Synthesis and activity of novel and selective Iks-channel blockers

Article abstract of DOI:10.1021/jm0109255

Since the discovery of the I_Ks-potassium channel as the slowly activating component of the delayed rectifier current (I_k) in cardiac tissue, the search for blockers of this current has been intense. During the screening of K_ATP<

Full text of DOI:10.1021/jm0109255

J . Med. Chem. 2001, 44, 3831-3837
3831
Syn th esis a n d Activity of Novel a n d Selective IKs-Ch a n n el Block er s
Uwe Gerlach,*,† J oachim Brendel,† Hans-J ochen Lang,† Erich F. Paulus,† Klaus Weidmann,†
Andrea Bru¨ggemann,‡ Andreas E. Busch,‡ Hartmut Suessbrich,‡ Markus Bleich,§ and Rainer Greger§
Aventis Pharma Deutschland GmbH, Medicinal Chemistry, DG Cardiovascular D-65926 Frankfurt/ Main, Germany, and
Albert-Ludwigs-Universita¨t Freiburg, Physiologisches Institut
Received May 9, 2001
Since the discovery of the IKs-potassium channel as the slowly activating component of the
delayed rectifier current (Ik) in cardiac tissue, the search for blockers of this current has been
intense. During the screening of KATP-channel openers of the chromanol type we found that
chromanol 293B was able to block IKs. Chromanol 293B is a sulfonamide analogue of the KATP
-
channel openers but had no activity on this target. Experiments were initiated to improve the
activity and properties based on this lead compound. As a screening model we used Xenopus
oocytes injected with human minK (KCNE1). Variations of the aromatic substituent and the
sulfonamide group were prepared, and their activity was evaluated. We found that the greatest
influence on activity was found in the aromatic substituents. The most active compounds were
alkoxy substituted. We chose HMR1556 ((3R, 4S)-(+)-N-[-3-hydroxy-2,2-dimethyl-6-(4,4,4-
trifluorobutoxy)chroman-4-yl]-N-methyl-ethanesulfonamide) 10a for development as an anti-
arrhythmic drug. The absolute configuration, resulting from an X-ray single-crystal structure
analysis, was determined.
In tr od u ction
Most of these ion currents and their ion channels have
been the target of antiarrhythmic therapy and have
been classified mechanistically into four main classes:
class I (sodium channel blockade), class II (â-adrenergic
blockade), class III (potassium channel blockade), and
class IV (calcium channel blockade).2
Cardiac arrhythmias are still a major cause of death
in the western world, especially in patients with is-
chemic heart disease. These irregularities are caused
by abnormalities in the electrical activity of the heart
which may result from excessive sympathetic stimula-
tion and/or changes in the ionic mechanism responsible
for the generation and propagation of the normal action
potential.
The shape of the action potential of heart cells is
strongly controlled by the correct interplay of ion
channels.1 The main ion channels contributing to the
action potential are sodium, calcium, and potassium
channels. The potassium channels form the most diverse
family, and they are responsible for the inward rectifi-
Some of the antiarrhythmic drugs however are not
specific to one mechanism or ion channel but act on
several modes; a prominent example is the most used
antiarrhythmic drug Amiodarone. It exerts a multiplic-
ity of pharmacological effects, which could be associated
with, in part, each of the class I-IV antiarrhythmic
agents and is an effective agent in the control of
ventricular tachyarrhythmias and fibrillation (VT/
VF).3,4
cation (IK1, IKACh, IKATP), sustained outward (IKur, IKr
Ks) and transient outward (Ito) rectification.
The depolarization (upstroke) of the membrane
,
In the 1980s CAST (Cardiac Arrhythmia Suppression
Trial), with the drugs encainide and flecainide, uncov-
ered the inefficacy and even proarrhythmic risk of
sodium channel blockers (class I antiarrhythmics) in
patients at relatively low long-term risk for cardiac
death.5-7 The elevated mortality in the treated group
was rationalized on the sodium channel blockade activ-
ity of these compounds, and the study was terminated.
I
potentialscaused by inward sodium currentsis followed
by a partial early repolarization caused by outward
potassium current through rapidly activating and in-
activating K+ channels. The plateau phase depends on
a balance of inward (depolarizing) and outward (repo-
larizing) currents. The depolarizing force not only is
mainly a Ca2+ influx that slowly declines as L-type Ca2+
channels inactivate but also a noninactivating Na+
current can support the plateau phase. The repolarizing
action depends on K+ efflux due to activation of several
voltage-gated potassium channels, mainly the rapidly
activating delayed rectifier (IKr) and the slowly activat-
ing delayed rectifier (IKs) potassium currents.1
To circumvent the problems with class I antiarrhyth-
mics, pharmacological and clinical research shifted
toward the class III agents, which act on the delayed
rectifier potassium current and therefore prolonging the
AP. Dofetilide, d-sotalol, E-4031, and MK-499 are
examples of so-called pure class III compounds.8 All of
these compounds act selectively on the rapid form of the
delayed rectifier potassium channel (IKr). The antiar-
rhythmic benefit afforded by class III agents is proposed
to result from a sufficient prolongation of myocardial
refractoriness such that the wavelength of activation
exceeds the path length of the reentrant circuit, thereby
preventing the initiation or maintenance of reentrant
excitation.9
* Corresponding author: Uwe Gerlach, Aventis Pharma Deut-
schland GmbH, Bldg G838, D-65926 Frankfurt/Main, Germany. Tel.:
int-(69)-30582774. Fax: int-(69)-305942380. E-mail: uwe.Gerlach@
aventis.com.
