 31E when incubated with human liver microsomes. E designates the hemifumarate
salt.

Synthesis and Evaluation of Ibutilide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1103
Ta ble 2. In Vivo Evaluation of Potential Efficacy and Safety in the Rabbit Proarrhythmia Model
d
no.
QTca
MAPD90
EADe
EAD amplitudef
PVTg
1El,m
31E
32E
33E
34E
36E
37
85b (0.25-5.0)j
112b (0.25)
65b (0.5-1.0)j
69b (0.25-1.0)
105b (0.25-5.0)
128b (0.25-0.5)
48b (0.25)
4/4 (1.7 ( 1.0)i
4/10 (0.2 ( 0.02)
3/10 (1.6 ( 1.0)
4/6 (0.3 ( 0.07)
2/6 (0.3 ( 0.05)
4/6 (0.3 ( 0.1)
2/6 (0.4 ( 0.04)
5/6 (0.9 ( 0.4)
4/4 (1.4 ( 0.8)
1/24 (0.25)
15 (3.9 ( 1.5)c
11 (0.3 ( 0.05)
22 (1.6 ( 1.0)
52 (0.8 ( 0.3)
11 (0.3 ( 0.05)
63 (0.3 ( 0.1)
15 (0.7 ( 0.2)
35 (1.5 ( 0.6)
64 (3.3 ( 0.7)
4 (0.25)
10 (0.5 ( 0.1)
20 (0.5)
29 (0.25)
24 (0.3 ( 0.02)
2/16 (1.0 ( 0.9)h
2/10 (0.3 ( 0.1)
1/10 (0.2)
145b (0.25)
142b (0.25-0.5)
71b (0.25)
1/6 (2.0)
2/6 (0.3 ( 0.1)
3/6 (0.2 ( 0.02)
2/6 (0.7 ( 0.3)
1/6 (0.25)
2/4 (3.6 ( 1.8)
1/24 (0.9)
166b (0.25)
143b (0.25)
96b (0.25)
118b (0.25-1.0)
96b (0.5-1.0)
178b (0.25-2.0)
76b (0.1-5.0)
90b (0.1-1.0)
58b (0.1-0.5)
123b (0.25-0.5)
92b (0.1-0.25)
69b (0.1-5.0)
59b (0.1-0.25)
56b (0.5-1.0)
52b (0.1-2.0)
90b (0.25-5.0)
133b (0.5-2.0)
38
39
136b (0.25)
174b (0.25-1.0)
105b (0.1-0.25)
130b (0.1-0.25)
118b (0.1-0.25)
154b (0.1-0.25)
106b (0.1-1.0)
83b (0.1-1.0)
92b (0.1-0.25)
94b (0.25-0.5)
96b (0.1-0.5)
105b (0.25-5.0)
75 (2.0)
40Ek
41Ek
42E
43E
44
4/24 (0.2 ( 0.03)
3/6 (0.5)
1/24 (0.4)
2/6 (0.25 ( 0.2)
2/6 (0.3 ( 0.1)
2/16 (0.3 ( 0.2)
0/24
2/24 (0.27 ( 0.02)
2/16 (1.1 ( 0.1)
1/16 (0.1)
3/6 (0.2 ( 0.04)
3/16 (0.3 ( 0.05)
0/24
6/24 (0.5 ( 0.3)
4/16 (0.2 ( 0.03)
1/16 (1.0)
45k
46E
47
48
49
10 (0.5 ( 0.3)
13 (0.4 ( 0.2)
6 (1.0)
0/16
4/4 (0.3 ( 0.06)
0/16
3/4 (1.5 ( 0.8)
50E
91 (0.4 ( 0.2)
a
b
Maximum increase in QTc interval (ms) from the methoxamine infusion baseline. Statistically significant, p e 0.05. c Mean
d
accumulated dose (mg/kg) of test compound when this value was measured. Maximum increase in the ventricular monophasic action
potential duration at 90% repolarization (ms) from the methoxamine infusion baseline. e Ratio of the number of animals that developed
early after depolarization to the total number of animals evaluated. f Maximum EAD amplitude (% of monophasic action potential plateau
g
height). Ratio of the number of animals that developed polymorphic ventricular tachycardia to the total number of animals evaluated.
h
i
Mean dose of test compound (mg/kg) when PVTs were observed. Mean dose (mg/kg) of test compound at which the EADs began to
develop. j Mean dose (mg/kg) of test compound at which a statistically significant increase was first observed and the dose for the maximum
k
l
m
increase. Both male and female rabbits were used for this evaluation. Some of these data have been published in ref 43. E designates
the hemifumarate salt.
similar to those of ibutilide (compare 33E to 1E in Table
1). In addition, like ibutilide it was equally effective at
the fast pacing rate (ERP3). This absence of a decline
in activity at the increased pacing rate, which is also
known as reverse use dependence and is encountered
with many class III antiarrhythmic agents, is expected
to be a beneficial property for compounds that are
intended to treat tachyarrhythmias.46 Unfortunately,
although 33E was more stable than ibutilide, it was still
metabolized quite rapidly by human liver microsomes
(Table 1). It was also found to have an unacceptable
propensity to produce EADs and PVT in the rabbit
proarrhythmia model (Table 2). The addition of a second
fluorine to the terminous of the ibutilide side chain gave
a compound (34E) with excellent stability and very
potent activity on ERP1; however, this activity was
greatly diminished at the faster pacing rate, and 34E
retained a considerable proarrhythmic potential. The
corresponding compound with a six-carbon side chain
(35E) also had good ERP1 activity but poor activity on
ERP3. When the fluorine was moved to the ω-1 position
of the seven-carbon side chain to give 36, very potent
activity on ERP1 was obtained. This compound also
retained diminished but potent activity on ERP3. It was
surprisingly more stable than the compound (33E) with
a terminal fluorine, but it had enhanced proarrhythmic
potential. Addition of a second fluorine to the ω-1 carbon
gave a compound (37) with very interesting activity on
both ERP1 and ERP3, but unfortunately, it retained
some proarrhythmic potential. When a methyl group
was added to the ω-1 position of 36 a compound (38)
with good activity on both ERP1 and ERP3 and excellent
stability was obtained. It still, however, retained some
proarrhythmic potential. The corresponding compound
(39) with a six-carbon side chain also had interesting
activity on both ERP1 and ERP3 but high potential for
proarrhythmic activity.
In the course of our studies with ibutilide, we had
prepared and evaluated its enantiomers (31E and
32E).36,41 In the rabbit proarrhythmia model it appeared
that the S-enantiomer (32E) was somewhat less pro-
arrhythmic than either the R-enantiomer (31E) or
ibutilide (1E, compare in Table 2). Similar results had
also been obtained for artilide36 and its S-entantiomer
(data not shown). We, therefore, investigated the S-
enantiomers of key members of this series to determine
if we could obtain compounds with improved activity
in the rabbit model of proarrhythmia. On the basis of
studies with ibutilide,41 we anticipated that the activi-
ties of these compounds on ERP1 and ERP3 would be
similar to those of the racemates. For the most part this
appeared to be the case (compare the S-enantiomers
40E, 41E, 42E, 43E, 44, and 45E with the correspond-
ing racemates 33E, 36, 34E, 35E, 37, and 38 in Table
1). Compounds 44 and 45E had exceptional activity in
this test system with only a slight decrease in activity
at the high pacing rate. Even more interesting, however,
was the apparent reduction of the proarrhythmic po-
tential for several of these compounds in the rabbit
model (compare 40E, 41E, 44, and 45 with 33E, 36E,
37, and 38, respectively, in Table 2). With compound
45 in particular, even though there was a statistically
significant lengthening of both QTc and MAPD90, it was
not possible to elicit either EADs or PVT with this
procedure. Evaluation of the R-enantiomer (46E) of this
interesting compound demonstrated that it had activity
similar to that of 45E for enhancing ERP1 and ERP3
but retained proarrhythmic potential in the rabbit
model. The prolongation of QTc and MAPD90 by 46E in
this model was very similar to that produced by 45
which suggested that these measures of antiarrhythmic
efficacy were not correlated with the compound’s ability
to produce PVT in this model. In this regard it is
interesting that Carlsson et al.42 found that the KATP

1104 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Hester et al.
agonist, pinacidil, was able to block the EADs and PVT
induced by clofilium in their methoxamine-treated rab-
bits without altering the prolonged monophasic action
potential.
EC25 value (185.8 nM) for increasing ERP in guinea pig
papillary muscles. The authors suggested that this lack
of correspondence may have been due to the possibility
that ibutilide has a combination of effects in addition
to those on IKr. Mouse atrial tumor myocytes (AT-1 cells)
have also been used to evaluate the activity of ibutilide
on IKr. In this study ibutilide was found to be a potent
blocker of IKr with activity that was qualitatively similar
to that of dofetilide.52 More recently the IKr blocking
properties of ibutilide were studied on rabbit sinoatrial
(SA) node and atrioventricular (AV) node cells.53 On the
basis of these studies, it would appear that there is no
general consensus regarding the mechanism of action
for ibutilide and by inference for other members of the
ibutilide family. We suspect that the activity of these
compounds on cardiac cells is the result of agonist or
antagonist activities on several different ion channels.
If, for example, a compound could enhance an inward
plateau current it would prolong the duration of the
action potential and the ERP which would block re-
entrant arrhythmias. If at the same time it could
enhance a delayed rectifier or inward rectifier potassium
current, it would increase the rate of repolarization
which might prevent the formation of EADs and PVT.
A compound that could block IKr but enhance IK1 might
have a similar effect. As mentioned above it has been
shown that the KATP agonist, pinacidil, can prevent
EADs and PVT induced by clofilium in the rabbit
proarrhythmia model.42 It has also been reported that
pinacidil can prevent EADs caused by Bay K 8644 or
ketanserin in canine ventricular myocytes.54 High con-
centrations of ibutilide that elicited an outward potas-
sium current were also reported to prevent EADs caused
by the IKr blocker, E-4031.51 We believe that the differ-
ent effects on ERP1, ERP3, EADs, and PVT produced
by the compounds in this series are the result of slightly
different net effects on the ion currents that generate
the action potential.
During the course of these experiments, we had
occasion to look at several compounds in which the
alcohol had been either reduced (47-49) or dehydrated
(50E). These compounds generally had interesting
activity on ERP1 and ERP3, and 49 like 45 had no
proarrhythmic activity in the rabbit model. Unfortu-
nately, these compounds had poor metabolic stability
and were not considered further.
With regard to the mechanism of action for this series
of class III antiarrhythmic agents, it is known that the
cardiac action potential is the result of an intricate
balance between ion currents that flow into and out of
cardiac cells. These currents are established by an array
of ion channels that can vary depending on the animal
species and the type of cardiac tissue investigated.
Initial depolarization of the ventricular myocyte is
achieved by a rapid influx of sodium (INa) through the
fast sodium channel. This is immediately followed by a
transient outward current (Ito) which contributes to the
repolarization process and is carried by two separate
channels. The plateau of the action potential is main-
tained by a balance between an inward calcium current
carried by the L-type and T-type calcium channels and
an outward potassium current that is carried by three
different delayed rectifier channels (IKr, IKs, and Ikur).
Final repolarization of the cell is facilitated by the
inward rectifier potassium current (IK1). The adenosine
triphosphate-regulated potassium channel (KATP) is also
present and is probably especially important during
ischemia.47 Class III antiarrhythmic activity has been
achieved either by enhancing an inward plateau current
or by blocking an outward repolarizing current. Many
of the classical class III antiarrhythmic agents such as
D-sotalol, sematilide, E4031, and dofetilide block the
rapidly activating delayed rectifier (IKr) which is be-
lieved to be the basis for their activity.48 On the other
hand, it has been reported that low, physiologically
relevant concentrations of ibutilide enhance a late
inward current in guinea pig ventricular cells49 and
human atrial cells.50 It was proposed that this current
is carried by sodium through the L-type Ca2+ channels
that in the absence of ibutilide are impermeable to
sodium.50 At higher concentrations in guinea pig ven-
tricular cells, ibutilide was found to increase a dofetilide-
resistant, time-independent outward current that re-
versed its effect on the APD to give a bell-shaped
concentration-response curve.51 High concentrations of
ibutilide have also been reported to give a concentration-
dependent block of Ito in human atrial cells.50 In a study
by Lynch and co-workers48 the displacement of high
affinity [3H]dofetilide binding in guinea pig ventricular
myocytes was used to measure the interaction of several
class III antiarrhythmic agents with IKr. It was found
that there was a good correspondence between the Ki
values of several selective IKr blockers in the binding
assay and the measured EC25 values for increasing ERP
by 25% over baseline in guinea pig papillary muscles.
In this study ibutilide was found to have one of the
lowest Ki values (16 ( 7 nM) for displacing high affinity
[3H]dofetilide binding but a greater than 10-fold higher
Because of its very interesting activity profile, 45E
was chosen for further evaluation in two canine models
of reentrant arrhythmias. In the first, a model of
inducible atrial tachycardia that resembles AFL was
created by introducing a Y-shaped lesion in the right
atrium according to the method of Frame and co-
workers.55 In this model, the arrhythmia which results
from a reentrant cycle in the atrial tissue above the
tricuspid ring55,56 is stable, is highly reproducible, and
can be consistently induced, terminated, and reinitiated
by rapid atrial pacing. It is characterized by a relatively
long excitable gap and incomplete recovery of excit-
ability; it, thus, lends itself to the evaluation of anti-
arrhythmic agents that increase the refractoriness of
atrial tissue, thereby increasing the wavelength of the
circulating wave front and reducing the excitable gap.
In this model, orally administered ibutilide in doses of
0.25-1.0 mg/kg was found to significantly increase the
atrial effective refractory period (AERP) and prevent
induction of AFL for 4-6 h.57 Intravenous administra-
tion of ibutilide in a second study at a mean dose of 6 (
1 µg/kg terminated AFL and prevented its reinduction
in all of the eight animals studied. This effect was
accompanied by a statistically significant increase in
both AERP and atrial flutter cycle length (AFLCL).58
In their original description of this AFL model Frame

Synthesis and Evaluation of Ibutilide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1105
Ta ble 3. Heart Rate and Electrophysiologic Parameters
Measured at Baseline and J ust After AFL Termination by 45E
obtained with increasing cumulative doses of 45E. In
these conscious animals no significant change in heart
rate (HR) and no adverse effects were observed through
the highest dose tested.
HRd
(bpm)
QTb
(ms)
AERPe
(ms)
VERPf AFLClg
(ms) (ms)
baseline
termination
(0.48 ( 0.12)a
125 ( 8
186 ( 4 116 ( 3
122 ( 3 151 ( 4
Compound 45E was also evaluated in the canine 24-h
infarction model. In this model the left anterior de-
scending coronary artery (LAD) is permanently ligated
in two stages to give a well-defined area of ischemic
tissue. As the infarct develops it generates a series of
spontaneous ventricular arrhythmias. In the early acute
phase, 30 min following coronary occlusion, the arrhyth-
mias are believed to result from both reentrant and
nonreentrant mechanisms; however, after 6-8 h and
lasting for 2-3 days, the spontaneous arrhythmias
(PVCs) result from nonreentrant ectopic depolarizations
in the ventricle. Class IC antiarrhythmic agents such
as encainide, but not class III agents, are particularly
effective for treating these spontaneous arrhythmias.59
Twenty-four hours after the occlusion, ventricular ta-
chyarrhythmias can be induced by programmed electri-
cal stimulation (PES). These arrhythmias are primarily
due to reentry in ischemia-damaged tissue bordering the
infarct. Class III antiarrhythmic agents such as ibutilide
are very effective for preventing the initiation of this
type of arrhythmia.59 Compound 45E was administered
intravenously to 11 animals to give cumulative doses
of 0.24, 0.72, and 2.4 µmol/kg. Hemodynamic and
electrophysiologic parameters were measured at base-
line and 15 min after each dose. The results are
presented in Table 5. There was a dose-dependent
increase in cardiac refractoriness which reached statis-
tical significance at 0.72 µmol/kg for AERP and at 2.4
µmol/kg for VERP. The latter was accompanied by a
significant increase in the QT interval and in the
ventricular MAPD90. Other ECG intervals (P, PQ, and
QRS) were not significantly affected by 45E (data not
shown). Although there was a dose-dependent decrease
in HR and idioventricular heart rate (IVR) which
became significant for HR at 2.4 µmol/kg, 45E had no
effect on BP. As expected 45E which does not have class
I antiarrhythmic activity also had no effect on the PVCs.
