Cardioselective KATP channel blockers derived from a new series of m-anisamidoethylbenzenesulfonylthioureas

Article abstract of DOI:10.1021/jm000985v

Sulfonylthioureas exhibiting cardioselective blockade of ATP-sensitive potassium channels (K_ATP channels) were discovered by stepwise structural variations of the antidiabetic sulfonylurea glibenclamide. As screening assays, reversal of rilmaka

Full text of DOI:10.1021/jm000985v

J . Med. Chem. 2001, 44, 1085-1098
1085
Ca r d ioselective KATP Ch a n n el Block er s Der ived fr om a New Ser ies of
m -An isa m id oeth ylben zen esu lfon ylth iou r ea s
Heinrich C. Englert,*,† Uwe Gerlach,† Heinz Goegelein,‡ J ens Hartung, Holger Heitsch,† Dieter Mania,† and
Sabine Scheidler‡
Medicinal Chemistry and DG Cardiovascular, Aventis Pharma Deutschland GmbH, D-65926 Frankfurt/ Main, Germany
Received May 11, 2000
Sulfonylthioureas exhibiting cardioselective blockade of ATP-sensitive potassium channels (KATP
channels) were discovered by stepwise structural variations of the antidiabetic sulfonylurea
glibenclamide. As screening assays, reversal of rilmakalim-induced shortening of the cardiac
action potential in guinea pig papillary muscles was used to probe for activity on cardiac KATP
channels as the target, and membrane depolarization in CHO cells stably transfected with
hSUR1/hKir6.2 was used to probe for unwanted side effects on pancreatic KATP channels.
Changing glibenclamide’s para-arrangement of substituents in the central aromatic ring to a
meta-pattern associated with size reduction of the substituent at the terminal nitrogen atom
of the sulfonylurea moiety was found to achieve cardioselectivity. An additional change from
a sulfonylurea moiety to a sulfonylthiourea moiety along with an appropriate substituent in
the ortho-position of the central aromatic system was a successful strategy to further improve
potency on the cardiac KATP channel. Among this series of sulfonylthioureas HMR1883, 1-[5-
[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3-methylthiourea, and its sodium salt
HMR1098 were selected for development and represent a completely new therapeutic approach
toward the prevention of life-threatening arrhythmias and sudden cardiac death in patients
with coronary heart disease.
In tr od u ction
can ameliorate many of the electrophysiological de-
rangements in early ischemia and prevented ischemic
ventricular fibrillation (VF) in isolated hearts and in
whole animals.10,11 However, antidiabetic sulfonylureas
cannot be regarded as an option for the prevention of
severe arrhythmias in cardiovascular patients since
they lack tissue selectivity. At least from animal experi-
ments it can be concluded that antiarrhythmic doses of
glibenclamide will be connected with the risk of severe
metabolic and hemodynamic disturbances.11
Sudden cardiac death is a leading cause of mortality
in western countries.1 In the United States it annually
accounts for 300 000 deaths and in Europe for 120 000
deaths. The majority of these victims suffer from
coronary artery disease suggesting that myocardial
ischemia may have triggered a lethal arrhythmia.2,3
Thus far, conventional antiarrhythmic therapy has
failed in the prevention of sudden cardiac death due to
an inherent proarrhythmic potential as highlighted by
large clinical trials such as CAST or SWORD.4,5 An
increase of extracellular potassium ions and a shorten-
ing of the cardiac action potential, well-established
derangement seen soon after the onset of ischemia, set
the stage for a re-entry movement of the cardiac