† Aventis Pharma Deutschland GmbH, Medicinal Chemistry.
‡ DG Cardiovascular.
§ Albert-Ludwigs-Universita¨t Freiburg, Physiologisches Institut
D-79104 Freiburg, Germany.
10.1021/jm0109255 CCC: $20.00 © 2001 American Chemical Society
Published on Web 10/11/2001

3832 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Ta ble 1: Inhibitory Activity of Chromanols on the Human
Gerlach et al.
IKs-channel blockers seem to offer a more desirable class
III antiarrhythmic profile than the IKr-channel blockers.
I
Ks-Channel Expressed in Xenopus Oocytes
Since the discovery that IK consists of two kinetically
distinct and identifiable currents,18 the search for selec-
tive IKs-channel blockers has begun. In 199623-25 the
potent and selective IKs-channel blocker Chromanol
293B 1 was described. Subsequently this compound was
tested in several models. In these studies 293B 1 showed
selectivity for the IKs-channel26 and confirmed the
proposed consequences of IKs-channel blockade. Ex-
amples of the latter include the higher activity under
â-adrenergic stimulation17,27 and the positive usedepen-
dence in human cells26 and the canine heart.28 Since
then IKs-channel blockers with different structures have
been published.29,30
compd
X
R1
R2
IC50 (µM)
chirality
1
CN
CN
CN
CN
H
F
F
F
Cl
OPr
OBn
OBn
OBn
OBu
Et
Et
Et
Bu
Et
Et
Et
Et
Me
Me
Me
Et
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
6.9
5,0
44,5
58
3.1
1.2
0.7
2.2
1.1
rac
1a
1b
2
3
4
4a
4b
5
6
7
8a
8b
9
10
10a
10b
3R,4S
3S, 4R
rac
rac
rac
3R,4S
3S,4R
rac
rac
rac
3R,4S
3S,4R
rac
rac
3R,4S
3S,4R
However, chromanol 293B 1 did not meet the profile
of a development drug. In this article we will describe
the variations made in the series of the chromanol
structure. Other variations have been described ear-
lier.31
0.9
0.2
0.05
0.4
0.25
0.24
0.12
0.44
Et
Me
Me
Me
Me
O(CH2)3CF3
O(CH2)3CF3
O(CH2)3CF3
This class of agents also underwent a series of clinical
trials. The SWORD-trial (Survival With Oral D-sotalol)
was terminated because of an increase in mortality in
the treated patients using the pure IKr-channel blocker
d-sotalol.10 Also in the recent study, DIAMOND11 (Dan-
ish Investigation of Mortality on Dofetilide) with pa-
tients, which were at higher risk of mortality than the
SWORD population, the outcome was neutral at the
best.
Resu lts
Starting from the pharmacophore of the KATP-channel
openers32 the first selective IKs-channel blocker chro-
manol 293B 1 was found. Besides its described selectiv-
ity toward other ion channels 1 was not active on the
original target the KATP-channel.24,25 We searched for
molecules with improved IKs-channel blocking activity
and discovered that variation at the 6-position on the
aromatic ring can greatly increase activity. The most
potent compounds were 6-ether-substituted compounds
8a and 10a . Table 1 shows the IC50 values for the
selected compounds.
These disappointing results have been attributed to
the so-called “negative use-dependence”, which was
already demonstrated preclinically with various IKr
-
channel blockers.12 This property has two effects:
1. An extended prolongation of the action potential
(AP) of heart cells at low heart frequency and at low
â-adrenergic status: This prolongation of the AP may
lead to early after depolarization (EAD) and under
certain circumstances to fatal Torsades de Pointes
(TdP).13,14
2. A weak prolongation of the AP at high heart rate15
and high â-adrenergic stimulation:16,17 This unsatisfac-
tory activity reduces the antiarrhythmic effect of these
drugs and the positive effect of the AP prolongation
expected from the activity on the AP at normal heart
frequency.
As a screening model for the compounds we used
Xenopus oocytes injected with c-RNA of human minK
(KCNE1), the â-subunit of KvLQT1.33 Together with the
endogenous XKvLQT1, minK forms the functional IKs
channel.
-
The lead compound 1 has an IC50 value on the IKs
-
It has been shown that IK consists of two compo-
nents18 (IKr and IKs). Negative use dependency has been
channel of 6.9 µM as a racemate and 5.0 and 44.5 µM
for the two separated enantiomers, respectively. The
absolute stereochemistry was determined by X-ray
crystallography34 and is in agreement with the expected
outcome of the chiral epoxidation.35 Increasing the size
of the sulfonyl residue from ethyl to butyl (compound
2) lowered the activity to 58 µM.
attributed to an increased contribution of the IKs
-
channel on the repolarization under elevated heart
rate15 and â-adrenergic activation.16
Furthermore, there is evidence that â-adrenergic
sympathetic activity is an important factor in the
genesis of malignant ventricular tachyarrhythmias.19 It
has been demonstrated that â-adrenergic stimulation
attenuates or even reverses the electrophysiological and
antiarrhythmic effects of various class I antiarrhythmic
agents20 and class III antiarrhythmics such as D-
Sotalol,21 E-4031,16 and sematilide.22 This may be due
to an increase of IKs under these conditions. Therefore
While the unsubstituted chromanol 3 had only a
slightly improved activity, the 6-fluoro 4 and 6-chloro 5
derivatives showed half-maximal inhibition of the IKs
-
channel at around 1 µM. In the case of the fluoro
compound the enantiomers 4a and 4b were prepared
separately and showed different inhibitory activities
with 0.7 and 2.3 µM, respectively.