In this experiment 8 animals served as saline-treated
controls. No significant changes in any of the measured
parameters were observed in this group. At the end of
the experiment each of the control animals received an
intravenous dose of 2.4 µmol/kg of 45E. The responses
to this treatment mirrored those obtained with the high
dose in the drug-treated group. Effects of 45E on PES-
induced arrhythmias are shown in Table 6. At baseline
in the drug-treated group arrhythmias could not be
induced (NI) in 3 animals, nonsustained ventricular
tachycardia (NSVT) was obtained in 3 animals, and
sustained ventricular tachycardia (SVT) was obtained
in 5 animals. After the 0.24 µmol/kg dose of 45E, 8
animals were NI, 2 had NSVT, and 1 had SVT. The 0.72
µmol/kg dose level gave 9 NI animals and 2 animals
with SVT. When 2.4 µmol/kg of 45E had been admin-
istered, 10 animals were NI and 1 of the previous SVT
animals had NSVT. In the saline control group 3-4
animals were NI, 3-4 were induced to SVT, and 1
animal consistently went into ventricular fibrillation
(VF). After administration of 2.4 µmol/kg of 45E, 7
animals became NI and the VF animal was induced to
SVT.
108 ( 12 202 ( 8 149 ( 10c 138 ( 2c 165 ( 9
a
b
Mean dose of 45E at AFL termination (µmol/kg). QT interval
determined at
a
paced cycle length of 300 ms. cStatistically
significant, p e 0.05 vs baseline. Heart rate. e Atrial effective
refractory period. f Ventricular effective refractory period. g Atrial
flutter cycle length.
d
Ta ble 4. Effects of Intravenous 45E on HR, QT Interval,
AERP, and VERP, Measured at Baseline and After AFL
Termination
dosec
nd HRe (bpm) QTa (ms) AERPf (ms) VERPg (ms)
baseline
0.24
0.6
1.2
2.4
4.8
7.2
9.6
12.0
8
3
7
8
8
8
8
8
8
124 ( 7
128 ( 10
111 ( 9
114 ( 8
113 ( 7
118 ( 9
127 ( 11
114 ( 7
122 ( 6
186 ( 4
196 ( 8
208 ( 6b
212 ( 7b
213 ( 6b
207 ( 8b
205 ( 9
204 ( 8
200 ( 9
118 ( 4
122 ( 3
160 ( 16b
153 ( 9b
160 ( 9b
166 ( 8b
166 ( 9b
162 ( 7b
165 ( 6b
164 ( 6b
142 ( 3b
141 ( 3b
144 ( 2b
143 ( 2b
142 ( 3b
140 ( 5b
139 ( 4b
137 ( 3b
a
QT interval determined at a paced cycle length of 300 ms.
Statistically significant, p e 0.05 vs baseline. c Cumulative dose
b
of 45E (µmol/kg). Number of animals. e Heart rate. f Atrial ef-
d
g
fective refractory period. Ventricular effective refractory period.
F igu r e 1. Effects of intravenous 45E on AFL termination.
and co-workers55 suggested that it might be a useful
model for the common form of human AFL. Since
ibutilide has been shown to be especially effective for
terminating AFL in humans,32 its excellent activity in
this model also suggests the utility of the model for
predicting the potential efficacy of antiarrhythmic can-
didates for treating human AFL.
Results from the evaluation of 45E in this model are
shown in Tables 3 and 4. Figure 1 shows the effect of
dose on arrhythmia termination. Intravenous doses of
45E were administered periodically to eight animals
with established arrhythmias so that cumulative doses
of 0.24-12.0 µmol/kg were obtained. It was found that
the arrhythmias were terminated in all of the animals
after a mean effective dose of 0.48 ( 0.12 µmol/kg. At
this time a statistically significant increase in both
AERP and ventricular effective refractory period (VERP)
but not AFLCL had been achieved. A statistically
significant increase in paced QT interval was also
obtained after a cumulative dose of 0.6 µmol/kg. It is
noteworthy that maximum values of AERP and VERP
and of QT were obtained at 0.24 and 0.6 µmol/kg,
respectively. No additional change in these values was

1106 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Hester et al.
Ta ble 5. Effects of 45E and Saline Control on Hemodynamic and Electrophysiologic Parameters in the Canine 24-h Infarction Model
l
HRg
(bpm)
IVRh
(bpm)
BPi
(mmHg)
QTj
(ms)
AERPk
(ms)
atrial MAPD90
(ms)
VERPm
(ms)
ventricularn MAPD90
(ms)
dose
PVCsf
Compound 45E (n ) 11)a
baseline
0.24b
0.72
152 ( 5
155 ( 5
146 ( 6
135 ( 8c
144 ( 8
138 ( 9
130 ( 8
124 ( 11
115 ( 5
112 ( 3
115 ( 4
119 ( 5
210 ( 5
135 ( 4
149 ( 6
166 ( 8c
140 ( 9
157 ( 4
162 ( 5
170 ( 7
185 ( 9c
160 ( 4
162 ( 5
170 ( 7
185 ( 9c
87 ( 14
68 ( 17
57 ( 17
73 ( 14
211 ( 6
218 ( 6
148 ( 9
146 ( 10
163 ( 11
2.4
240 ( 6c 194 ( 9c
Saline Control (n ) 8)a
baseline
162 ( 9
158 ( 7
149 ( 6
153 ( 10
150 ( 8
155 ( 7
147 ( 8
148 ( 10
122 ( 6
114 ( 6
119 ( 9
117 ( 7
111 ( 7
210 ( 7
212 ( 7
216 ( 8
203 ( 8
128 ( 4
132 ( 3
132 ( 3
144 ( 13
159 ( 11
158 ( 12
159 ( 14
156 ( 13
209 ( 13c
151 ( 5
152 ( 7
151 ( 7
150 ( 7
180 ( 6c
166 ( 6
164 ( 8
172 ( 12
171 ( 9
201 ( 12c
105 ( 19
111 ( 14
86 ( 21
85 ( 21
53 ( 16
1d
2
3
45E (2.4)e 127 ( 10c 111 ( 11c
238 ( 9c 179 ( 7c
a
b
d
Number of animals. Cumulative intravenous dose of 45E (µmol/kg). c Statistically significant, p e 0.05 vs baseline. Vehicle dose
number e Single intravenous dose of 45E (µmol/kg). f Spontaneous arrhythmias, number per minute. g Heart rate. Idioventricular heart
rate. Blood pressure. QT interval. Atrial effective refractory period. Atrial monophasic action potential duration recorded at 90%
repolarization. Ventricular effective refractory period. Ventricular monophasic action potential duration recorded at 90% repolarization.
h
i
j
k
l
m
n
1
Ta ble 6. Effects of 45E and Saline Control on PES-Induced
on mineral oil mulls. H NMR spectra were obtained on 300-
MHz instruments using tetramethylsilane as an internal
standard; other physical and analytical data were obtained
by the physical and analytical chemistry group at Pharmacia.
(S)-(-)-N-[4-[4-[Eth yl(6-flu or o-6-m eth ylh ep tyl)a m in o]-
1-h yd r oxybu tyl]p h en yl]m eth a n esu lfon a m id e (45). P r o-
ced u r e A. A stirred mixture of 5 (6.00 g, 0.0210 mol), 15 (5.12
g, 0.0231 mol), NaHCO3 (3.52 g, 0.0419 mol) and acetonitrile
(180 mL) was refluxed under nitrogen for 16 h, cooled and
filtered. The filtrate was concentrated in vacuo and the residue
was chromatographed on silica gel with 5% MeOH-0.5%
NH4OH-CH2Cl2. A solution of the product in EtOAc was
washed with saturated NaHCO3 and brine, dried (MgSO4) and
concentrated to give 7.00 g (80.0%) of 45: 1H NMR (CDCl3) δ
1.10 (t, J ) 7.2 Hz, 3H), 1.30 (s, 3H), 1.37 (s, 3H), 1.30-1.70
(m, 11H), 1.95 (m, 1H), 2.39-2.76 (m, 6H), 2.92 (s, 3H), 4.60
(m, 1H), 7.16 (d, J ) 8.5 Hz, 2H), 7.33 (d, J ) 8.5 Hz, 2H); MS
(EI) m/z (relative intensity) 416 (M+, 5.3), 401 (2.9), 396 (2.1),
337 (20.5), 317 (9.1), 299 (52.6), 188 (100), 168 (74.5), 72 (28.3);
HRMS (FAB) calcd for C21H38FN2O3S 417.2587 (M + H)+,
found 417.2602.
Arrhythmias
dose
NIa,f
NSVTa,g
SVTa,h
VFa,i
Compound 45E (n ) 11)e
3
8
9
10
baseline
0.24b
0.72
3
2
0
1
5
1
2
0
0
0
0
0
2.4
Saline Control (n ) 8)e
baseline
3
4
3
4
7
1
0
0
0
0
3
3
4
3
1
1
1
1
1
0
1d
2
3
45E (2.4)c
a
Number of animals in this arrhythmia category after PES.
Cumulative intravenous dose of 45E (µmol/kg). c Single intra-
b
venous dose of 45E (µmol/kg). Vehicle dose number. e Number
d
of animals. f Noninducible. Nonsustained ventricular tachycar-
g
h
i
dia. Sustained ventricular tachycardia. Ventricular fibrillation.
(S)-(-)-N-[4-[4-[Eth yl(7-flu or oh eptyl)am in o]-1-h ydr oxy-
b u t yl]p h en yl]m et h a n esu lfon a m id e (E)-2-Bu t en ed ioa t e
(2:1) Sa lt (40E). P r oced u r e B. A stirred mixture of 5 (2.58
g, 0.00900 mol), 17 (2.0 g, 0.010 mol), NaHCO3 (1.68 g, 0.0200
mol) and acetonitrile (80 mL) was refluxed, under nitrogen
for 18 h and then concentrated in vacuo. A mixture of the
residue and water was extracted with EtOAc; the extracts were
washed with water and brine, dried (MgSO4) and concentrated.
The residue was chromatographed on silica gel with 0.3%
NH4OH-6% MeOH-CHCl3. A solution of the product in
EtOAc was washed with saturated NaHCO3, water and brine,
dried (MgSO4) and concentrated to give 1.93 g (4.76 mmol) of
the free base. This was combined with 0.276 g (2.38 mmol) of
fumaric acid and the salt was crystallized from acetone to give
Con clu sion s
We prepared a series of compounds in which the
heptyl side chain of ibutilide was modified by fluorine
substitution to prevent its rapid metabolism. Like
ibutilide many of these compounds prolonged cardic
refractoriness in vitro and in addition had increased
stability when incubated with human liver microsomes.
However, they retained the ability to induce EADs and
PVT in a rabbit proarrhythmia model. It was found that
the S-enantiomers of these alcohols were generally less
proarrhythmic than the racemates. One of these enan-
tiomers (45E, trecetilide fumarate) was devoid of pro-
arrhythmic activity in this model. Further evaluation
of 45E demonstrated that it had excellent activity in
canine models of reentrant AFL and ventricular tach-
yarrhythmias. This compound is currently undergoing
clinical evaluation for the treatment of atrial arrhyth-
mias.60
1.78 g (42.9%) of 40E: mp 126-127 °C; [R]24 -15° (c 0.997,
D
EtOH); MS m/z (relative intensity) 402 (M+, 4.9), 323 (16.6),
299 (26.4), 232 (28.1), 174 (100), 91 (22.1); IR 3369, 2748, 2708,
1
1614, 1576 cm-1; H NMR [(CD3)2SO] δ 1.00 (t, 3H) 1.2-1.7
(m, 14H), 2.58 (m, 6H), 2.94 (s, 3H), 3.62 (br s, 2H), 4.33 (t,
1H), 4.50 (m, 2H), 6.46 (s, 1H), 7.15 (d, 2H), 7.26 (d, 2H). Anal.
(C22H37FN2O5S) C, H, N, S.
N-[4-[4-[Eth yl(7-flu or oh ep tyl)a m in o]-1-h yd r oxybu tyl]-
p h en yl]m eth a n esu lfon a m id e (E)-2-Bu ten ed ioa te (2:1)
Sa lt (33E). As described in procedure B, 4 (1.30 g, 0.00454
mol) was alkylated with 17, the product was flash chromato-
graphed on silica gel with 7.5% MeOH-0.5% NH4OH-CHCl3
and the salt was crystallized from acetone to give 1.06 g
(50.7%) of 33E: mp 136.5-137.5 °C; 1H NMR [(CD3)2SO] δ
0.99 (t, J ) 7.1 Hz, 3H), 1.25-1.70 (m, 14H), 2.57 (m, 6H),
2.94 (s, 3H), 4.34 (t, J ) 6.1 Hz, 1H), 4.50 (m, 2H), 6.48 (s,
1H), 7.15 (d, J ) 8.4 Hz, 2H), 7.27 (d, J ) 8.5 Hz, 2H); IR
3380 cm-1; MS (EI) m/z (relative intensity) 402 (M+, 7.0), 174
(100). Anal. (C22H37FN2O5S) C, H, N, S.
Exp er im en ta l Section
Ch em istr y. Melting points taken in capillary tubes are
uncorrected. Preparative flash chromatography was carried
out on Kieselgel (230-400 mesh ASTM silica gel) from EM
Reagents and low-pressure chromatography on silica gel 60
(70-230 mesh ASTM) from EM Reagents. The progress of
reactions and the purity of products were evaluated by TLC
on silica gel GF 240-µm slides from Analtech, Inc., Newark,
DE. Unless otherwise indicated, IR spectra were determined

Synthesis and Evaluation of Ibutilide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1107
N-[4-[4-[(7,7-Diflu or oh ep t yl)et h yla m in o]-1-h yd r oxy-
bu t yl]p h en yl]m et h a n esu lfon a m id e (E)-2-Bu t en ed ioa t e
(2:1) Sa lt (34E). As described in procedure B, 4 (1.0 g, 0.0035
mol) was alkylated with 20, the product was flash chromato-
graphed on silica gel with 10% MeOH-0.5% NH4OH-CHCl3
and the salt was crystallized from acetone to give 0.69 g (41%)
of 34E: mp 147-148 °C; IR 3375 cm-1; 1H NMR [(CD3)2SO] δ
0.99 (t, J ) 7.0 Hz, 3H), 1.23-1.60 (m, 12H), 1.79 (m, 2H),
2.59 (m, 6H), 2.94 (s, 3H), 3.63 (br s), 4.49 (t, 1H), 5.87, 6.05,
6.25 (t, t, t, 1H), 6.46 (s, 1H), 7.15 (d, J ) 8.5 Hz, 2H), 7.27 (d,
J ) 8.5 Hz, 2H); MS (EI) m/z (relative intensity) 420 (M+, 7.2),
405 (1.3), 341 (21.2) 299 (34.3), 269 (7.0), 240 (13.2), 192 (100).
Anal. (C22H36F2N2O5S) C, H, N, S.
HRMS (FAB) calcd for C21H38FN2O3S 417.2587 (M + H+),
found 417.2579.