excitation wave underlying ischemic ventricular tachy-
cardias and fibrillation.6 In this context the opening of
KATP channels has been shown to play a pivotal role.7-9
Among all ion channels controlling the shape of the
cardiac action potential, the KATP channel is unique
since it is activated only during myocardial ischemia but
does not contribute to the shape in the absence of
ischemia. Consequently, a blocker of this channel should
have the unique property to be pharmacologically silent
in the absence of ischemia, whereas it has the potential
to abrogate ischemia-related electrophysiological de-
rangements and, in turn, to prevent the formation of
life-threatening arrhythmias. KATP channels can be
blocked by antidiabetic sulfonylureas such as glibencla-
mide. Indeed, it was demonstrated that glibenclamide
Glibenclamide predominantly triggers insulin secre-
tion via blockade of pancreatic KATP channels,12,13
potently interferes with KATP channels in vascular
smooth muscles,14 and inhibits ischemic precondition-
ing15 as a consequence of mitochondrial KATP channel
blockade.16 Recently, HMR1883, a member of the m-
anisamidoethylbenzenesulfonylthioureas, was reported
to block cardiac KATP channels more potently than
pancreatic and vascular channels without affecting
other types of cardiac potassium currents such as Ikr
and Iks.17 This compound prevented sudden cardiac
death in conscious dogs subjected to exercise and
myocardial ischemia without the untoward side effects
of glibenclamide such as hypoglycemia and a reduction
in coronary flow.18 Cardioselectivity of HMR1883 was
also confirmed in rats with coronary ligation and
reperfusion19 where the compound exerted antifibrilla-
tory effects at a dose range that showed no effects on
insulin, while glibenclamide potently released insulin
even at the lowest antifibrillatory dose. Also not opti-
mized for this property, HMR1883 showed no interfer-
ence with mitochondrial KATP channels in a model of
diazoxide (100 µM)-induced flavoprotein oxidation.20
This observation explains why HMR1883, in contrast
* To whom correspondence should be addressed. Tel: +49 69 305
17624. Fax: +49 69 331399. E-mail: Heinrich.Englert@aventis.com.
† Medicinal Chemistry.
‡ DG Cardiovascular.
10.1021/jm000985v CCC: $20.00 © 2001 American Chemical Society
Published on Web 02/24/2001

1086 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Englert et al.
to glibenclamide, has no impact on myocardial precon-
ditioning.21 Thus, for the first time a sulfonylurea is
available to safely explore the clinical potential of
cardiac plasmalemmal KATP blockade as a new anti-
fibrillatory approach in patients with coronary artery
disease.
As predicted for a selective blocker of plasmalemmal
cardiac KATP channel, HMR1883 was indeed shown in
preclinical studies to have no effect on the ECG under
nonischemic conditions but to prevent ECG abnormali-
ties as soon as ischemia comes into play.22 The well-
established proarrhythmic potential of existing antiar-
rhythmics, however, is generally attributed to a continu-
ous impact of these agents on the ECG. In this context
HMR1883 should bear no proarrhythmic potential, and
so far proarrhythmic effects could not be seen in any of
the preclinical studies. Given this unique pharmacologi-
cal profile, HMR1883 was selected for development as
an agent for the prevention of malignant arrhythmias
and sudden cardiac death.
ever, displayed no cardioselectivity. This prompted us
to include regioisomers of glibenclamide which might
be more sensitive to this kind of structural variation.