Novel and Selective IKs-Channel Blockers
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3833
Sch em e 1: Synthesis of (3R,
4S)-(+)-N-[-3-Hydroxy-2,2-dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methylethanesulfonamide 10a
Surprisingly, a major improvement in the activity was
found with the 6-alkoxy derivatives especially with more
lipophilic side chains. The 6-propoxy substituted chro-
manol 6 produced an IC50 of 0.9 µM and the slightly
bigger butoxy- and trifluorobutoxyether derivatives
(entries 9 and 10) showed inhibitory activities of 0.25
and 0.24 µM, respectively. The enantiomers of the
trifluorobutoxy compound were synthesized separately
and showed activities of 0.12 µM (10a ) and 0.24 µM
(10b), respectively. The benzyl ether 8a was the most
potent compound, which showed an IKs-blocking activity
of 50 nM.
HCN2 were blocked little or not at all by 10 µmol/L
HMR 1556, showing the selectivity of the compound.36
In isolated ventricular myocytes from the guinea pig
the whole cell patch clamp method revealed inhibition
of the IKs current with an IC50 of 34 nM. Other current
components, like IKr and IK1, were only slightly blocked
by 10a with a concentration of 10 µmol/L, whereas 10
µmol/L 10a inhibited the transient outward current Ito
and the sustained outward current Isus in rat ventricular
myocytes by 25% and 36%, respectively. The L-type Ca2+
channel in guinea pig cardiomyocytes was blocked by
10 µmol/l 10a by 31%,36 showing a selectivity of ap-
proximately 300-fold to the other ion channels. Further
in vitro and in vivo studies have been performed and
confirm the proposed activity on cardiac repolariza-
tion.36
In all cases examined we found the enantiomer with
the 3R,4S-configuration to have the higher activity.
Ch em istr y
The synthesis of 10a is shown in Scheme 1 and
exemplifies the general synthesis strategy for this class
of compounds. We started from the commercially avail-
able 2,5-dihydroxyacetophenone 13, which was cyclized
with acetone and pyrrolidine by a variation of a litera-
ture procedure.37 6-Hydroxy-2,2-dimethylchromanone
14 was obtained in 82% yield. The phenol 14 was
alkylated with 4-trifluorobutyl iodid under standard
conditions in 95% yield. The chromanone 15 was
reduced to the 4-chromanol 16 with NaBH4 (97% yield).
Elimination of water under acid catalysis gave rise to
6-trifluorobutyl-2,2-dimethylchromene 17 in 91% yield.
For the synthesis of the chiral epoxide we used (R,R)-
(-)-N,N′-bis(3,5-di-tert-butylsalicyliden)-1,2-diaminocy-
clohexanmanganese(III) chloride (J acobsen catalyst).38
We obtained the 3R,4R-epoxide 18 in high optical yield.
The epoxide 18 was then opened regio- and stereose-
lectively by N-methylmethanesulfonamide/NaH. The
The influence of the 3-hydroxy-group was checked by
acetylation (11) and methylation (12) of the 6-benzyl-
ether 7 (IC50 ) 200 nM). In both cases the activity
decreased to 13 µM (11) and 6.5 µM (12), respectively.
(3R,4S)-(+)-N-[-3-Hydroxy-2,2-dimethyl-6-(4,4,4-trifluoro-
but oxy)chrom a n-4-yl]-N-m et hylet ha n esulfona m ide
10a was chosen as development compound with the
company code HMR1556 and the selectivity toward
several other ion channels was evaluated thoroughly.36
HMR1556 10a inhibits the potassium current of IKs
-
channels expressed in Xenopus laevis oocytes half-
maximally at a concentration of 120 nM (IC50).36 In
contrast the currents of the expressed K+ channels herg,
Kv1.5, Kv1.3, and Kir2.1, and also the cationic current

3834 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Gerlach et al.
rhythmic drugs in several animal models. This gives us
the opportunity to evaluate a highly active and selective
IKs-channel blocker in various models of arrhythmia and
to prove this new concept for antiarrhythmic drugs. The
first more detailed in vitro and in vivo data on HMR1556
10a were published recently.36
Exp er im en ta l Section
I. Ch em istr y. P h ysica l Meth od s. Solvents and other
reagents were used without further purification unless oth-
erwise stated. Column chromatography was carried out on E.
Merck silica gel 60 (35-70 and 70-230 mesh). Thin-layer
chromatography carried out on TLC glass sheets with silica
gel 60F254, layer thickness 0.2 mm, from Merck. The NMR
spectra were recorded either on a Varian Gemini 200, a Varian
Unity 300, or a Bruker DRX 400. Chemical shifts are reported
as δ values from an internal tetramethylsilane standard. DCI
mass spectra were measured on a TRIO 2000 using isobutane
as reagent gas and ESI mass spectra on a VG BIO-Q. Positive
FAB mass spectra were obtained on a VG ZAB2 SEQ in a
3-nitrobenzylic-alcohol matrix using cesium as the target gas.