N-[4-[4-[Ethyl(5-flu or o-5-m ethylh exyl)am ino]-1-h ydr oxy-
bu tyl]p h en yl]m eth a n esu lfon a m id e (39). As described in
procedure A, 4 (0.889 g, 0.00311 mol) was allowed to react with
16 in refluxing acetonitrile. The product was chromatographed
on silica gel with 10% MeOH-1% NH4OH-CHCl3 to give 0.530
g (50.9%) of 39: 1H NMR (CDCl3) δ 1.19 (t, J ) 7.09 Hz, 3H),
1.30 (s, 3H), 1.37 (s, 3H), 1.44 (m, 2H), 1.73 (m, 8H), 2.73 (m,
6H), 2.95 (s, 3H), 4.62 (m, 1H), 7.21 (d, J ) 8.50 Hz, 2H), 7.30
(d, J ) 8.45 Hz, 2H); MS (EI) m/z (relative intensity) 402 (M+,
14.3), 387 (5.7), 323 (36.0), 299 (55.5), 174 (100); HRMS (EI)
calcd for C20H33FN2O3S 402.2352, found 402.2350.
N -[4-[4-[(6,6-Diflu or oh e xyl)e t h yla m in o]-1-h yd r oxy-
bu t yl]p h en yl]m et h a n esu lfon a m id e (E)-2-Bu t en ed ioa t e
(2:1 Sa lt) (35E). As described in procedure B, 4 (1.33 g,
0.00466 mol) was alkylated with 18, the product was flash
chromatographed on silica gel with 10% MeOH-0.5% NH4OH-
CHCl3 and the salt was crystallized from acetone-Et2O to give
0.7 g (32%) of 35E: mp 88-90 °C; IR 3323 cm-1; MS (EI) m/z
(relative intensity) 406 (M+, 6.6), 327 (19.1), 299 (30.0), 178
(100): 1H NMR [(CD3)2SO] δ 1.00 (t, J ) 7.1 Hz, 3H), 1.26-
1.59 (m, 10H), 1.79 (m, 2H), 2.59 (m, 6H), 2.94 (s, 3H), 3.69
(br s), 4.49 (t, 1H), 5.87, 6.05, 6.24 (t, t, t, 1H), 6.46 (s, 1H),
7.15 (d, J ) 8.5 Hz, 2H), 7.27 (d, J ) 8.5 Hz, 2H). Anal.
(C21H34F2N2O5S) C, H, N, S.
(S)-(-)-N-[4-[4-[Eth yl(6-flu or oh eptyl)am in o]-1-h ydr oxy-
bu t yl]p h en yl]m et h a n esu lfon a m id e (E)-2-Bu t en ed ioa t e
(2:1) Sa lt (41E). As described in procedure B, 5 (2.58 g,
0.00900 mol) was alkylated with 19, the product was flash
chromatographed on silica gel with 6% MeOH-0.3% NH4OH-
CHCl3 and the salt was crystallized from acetone to give 1.26
g (30.5%) of 41E: mp 109-110.5 °C; [R]24 -14° (c 0.980,
D
EtOH); MS m/z (relative intensity) 402 (M+ 4.9), 323 (19.2),
299 (34.5), 240 (15.3), 174 (100) 162 (10.8); IR 3315, 3097, 3025,
2758, 2712, 2507, 1614, 1570 cm-1; 1H NMR [(CD3)2SO] δ 0.99
(t, 3H) 1.21-1.55 (m, 15H), 2.55 (m, 6H), 2.94 (s, 3H), 3.51 (br
s), 4.49 (m, 1H), 4.56 (m, 0.5H), 4.71 (m, 0.5H), 6.46 (s, 1H),
7.16 (d, 2H), 7.26 (d, 2H). Anal. (C22H37FN2O5S) C, H, N, S.
N-[4-[4-[Eth yl(6-flu or oh ep tyl)a m in o]-1-h yd r oxybu tyl]-
p h en yl]m eth a n esu lfon a m id e (36). Alkylation of 4 (1.65 g,
0.00578 mol) with 19 (1.23 g, 0.00624 mol) as described in
procedure A and flash chromatography of the product on silica
gel with 5% MeOH-0.25% NH4OH-CHCl3 gave 1.54 g (66.4%)
of 36: 1H NMR (CDCl3) δ 1.10 (t, J ) 7.1 Hz, 3H), 1.32 (d, d,
J ) 6.1, 24.0 Hz, 3H), 1.27-1.76 (m, 11H), 1.98 (m, 1H), 2.48
(m, 5H), 2.68 (m, 1H), 2.95 (s, 3H), 4.60 (m, 1H), 4.60, 4.73
(m, m, 1H), 7.16 (d, J ) 8.5 Hz, 2H), 7.37 (d, J ) 8.4 Hz, 2H);
MS (EI) m/z (relative intensity) 402 (M+, 11.4), 323 (32.1) 299
(47.2), 174 (100); HRMS calcd for C20H35FN2O3S 402.2352,
found 402,2347.
(S)-(-)-N-[4-[4-[(7,7-Diflu or oh ep tyl)eth yla m in o]-1-h y-
d r oxybu tyl]p h en yl]m eth a n esu lfon a m id e (E)-2-Bu ten e-
d ioa te (2:1) Sa lt (42E). According to procedure B the alkyl-
ation of 5 (3.64 g, 0.0127 mol) with 20 (2.74 g, 0.0127 mol)
and crystallization of the salt from acetone gave 2.61 g (42.8%)
of 42E: mp 109-111 °C; [R]24 -14° (c 1.00, EtOH); MS (EI)
D
m/z (relative intensity) 420 (M+, 4.3), 341 (13.3), 299 (23.7),
192 (100), 72 (42.8), 58 (33.4); IR 3363 cm-1 1H NMR
;
[(CD3)2SO] δ 1.00 (t, J ) 7.1 Hz, 3H), 1.27-1.58 (m, 12H), 1.78
(m, 2H), 2.56 (m, 6H), 2.94 (s, 3H), 4.49 (t, 1H), 5.87, 6.05.
6.23 (t,t,t, 1H), 6.47 (s, 1H), 7.15 (d, J ) 8.5 Hz, 2H), 7.27 (d,
J ) 8.5 Hz, 2H). Anal. (C22H36F2N2O5S) C, H, N, S.
N-[4-[4-[Eth yl(6-flu or oh ep tyl)a m in o]-1-h yd r oxybu tyl]-
ph en yl]m eth an esu lfon am ide (E)-2-Bu ten edioate (2:1 Salt)
(36E). A solution of 36 (2.5 g, 0.0062 mol) in EtOAc was
washed with saturated aqueous NaHCO3, dried (MgSO4) and
concentrated. A solution of the residue in acetonitrile was
treated with fumaric acid (0.36 g, 0.0031 mol) and crystallized
to give 2.1 g (73.5%) of 36E: mp 119-122 °C; 1H NMR
[(CD3)2SO] δ 0.99 (t, 3H), 1.20-1.60 (m, 15H), 2.94 (s, 3H),
4.50 (m, 1H), 4.57, 4.72 (m, m, 1H), 6.47 (s, 1H), 7.16 (d, 2H),
7.26 (d, 2H). Anal. (C22H37FN2O5S) C, H, N, S.
N-[4-[4-[(6,6-Diflu or oh ep t yl)et h yla m in o]-1-h yd r oxy-
bu tyl]ph en yl]m eth an esu lfon am ide (37). An ice-cold, stirred
suspension of LiAlH4 (0.11 g, 2.89 mmol) in THF (2 mL) under
nitrogen was treated dropwise with a solution of 9 (0.379 g,
0.877 mol) in THF (5 mL), kept in the bath for 2.5 h and then
treated carefully with a saturated aqueous solution of potas-
sium sodium tartrate (1.4 mL). This mixture was stirred for
20 min and filtered through Celite. The filtrate was concen-
trated and the residue was chromatographed on silica gel with
5% MeOH-0.5% NH4OH-CH2Cl2 to give 0.228 g (61.8%) of
37, an oil: 1H NMR (CDCl3) δ 1.12 (t, J ) 7.1 Hz, 3H), 1.35
(m, 2H), 1.58 (t, J ) 18.4 Hz, 3H), 1.47-1.97 (m, 10H), 2.60
(m, 6H), 2.95 (s, 3H), 4.60 (m, 1H), 7.18 (d, J ) 8.5 Hz, 2H),
7.34 (d, J ) 8.5 Hz, 2H); MS (EI) m/z (relative intensity) 420
(M+, 9.7), 405 (2.5), 341 (26.3), 299 (40.6), 192 (100); HRMS
(EI) calcd for C20H34F2N2O3S 420.2258, found 420.2265.
(S)-(-)-N-[4-[4-[(6,6-Diflu or oh exyl)et h yla m in o]-1-h y-
d r oxybu tyl]p h en yl]m eth a n esu lfon a m id e (E)-2-Bu ten e-
d ioa te (2:1) Sa lt (43E). As described in procedure B, 5 (3.53
g, 0.0123 mol) was alkylated with 18, the product was
chromatographed on silica gel with 5% MeOH-0.25% NH4OH-
CHCl3 and the salt was crystallized from acetone to give 1.98
g (34.7%) of 43E: mp 110-111 °C; [R]24D -14° (c 0.996, EtOH);
IR (Nujol) 3347, 3085, 2754, 2627, 2510, 1614, 1571 cm-1; MS
(EI) m/z (relative intensity) 406 (M+, 2.6), 327 (8.0), 299 (11.4),
270 (7.7), 178 (100); 1H NMR [(CD3)2SO] δ 0.99 (t, J ) 7.1 Hz,
3H), 1.30-1.57 (m, 10H), 1.79 (m, 1H), 2.56 (s, 6H), 2.94 (s,
3H), 4.49 (t, 1H), 5.87, 6.05, 6.25 (t,t,t, 1H), 6.47 (s, 1H), 7.15
(d, J ) 8.5 Hz, 2H), 7.27 (d, J ) 8.5 Hz, 2H). Anal.
(C21H34F2N2O5S) C, H, N, S.
(S)-(-)-N-[4-[4-[Eth yl(6,6-d iflu or oh ep tyl)a m in o]-1-h y-
d r oxybu tyl]p h en yl]m eth a n esu lfon a m id e (44). According
to procedure A, 5 (3.33 g, 0.0116 mol) was allowed to react
with 26 (2.75 g, 0.0128 mol) and the product was chromato-
graphed on silica gel with mixtures of MeOH-NH4OH-CH2Cl2
containing 3-5% MeOH and 0.3-0.5% NH4OH to give 2.84 g
(58.2%) of 44: 1H NMR (CDCl3) δ 1.12 (t, J ) 7.12 Hz, 3H),
1.58 (t, J ) 18.4 Hz, 3H), 1.28-2.00 (m, 14H), 2.39-2.81 (m,
6H), 2.94 (s, 3H), 4.59 (d, 1H), 7.18 (d, J ) 8.48 Hz, 2H), 7.33
(d, J ) 8.46 Hz, 2H); 19F NMR (282.2 MHz, CDCl3) δ -94.83
(6 peaks); MS m/z (relative intensity) 420 (M+ 3.0), 405 (0.8),
341 (9.7), 299 (17.1), 220 (1.0), 192 (100), 72 (36.5); HRMS (EI)
24
calcd for C20H34N2O3F2 420.2258, found 420.2266; [R]D -16°
N-[4-[4-[E t h yl(6-flu or o-6-m et h ylh ep t yl)a m in o]-1-h y-
d r oxyb u t yl]p h en yl]m et h a n esu lfon a m id e (38). As de-
scribed in procedure A, 4 (0.37 g, 0.00128 mol) was allowed to
react with 15 in refluxing acetonitrile. The product was
chromatographed on silica gel with 10% MeOH-CH2Cl2 to give
0.332 g (62.3%) of 38: 1H NMR (CDCl3) δ 1.30 (s, 3H), 1.36
(m, 7H), 1.37 (s, 3H), 1.76 (m, 8H), 2.95 (s, 3H), 2.97 (m, 6H),
4.65 (m, 1H), 7.24 (m, 4H); MS (EI) m/z (relative intensity)
416 (M+, 3.4), 401 (1.8), 396 (8.9), 381 (2.0), 337 (10.2), 317
(22.9), 299 (59.3), 269 (8.5), 240 (17.1), 188 (36.1), 168 (100);
(c 0.6598, EtOH); IR (film) 3255, 3155, 1614, 1512 cm-1
.
(S)-(-)-N-[4-[4-[Eth yl(6-flu or o-6-m eth ylh ep tyl)a m in o]-
1-h yd r oxybu tyl]p h en yl]m eth a n esu lfon a m id e (E)-2-Bu -
ten ed ioa te (2:1 Sa lt) (45E). A solution of 45 (6.68 g, 0.0160
mol) in acetone (200 mL), under nitrogen was treated with
fumaric acid (0.93 g, 0.0080 mol) and warmed to obtain
solution. The resulting salt was crystallized from acetone to
give 3.99 g (52.5%) of 45E: mp 135.5-137 °C; [R]24 -14° (c
D
0.934, EtOH); IR 3320, 3094, 3021, 2752, 2704, 2511, 1575,

1108 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
1512 cm-1 1H NMR [(CD3)2SO] δ 1.00 (t, 3H), 1.25 (s, 3H),
1.32 (s, 3H), 1.23-1.61 (m, 12H), 2.59 (m, 6H), 2.95 (s, 3H),
3.49 (br s), 4.49 (t, 1H), 6.47 (s, 1H), 7.15 (d, J ) 8.5 Hz, 2H),
7.27 (d, J ) 8.5 Hz, 2H). Anal. (C23H39FN2O5S) C, H, F, N, S.
Hester et al.
;
N-[4-[4-(Eth yla m in o)-1,4-d ioxobu tyl]p h en yl]m eth a n e-
su lfon a m id e (8). A stirred slurry of 1231 (20 g, 0.0737 mol)
in THF (600 mL) was treated with triethylamine (13.7 mL,
0.0981 mol), cooled to -12 °C and treated, dropwise, with
isobutyl chloroformate (12.7 mL, 0.0981 mol). This mixture
was stirred at -12 °C for 1.5 h, treated, dropwise, with a
solution of ethylamine (4 g, 0.09 mol) and triethylamine (13.7
mL, 0.0981 mol) in THF (173 mL), kept for 3 h at -12 °C and
poured into 780 mL of a mixture of ice and 1 N HCl. A stream
of nitrogen was bubbled through this mixture for 18 h to
remove most of the THF; the resulting solid was collected by
filtration, washed with dilute NaHCO3 and water and dried
in vacuo to give 14.3 g of product. The filtrate was extracted
with EtOAc to give an additional 4 g of product. The combined
product was washed with MeOH and dried to give 13.8 g
(62.5%) of 8. A sample, recrystallized from acetonitrile, had:
(R)-(+)-N-[4-[4-[Eth yl(6-flu or o-6-m eth ylh ep tyl)a m in o]-
1-h yd r oxybu tyl]p h en yl]m eth a n esu lfon a m id e (E)-2-Bu -
ten ed ioa te (2:1) Sa lt (46E). According to procedure B, the
alkylation of 6 (2.5 g, 0.00873 mol) with 15, flash chromatog-
raphy of the product on silica gel with 8% MeOH-0.4%
NH4OH-CHCl3 and crystallization of the salt from acetone
gave 0.521 g (12.6%) of 46E which was identical to 45E in all
respects except for the sign of its rotation: mp 135-137 °C;
[R]24 +14° (c 0.9697, EtOH); MS m/z (relative intensity) 416
D
(M+, 9.4), 401 (4.5), 337 (30.8), 299 (58.7), 269 (13.5), 240 (24.6),
188 (100), 168 (31.0), 269 (13.5), 240 (24.6), 188 (100), 168
(31.0), 162 (17.3), 144 (15.0), 98 (30.0); IR 3317, 1575 cm-1
;
mp 210-213 °C; IR 3375, 3145, 3060, 1667, 1649, 1604 cm-1
;
1H NMR [(CD3)2SO] δ 0.95 (t, 3H) 1.27 (d, J ) 21.5 Hz, 6H),
1.23-1.58 (m, 12H), 2.52 (m, 6H), 2.92 (s, 3H), 3.35 (br s), 4.46
MS m/z (relative intensity) 298 (M+, 14.3), 254 (8.4), 226 (5.5),
198 (100), 119 (23.5), 100 (13.9): 1H NMR [(CD3)2NCOD] δ
1.01 (t, J ) 7.2 Hz, 3H), 2.51, (t, J ) 6.6 Hz, 2H), 3.12 (t, J )
7.2 Hz, 2H), 3.15 (s, 3H), 3.24 (t, J ) 6.6 Hz, 2H). Anal.
(C13H18N2O4S) C, H, N, S.