Ch em istr y
Scheme 1 describes the synthesis of the majority of
the sulfonylthioureas starting from appropriately sub-
stituted and in most cases readily available phenylethy-
lamines 3 as the key intermediates. These amines were
coupled either with 5-chloro-2-methoxybenzoic acid us-
ing standard coupling reagents such as N,N′-carbonyl-
diimidazole or with 5-chloro-2-methoxybenzoic acid
chloride in pyridine as solvent. Introduction of the
sulfonamide group into amides 4 was achieved by
chlorosulfonic acid and subsequent treatment of the
resulting sulfonyl chloride intermediates with aqueous
ammonia in acetone. Sulfonamides 5 are readily trans-
formed into sulfonylthioureas 6 by treatment with
isothiocyanates in the presence of an appropriate base
such as K2CO3. Phenethylamines 3f,h -j were prepared
via known procedures starting from 4-substituted ben-
zaldehydes, which were treated with Meldrum’s acid in
tetraethylammonium formiate (TEAM) to give 4-sub-
stituted phenylpropionic acids.26 Treatment of these
acids with azidodiphenylphosphate in tert-butanol af-
forded amines 3 via their tert-butoxycarbonyl-protected
derivatives. The amide 4e was transformed into its iodo
derivative 4f via reduction of the nitro group in 4e using
SnCl2 and subsequent Sandmeyer reaction of the inter-
mediate amine in approximately 50% yield. The N-
morpholino derivative 5f was obtained by refluxing the
fluoro derivative 5b in morpholine. The yield, however,
was only 10%. Cleavage of the methoxy ethers was
observed as the main reaction. 2-Methylsulfinyl and
2-methylsulfonyl derivatives 5h ,i were obtained from
the corresponding methylmercapto precursor 5g by
oxidation with aqueous H2O2 in acetic acid at either 0
or 80 °C. H2O2 in aqueous NaOH was the reagent of
choice to obtain the sulfonylureas 7 from the corre-
sponding sulfonylthioureas 6.
In the present study the discovery of HMR1883 as
well as a structure-activity relationship (SAR) among
this new series of sulfonylthioureas regarding effects on
plasmalemmal cardiac and pancreatic KATP channels
will be elucidated. The design of new sulfonylureas with
a cardioselective profile was based on observations
among existing antidiabetic sulfonylureas such as glime-
piride, glibenclamide, and tolbutamide.
Scheme 2 shows the synthesis of sulfonylthioureas
6p -w . Compounds 6p -v are higher homologues of
HMR1883 containing more than one carbon atom in the
adjacent alkoxy group. In the preparation of these
compounds via the route described in Scheme 1, the
chlorosulfonation of the corresponding alkoxy amide
analogues of 4 ended up with yields lower than 10%,
apparently due to steric hindrance in the adjacent ortho-
position by the bulky alkoxy substituents. To avoid these
shortcomings, compound 8a 27 was chosen as a conve-
nient starting material in which the sulfamoyl group
was already introduced in the presence of the methoxy
group and the phenethylamino moiety was protected by
trifluoroacetylation. The sulfamoyl group was addition-
ally proteced by its corresponding N,N-dimethylforma-
midine derivative 8b. The methoxy ether was cleaved
using boron tribromide to give 9 as a versatile inter-
mediate which was well-suited for O-alkylation by
standard procedures. Deprotected compounds 10a -g
were subsequently converted via amides 5p -v into
corresponding sulfonylthioureas 6p -v as described in
Scheme 1. Compound 6w is the “demethoxy” derivative
of HMR1883. It was analoguously synthesized from the
already known intermediate 10h .27
Tolbutamide, for example, exerts little if any effect
on cardiac KATP channels while potently interfering with
the pancreatic SUR1 component of KATP channels.23 In
contrast, glibenclamide acts on both types of KATP
channels suggesting that the methoxychlorobenzamide
moiety is a good option to achieve additional cardiac
activity since tolbutamide lacks this structural feature.
On the other hand, a bulky lipophilic substituent
attached to the terminal nitrogen of the sulfonylurea
moiety is present in both compounds and in addition is
a key structural feature of all other antidiabetic sulfo-
nylureas known so far.24 In the following we focused on
structural variations of glibenclamide-like molecules
keeping the methoxychlorobenzamide moiety unchanged
and, in addition, tried to reduce the size of the lipophilic
substituent at the sulfonylurea moiety. However, this
concept failed in the glibenclamide series itself. Replac-
ing glibenclamide’s c-hexyl group by methyl leads to the
known compound HB985, an investigational tool used
to probe for pancreatic KATP channels.25 HB985, how-

Cardioselective KATP Channel Blockers
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1087
Sch em e 1. Synthesis of Sulfonylthioureas 6a -o and Sulfonylureas 7a ,n a
a
Reagents: (a) Meldrum’s acid, TEAF; (b) azidodiphenylphosphate, TEA, tert-butanol; (c) 2 N HCl, MeOH; (d) (i) N,N′-carbonyldiimi-
dazole, TEA, 5-chloro-2-methoxybenzoic acid, (ii) 5-chloro-2-methoxybenzoic acid chloride, pyridine; (e) SnCl2, HCl, NaNO2, KJ ; (f) ClSO3H;
(g) NH4OH, acetone; (h) morpholine; (i) AcOH, H2O2, 0 °C; (j) AcOH, H2O2, reflux; (k) CH3NCS, KOtBu, DMF; (l) NaOH, H2O2.