Melting points were obtained with a Bu¨chi melting point B-540
and are not corrected. Enantiomeric purity was determined
by a ThermoQuest-HPLC device, using chiral DNBPG- or
using a CSP S Whelk-01 column from Daicel.
A crystal of 0.2 × 0.12 × 0.03 mm3 (crystallized from
methanol) was used for the single-crystal structure analysis
of 10a : Bruker AXS four circle diffractometer equipped with
a CCD area-detector, Mo-KR radiation (rotating anode: 0.5
× 5 mm2 focus), direct methods for solving the phase problem,39
determination of the absolute configuration with a very high
significance [Flack parameter: 0.03(9)], R1 (all 2091 unique
data) ) 0.0359. Supporting material for the X-ray structure
analysis is available: crystal data and structure refinement,
atomic coordinates and equivalent isotropic displacement
parameters, bond lengths and angles, anisotropic displacement
parameters, hydrogen coordinates, torsion angles, hydrogen
bonds (2.864 Å) in the crystal cell.
F igu r e 1. X-ray analysis of 10a .
other possible regio-isomer was not found at all. The
absolute stereochemistry of the chromanol 10a was
proven by X-ray analysis (see Figure 1), and the ster-
eochemical purity was checked by chiral HPLC.
The racemic compounds were synthesized by the same
sequence with exception of the epoxidation, which was
done in two steps with the bromo hydrin as racemic
intermediate as described for similar compounds in the
literature.32
(3R,4S)-(+)-N-[-3-Hyd r oxy-2,2-d im eth yl-6-(4,4,4-tr iflu o-
r obu toxy)ch r om an -4-yl]-N-m eth yleth an esu lfon am ide 10a.
2,2-Dim eth yl-6-h yd r oxych r om a n -4-on e 14. A reaction mix-
ture of 100 g (0.65 mol) of commercially available 2,5-
dihydroxyacetophenone 13 in 1 L of acetonitrile, 130 mL (1.55
mol) of pyrrolidine, and 290 mL (3.95 mol) of acetone was
heated at 45 °C for 8 h. The solvents were then removed in a
vacuum, and the residue was dissolved in 1 L of ethyl acetate.
The organic phase was washed twice with dilute hydrochloric
acid, stirred with charcoal, and dried over magnesium sulfate
and substantially concentrated. The residue was stirred with
petroleum ether, and the precipitate was filtered off with
suction giving 102 g (82%) of 2,2-dimethyl-6-hydroxychroman-
Su m m a r y
There is high medical need for safe and efficient
antiarrhythmic drugs. IKs-channel blockers may provide
this kind of drug. Investigation of chromanol structures
of the KATP-channel openers revealed the lead structure
chromanol 293B 1. We succeeded in greatly improving
the activity of this class of compounds in blocking the
IKs-channel. We prepared several molecules with various
substituents at the 6-position of the aromatic ring and
the sulfonamide functionality. Even with only one
example shown, a decrease of activity with bulkier
substituents on the sulfonyl residue was seen. The
major improvements were made by changes in the
aromatic substituents. Higher alkoxy substituents such
as butoxy exhibited the highest potency. We found
compounds with an IC50 of as low as 50 nM (8a ).
Enantioselective synthesis was achieved by J acobson
epoxidation of the chromene intermediates and opening
of the epoxide without loss of stereochemical informa-
tion. The two enantiomers had different activities, and
the absolute configuration of the more potent compound
was determined by X-ray structure analysis and is
shown in Figure 1. Surprisingly, the absolute configu-
1
4-one: mp 161 °C; H NMR (DMSO-d6) δ [ppm] 2.44 (s, 6H);
2.82-3.05 (m, 2H); 7,15-7,25 (m, 4H); MS (DCI) m/e 204
(M+H+).
2,2-Dim eth yl 6-(4,4,4-Tr iflu or obu toxy)ch r om a n -4-on e
15. A solution of 13.4 g (70 mmol) of 2,2-dimethyl-6-hydroxy-
chroman-4-one 14 in 250 mL of DMF was added dropwise to
a solution of 2.65 g (88 mmol) of 80% sodium hydride in 170
mL of DMF. The mixture was stirred at room temperature
for 1 h, 14.6 g (76 mmol) of 4,4,4-trifluorobutyl iodide was
added, and the mixture was left to stand at room temperature
overnight. The reaction mixture was poured into 3 L of water.
The precipitated product was filtered off with suction, washed
with water, and dried under reduced pressure. This gave 20.0
g (95%) of 6-(4,4,4-trifluorobutoxy)-2,2-dimethylchroman-4-one
as colorless solid: mp 62 °C; 1H NMR (CDCl3) δ [ppm] ) 1.43
(s, 6H), 1,9-2,4 (m, 4H), 2.7 (s; 2H), 4.0 (t; 2H), 6.85 (d; 1H),
7.1 (dd; 1H), 7.25 (d; 1H).
2,2-Dim eth yl 6-(4,4,4-Tr iflu or obu toxy)ch r om an -4-ol 16.