(t, 1H), 6.46 (s, 1H), 7.13 (d, 2H), 7.25 (d, 2H). Anal. (C23H39
FN2O5S) C, H, N.
-
N-[4-[4-[E t h yl(6-flu or oh ep t yl)a m in o]b u t yl]p h en yl]-
m eth a n esu lfon a m id e (47). Alkylation of 7 (1.11 g, 0.00411
mol) with 19 (0.900 g, 0.00457 mol) as described in procedure
A and flash chromatography of the product over silica gel with
5% MeOH-0.25% NH4OH-CHCl3 gave 0.94 g (59.2%) of 47:
1H NMR (CDCl3) δ 1.01 (t, J ) 7.1 Hz, 3H), 1.31 (d,d J ) 6.16,
24.1 Hz, 3H), 1.26-1.68 (m, 12H), 2.38-2.63 (m, 8H), 2.98 (s,
3H), 4.56, 4.72 (m,m, 1H), 7.16 (s, 4H); FAB MS m/z (relative
intensity) 387 (M + H+, 100), 369 (11.9), 283 (31.9), 184 (5.6),
174 (59.9), 160 (6.9); HRMS (FAB) calcd for C20H36FN2O2S
387.2481 (M + H+), found 387.2483.
N-[4-[4-[E t h yl(7-flu or oh ep t yl)a m in o]b u t yl]p h en yl]-
m eth a n esu lfon a m id e (48). Alkylation of 7 (3.51 g, 0.0130
mol) with 17 (3.40 g, 0.0173 mol) as described in procedure A
and chromatography of the product on silica gel with 5%
MeOH-0.25% NH4OH-CHCl3 gave 2.38 g (47.4%) of 48: 1H
NMR (CDCl3) δ 1.01 (t, J ) 7.1 Hz, 3H), 1.23-1.76 (m, 14H),
2.38-2.63 (m, 8H), 2.98 (s, 3H), 4.44 (t,t, J ) 47.3, 6.11 Hz,
2H), 7.15 (s, 4H); MS (EI) m/z (relative intensity) 386 (M+,
4.3), 371 (3.0), 307 (8.0), 283 (88.4), 174 (100), 102 (25.1);
HRMS (EI) calcd for C20H35FN2O2S 386.2403, found 386.2395.
N-[4-[4-[Eth yl(6-flu or o-6-m eth ylh ep tyl)a m in o]bu tyl]-
p h en yl]m eth a n esu lfon a m id e (49). Alkylation of 7 (2.0 g,
0.0074 mol) with 15 (1.72 g, 0.00814 mol) as described in
procedure A and chromatography of the product on silica gel
with 4% MeOH-0.4% NH4OH-CH2Cl2 gave 2.59 g (87.4%) of
49: 1H NMR (CDCl3) δ 1.13 (t, J ) 7.1 Hz, 3H), 1.30 (s, 3H),
1.37 (s, 3H), 1.38 (m, 4H), 1.60 (m, 8H), 2.61 (m, 6H), 2.71 (m,
2H), 2.98 (s, 3H), 7.17 (d,d, J ) 8.6 Hz, 4H); MS (EI) m/z
(relative intensity) 400 (M+, 2.9), 3.85 (4.8), 380 (3.7), 365 (2.1),
321 (3.5), 301 (6.7), 283 (100), 188 (50.3), 168 (48.0), 72 (27.4);
HRMS (FAB) calcd for C21H38N2O2FS 401.2638 (M + H+),
found 401.2645.
(E)-N-[4-[4-[Ethyl(6-fluoroheptyl)amino]-1-butenyl]phen-
yl]m eth a n esu lfon a m id e (E)-2-Bu ten ed ioa te (2:1) Sa lt
(50E). A stirred, ice-cold solution of 36 (0.93 g, 2.31 mmol) in
5 mL of CH2Cl2, under nitrogen was treated dropwise during
20 min with 3.0 mL of trifluoroacetic acid, kept in the ice bath
for 30 min and at ambient temperature for 22 h and concen-
trated under a stream of nitrogen. The residue was mixed with
ice, neutralized with saturated NaHCO3 and extracted with
EtOAc. The extract was washed with water and brine, dried
(MgSO4) and concentrated. Chromatography of the residue on
silica gel with 5% MeOH-0.25% of NH4OH-CHCl3 gave 0.29
g (0.76 mmol) of product which was treated with fumaric acid
(0.044 g, 0.38 mmol) and crystallized from acetone to give 0.24
g (23.5%) of 50E: mp 109-111 °C; 1H NMR [(CD3)2SO] δ 1.03
(t, J ) 7.1 Hz, 3H), 1.20, 1.28 (d, d, J ) 6.2 Hz, 3H), 1.42 (m,
8H), 2.36 (m, 2H), 2.63 (m, 9H), 2.97 (s, 3H), 4.56, 4.72 (m, m,
1H), 6.20 (t, t, J ) 15 Hz, 9 Hz, 1H), 6.41 (d, J ) 15 Hz, 1H),
6.50 (s, 1H), 7.14 (d, J ) 8.6 Hz, 2H), 7.34 (d, J ) 8.6 Hz, 2H);
IR 2475, 2379, 2299, 1608, 1582 cm-1; MS m/z (relative
intensity) 384 (M+, 0.1), 369 (0.4), 281 (1.4), 174 (100). Anal.
(C22H35FN2O4S) H, N, S; C: calcd, 59.70; found, 59.28.
N-[4-[4-(Eth ylam in o)-1-h ydr oxybu tyl]ph en yl]m eth an e-
su lfon a m id e (4). Compound 8 (3.0 g, 0.010 mol) was added,
portionwise to an ice-cold, stirred slurry of LiAlH4 (1.15 g,
0.030 mol) in THF (75 mL), under nitrogen. The mixture was
stirred in the ice bath for 1 h and at ambient temperature for
2 h; it was then diluted with THF (100 mL), warmed briefly
to the reflux temperature and kept at ambient temperature
for 18 h. The stirred mixture was treated carefully with 69
mL of saturated potassium sodium tartrate, kept for 1 h, and
extracted with EtOAc. The product remained in the aqueous
layer which was freeze-dried. The solid residue was extracted
with MeOH. The extract was concentrated and the semisolid
residue was extracted with CH2Cl2. Concentration of this
extract gave the crude product which was chromatographed
on silica gel (300 g) with 10-20% MeOH-1% NH4OH-CHCl3
and crystallized from MeOH-EtOAc to give 540 mg (18.9%)
of 4: mp 178.5-180.5 °C; IR 3387, 3127 cm-1; MS m/z (relative
intensity) 268 (M+, 9.0), 253 (6.2), 207 (39.5), 162 (70.3), 58
(100); 1H NMR [(CD3)2SO] δ 1.00 (t, 3H), 1.4, (m), 1.58 (t), 2.93
(s, 3H), 3.70 (s), 4.46 (t). Anal. (C13H22N2O3S) C, H, N, S.
(S)-(-)-N-[4-[4-(Eth ylam in o)-1-h ydr oxy-4-oxobu tyl]ph en -
yl]m eth a n esu lfon a m id e (10). A stirred mixture of 8 (490.1
g, 1.64 mol) and THF (4 L) was cooled, under nitrogen, to -30
to -35 °C and treated during 1.5 h with a solution of (-)-B-
chlorodiisopinocampheylborane (920 g, 2.86 mol) in THF (2
L). The mixture was stirred at -25 °C for 3.5 h, treated with
diethanolamine (600 mL) and kept at 0-10 °C for 10 min and
at ambient temperature for 18 h. The resulting mixture was
concentrated to a slurry while adding MeOH to displace the
residual solvent. The concentrate was mixed with MeOH and
washed with heptane. The resulting MeOH solution was
concentrated and the residual oil was combined with the
product from a similar reduction of 53 g (0.178 mol) of 8 and
chromatographed on silica gel with mixtures of MeOH-CH2Cl2
contining 0-10% MeOH. The product was crystallized from
acetonitrile-tert-butyl methyl ether at 0 °C to give 71.7 g
24
(13.1%) of 10: mp 137-138 °C; [R]D -16 (c 0.95, EtOH]; MS
m/z (relative intensity) 300 (M+, 3.5), 282 (1.2), 214 (3.2), 200
(4.5), 130 (5.7), 121 (5.0), 101 (14.9), 87 (100), 71 (28.6); IR
3370, 3116, 3053, 3033, 3017, 1642, 1612 cm-1 1H NMR
;
[(CD3)2SO] δ 0.97 (t, J ) 7.2 Hz, 3H), 1.78 (m, 2H), 2.07 (m,
2H), 2.95 (s, 3H), 3.02 (m, 2H), 4.46 (m, 1H), 5.26 (d, 1H), 7.15
(d, J ) 8.5 Hz, 2H), 7.26 (d, J ) 8.5 Hz, 2H), 7.78 (m, 1H),
9.66 (br s, 1H). Anal. (C13H20N2O4S) C, H, N, S.
The chiral purity of this sample of 10 was found to be 99.5%
by allowing it to react with 1-naphthyl isocyanate and analyz-
ing the resulting carbamate by HPLC on a Pirkle covalent
5-µm N-(3,5-dinitrobenzyl)-D-phenylglycine analytical column
with 20% hexane-80% EtOH which contained 0.1% TEA and
0.1% TFA.36 The mother liquors from this crystallization were
concentrated in vacuo and the residue was dissolved in warm
CH3CN and washed with heptane. The resulting CH3CN

Synthesis and Evaluation of Ibutilide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1109
solution was concentrated in vacuo and the residue was
ylamino)phenyl]butyric acid61 (29.9 g, 0.116 mol) and triethyl-
amine (21.5 mL, 0.154 mol) in THF (1300 mL) under nitrogen
was cooled in an ice-2-propanol bath and treated dropwise
during 10 min with isobutyl chloroformate (20.0 mL, 0.154
mol). It was stirred for 1.25 h and treated during 25 min with
a solution of 2 M ethylamine in THF (100 mL) and triethyl-
amine (21.5 mL), stirred for 2.5 h and filtered. The filtrate
was concentrated and the residue crystallized from EtOAC to
give 14.9 g (45.3%) of 51: mp 122-123 °C; 1H NMR (CDCl3) δ
1.14 (t, J ) 7.2 Hz, 3H), 1.94, (m, 2H), 2.17 (t, J ) 7.2 Hz,
2H), 2.62 (t, J ) 7.5 Hz, 2H), 2.99 (s, 3H), 3.30 (m, 2H), 5.48
(br s, 1H), 6.87 (s, 1H), 7.16 (s, 4H); MS m/z (relative intensity)
284 (M+, 27.9), 240 (3.5), 205 (8.2), 132 (26.6), 118 (18.9), 106
crystallized from MeOH-tert-butyl methyl ether at 0 °C to give
323 g (59.1%) of additional 10: mp 138-139.5 °C; [R]24 -16°
D
(c 0.954, EtOH) which had a chiral purity of 99.4% by HPLC.
(S)-(-)-N-[4-[4-(Eth yla m in o)-1-h yd r oxybu tyl]p h en yl]-
m eth a n esu lfon a m id e (5). A 65% solution of sodium bis(2-
methoxyethoxy)aluminum hydride in toluene (44 mL, 0.146
mol) was mixed with THF (100 mL), under nitrogen, and the
stirred mixture was treated, portionwise during 1 h 20 min
with a suspension of 10 (11.5 g, 0.0381 mol) in THF (360 mL);
a slight exothermic reaction raised the temperature of the
mixture to 30 °C during the addition. The mixture was stirred
at ambient temperature for 18 h, cooled to 4 °C and treated,
dropwise with 22.4 mL of 6 M H2SO4. The first few drops of
acid caused a vigorous reaction. When this was no longer
evident, the cooling bath was removed and the remainder of
the acid was added during 40 min. After an additional 10 min
MeOH (150 mL) was added to the mixture. Since the pH of
the mixture was 4, NaHCO3 (2.47 g) was added and stirring
was continued for 1.5 h; the pH of the mixture was now 9-10.
The solid was collected by filtration and washed successively
with 10% MeOH-THF (500 mL), 10% MeOH-CH2Cl2 (1 L)
and 10% MeOH-CHCl3 (2 L). The filtrates were concentrated
and the product was crystallized from acetonitrile to give 7.29
g (66.8%) of 5: mp 168-170 °C; [R]24D -20° (c 0.8515, MeOH);
MS (EI) m/z (relative intensity) 286 (M+, 1.1), 268 (21.0), 253
(47.8), 207 (12.7), 184 (25.1), 162 (32.1), 98 (48.0), 58 (100); 1H
NMR [(CD3)2SO] δ 0.98 (t, J ) 7.2 Hz, 3H), 1.40, (m, 2H), 1.59
(m, 2H), 2.48 (m, 4H), 2.92 (s, 3H), 4.45 (t, J ) 6.0 Hz, 1H),
4.57 (br s, 2H), 7.12 (d, J ) 8.4 Hz, 2H), 7.25 (d, J ) 8.4 Hz,
2H); IR 3478, 3385, 3139, 2651, 2500, 2378, 1605 cm-1. Anal.
(C13H22N2O3S) C, H, N, S.
(20.7), 87 (100), 72 (69.1); IR 3365, 3141, 1646, 1616 cm-1
Anal. (C13H20N2O3S) C, H, N, S.
.
N -[4-[4-(E t h yla m in o)b u t yl]p h e n yl]m e t h a n e su lfon -
a m id e (7). A stirred, ice-cold suspension of LiAlH4 (2.9 g,
0.0763 mol) in THF (68 mL) under nitrogen was treated
dropwise during 70 min, with a solution of 51 (9.88 g, 0.0347
mol) in THF (200 mL). The mixture was kept at ambient
temperature for 1 h, at reflux for 4.5 h and at ambient
temperature for 18 h. It was then cooled in an ice bath, treated
cautiously with 125 mL of a saturated aqueous potassium
sodium tartrate solution, stirred at ambient temperature for
1 h, and extracted with EtOAc; the extracts were washed with
water and brine, dried (MgSO4) and concentrated. The residue
was crystallized from acetonitrile to give 6.03 g (64.3%) of 7:
1
mp 108-109 °C; H NMR (CDCl3) δ 1.11 (t, J ) 7.2 Hz, 3H),
1.52, (m, 2H), 1.61 (m, 2H), 2.64 (m, 6H), 2.96 (s, 3H), 3.42 (br
s, 2H), 7.13 (s, 4H); MS (EI) m/z (relative intensity) 270 (M+,
5.1), 255 (3.0), 191 (31.3), 146 (22.0), 58 (100); IR 3101, 2337,
1610, 1505 cm-1. Anal. (C13H22N2O2S) C, H, N, S.