Sch em e 2. Synthesis of Sulfonylthioureas 6p -w with Modified Alkoxy Substituents in Position 2 of the Central
Aromatic Ringa
a
Reagents: (a) N,N-dimethylformamide dimethylacetal, DMF; (b) BBr3; (c) R′1-Hal (R′1 ) 1-deoxy-R1), K2CO3; (d) 5.5 N HCl, reflux;
(e) N,N-carbonyldiimidazole, TEA, 5-chloro-5-methoxybenzoic acid; (f) CH3NCS, KOtBu, DMF.
Compounds 5j (Scheme 1) and 13a -h (Scheme 3) are
“deoxy” derivatives of HMR1883 bearing substituents
attached via a carbon atom in position 2 of the central
aromatic ring. Except for the methyl derivative 5j,
which is readily available via the synthetic path de-
scribed in Scheme 1, the higher homologues 13a -h
were more favorably synthesized via a different syn-
thetic route as depicted in Scheme 3 with transition
metal-mediated C-C bond formations in the presence
of the already introduced sulfonamide group as the key
synthetic step, thus avoiding again sluggish chlorosul-
fonation in the presence of large size substituents R
(Table 3).
Key intermediates in the synthesis of these sulfony-
lureas are the N,N-dimethylformamidino-protected 2-bro-
mo or 2-iodo sulfonamides 11a ,b, which were readily
available by treatment of the sulfonamides 5d ,e with
N,N-dimethylformamide dimethylacetal in DMF.28 The
alkyl-substituted sulfonamides 12a -c were prepared
via a Pd(0)-catalyzed Nigishi-Kumada-type cross-cou-

1088 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Englert et al.
Sch em e 3. Synthesis of Sulfonylthioureas 13a -h via Pd(0)-Catalyzed Cross-Coupling Reactionsa
a
Reagents: (a) (CH3O)2CHN(CH3)2, DMF, 20 °C; (b) 12a -c: RMgBr, ZnCl2, Pd(dppf)Cl2, CuI, THF, 12d ,f,i: RSnBu3, Pd(PPh3)2Cl2,
THF, 12g,h : RSnMe3, Pd(PPh3)2Cl2, THF, 12e,h : RB(OH)2, Pd(PPh3)4, Cs2CO3, toluene/EtOH; (c) concd HCl, MeOH; (d) CH3NCS, KOtBu,
DMF.
Sch em e 4. Synthesis of Sulfonylthioureas 6x,y and Sulfonylureas 7b,ca
a
Reagents: (a) CS2, ClCOOC2H5, NH3; (b) c-C6H11NCS, KOtBu, DMF; (c) CS2, ClCOOC2H5, (CH3)2NH; (d) 1 N NaOH, H2O2.
pling reaction29 of the iodide 11b with the appropriate
alkylzinc reagent and copper(I) as cocatalyst followed
by removal of the amidino protecting group. The acety-
lene, the 2-furyl, and the 2- and 3-pyridyl substituents
of 12d ,f-h were introduced by a Pd(0)-catalyzed Stille-
type cross-coupling reaction of the appropriate trialkyl-
stannanes with either the bromide or the iodide 11a ,b.30
It is noteworthy that the introduction of pyridyl residues
could only be achieved in satisfactory yields by using
freshly prepared 2- or 3-(trimethylstannyl)pyridine,
respectively.31 Subsequent cleavage of the amidino
protecting group yielded the corresponding sulfonamides
12d ,f-h . The 2-phenyl-substituted sulfonamide 12e
was finally derived from a Pd(0)-catalyzed Suzuki-type
cross-coupling reaction32 of bromide 11a with ben-
zeneboronic acid and subsequent removal of the amidino
protecting group.