A solution of 20 g (66 mmol) of 2,2-dimethyl 6-(4,4,4-trifluo-
robutoxy)chroman-4-one 15 and 2.5 g (66 mmol) of sodium
borohydride in 100 mL of methanol was stirred at room
temperature overnight. The reaction mixture was poured into
ration is opposite to that of the more potent KATP
-
channel opener compounds, which were the starting
point for our investigation. The compounds described
are currently under in vivo investigation as antiar-

Novel and Selective IKs-Channel Blockers
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23 3835
ice water, mixed with common salt, and extracted 4 times with
ethyl acetate. Drying and concentration of the organic phase
gave 19.5 g (97%) of 6-(4,4,4-trifluorobutoxy)-2,2-dimethyl-
chroman-4-ol that was directly converted in the following step.
2,2-Dim eth yl 6-(4,4,4-Tr iflu or obu toxy)ch r om en e 17. A
solution of 19.5 g (64 mmol) of 2,2-dimethyl 6-(4,4,4-trifluo-
robutoxy)chroman-4-ol 16 in 200 mL of toluene was mixed with
0.2 g of p-toluenesulfonic acid monohydrate and heated at 100
°C for 22 h. After cooling, the batch was extracted twice with
120 mL of sodium bicarbonate solution each time and stirred
with activated carbon. Filtration and concentration under
reduced pressure gave 16.7 g (91%) of 6-(4,4,4-trifluorobutoxy)-
2,2-dimethyl-2H-chromene 17 as a colorless liquid: 1H NMR
(CDCl3) δ [ppm] ) 1.4 (s, 6H), 1,9-2,4 (m, 4H), 3.95 (t; 2H),
5.65 (d; 1H), 6.25 (d; 1H), 6.5 (d; 1H), 6.6-6.7 (m; 2H).
(3R,4R)-(+)-2,2-Dim eth yl-6-(4,4,4-tr iflu or obu toxy)-3,4-
ep oxych r om a n 18. At 0 °C, 38.5 mL (22 mmol) of a 0.55 M
sodium hypochlorite solution which had been adjusted to pH
11.3 using disodium hydrogen phosphate were added dropwise
to a solution of 2.86 g (10 mmol) of 2,2-dimethyl 6-(4,4,4-
trifluorobutoxy)chromene 17 and 0.26 g (0.4 mmol) of (R,R)-
(-)-N,N′-bis(3,5-di-tert-butylsalicylidene)-1,2-diaminocyclohex-
anemanganese(III) chloride38 in 11 mL of methylene chloride.
The reaction mixture was stirred vigorously for 1 h, the organic
phase was then separated off, and the aqueous phase was
extracted once more with a little methylene chloride. The
organic phase was filtered through a short silica gel column,
and the fractions were concentrated under reduced pressure.
This gave 1.65 g (55%) of (3R,4R)-(+)-2,2-dimethyl-6-(4,4,4-
trifluorobutoxy)-3,4-epoxychroman 18a as a solid (mp 90 °C):
optical rotation +40,7° (c ) 1, toluene), +40,5° (c ) 2, toluene).
(3R ,4S)-(+)-N -[-3-H yd r oxy-2,2-d im e t h yl-6-(4,4,4-t r i-
flu or ob u t oxy)ch r om a n -4-yl]-N-m et h ylm et h a n esu lfon -
a m id e 10a . N-Methylmethanesulfonamide (0.77 g, 7.1 mmol)
was added to a suspension of 65 mg (2.7 mmol) of 80% sodium
hydride in 3 mL of DMSO under argon, and the mixture was
stirred at room temperature for 20 min. (3R,4R)-(+)-2,2-
Dimethyl-6-(4,4,4-trifluorobutoxy)-3,4-epoxychroman (1.65 g,
5.5 mmol) 18, dissolved in 5 mL of DMSO, was added dropwise,
and the batch was left to stand at room temperature for 4 days
and then heated at 45 °C for a further 9 h. The mixture was
subsequently poured into water, and the precipitate was
filtered off with suction and dried thoroughly under reduced
pressure, giving 1.9 g (84%) of (3R,4S)-(+)-[3-hydroxy-2,2-
dimethyl-6-(4,4,4-trifluorobutoxy)chroman-4-yl]-N-methyl-
methanesulfonamide, which was recrystallized from a little
2-propanol (1.4 g; mp 178-179 °C): 1H NMR (CDCl3) δ [ppm]
1.21 (s, 3H); 1.50 (s, 3H); 1.92 -2.10 (m, 2H); 2.25-2.41 (m,
3H); 2.69 (s, 3H); 3.13 (s, 3H); 3.80 (dd, J ) 10.0 Hz, J ) 5.1
Hz, 1H); 3.95 (t, J ) 5.8 Hz, 2H); 4.91 (d, J ) 10.0 Hz, 1H);
6.73-6.83 (m, 3H); optical purity (HPLC) 100%, [R] ) +2.8°
(c ) 1; MeOH), +2.9° (c ) 2; MeOH).
J ) 8.0 Hz, 3H); 1.45-1.63 (m, 5H); 1.82-1.98 (m, 2H); 2.68-
2.74 (m, 4H); 3.22-3.37 (m, 2H); 3.73-3.84 (m, 1H); 4.90 (d,
J ) 10 Hz, 1H); 6.88-6.95 (m, 1H); 7.45-7.49 (m, 1H); 7.63-
7.67 (m, 1H); mp 171 °C.
Anal. Calcd for C17H24N2O4S: C, 57.93; H, 6.86; N, 7.95.
Found: C, 58.08; H, 6.95; N 8.07%.