(R)-(+)-N-[4-[4-(E t h yla m in o)-4-oxo-1-a cet yoxyb u t yl]-
p h en yl]m eth a n esu lfon a m id e (11). This material (11) was
obtained as a byproduct from the preparation of 10 from the
racemate by a lipase mediated acylation. [Pseudomonas ce-
paica (PS-30) supported on Celite and isopropenyl acetate in
THF at 40-45 °C. A quantitative conversion of the R-
enantiomer to the O-acetate was obtained.]37 It was recrystal-
lized to constant melting point from EtOAc: mp 102-104 °C;
[R]24D +68° (c 0.9785, EtOH); IR 3373, 3288, 1727, 1667, 1649,
1613 cm-1; FAB MS m/z (relative intensity) 343 (M + H+, 2.2),
342 (M+, 4.4), 299 (7.2), 283 (100); 1H NMR (CDCl3) δ 1.12 (t,
J ) 7.2 Hz, 3H), 2.07 (s, 3H), 2.16 (m, 4H), 2.98 (s, 3H), 3.27
(m, 2H), 5.65 (m, 1H), 5.71 (m, 1H), 7.23 (m, 4H), 7.50 (s, 1H).
Anal. (C15H22N2O5S) C, H, N.
N-Eth yl-5-a cetylva ler a m id e (28). A stirred solution of
5-acetylvaleric acid (1.00 g, 6.94 mmol) and triethylamine (1.29
mL, 9.23 mmol) in THF (50 mL) was cooled, under nitrogen,
in an ice-2-propanol bath (-5 to -10 °C) and treated,
dropwise with isobutyl chloroformate (1.2 mL, 9.2 mmol). The
thick mixture was kept in the bath for 3 h, treated during 8.5
min with a solution of ethylamine (0.7 mL, 10.4 mmol) and
triethylamine (1.29 mL, 9.23 mmol) in THF (15 mL) and
stirred for 2.75 h. The solid was collected by filtration and the
filtrate was concentrated. Chromatography of the residue on
silica gel with 3% MeOH-CH2Cl2 and crystallization of the
product from Et2O gave 0.681 g (57.3%) of 28: mp 55.5-58
°C; 1H NMR (CDCl3) δ 1.15 (t, J ) 7.3 Hz, 3H), 1.61, (m, 4H),
2.15 (s, 3H), 2.18 (m, 2H), 2.48 (m, 2H), 3.30 (m, 2H), 5.67 (br
s, 1H). Anal. (C9H17NO2) C, H, N.
(R)-(+)-N-[4-[4-(Eth yla m in o)-1-h yd r oxybu tyl]p h en yl]-
m eth a n esu lfon a m id e (6). A stirred mixture of a 70% toluene
solution of sodium bis(2-methoxyethoxy)aluminum hydride
(155.7 g, 0.539 mol) in THF (600 mL), under nitrogen was
treated, dropwise during 95 min with a solution of 11 (16.0 g,
0.0467 mol) in THF (120 mL) keeping the temperature of the
mixture at 21-29 °C. It was kept at ambient temperature for
20 h, cooled in an ice bath and treated dropwise during 50
min with 20 drops of 6 M H2SO4; this was accompanied by a
vigorous evolution of hydrogen; the temperature of the mixture
was maintained at 5-7 °C during this addition. The remainder
of a total of 76.5 mL of 6 M H2SO4 was then added dropwise
during 90 min at ambient temperature. The mixture was
stirred for 20 min, treated with MeOH (355 mL) and stirred
for 30 min. The pH of the mixture was 4. Solid NaHCO3 (6.0
g) was added and the mixture was stirred for 90 min (pH 7-8)
and filtered. The solid was washed with 1.4 L of 20% MeOH-
CH2Cl2 and the filtrate was concentrated in vacuo. Chroma-
tography of the residue on silica gel with mixtures of MeOH-
NH4OH-CHCl3 containing 10-15% MeOH and 0.5-1%
NH4OH gave the product which was crystallized from aceto-
nitrile to give 3.08 g (23.1%) of 6: mp 167-169 °C; [R]24D +18°
(c 0.9445, MeOH); MS (ES) m/z 287 (M + H)+; 1H NMR
[(CD3)2SO] δ 0.96 (t, J ) 7.1 Hz, 3H), 1.39, (m, 2H), 1.57 (m,
2H), 2.48 (m, 4H), 2.91 (s, 3H), 4.44 (t, J ) 6.3 Hz, 1H), 7.11
(d, J ) 8.5 Hz, 2H), 7.24 (d, J ) 8.5 Hz, 2H).
N-Eth yl-5-a cetylva ler a m id e Eth ylen e Dith iok eta l (29).
According to the method of Sondej and Katzenellenbogen,40
a
stirred mixture of 28 (0.5 g, 2.92 mmol) and 1,2-ethanedithiol
(0.49 mL, 5.84 mmol), under nitrogen, was treated with boron
trifluoride-acetic acid complex (0.41 mL, 2.9 mmol) and kept
at ambient temperature for 15 min. It was then diluted with
EtOAc, washed with aqueous NaHCO3, 15% NaOH and brine,
dried (MgSO4) and concentrated. Chromatography of the
residue over silica gel with 1.5% MeOH-0.05% Et3N-CH2Cl2
and crystallization of the product from Et2O-pentane gave
1
0.597 g (82.7%) of 29: mp 54-55 °C; H NMR (CDCl3) δ 1.14
(t, J ) 7.3 Hz, 3H), 1.54, (m, 2H), 1.68 (m, 2H), 1.75 (s, 3H),
1.95 (m, 2H), 2.18 (t, J ) 7.1 Hz, 2H), 3.31 (m, 6H), 5.46 (br s,
1H); MS (EI) (relative intensity) 247 (M+, 22.5) 214 (10.5), 203
(2.1), 188 (40.0), 154 (50.1), 119 (100), 87 (47.4); IR 3300, 3206,
3098, 1641 cm-1. Anal. (C11H21N1O1S2) C, H, N, S.
N-Eth yl-6,6-d iflu or oh ep ta n a m id e (30). According to the
method of Sondej and Katzenellenbogen,40 a stirred suspension
of 1,3-dibromo-5,5-dimethylhydantoin (0.116 g, 0.404 mmol)
in CH2Cl2 (0.8 mL) was cooled, under nitrogen, in a dry ice-
acetone bath and treated with hydrogen fluoride-pyridine (0.2
mL) followed by a solution of 29 (0.10 g, 0.40 mmol) in CH2Cl2
(0.2 mL). It was kept in the dry ice bath for 10 min and at
ambient temperature for 15 min, adsorbed on a basic alumina
(3 mL) column and eluted with CH2Cl2. The eluate was
concentrated and the residue chromatographed on silica gel
with 1-2% MeOH-CH2Cl2 to give 0.021 g (27%) of crystalline
N -[4-[4-(E t h yla m in o)-4-oxob u t yl]p h e n yl]m e t h a n e -
su lfon a m id e (51). A stirred mixture of 4-[4-(methanesulfon-

1110 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Hester et al.
product 30: mp 41-42 °C; 1H NMR (CDCl3) δ 1.14 (t, J ) 7.2
Hz, 3H), 1.52, (m, 2H), 1.58 (t, J ) 30.7 Hz, 3H), 1.67 (m, 2H)
1.85 (m, 2H), 2.19 (t, J ) 7.2 Hz, 2H), 3.30 (m, 2H), 5.51 (br
s); MS (EI) m/z (relative intensity) 193 (M+, 1.9), 178 (4.5),
149 (3.4), 129 (6.2), 114 (6.6), 100 (9.9), 87 (100).
1.44 (m, 4H), 1.62 (m, 2H), 1.88 (m, 2H), 3.42 (t, 2H); MS (EI)
m/z (relative intensity) 190 (4.2), 135 (6.9), 111 (59.0), 61 (100).
4-Ch lor obu tyl THP Eth er (55). A stirred solution of
4-chloro-1-butanol (23.0 mL, 0.230 mol) and 3,4-dihydro-2H-
pyran (32.0 mL, 0.351 mol) in Et2O (500 mL) was treated with
10-camphorsulfonic acid (5.33 g, 0.023 mol) and kept, under
nitrogen, at ambient temperature for 18 h. Additional 3,4-
dihydro-2H-pyran (5 mL, 0.0548 mol) as added and the
reaction was continued for 5 h. The mixture was washed with
8% NaHCO3, water and brine, dried (MgSO4) and concen-
trated. The residue was distilled to give 55: bp 58 °C (0.01
kPa).
(6,6-Diflu or oh ep tyl)eth yla m in e (27). An ice-cold stirred
suspension of LiAlH4 (0.21 g, 5.65 mmol) in THF (5 mL) under
nitrogen, was treated dropwise with a solution of 30 (0.464 g,
2.4 mmol) in THF (5 mL) and kept in the ice bath for 10 min,
at ambient temperature for 1 h and at 80 °C for 2.5 h. It was
then cooled in an ice bath and treated successively with water
(0.2 mL), 15% NaOH (0.2 mL) and water (0.6 mL), stirred at
ambient temperature for 1 h and filtered through Celite. The
filtrate was concentrated and the residue was chromato-
graphed on silica gel with 5% MeOH-0.5% NH4OH-CH2Cl2
to give 0.336 g (78.1%) of 27: 1H NMR (CDCl3) δ 1.12 (t, J )
7.1 Hz, 3H), 1.5, (m, 7H), 1.58 (t, J ) 30.7 Hz, 3H), 1.84 (m,
2H) 2.65 (m, 4H).
5-Hyd r oxy-5-m eth ylh exyl THP Eth er (56). A mechani-
cally stirred refluxing mixture of magnesium turnings (1.27
g, 0.052 mol) and THF (5 mL), under nitrogen, was treated
dropwise with a solution of 55 (5.00 g, 0.260 mol) in THF (27
mL). After a small amount of 55 had been added, the reaction
was started by the addition of several drops of 1,2-dibromo-
ethane and crushing some of the magnesium. After the
addition, the mixture was refluxed for 1 h, cooled in an ice
bath, and treated dropwise with a solution of acetone (2.29
mL, 0.0312 mol) in THF (24 mL). This mixture was kept at
ambient temperature for 20 h, cooled in an ice bath and
treated, dropwise with saturated NH4Cl (29.5 mL). It was
stirred for 1 h and then extracted with EtOAc. The extracts
were washed with dilute aqueous NaCl, dried (MgSO4) and
concentrated. The residue was chromatographed over silica gel
with 5-20% EtOAc-0.05% Et3N-hexane to give 1.64 g
(29.2%) of 56: 1H NMR (CDCl3) δ 1.22 (s, 6H), 1.58 (s, 13H),
3.47 (m, 2H), 3.82 (m, 2H), 4.58 (m, 1H); MS m/z (relative
intensity) 115 (18.7), 101 (15.3), 85 (100), 59 (25.3); IR (film)
N -[4-[4-[(6,6-Diflu or oh e p t yl)e t h yla m in o]-1,4-d ioxo-
bu tyl]p h en yl]m eth a n esu lfon a m id e (9). A stirred mixture
of 1231 (0.56 g, 2.06 mmol) and triethylamine (0.33 mL, 2.38
mmol) in THF (10 mL) was cooled, under nitrogen, in an ice-
methanol bath and treated with isobutyl chloroformate (0.31
mL, 2.38 mmol). It was kept in the bath for 2 h, treated with
a solution of 27 (0.336 g, 1.87 mmol) and triethylamine (0.33
mL, 2.38 mmol) in THF (0.7 mL), kept in a cold bath for 21 h
and filtered. The filtrate was concentrated and the residue was
chromatographed on silica gel with 2% MeOH/CH2Cl2 to give
0.379 g (46.9%) of 9: mp 103-108 °C; 1H NMR (CDCl3) δ 1.48
(br m, 14H), 2.82 (m, 2H), 3.01 (s, 3H), 3.27 (m, 2H), 3.42 (m,
4H), 7.21 (d, J ) 8.7 Hz, 2H), 7.81 (d, J ) 8.7 Hz, 2H), 8.61 (d,
1H); MS (EI) m/z (relative intensity) 432 (M+, 9.3), 254 (100),
234 (28.0), 198 (32.8), 178 (49.2), 119 (14.3).
3452 cm-1
.
5-F lu or o-5-m eth ylh exyl THP Eth er (57). The reaction
of 56 (7.4 mmol) with DAST was carried out as described for
the preparation of 14 to give a 75.6% yield of 57: 1H NMR
(CDCl3) δ 1.31 (s, 3H), 1.38 (s, 3H), 1.6 (m, 12H), 3.47 (m, 2H),
3.82 (m, 2H), 4.58 (m, 1H).
5-F lu or o-5-m eth ylh exa n ol (58). A stirred solution of 57
(1.22 g, 5.59 mmol) and 10-camphorsulfonic acid (0.233 g, 1
mmol) in MeOH (144 mL) was kept at ambient temperature,
under nitrogen for 20 h and concentrated. The residue was
mixed with EtOAc (100 mL), washed with saturated NaHCO3,
dried (MgSO4) and concentrated. The residue was chromato-
graphed on silica gel with 5-30% EtOAc-hexane to give 0.400
g (53.4%) of 58: 1H NMR (CDCl3) δ 1.31 (s, 3H), 1.36 (s, 3H),
1.58 (m, 6H), 2.72 (s, 1H), 3.64 (t, J ) 6.28 Hz, 2H).
1-Br om o-5-flu or o-5-m eth ylh exa n e (16). P r oced u r e C.
A stirred solution of 58 (0.400 g, 2.98 mmol) and triphenyl-
phosphine (0.859 g, 3.28 mmol) in benzene (5.4 mL), under
nitrogen, was cooled in an ice bath and treated, portionwise
during 20 min, with NBS (0.580 g, 3.28 mmol). The mixture
was kept in the ice bath for 30 min and at ambient temper-
ature for 5 h, diluted with pentane (20 mL) and cooled in an
ice bath. The solid was collected by filtration and washed with
pentane. The filtrate was concentrated and the residue was
mixed with pentane, cooled in an ice bath and filtered. The
filtrate was concentrated and the residue was mixed with
Et2O, washed with cold 5% sodium thiosulfate, 0.5 N NaOH
and brine, dried (MgSO4) and concentrated to give 0.51 g
(86.8%) of 16 which was used without further purification in
the next reaction.
7-Br om oh ep ta n ol (53). A solution of 8-bromo-1-octene (5.0
g, 26 mmol) in a mixture of 25 mL of MeOH and 5 mL of
CH2Cl2 was cooled to -50 °C and treated with O3 until a blue
color persisted (45 min) and then for an additional 10 min.
The cold mixture was purged with N2, allowed to warm to -20
°C and treated with 1.3 g (34 mmol) of sodium borohydride in
portions over 30 min. The mixture was stirred for 30 min at
-20 °C then treated dropwise with 20 mL of H2O. This mixture
was stirred for 10 min, and extracted with hexane; the organic
extracts were washed with water and brine, dried (Na2SO4)
and concentrated to give 3.65 g (72%) of 53: 1H NMR (CDCl3)
δ 1.44 (m, 9H), 1.85 (m, 2H), 3.41 (t, J ) 6.84, 2H), 3.65 (t, J
) 6.53 Hz, 2H).
6-Hyd r oxy-6-m eth ylh ep tyl THP Eth er (13). Compound
13 was prepared in 56% yield by the reaction of the THP ether
of 5-hydroxypentylmagnesium chloride with acetone according
to the procedure of Buendia.38 It was purified by silica gel
chromatography with mixtures of EtOAc, Et3N and hexane
that contained 10-20% EtOAc and 0.05% Et3N. It had: 1H
NMR (CDCl3) δ 1.21 (s, 6H), 1.5 (m, 14H), 3.40 (m, 1H), 3.52
(m, 1H), 3.73 (m, 1H), 3.87 (m, 1H), 4.58 (m, 1H); MS (CI) m/z
(relative intensity) 231 (M + H+, 63.8), 461 (2 M + H+, 7.1),
213 (100); IR 3436 cm-1
.