N-[3-H yd r oxy-2,2-d im et h ylch r om a n -4-yl]-N-m et h yle-
1
th a n esu lfon a m id e 3. H NMR (CDCl3) δ [ppm] 1.24 (s, 3H);
1.45-1.56 (m, 6H); 2.64-2.71 (m, 4H); 3.30 (q, J ) 7.5 Hz,
2H); 3.80 (dd, J ) 10 Hz, J ) 4.0 Hz, 1H); 4.88 (d, J ) 10 Hz,
1H); 6.81-6.86 (m, 1H); 6.91-6.99 (m, 1H); 7.16-7.28 (m, 2H);
mp 150 °C.
Anal. Calcd for C14H21NO4S: C, 56.17; H, 7.07; N, 4.68.
Found: C, 56.01; H, 7.25; N 4.88%.
N-[3-H yd r oxy-2,2-d im et h yl-6-flu or och r om a n -4-yl]-N-
m eth yleth a n esu lfon a m id e 4. 1H NMR (CDCl3) δ [ppm] 1.22
(s, 3H); 1.44-1.51 (m, 6H); 2.55-2.57 (d, J ) 4.6 Hz, 1H); 2.70
(s, 3H); 3.28 (q, J ) 7.6 Hz, 1H); 3.76-3.84 (m, 1H); 4.85 (d, J
) 10.0 Hz, 1H); 6.73-7.02 (m, 3H); mp 142 °C.
Anal. Calcd for C14H20FNO4S: C, 52.98; H, 6.35; N, 4.41.
Found: C, 53.07; H, 6.49; N 4.55%.
(3R,4S)-N-[3-Hyd r oxy-2,2-d im eth yl-6-flu or och r om a n -
4-yl]-N-m eth yleth a n esu lfon a m id e 4a . Mp 147 °C; [R] )
+38.5° (c ) 2, MeOH), NMR analogue 4.
Anal. Calcd for C14H20FNO4S: C, 52.98; H, 6.35; N, 4.41.
Found: C, 52.87; H, 6.39; N 4.56%.
(3S,4R)-N-[3-Hyd r oxy-2,2-d im eth yl-6-flu or och r om a n -
4-yl]-N-m eth yleth a n esu lfon a m id e 4b. Mp 143 °C; [R] )
-42.1° (c ) 2, MeOH), NMR analogue 4.
Anal. Calcd for C14H20FNO4S: C, 52.98; H, 6.35; N, 4.41.
Found: C, 52.79; H, 6.43; N 4.45%.
N-[6-Ch lor o-2,2-d im eth yl-3-h yd r oxych r om a n -4-yl]-N-
m eth ylm eth a n esu lfon a m id e 5. Mp 167 °C; 1H NMR (CDCl3)
δ [ppm] ) 1.23 (s, 3H), 1.51 (s, 3H), 2.46 (d, J ) 5.1 Hz, 1H),
2.70 (s, 3H), 3.13 (s, 3H), 3.80 (dd, J ) 10 Hz und 5.1 Hz; 1H),
4.90 (d, J ) 10 Hz, 1H), 6.75 (d, J ) 8.5 Hz; 1H), 7.14 (dd, J
) 8.5 Hz und 2.5 Hz, 1H), 7.25 (d, J ) 2.5 Hz, 1H).
Anal. Calcd for C13H18ClNO4S: C, 48.82; H, 5.67; N, 4.38.
Found: C, 49.00; H, 5.59; N 4.46%.
N-[2,2-Dim et h yl-3-h yd r oxy-6-p r op oxych r om a n -4-yl]-
N-m eth ylm eth a n esu lfon a m id e 6. Mp 150 °C; 1H NMR
(CDCl3) δ [ppm] ) 1.02 (t, J ) 7.3 Hz, 3H), 1.21 (s, 3H), 1.50
(s, 3H), 1.77 (sext., J ) 7.3 Hz, 2H), 2.4 (s br., 1H), 2.69 (s,
3H), 3.13 (s, 3H), 3.8 (d, J ) 9.8 Hz, 1H), 3.86 (t, J ) 7 Hz,
2H), 4.90 (d, J ) 9.8 Hz, 1H), 6.7-6.82 (m, 3H).
Anal. Calcd for C16H25NO5S: C, 55.96; H, 7.34; N, 4.08.
Found: C, 56.05; H, 7.39; N 4.02%.
N-[6-Ben zyloxy-2,2-d im eth yl-3-h yd r oxych r om a n -4-yl]-
N-m eth ylm eth a n esu lfon a m id e 7. Mp 163 °C; 1H NMR
(CDCl3) δ [ppm] ) 1.2 (s, 3H), 1.48 (s, 3H), 2.36 (d, J ) 5.5
Hz, 1H), 2.6 (s, 3H), 3.05 (s, 3H), 3.75 (dd, J ) 11 Hz and 5.5
Hz, 1H), 4.85 (d, J ) 11 Hz, 1H), 5.0 (s, 2H), 6.7-6.9 (m, 3H),
7.3-7.45 (m, 5H).
Anal. Calcd for C17H24F3NO5S: C, 49.63; H, 5.88; N, 3.40.
Found: C, 49.74; H, 5.75; N 3.46%.
Sp ectr a l a n d An a lytica l Da ta . N-[6-Cya n o -3-h yd r oxy-
2,2-d im e t h y l-c h r o m a n -4-y l]-N -m e t h y le t h a n e s u lfo n -
a m id e 1. 1H NMR (CDCl3) δ [ppm] 1.26 (s, 3H); 1.44-1.61
(m, 6H); 2.69 (s, 3H); 2.70-2.72 (m, 1H); 3.24-3.35 (m, 2H);
3.77-3.85 (m, 1H); 4.87-4.93 (m, 1H); 6.87-6.91 (m, 1H);
7.45-7.50 (m, 1H); 7.62-7.64 (m, 1H); mp 139 °C.
Anal. Calcd for C15H20N2O4S: C, 55.54; H, 6.21; N, 8.64.
Found: C, 55.44; H, 6.12; N 8.46%.
(3R,4S)-N-[6-Cya n o-3-h yd r oxy-2,2-d im eth ylch r om a n -
4-yl]-N-m eth yleth a n esu lfon a m id e 1a . Mp 192 °C; [R] )
+3.2° (c ) 2; MeOH). NMR as 1.
Anal. Calcd for C20H25NO5S: C, 61.36; H, 6.44; N, 3.58.
Found: C, 61.27; H, 6.59; N 3.56%.
(3R,4S)-N-[6-Ben zyloxy -2,2-d im eth yl-3-h yd r oxych r o-
m a n -4-yl]-N-m eth yleth a n esu lfon a m id e 8a . Mp 166 °C; 1H
NMR (CDCl3) δ [ppm] ) 1.2 (s, 3H), 1.45 (t, J ) 7.3 Hz, 3H),
1.49 (s, 3H), 2.59 (d, OH), 2.60 (s, 3H), 3.20 (q, J ) 7.3 Hz,
2H), 3.76 (dd, J ) 10 and 5.5 Hz, 1H), 4.80 (d, J ) 10 Hz, 1H),
5.02 (s, 2H), 6.7-6.9 (m, 3H), 7.3-7.45 (m, 5H); [R] ) + 40.5°
(c ) 2, MeOH).
Anal. Calcd for C21H27NO5S: C, 62.20; H, 6.71; N, 3.45.
Found: C, 62.17; H, 6.59; N 3.56%.
Anal. Calcd for C15H20N2O4S: C, 55.54; H, 6.21; N, 8.64.
Found: C, 55.65; H, 6.22; N 8.77%.
(3S,4R)-N-[6-Cya n o -3-h yd r oxy-2,2-d im eth ylch r om a n -
4-yl]-N-m eth yleth a n esu lfon a m id e 1b. Mp 192 °C; [R] )
-4.2° (c ) 2; MeOH). NMR as 1.
(3S,4R)-N-[6-Ben zyloxy -2,2-d im eth yl-3-h yd r oxych r o-
m a n -4-yl]-N-m eth yleth a n esu lfon a m id e 8b. Mp 173 °C.
NMR see 8a . [R] ) - 41° (c ) 2, MeOH).
Anal. Calcd for C21H27NO5S: C, 62.20; H, 6.71; N, 3.45.
Found: C, 62.27; H, 6.65; N 3.44%.
Anal. Calcd for C15H20N2O4S: C, 55.54; H, 6.21; N, 8.64.
Found: C, 55.39; H, 6.15; N 8.57%.
N-[6-Bu toxy -2,2-d im eth yl-3-h yd r oxych r om a n -4-yl]-N-
m eth ylm eth a n esu lfon a m id e 9. Mp 139 °C; 1H NMR (CDCl3)
δ [ppm] ) 0.96 (t, J ) 7.2 Hz, 3H), 1.21 (s, 3H), 1.49 (s, 3H),
1.4-1.8 (m, 4H), 2.37 (s, br., 1H), 2.69 (s, 3H), 3.13 (s, 3H),
6-[Cyan o-3-h ydr oxy-2,2-dim eth ylch r om an -4-yl)-N-m eth -
1
yl bu ta n esu lfon a m id e 2. H NMR (CDCl3) δ [ppm] 1.00 (t,

3836 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Gerlach et al.
(7) (a) Woosley, R. L. CAST: Implications for Drug Development.
Clin. Pharmacol. Ther. 1990, 47, 553-556. (b) Pratt, C. M.;
Moye, L. A. The Cardiac Arrhythmia Suppression Trial: back-
ground, interim results and implications. Am. J . Cardiol. 1990,
65(4), 20B-29B.
3.79 (d, J ) 9.8 Hz, 1H), 3.89 (t, J ) 6.3 Hz, 2H), 4.88 (d, J )
9.8 Hz, 1H), 6.70-6.80 (m, 3H).
Anal. Calcd for C17H27NO5S: C, 57.12; H, 7.61; N, 3.92.
Found: C, 57.07; H, 7.59; N 4.01%.
(8) Singh, B. N. The coming of Age of the Class III Antiarrhythmic
Principle: Retrospective and Future Trends. Am. J . Cardiol.
1996, 78 (suppl 4A), 17-27.
(9) Wellens, H. J .; Brugada, P.; Faber, J . Ventricular arrhythmias:
Mechanisms and actions of antiarrhythmic drugs. Am. Heart J .
1984, 107, 1053-1057.
N-[-3-Hyd r oxy-2,2-d im eth yl-6-(4,4,4-tr iflu or obu toxy)-
ch r om a n -4-yl]-N-m eth ylm eth a n esu lfon a m id e 10. Mp 162
°C. NMR see 10a .