6-F lu or o-6-m et h ylh ep t yl TH P E t h er (14). A stirred
solution of 4.6 mL (34.5 mmol) of DAST in CH2Cl2 (12 mL),
under nitrogen was cooled in a dry ice-acetone bath and
treated during 4-5 min with a solution of 13 (3.97 g, 17.3
mmol) in CH2Cl2 (12 mL). The mixture was kept in the dry
ice bath for 15 min and in an ice bath for 10 min. It was then
mixed with 10% aqueous Na2CO2 (60 mL). The layers were
separated and the CH2Cl2 layer was washed with water, dried
(MgSO4) and concentrated. Chromatography of the residue on
silica gel with 2.5% EtOAc-0.05% Et3N-hexane gave 3.36 g
(83.6%) of 14 which had: 1H NMR (CDCl3) δ 1.30 (s, 3H), 1.37
(s, 3H), 1.40 (m, 4H), 1.62 (m, 10H), 3.39 (m, 1H), 3.52 (m,
1H), 3.74 (m, 1H), 3.87 (m, 1H), 4.58 (m, 1H).
6-F lu or o-6-m eth ylh ep ta n ol (52). A stirred solution of 14
(3.34 g, 14.4 mmol) and pyridinium tosylate (0.47 g, 1.87 mmol)
in absolute EtOH (120 mL) was kept under nitrogen at
ambient temperature for 41 h and concentrated in vacuo. A
solution of the residue in EtOAc was washed with aqueous
NaHCO3 and brine, dried over MgSO4 and concentrated in
vacuo. The residue, combined with the product from a previous
reaction (0.844 mmol), was chromatographed over silica gel
with 5-20% EtOAc-hexane to yield 1.86 g (82.2%) of 52: 1H
NMR (CDCl3) δ 1.30 (s, 3H), 1.38 (s, 3H), 1.41 (m, 5H), 1.59
(m, 4H), 3.65 (t, 2H); MS (EI) m/z (relative intensity) 1.28
(12.9), 111 (8.1), 110 (9.5), 95 (41.3); IR 3581, 3345 cm-1
.
1-Br om o-6-flu or o-6-m eth ylh ep ta n e (15). As described in
procedure C, 52 (0.427 g, 0.00288 mol) was allowed to react
with NBS and triphenylphosphine. Chromatography of the
product on silica gel with 1-3% EtOAc-hexane gave 0.440 g
(72.3%) of 15: 1H NMR (CDCl3) δ 1.30 (s, 3H), 1.38 (s, 3H),

Synthesis and Evaluation of Ibutilide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1111
Distillation of the residue gave 5.38 g (68%) of 61: bp 85-87
1-Br om o-7-flu or oh ep ta n e (17). A stirred solution of 53
(1.53 g 7.85 mmol) in 2.5 mL of CCl4 was cooled in an ice bath,
under nitrogen, an treated with 2.25 mL (17.0 mmol) of DAST;
the flask was stoppered, kept in the ice bath for 30 min and
at ambient temperature 4.5 h. Additional DAST (0.7 mL, 5.3
mmol) was added and the mixture was stirred at ambient
temperature for 18 h. It was then added dropwise to 25 mL of
ice water and extracted with hexane. The organic extracts were
washed with water, 10% aqueous Na2CO3, and brine, dried
(MgSO4) and concentrated. The residue was chromatographed
under pressure over silica gel with 4% CH2Cl2-hexane to give
0.9 g (53%) of 17: 1H NMR (CDCl3) δ 1.43 (m, 6H), 1.71 (m,
2H), 1.87 (m, 2H), 3.42 (t, J ) 6.84, 2H), 4.37 (t, J ) 6.07 Hz,
1H), 4.52 (t, J ) 6.07 Hz, 1H).
6-Br om oh exa n a l (54). A stirred solution of oxalyl chloride
(6.7 mL, 77 mmol) in 50 mL of CH2Cl2, under nitrogen, was
cooled to -70 °C, treated dropwise over 15 min with 10.9 mL
(154 mmol) of DMSO in 50 mL of CH2Cl2, kept at -70 °C for
20 min and treated over 7 min with 6-bromohexanol (6.8 g,
37.6 mmol) in 50 mL of CH2Cl2. The mixture was allowed to
warm to -20 °C during 2.5 h. It was kept at this temperature
for 1.5 h, recooled to -65 °C and treated, dropwise during 5
min with Et2N (32.1 mL). This mixture was warmed to
ambient temperature during 30 min, diluted with CH2Cl2,
washed with water and brine, dried (MgSO4) and concentrated.
A solution of the residue in hexane was washed with water
and brine, dried (MgSO4) and concentrated in vacuo to give
6.38 g (95%) of 54: 1H NMR (CDCl3) δ 1.42 (m 2H), 1.58 (m,
2H), 1.82 (m, 2H), 2.41 (m, 2H), 3.35 (t, 2H), 9.71 (s, 1H).
1-Br om o-6,6-d iflu or oh exa n e (18). An ice-cold, stirred
solution of 54 (1.0 g, 5.58 mmol) in 1.5 mL of CCl4, under
nitrogen was treated with 1.5 mL (1.8 g, 11.2 mmol) of DAST.
The flask was stoppered, kept in the ice bath for 90 min and
at ambient temperature for 18 h. The resulting mixture was
added dropwise with stirring to ice water (20 mL), neutralized
with Na2CO3 and extracted with hexane. The extract was
washed with water and brine, dried (MgSO4) and concentrated.
Chromatography of the residue over silica gel with 2.5%
CH2Cl2-hexane gave 0.37 g (33%) of 18: 1H NMR (CDCl3) δ
1.50 (m, 4H), 1.89 (m, 4H), 3.42 (t, J ) 6.7 Hz, 2H), 5.63, 5.82,
6.00 (t,t,t, J ) 4.4 Hz, 1H).
Eth yl 6-Hyd r oxyh ep ta n oa te (59). A solution of 6-methyl-
ꢀ-caprolactone62 (18.94 g, 0.148 mol) in 65 mL of absolute EtOH
was treated with 0.8 mL of concentrated H2SO4, stirred at
ambient temperature for 7 h and concentrated in vacuo. The
residue was treated with ice, neutralized with dilute NaHCO3
and extracted with Et2O. The extracts were washed with water
and brine, dried (MgSO4) and concentrated. Distillation of the
residue (24.4 g) combined with 6.2 g of product from a previous
reaction gave 18.5 g, bp 96 °C (0.29 kPa), and 6.73 g, bp 91 °C
(0.1 kPa), of 59: 1H NMR (CDCl3) δ 1.19 (d, J ) 6.21 Hz, 3H),
1.26 (t, J ) 7.08 Hz, 3H) 1.43 (m, 5H), 1.65 (m, 2H), 2.32 (t, J
) 7.37 Hz, 2H), 3.81 (m, 1H), 4.12 (q, J ) 7.19 Hz, 2H).
1
°C (1.2 kPa); H NMR (CDCl3) δ 1.27, 1.35 (d,d, J ) 6.16 Hz,
3H), 1.55 (m, 9H), 3.65 (t, J ) 6.48 Hz, 2H) 4.58, 4.73 (m,m,
1H).
1-Br om o-6-flu or oh ep ta n e (19). In the manner described
in procedure C, 61 (4.8 g, 0.0358 mol) was allowed to react
with NBS and triphenylphosphine to give 6.6 g (93.6%) of 19:
1H NMR (CDCl3) δ 1.22, 1.28 (d,d, J ) 6.21 Hz, 3H), 1.57 (m,
6H), 1.88 (m, 2H), 3.42 (t, J ) 6.8 Hz, 2H) 4.57, 4.73 (m,m,
1H).
1-Br om oh ep ta n a l (62). A solution of 8-bromo-1-octene (5.0
g, 0.026 mol) in MeOH (25 mL) and CH2Cl2 (5 mL) was cooled
to -40 to -60 °C, treated during 40 min with excess ozone
and purged with a stream of nitrogen. It was then treated with
dimethyl sulfide (2.5 mL), warmed to -10 °C during 3 h and
concentrated. The residue was mixed with water and extracted
with hexane; the extracts were washed with water and brine,
dried (MgSO4) and concentrated. Flash chromatography of the
residue on silica gel with 5-10% EtOAc-hexane gave 1.75 g
1
(34.9%) of 62: H NMR (CDCl3) δ 1.41 (m, 4H), 1.63 (m, 2H),
1.87 (m, 2H), 2.45 (m, 2H), 3.41 (m, 2H), 9.78 (s, 1H).
1-Br om o-7,7-d iflu or oh ep ta n e (20). A stirred solution of
62 (0.65 g, 3.4 mmol) in CCl4 (1 mL) was cooled in an ice bath,
under nitrogen, and treated with DAST (1.0 mL, 7.6 mmol).
The flask was stoppered and the mixture was kept at ambient
temperature for 7 h, mixed with ice, neutralized with 10%
aqueous NaCO3, and extracted with hexane. The extract was
washed with water and brine, dried (MgSO4) and concentrated.
Flash chromatography of the residue on silica gel with 5%
CH2Cl2-hexane gave 0.53 g (72.5%) of 20: 1H NMR (CDCl3)
δ 1.47 (m, 6H), 1.84 (m, 4H), 3.41 (t, J ) 6.7 Hz, 2H), 5.61,
5.80, 5.99 (t,t,t, J ) 4.5 Hz, 1H).
6-Hep ten oic Acid ter t-Bu tyl Ester (21).63 A stirred
solution of diisopropylamine (15.4 g, 0.152 mol) in THF (150
mL) was cooled in an ice bath, under nitrogen and treated
dropwise during 14 min with 1.6 N n-butyllithium in hexane
(95.3 mL, 0.152 mol). This mixture was kept in the ice bath
for 20 min and then cooled in a dry ice-acetone bath and
treated dropwise during 10 min with a solution of tert-butyl
acetate (17.7 g, 0.152 mol) in THF (25 mL). This mixture was
stirred for 45 min and then treated dropwise during 15 min
with a solution of 5-bromo-1-pentene (25.0 g, 0.168 mol) in
hexamethylphosphoramide (27 g, 0.152 mol). Stirring was
continued for 1 h when the mixture was warmed in an ice bath
for 1.5 h and at ambient temperature for 1.5 h. It was treated,
dropwise, during 10 min with saturated aqueous NH4Cl (75
mL) and mixed with Et2O (280 mL). The aqueous layer was
extracted with Et2O and the organic solution was dried
(MgSO4) and concentrated in vacuo. Distillation of the oily
residue gave 12.8 g (45.8%) of 21: bp 45-56 °C (0.09 kPa); 1H
NMR (CDCl3) δ 1.44 (m, 2H), 1.44 (s, 9H), 1.60 (m, 2H), 2.06
(m, 2H), 2.22 (m, 2H), 4.98 (m, 2H), 5.80 (m. 1H).
7-Br om o-6-flu or oh eptan oic Acid ter t-Bu tyl Ester (22).39
A stirred mixture of 21 (22.1 g, 0.120 mol), and NBS (25.6 g,
0.144 mol) in CH2Cl2 (63 mL) was cooled in an ice bath under
nitrogen and treated dropwise during 21 min with a solution
of triethylamine trihydrofluoride (38.6 g, 0.240 mol) in CH2Cl2
(63 mL). This mixture was kept in the ice bath for 4.5 h; the
solid slowly dissolved during 4 h and then the solution became
yellow. The mixture was poured into ice water (1 L) and the
pH was adjusted to 9 with about 36.5 mL of NH4OH. It was
extracted with CH2Cl2. The extract was washed successively
with cold 0.1 N HCl and aqueous NaHCO3, dried (MgSO4) and
concentrated in vacuo. Distillation of the residue gave 25.3 g
(76.6%) of 22: bp 94-102 °C (0.03-0.08 kPa); MS (EI) m/z
(relative intensity) 267 (0.13), 226 (0.40), 209 (8.6), 207 (3.4),
Eth yl 6-F lu or oh ep ta n oa te (60). A stirred solution 59
(18.4 g, 0.106 mol) in 200 mL of CH2Cl2, under nitrogen, was
cooled in a dry ice-acetone bath and treated dropwise with a
solution of 30 mL (0.225 mol) of DAST in CH2Cl2 (195 mL)
over 1 h. The mixture was kept at -70 °C for 1 h, warmed to
5 °C during 2 h 40 min and poured into a stirred mixture of
600 mL of 10% Na2CO3 and 200 mL of ice. This was extracted
with Et2O; the extracts were washed with water and brine,
dried (MgSO4) and concentrated. Distillation of the residue
1
gave 7.16 g (38.5%) of 60: bp 76-78 °C (0.77 kPa); H NMR
(CDCl3) δ 1.26 (m, 4.5H), 1.35 (d, J ) 6.11 Hz, 1.5H), 1.57 (m,
6H), 2.32 (t, J ) 7.32 Hz, 2H) 4.13 (q, J ) 7.13 Hz, 2H), 4.57,
4.72 (m,m, 1H).
1
189 (0.72), 129 (21.9), 101 (7.0), 57 (100); H NMR (CDCl3) δ
6-F lu or oh ep ta n ol (61). A solution of 60 (10.4 g, 0.059 mol)
in Et2O (35 mL) was added during 45 min, under nitrogen, to
a stirred ice-cold mixture of LiAlH4 (3.64 g, 0.096 mol) in Et2O
(200 mL). The mixture was kept in the ice bath for 15 min
and allowed to warm to ambient temperature during 100 min.
It was again cooled in an ice bath and treated during 40 min
with saturated aqueous Na2SO4 (35 mL). This mixture was
filtered through Na2SO4 and the filtrate was concentrated.
1.45 (s, 9H), 1.62 (m, 6H), 2.24 (t, J ) 7.3 Hz, 2H), 3.48 (m,
2H), 4.57, 4.73 (m,m, 1H); 19F NMR (282.203 MHz, CDCl3) δ
-4.97 (13 peaks CHF), -36.60 (6 peaks, CH2F). The area
under the CH2F peaks was 4% of the total area.
6-F lu or o-6-h ep ten oic Acid ter t-Bu tyl Ester (23). A
stirred 1 M solution of potassium tert-butoxide in THF (107
mL, 0.107 mol) was cooled, under nitrogen in an ice bath, and

1112 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Hester et al.
treated dropwise during 17 min with 22 (25.3 g, 0.0893 mol)
and about 10 mL of THF. A dark precipitate formed during
the addition. The mixture was kept in the ice bath for 50 min,
poured into ice water (250 mL), and extracted with EtOAc.
The extract was washed with brine, dried (MgSO4), concen-
trated and distilled to give 15.5 g (85.8%) of 23: bp 46-49 °C
(0.009-0.02 kPa); MS (EI) m/z (relative intensity) 146 (4.0),
2. In Vitr o Deter m in a tion of Meta bolic Sta bility.
Ma ter ia ls: Human liver microsomes were prepared according
to a standard method of Lu and Levin.64 A stock NADPH
generating system was prepared, consisting of 10 mM â-NADP+,
50 mM trisodium isocitrate, 50 mM magnesium chloride, and
4 units/mL isocitrate dehydrogenase. The test compounds
(substrates) were each dissolved in 0.9% sodium chloride or a
pH 7.0 buffer.
1
129 (21.5), 109 (1.8), 81 (19.0), 57 (100); H NMR (CDCl3) δ
1.45 (s, 9H), 1.54 (m, 4H), 2.21 (m, 4H), 4.22 (d,d, J ) 2.77,
50.3 Hz, 1H), 4.50 (d,d, J ) 2.66, 17.6 Hz, 1H).
Meth od s: The in vitro metabolic stabilities of test com-
pounds were determined in three experiments. Although the
conditions varied slightly between the experiments, 31E was
included in each experiment and the data were normalized to
this compound. Incubations were prepared at a final volume
of 1 mL. Human liver microsomes (1 mg protein), obtained
from pooled human liver tissue, were diluted with 50 mM
potassium phosphate buffer, pH 7.4. The test compounds were
added from stock solutions to a final concentration of 0.4-0.5
µM. Following preincubation at 37 °C, reaction was started
by addition of 100 µL NADPH generating system. At various
times up to 20 min, 100-µL aliquots were removed and
quenched by dilution with 1-2 volumes of acetonitrile contain-
ing 2% triethylamine and/or 5-20% methanol. Samples were
frozen, and subsequently remaining substrate was quantitated
by reversed-phase HPLC (Zorbax stable bond cyano column,
250 × 4.6 mm) using fluorescence detection (225-233 nm
excitation, 312-314 nm emission). The rate of disappearance
of each compound was calculated by linear regression analysis
as the slope of a plot of log(substrate concentration) vs time.