Anal. Calcd for C17H24F3NO5S: C, 49.63; H, 5.88; N, 3.40.
Found: C, 49.54; H, 5.79; N 3.36%.
(10) Waldo, A. L.; Camm, A. J .; DeRuyter, H.; Friedman, P. L.;
MacNeil, D. J .; Pauls, J . F.; Pitt, B.; Pratt, C. M.; Schwartz, P.
J .; Veltri, E. P. for the SWORD Investigators. Effect of d-sotalol
on mortality in patients with left ventricular dysfunction after
recent and remote myocardial infarction. Lancet 1996, 348,
7-12.
(11) Torp-Pedersen, C.; Moller, M.; Bloch-Thomsen, P. E.; Kober, L.;
Sandoe, E.; Egstrup, K.; Agner, E.; Carlsen, J .; Videbaek, J .;
Marchant, B.; Camm, A. J ., Dofetilide in patients with congestive
heart failure and left ventricular dysfunction. Danish Investiga-
tions of Arrhythmia and Mortality on Dofetilide Study Group.
N. Engl. J . Med. 1999, 341, 857-65.
(3S, 4R)-(+)-N-[-3-Hyd r oxy-2,2-d im eth yl-6-(4,4,4-tr i-
flu o r o b u t o x y )c h r o m a n -4-y l]-N -m e t h y lm e t h a n e s u l-
fon a m id e 10b. Mp 179 °C. NMR see 10a . [R] ) -2.6° (c ) 2,
MeOH).
Anal. Calcd for C17H24F3NO5S: C, 49.63; H, 5.88; N, 3.40.
Found: C, 49.64; H, 5.85; N 3.49%.
II. P h a r m a cologica l Meth od s. Heterologous expression
of IKs in Xenopus oocytes.
Handling and injection of Xenopus oocytes has been de-
scribed previously in detail.40,41 Xenopus laevis were anaes-
thetized by immersion in 3-aminobenzoic acid ethyl ester (1
g/L) and put on ice. A small incision was made to retrieve sacs
of oocytes, and then the incision was sutured with absorbable
surgical thread. The ovaries of Xenopus laevis were cut into
small pieces and the oocytes were first washed in a Ca2+-free
Or-2 solution containing (mM): 82.5 NaCl, 2 KCl, 1 MgCl2, 5
HEPES, pH 7.4, and subsequently digested with the same Or-2
solution to which 1 mg mL-1 collagenase A (Worthington, type
II) was added until no follicle was detectable on the surface of
the oocytes. Oocytes were stored in recording solution ND-96
containing (mM) 96 NaCl, 2 KCl, 1.8 CaCl2, 1 MgCl2, 5 HEPES,
pH 7.4) with additional Na-pyruvate (275 mg/L), theophylline
(90 mg/L), and gentamycin (50 mg/L) at 18 °C. The oocytes
were individually injected with cRNA encoding for the human
potassium channel â-subunit of KvLQT1 (hminK). From 12 h
on after the injection, two-microelectrode voltage-clamp re-
cordings were carried out using a GeneClamp amplifier (Axon
Instruments, Foster City, USA) and MacLab A/D converter
and software for data acquisition and analysis (ADInstru-
ments, Castle Hill, Australia). The microelectrodes were filled
with 3 M KCl solution and had resistances between 0.5 and 1
MΩ. During the electrophysiological experiments the oocytes
were continuously superfused with ND96 at room tempera-
ture. The test compounds were dissolved in DMSO at a
concentration of 10 mM. This solution was added to ND96
shortly before the experiment.
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Agents Have A Lot of Potential but a Long Way To Go: Reduced
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Bedside, 2nd ed., Zipes D. P., J alife, J ., Eds.; Saunders: Phila-
delphia, 1995; pp 885-899.
(15) J urkiewicz, N. K.; Sanguinetti, M. C. Rate Dependent Prolonga-
tion of Cardiac Action Potentials By a Methanesulfonanilide
Class III Antiarrhythmic Agent: Specific Block of a Rapidly
Activating Delayed Rectifier K+ Current By Dofetilide. Circ. Res.
1993, 72, 75-83.
(16) Sanguinetti, M. C.; J urkiewicz, N. K.; Scott, A.; Siegl, P. K. S.
Isoproterenol antagonizes prolongation of refractory period by
the class III antiarrhythmic agent E-4031 in guinea pig
myocytes. Circ. Res. 1991, 68, 77-84.
(17) Schreieck, J .; Wang, Y.; Gjini, V.; Korth, M.; Zrenner, B.;
Scho¨mig, A.; Schmitt, C. Differential Effect of â-Adrenergic
Stimulation on the Frequency-Dependent Electrophysiologic
Actions of the New Class III Antiarrhythmics Dofetilide, Am-
basilide, and Chromanol 293B. J . Cardiovasc. Electrophysiol.
1997, 8, 1420-1430.
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Ack n ow led gm en t. We wish to thank H. Ahlborn,
Dr. A. Burgard, F. Chlosta, G. Erhard, O. Fischer, P.
Hess, R. Loder, J . Lo¨ffert, F. Roll, Dr. V. Santagada, T.
Spors, T. Trong, and P. Voss for their excellent technical
assistance in the synthesis of the compounds and also
W. Heyse and H. Schweitzer for their excellent technical
assistance in the X-ray single crystal structure analysis.
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