The values of the slopes from each series of experiments were
normalized by calculating the ratio of 31E slope/test compound
slope. A value greater than 1 indicated that the compound was
metabolically more stable than 31E. Values greater than 20
could not be measured reliably because the compound disap-
peared too slowly; such compounds were considered to be
‘stable’ under the assay conditions.
7-Br om o-6,6-d iflu or oh ep ta n oic Acid ter t-Bu tyl Ester
(24). A stirred mixture of 23 (15.6 g, 0.0772 mol) and NBS
(16.5 g, 0.0926 mol) in CH2Cl2 (40 mL) was cooled under
nitrogen in an ice bath. A solution of triethylamine trihydro-
fluoride (24.9 g, 25.2 mL, 0.154 mol) in CH2Cl2 (40 mL) was
then added dropwise. After about 25 mL of this solution had
been added the temperature of the mixture began to rise and
very quickly reached 35 °C; the addition was stopped and a
light yellow solution was obtained. When the temperature
again reached 5 °C, the remaining triethylamine trihydro-
fluoride solution was added; no additional increase in tem-
perature was observed; the addition required 23 min. The
mixture was kept in the ice bath for 4 h; by TLC the reaction
was not complete. Additional NBS (3.4 g, 0.019 mol) and after
35 min, a solution of triethylamine trihydrofluoride (6.3 mL,
0.039 mol) in CH2Cl2 (10 mL) were added. The mixture was
kept in the ice bath for 55 min and poured into ice water (600
mL). The pH was adjusted to 9 with NH4OH and the mixture
was extracted with CH2Cl2. The extract was washed with cold
0.1 N HCl and aqueous NaHCO3, dried (MgSO4) and concen-
trated. Distillation of the residue under reduced pressure
separated unreacted 23 from the product which was mixed
with hexane, filtered to remove a solid impurity, concentrated
and redistilled to give 7.78 g (33.5%) of 24: bp 84-87 °C (0.01-
0.02 kPa); FAB MS m/z (relative intensity) 301 (M + H+, 13.2)
245 (17.4), 227 (14.9), 57 (100); 1H NMR (CDCl3) δ 1.45 (s, 9H),
1.52 (m, 2H), 1.66 (m, 2H), 2.05 (m, 2H), 2.25 (t, J ) 7.37 Hz,
2H), 3.51 (t, J ) 12.9 Hz, 2H); 19F NMR (282.2 MHz, CDCl3)
δ -103.08 (9 peaks).
6,6-Diflu or o-1-h ep t a n ol (25). A stirred 1 M solution of
LiAlH4 in THF (54.4 mL, 0.054 mol) was cooled in an ice bath,
under nitrogen, treated dropwise during 15 min with a solution
of 24 (7.28 g, 0.0242 mol) in THF (30 mL) and kept at ambient
temperature for 5.25 h. It was then treated with additional 1
M LiAlH4 in THF (12 mL, 0.012 mol), kept at ambient
temperature for 17 h, cooled in an ice bath and treated with
H2O (2.5 mL), 15% NaOH (2.5 mL) and H2O (7.5 mL). This
mixture was stirred at ambient temperature for 45 min and
filtered. The filtrate was concentrated and the residue was
combined with the product from a similar 0.00332 mol reaction
and chromatographed on silica gel with 15% EtOAc-hexane
to give 2.03 g (48.5%) of 25: 1H NMR (CDCl3) δ 1.52 (m, 10H),
1.85 (m, 2H), 3.65 (t, J ) 6.5 Hz, 2H); 19F NMR (282.2 MHz,
CDCl3) δ -79.82 (12 peaks); MS (NH3-CI) m/z (relative
intensity) 170 (M + NH4+, 100), 52 (40.0).
3. In Vivo Eva lu a tion of P r oa r r h yth m ia P oten tia l a n d
Cla ss III An t ia r r h yt h m ic E ffica cy in a R a bb it Mod el.
Male New Zealand white rabbits (2.5-3.5 kg) were anesthe-
tized and instrumented for measurement of heart rate, aortic
blood pressure, QT interval, and monophasic action potential
duration. They were then allowed to equilibrate for 10 min
before baseline measurements were made. Following baseline
measurements, the R1 agonist methoxamine was infused at a
constant rate of 10 µg/kg/min at an infusion volume of 12.0
mL/h. After an additional 15 min, the methoxyamine baseline
measurements were made and the test compounds, dissolved
in 0.1 M fumaric acid in absolute EtOH and diluted with
saline, were then administered by a continuous infusion
intravenously at the rate of 5 mg/kg during 30 min in an
infusion volume of 15 mL. Measurements of heart rate, aortic
blood pressure, QTc (QT interval divided by the square root
of the R-R interval), and monophasic action potential duration
at 90% repolarization (MAPD90) were reported at several time
intervals to provide dose-response relationships. Data were
analyzed as means ( SEM using one-way analysis of variance;
differences with p e 0.05 were considered to be statistically
significant. The first incidence of polymorphic ventricular
tachycardia (PVT), the occurrence of three or more closely
coupled repetitive extrasystoles with a twisting or torsioning
QRS morphology, was noted and the administered dose of test
compound at this time was determined. The appearance of
early after depolarizations (EADs), characterized as secondary
upstrokes in the monophasic action potential prior to full
repolarization, was also determined and reported as a percent-
age of the monophasic action potential plateau height. Selected
data from these studies are presented in Table 2. Values for
QTc and MAPD90 are maximum differences from baseline in
milliseconds; the dose of test compound that had been admin-
istered at the time of this observation is recorded. PVT is
reported as the number of animals that experienced the
arrhythmia over the total number of animals evaluated with
the test compound. The dose of test compound administered
at the time that PVT was initiated is presented. The maximum
EAD values and the accumulated dose at which they occurred
1-Br om o-6,6-d iflu or oh ep ta n e (26). In the manner de-
scribed in procedure C, 25 (2.03 g, 0.0133 mol) was allowed to
react with NBS and triphenylphosphine to give 2.75 g (96.1%)
of 26: 1H NMR (CDCl3) δ 1.51 (m, 4H), 1.59 (t, J ) 18.4 Hz,
3H), 1.88 (m, 4H), 3.42 (t, J ) 6.68 Hz, 2H).
Biology. 1. In Vitr o Ca r d ia c Electr op h ysiology. ERPs,
the longest coupling intervals between the basic drive impulse
S1 and the premature impulse S2 that fail to propogate
through the tissue, were determined on right ventricular
papillary muscles isolated from New Zealand white rabbits
using S1 frequencies of 1 and 3 Hz. Automaticity was
measured in beats per minute on isolated right atria which
were allowed to contract spontaneously. Working and stock
solutions of test compounds were prepared by dissolving the
salts in glass distilled water. Compounds evaluated as the free
base were first dissolved in ethanol that contained an equiva-
lent of fumaric acid. The solutions were then diluted with
distilled water. A detailed description of this procedure has
been reported.31

Synthesis and Evaluation of Ibutilide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1113
are also presented. A more detailed description of this proce-
dure has been reported.43
stimulus to capture and produce a propogated response, was
reached. The atrial and ventricular MAPD90 and the QT
interval were also recorded at a pacing cycle length of 300 ms.
Spontaneous arrhythmias (PVCs) were recorded over three
1-min intervals during a 10-min period. Programmed electrical
stimulation (PES) to induce ventricular tachyarrhythmias was
performed at a pacing cycle length of 300 ms using a standard
protocol of up to three premature stimuli. These arrhythmias
were defined as monomorphic ventricular tachycardia char-
acterized by a rapid ventricular rate (greater than 200 bpm)
with no discernible P or T wave and a wide QRS complex or
as ventricular fibrillation (VF) characterized by irregular
chaotic heart rate with no discernible P, Q, R, S or T waves.
Responses to PES were recorded as: noninducible (NI) e 15
arrhythmic ventricular beats; nonsustained ventricular ta-
chycardia (NSVT) > 15 beats but spontaneously terminating
within 30 s; sustained ventricular tachycardia (SVT) > 30 s
of tachycardia requiring pacing conversion or electrical car-
dioversion (10-20 J internally) for arrhythmia termination;
and VF. An initial positive response to PES was repeated to
demonstrate its reproducibility. Detailed descriptions of this
procedure have been published.59,66
Following surgical instrumentation baseline measurements
were obtained and attempts to elicit arrhythmias by PES were
made. A solution of 45E (6.0 µmol/mL) in saline was then
administered in sequential intravenous doses calculated to
deliver cumulative doses of 0.24, 0.72, and 2.4 µmol/kg.
Measurements were repeated 15 min following each dose and
attempts to elicit ventricular tachycardia by PES were made.
Control animals were treated in the same manner with
intravenous doses of saline replacing the active compound.
Data are presented in Table 5 as means ( SEM. They were
analyzed using the RS1 statistical package, employing a paired
t-test for equality of means. Differences with p e 0.05 were
considered to be statistically significant.
4. In Vivo Eva lu a tion of th e An tia r r h yth m ic a n d
Electr op h ysiologic Effects of 45E on a Ch r on ic Ca n in e
Mod el of AF L. Eight male mongrel dogs weighing 18-24 kg
were surgically prepared for this study. A right thoracotomy
was performed in the fourth intercostal space, the pericardium
was opened and the intercaval section of the right atrium was
clamped with a vena cava clamp. The intercaval tissue was
incised then sutured with surgical silk. A connecting incision
of approximately 3-4 cm which extended along the center of
the right atrial free wall was made and sutured. Bipolar
platinum pacing and recording electrodes with a 2-mm inter-
electrode distance were sutured to the right atrium for atrial
pacing and measurement of AERP; the electrode leads were
exteriorized in the interscapular region. The animals were
allowed to recover for 2 weeks prior to evaluation of the test
compound. These experiments were conducted in an isolation
room which minimized excessive external stimuli. The dogs
were fully conscious and loosely restrained in a support sling.
They had been acclimated to mock study conditions in the
isolation room during 1 week prior to experimentation. A
cephalic vein was cannulated for administration of the test
compound, and the animal was instrumented for recording the
heart rate (HR), recording the lead II ECG, recording the atrial
and ventricular effective refractory periods (AERP and VERP),
inducing atrial flutter (AFL), and recording measuring atrial
flutter cycle length (AFLCL).
AERP and VERP were determined by pacing at a cycle
length of 300 ms and interjecting a single premature stimulus
every eighth beat. Each drive cycle was separated by a 2-s
pause. The cycle length of the premature stimulus was
shortened by 10-ms decrements until the ERP was reached.
Induction of AFL was attempted by pacing for 2-3-s
intervals at cycle lengths starting at 150 ms and then
shortened by 10-ms decrements to a minimum cycle length
50 ms. AFL was considered to be sustained if it did not
spontaneously terminate during a 5-min period.
At the start of the experiment, baseline measurements were
made and AFL was induced. Compound 45E, dissolved in
saline, was then administered intravenously every 5 min to
give cumulative doses of 0.024, 0.06, 0.12, 0.24, 0.6, 1.2, 2.4,
4.8, 7.2, 9.6 and 12.0 µmol/kg. When AFL terminated, the dose
of 45E and the AFLCL were noted and the HR, QT interval,
AERP, VERP and ability to reinduce AFL were determined.
Following these measurements, doses of 45E were continued
until a total of 12.0 µmol/kg had been administered. Heart rate
and electrophysiologic measurements were made 3 min after
each dose. Data are presented in Tables 3 and 4 as means (
SEM. They were analyzed using the RS1 statistical package
employing a pared t-test for equality of means. Differences
with p e 0.05 were considered to be statistically significant.
At the end of the experiment the hearts were removed,
stained with 2,3,5-triphenyltetrazolium chloride and carefully
dissected to separate infarcted and noninfarcted left ventricu-
lar tissue. The infarct size, determined as a percentage of the
left ventricle by wet weight, was not statistically different
between the treatment (30.7 ( 2.0%) and control (30.9 ( 2.0%)
groups.
Su p p or tin g In for m a tion Ava ila ble: Elemental analyses
calculated/found. This material is available free of charge via
the Internet at http://pubs.acs.org.
Refer en ces
(1) Feinberg, W. M.; Blackshear, J . L.; Laupacis, A.; Kronmal, R.;
Hart, R. G. Prevalence, Age Distribution and Gender of Patients
with Atrial Fibrillation: Analysis and Implications. Arch. Intern.
Med. 1995, 155, 469-473.
(2) Obel, O. A.; Camm, A. J . The Use of Drugs for Cardioversion of
Recent Onset Atrial Fibrillation and Flutter. Drugs Aging 1998,
12, 461-476.
(3) Benjamin, E. J .; Wolf, P. A.; D’Agostino, R. B.; Silbershatz, H.;
Kannel, W. B.; Levy, D. Impact of Atrial Fibrillation on the Risk
of Death. The Framingham Heart Study. Circulation 1998, 98,
946-952.
This canine model of AFL was developed by Frame and co-
workers.55 A more detailed description from our laboratory has
been published.58
5. In Vivo Eva lu a tion of th e An tia r r h yth m ic Effica cy
of 45E on Sp on ta n eou s a n d In d u ced Ven tr icu la r Ar -
r h yth m ia s in th e Ca n in e 24-h In fa r ction Mod el. The left
anterior descending coronary artery (LAD) of 19 male mongrel
dogs weighing 16-22 kg was permanently ligated in two stages
with surgical silk as described by Harris.65 The animals were
allowed to recover for 24 h when they were prepared for the
electrophysiologic evaluation of 45E and placebo. They were
reanesthetized with pentobarbitol and instrumented for the
(4) Krahn, A. D.; ManFreda, J .; Tate, R. B.; Mathewson, F. A. L.;
Cuddy, T. E. The Natural History of Atrial Fibrillation: Inci-
dence, Risk Factors, and Prognosis in the Manitoba Follow-Up
Study. Am. J . Med. 1995, 98, 476-484.
(5) Waldo, A. L. Pathogenesis of Atrial Flutter. J . Cardiovasc.
Electrophysiol. 1998, 9, S18-S25.
(6) Zipes, D. P.; Wellens, H. J . J . Sudden Cardiac Death. Circulation
1998, 98, 2334-2351.
(7) Waldo, A. L.; Wit, A. L. Mechanisms of Cardiac Arrhythmias.
Lancet 1993, 341, 1189-1193.
measurement of right atrial and right ventricular MAPD90
,
heart rate (HR), idioventricular heart rate (IVR), mean aortic
blood pressure (BP), and the ECG intervals (P, PQ, QRS, and
QT). Atrial and ventricular effective refractory periods (AERP
and VERP) were determined to the nearest 5 ms using the
extra stimulus technique by pacing at a cycle length of 300
ms and interjecting a single premature stimulus every eighth
beat. Each drive cycle was separated by a 2-s pause. The cycle
length of the premature stimulus was shortened by 5-ms
decrements until the ERP, characterized by failure of the
(8) Morgan, P. H.; Mathison, I. W. Arrhythmias and Antiarrhythmic
Drugs: Mechanism of Action and Structure-Activity Relation-
ship I. J . Pharm. Sci. 1976, 65, 467-482.
(9) Singh, B. N. Antiarrhythmic Drugs: A Reorientation in Light
of Recent Developments in the Control of Disorders of Rhythm.
Am. J . Cardiol. 1998, 81 (6A), 3D-13D.
(10) Vaughan Williams, E.M. Classification of Antiarrhythmic Drugs.
In Symposium on Cardiac Arrhythmias; Sandoe, E., Flenstedt-
J ensen, E., Olesen, K. H., Eds.; AB Astra: Sodertalje, Sweden,
1970; pp 440-469.

1114 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Hester et al.
(11) The Cardiac Arrhythmia Suppression Trial (CAST) Investiga-
tors. Preliminary Report: Effect of Encainide and Flecainide on
Mortality in a Randomized Trial of Arrhythmia Suppression
After Mycardial Infarction. N. Engl. J . Med. 1989, 321, 406-
412.
(12) The Cardiac Arrhythmia Suppression Trial II (CAST) Investiga-
tors. Effect of the Antiarrhythmic Agent Moricizine on Survival
After Myocardial Infarction. N. Engl. J . Med. 1992, 327, 227-
233.
(13) Nattel, S. Experimental Evidence for Proarrhythmic Mecha-
nisms of Antiarrhythmic Drugs. Cardiovasc. Res. 1998 37, 567-
577.
(14) Camm A. J .; Yap, Y. G. What Should We Expect From the Next
Generation of Antiarrhythmic Drugs? J . Cardiovasc. Electro-
physiol. 1999, 10, 307-317.
(15) Singh, B. N.; Vaughan Williams, E. M. A Third Class of Anti-
Arrhythmic Action. Effects on Atrial and Ventricular Intra-
cellular Potentials, and Other Pharmacological Actions on
Cardiac Muscle, of MJ 1999 and AH 3474. Br. J . Pharmacol.
1970, 39, 675-687.
(16) Singh, B. N.; Vaughan Williams, E. M. The Effect of Amiodarone,
A New Anti-Anginal Drug, on Cardiac Muscle. Br. J . Pharmacol.
1970, 39, 657-667.
(17) Colatsky, T. J .; Argentieri, T. M. Potassium Channel Blockers
as Antiarrhythmic Drugs. Drug Dev. Res. 1994, 33, 235-249.
(18) Singh, B. N. Current Antiarrhythmic Drugs: An Overview of
Mechanisms of Action and Potential Clinical Utility. J . Cardio-
vasc. Electrophysiol. 1999, 10, 283-301.
(19) Capucci, A.; Villani, G. Q.; Aschieri, D.; Piepoli, M. Effects of
Class III Drugs on Atrial Fibrillation. J . Cardiovasc. Electro-
physiol. 1998, 9, S109-S120.
(20) Lazzara, R. Antiarrhythmic Drugs and Torsade de Pointes. Eur.
Heart J . 1993, 14 (Suppl. H), 88-92.
(21) Singh, B. N. Arrhythmia Control by Prolonging Repolarization:
the Concept and Its Potential Therapeutic Impact. Eur. Heart
J . 1993, 14 (Suppl. H), 14-23.
(22) Ackerman, M. J . The Long QT Syndrome: Ion Channel Diseases
of the Heart. Mayo Clin. Proc. 1998, 73, 250-269.
(23) Donger, C.; Denjoy, I.; Berthet, M.; Neyroud, N.; Cruaud, C.;
Bennaceur, M.; Chivoret, G.; Schwartz, K.; Coumel, P.; Guicheney,
P. KVLQT1 C-Terminal Missence Mutation Causes a Form
Fruste Long QT Syndrome. Circulation 1997, 96, 2778-2781.
(24) Chen, Q.; Zhang, D.; Gingell, R. L.; Moss, A. J .; Napolitano, C.;
Priori, S. G.; Schwartz, P. J .; Kehoe, E.; Robinson, J . L.; Schulze-
Bahr, E.; Wang, Q.; Towbin, J . A. Homozygous Deletion in
KVLQT1 Associated with J ervell and Lange-Nielsen Syndrome.
Circulation 1999, 1344-1347.
(36) Perricone, S. C.; Chidester, C. G.; Hester, J . B. Synthesis of (R)-
N-[4-[4-(Dibu t yla m in o)-1-h ydr oxybu t yl]ph en yl]m et h a n e-
sulfonamide, (E)-2-Butenedioate (2:1) Salt (Artilide Fumarate)
and the Enantiomers of N-[4-[4-(Ethylheptylamino)-1-hydroxy-
butyl]phenyl]methanesulfonamide, (E)-2-Butenedioate (2:1) Salt
(Ibutilide Fumarate). Tetrahedron: Asymmetry 1996, 7, 677-
690.
(37) Sih, J . C.; Sutton, J . W. Unpublished results.
(38) Buendia, J . No. 463 - Pre´paration d’alcools a` Fonctions Com-
plexes et d’alce´nylte´trahydro Furannes. Bull. Soc. Chim. Fr.
1996, 2778-2785.
(39) See Suga, H.; Hamatani, T.; Guggisberg, Y.; Schlosser, M. Vicinal
Bromofluoroalkanes. Their Regioselective Formation and Their
Conversion to Fluoroolefins. Tetrahedron 1990, 46, 4255-4260.
(40) Sondej, S. C.; Katzenellenbogen, J . A. Gem-Difluoro Com-
pounds: A Convenient Preparation from Ketones and Aldehydes
by Hydrogen Fluoride Treatment of 1,3-Dithiolanes. J . Org.
Chem. 1986, 51, 3508-3513.
(41) Cimini, M. G.; Brunden, M. N.; Gibson, J . K. Effects of Ibutilide
Fumarate. A Novel Antiarrhythmic Agent, and Its Enantiomers
on Isolated Rabbit Myocardium. Eur. J . Pharmacol. 1992, 222,
93-98.
(42) Carlsson, L.; Almgren, O.; Duker, G. QTU-Prolongation and
Torsades de Pointes Induced by Putative Class III Antiarrhyth-
mic Agents in the Rabbit: Etiology and Interventions. J .
Cardiovasc. Pharmacol. 1990, 16, 276-285.
(43) Buchanan, L. V.; Kabell, G.; Brunden, M. N.; Gibson, J . K.
Comparative Assessment of Ibutilide, d-Sotalol, Clofilium, E-4031
and UK 68798 in a Rabbit Model of Proarrhythmia. J . Cardio-
vasc. Pharmacol. 1993, 220, 540-549.
(44) O’Hagan, D.; Rzepa, H. S. Some Influences of Fluorine in
Bioorganic Chemistry. Chem. Commun. 1997, 645-652.
(45) Park, B. K.; Kitteringham, N. R. Effects of Fluorine Substitution
on Drug Metabolism: Pharmacological and Toxicological Impli-
cations. Drug Metab. Rev. 1994, 26, 605-643.
(46) Hondeghem, L. M. Development of Class III Antiarrhythmic
Agents. J . Cardiovasc. Pharmacol. 1992, 20, S17-S22.
(47) See: Rees, S.; Curtis, M. J . Which Cardiac Potessium Channel
Subtype is the Preferable Target for Suppression of Ventricular
Arrhythmias? Pharmacol. Ther. 1996, 69, 199-217. Roden, D.
M.; George, A. L. The Cardiac Ion Channels: Relevance to
Management of Arrhythmias. Annu. Rev. Med. 1996, 47, 135-
148.
(48) Lynch, J . J ., J r.; Baskin, E. P.; Nutt, E. M.; Guinosso, P. J ., J r.;
Hamill, T.; Salata, J . J .; Woods, C. M. Comparison of Binding
to Rapidly Activating Delayed Rectifier K+ Channel, IKr, and
Effects on Myocardial Refractoriness for Class III Antiarrhyth-
mic Agents. J . Cardiovasc. Pharmacol. 1995, 25, 336-340.
(49) Lee, K. S. Ibutilide, a New Compound with Potent Class III
Antiarrhythmic Activity, Activates a Slow Inward Na+ Current
in Guinea Pig Ventricular Cells. J . Pharmacol. Exp. Ther. 1992,
262, 99-108.
(50) Lee, K. S.; Lee, E. W. Ionic Mechanism of Ibutilide in Human
Atrium: Evidence for a Drug Induced Na Current Through a
Nifedipine Inhibited Inward Channel. J . Pharmacol. Exp. Ther.
1998, 286, 9-22.
(51) Lee, K. S.; Tsai, T. D.; Lee, E. W. Membrane activity of Class
III antiarrhthmic Compounds; A Comparison Between Ibutilide,
d-Sotalol, E-4031, Sematilide and Dofetilide. Eur. J . Pharmacol.
1993, 234, 43-53.
(52) Yang, T.; Snyders, D. J .; Roden, D. M. Ibutilide, a Methane-
sulfonanilide Antiarrhythmic, Is a Potent Blocker of the Rapidly
Activating Delayed Rectifier K+ Current (IKr) in AT-1 Cells.
Circulation 1995, 91, 1799-1806.
(53) Sato, N.; Tanaka, H.; Habuchi, Y.; Giles, W. R. Electrophysi-
ological Effects of Ibutilide on the Delayed Rectifier K+ Current
in Rabbit Sinoatrial and Atrioventricular Node Cells. Eur. J .
Pharmacol. 2000, 404, 281-288.
(54) Spinelli, W.; Sorota, S.; Siegal, M.; Hoffman, B. F. Antiarrhyth-
mic Actions of the ATP-Regulated K+ Current Activated by
Pinacidil. Circ. Res. 1991, 68, 1127-1137.
(55) Frame, L. H.; Page, R. L.; Hoffman, B. F. Atrial Reentry Around
an Anatomic Barrier with a Partially Refractory Excitable Gap.
A Canine Model of Atrial Flutter. Circ. Res. 1986, 58, 495-511.
(56) Frame, L. H.; Page, R. L.; Boyden, P. A.; Fenoglio, J . J .; Hoffman,
B. F. Circus Movement in the Canine Atrium Around the
Tricuspid Ring During Experimental Atrial Flutter and During
Reentry In vitro. Circulation 1987, 76, 1155-1175.
(57) Buchanan, L. V.; Turcotte, U. M.; Kabell, G.; Gibson, J . K.
Antiarrhythmic and Electrophysiologic Effects of Ibutilide in a
Chronic Canine Model of Atrial Flutter. J . Cardiovasc. Phar-
macol. 1993, 33, 10-14.
(58) Buchanan, L. V.; Kabell, G.; Gibson, J . K. Acute Intravenous
Conversion of Canine Atrial Flutter: Comparison of Antiar-
rhythmic Agents. J . Cardiovasc. Pharmacol. 1995, 25, 539-544.
(25) Priori, S. G.; Napolitano, C.; Schwartz, P. J . Low Penetrance in
the Long QT Syndrome Clinical Impact. Circulation 1999, 99,
529-533.
(26) Priori, S. G.; Barhanin, J .; Hauer, R. N. W.; Haverkamp, W.;
J ongsma, H. J .; Kleber, A. G.; McKenna, W. J .; Roden, D. M.;
Rudy, Y.; Schwartz, K.; Schwartz, P. J .; Towbin, J . A.; Wilde,
A. M. Genetic and Molecular Basis of Cardiac Arrhythmias:
Impact on Clinical Management. Parts I and II. Circulation
1999, 99, 518-528; Part III. Circulation 1999, 99, 674-681.
(27) Roden, D. M. Mechanisms and Management of Proarrhythmia.
Am. J . Cardiol. 1998, 82, 49I-57I.
(28) Foster, R. H.; Wilde, M. I.; Markham, A. Ibutilide a Review of
Its Pharmacological Properties and Clinical Potential in the
Acute Management of Atrial Flutter and Fibrillation. Drugs
1997, 54, 312-330.
(29) Myerburg, R. J .; Kloosterman, M.; Yamamura, K.; Mitrani, R.;
Interian J r., A.; Castellanos, A. The Case for Inpatient Initiation
of Antiarrhythmic Therapy. J . Cardiovasc. Electrophysiol. 1999,
10, 482-487.
(30) Pratt, C. M. Predicting Antiarrhythmic Performance. J . Car-
diovasc. Electrophysiol. 1999, 10, 302-306.
(31) Hester, J . B.; Gibson, J . K.; Cimini, M. G., Emmert, D. E.; Locker,
P. K.; Perricone, S. C.; Skaletzky, L. L.; Sykes, J . K.; West, B.
E. N-[(ω-Amino-1-hydroxyalkyl)phenyl]methanesulfonamide De-
rivatives with Class III Antiarrhythmic Activity. J . Med. Chem.
1991, 34, 308-315.
(32) Wood, M. A.; Clemo, H. S.; Ellenbogen, K. A. Ibutilide Fuma-
rate: A New Class III Agent for Termination of Atrial Fibrilla-
tion and Atrial Flutter. Exp. Opin. Invest. Drugs 1996, 5, 1511-
1522.
(33) Wood, M. A.; Stambler, B. S.; Ellenbogen, K. A.; Gilligan, D. M.;
Perry, K. T.; Wakefield, L. K.; Vanderlugt, J . T. Suppression of
Inducible Ventricular Tachycardia by Ibutilide in Patients with
Coronary Artery Disease. Am. Heart J . 1998, 135, 1048-1054.
(34) Wickrema Sinha, A. J .; Thornburgh, B. A. Species Comparison
of the Disposition of [14C]Ibutilide Fumarate in Rat, Dog, and
Human. ISSX Proc. 1996, 10, 302.
(35) Hester, J . B., J r.; Perricone, S. C.; Gibson, J . K. Antiarrhythmic
Methanesulfonamides. U.S. Patent 5,405,997, 1995.

Synthesis and Evaluation of Ibutilide Analogues
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1115
(59) Buchanan, L. V.; Kabell, G.; Turcotte, U. M.; Brunden, M. N.;
Gibson, J . K. Effects of Ibutilide on Spontaneous and Induced
Ventricular Arrhythmias in 24-Hour Canine Myocardial Infar-
action: A Comparative Study with Sotalol and Encainide. J .
Cardiovasc. Pharmacol. 1992, 19, 256-263.
(60) In response to a reviewer’s request for additional pharmaco-
kinetic information: The PK of compound 45E has been evalu-
ated in several animal species and in humans. The absolute oral
bioavailability was 75 ( 20% in dogs. In humans the preliminary
value for this parameter was 59 ( 12% (Gail L. Yungbluth,
unpublished results).
(61) Oxford, A. W.; Coates, I. H.; Bays, D. E.; Webb, C. F.; Dowle, M.
D.; Mills, K.; Eldred, C. D. Indole Derivatives. U.S. Patent
4,855,314, 1989.
(62) Schwab, J . M.; Li, W.; Thomas, L. P. Cyclohexanone Oxygen-
ase: Stereochemistry, Enantioselectivity, and Regioselectivity
of an Enzyme-Catalyzed Baeyer-Villiger Reaction. J . Am. Chem.
Soc. 1983, 105, 4800-4808.
(63) For a review of this chemistry, see: Petragnani, N.; Yonashiro,
M. The Reactions of Dianions of Carboxylic Acids and Ester
Enolates. Synthesis 1982, 521-578.
(64) Lu, A.; Levin, W. Partial Purification of Cytochrome P-450 and
Cytochrome P-448 From Rat Liver Microscomes. Biochem.
Biophys. Res. Commun. 1992, 46, 1334-1339.
(65) Harris, A. S. Delayed Development of Ventricular Ectopic
Rhythm Following Experimental Coronary Occlusion. Circula-
tion 1950, 1, 1318-1328.
(66) Buchanan, L. V.; Kabell, G.; Turcotte, U. M.; Brunden, M. N.;
Gibson, J . K. Effects of Artilide on Spontaneous and Induced
Ventricular Arrhythmias in 24-Hour Canine Myocardial Infarc-
tion. Drug Dev. Res. 1993, 30, 30-36.
J M0004289