Treatment of likewise thus obtained sulfonamides
with methyl isothiocyanate finally gave the desired
sulfonylthioureas 13a -h .
Compound 6y (Scheme 4) is a HMR1883 derivative
with the unsubstituted terminal nitrogen of the sulfo-
nylthiourea moiety. This compound could not be ob-
tained by using potassium or sodium isothiocyanate in
a protic solvent, although corresponding reactions with
benzenesulfonamides without adjacent substituents
were found in our laboratory to proceed smoothly.
Therefore, we chose the rather complicated route via a
sulfonyl isothiocyanate intermediate that readily reacts
with ammonia to give 6y. To this end the sulfonamide

Cardioselective KATP Channel Blockers
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1089
Sch em e 5. Synthesis of Chromane-Derived Sulfonyl(thio)ureas 19a -d with a Chromane Frameworka
a
Reagents: (a) phosphonoacetic acid trimethyl ester, NaH, THF; (b) (1) Pd/C (10%), H2, (2) 2 N NaOH, EtOH; (c) (1) azidodiphe-
nylphosphate, TEA, tBuOH, (2) 2 N HCl, MeOH; (d) (+)- or -(-)-mandelic acid, EtOH; (e) N,N′-carbonyldiimidazole, TEA, 5-chloro-2-
methoxybenzoic acid; (f) ClSO3H, NH4OH; (g) CH3NCS, K2CO3, DMSO; (h) CCl3CONHCH3, NaOH (powder), DMSO.
5a was reacted with carbon disulfide to give a dipotas-
sium salt of a dithioxanthogenate which was subse-
quently treated with ethyl chloroformate to enable the
formation of an intermediate sulfonyl isothiocyanate.
This intermediate was then treated with aqueous am-
monia to provide 6y. The N-cyclohexyl derivatives of
HMR1883, 6x and 7c, were obtained as described in
Scheme 1 using H2O2 in 2 N NaOH. The dimethyl
derivative 7b was obtained in the same way as 6y by
reaction of aqueous dimethylamine instead of aqueous
ammonia with the sulfonyl isothiocyanate and subse-
quent oxidation of the thiosulfonylurea.
Resu lts a n d Discu ssion
Our final goal was to provide a compound that
prevents ischemic arrhythmias without affecting meta-
bolic parameters for at least up to the 10-fold minimally
effective antiarrhythmic dose level in a given species.
However, animal models that are available for this
purpose are rather sophisticated and, hence, cannot be
used for compound screening. As a surrogate for insulin
secretion we chose membrane depolarization in hSUR1/
hKir6.2 (the cloned components of the pancreatic KATP
channel) transfected CHO cells. As indicated by the
potency of glibenclamide, this testing system can be
regarded as a validated model with respect to results
obtained in native pancreatic tissue and, hence, is well-
suited for evaluations of new sulfonylureas. It is im-
portant to keep in mind that insulin secretion in native
tissue is triggered only when depolarization reaches a
certain threshold of membrane potential. Unfortunately
such an accepted model with a proven equivalence to
native tissue was not available for the cloned cardiac
SUR2A/Kir6.2 KATP channel. The poor potency described
in this system for glibenclamide is at variance with our
own observations showing a high potency of glibencla-
mide in native cardiac tissue, such as isolated cardi-
omyocytes34 or papillary muscles. This indicates that
the presently available SUR2a/Kir6.2 system still lacks
some important intrinsic modulators. Therefore, we
decided to use a native tissue preparation to avoid these
shortcomings. The reversal of action potential shorten-
ing in the isolated papillary muscle subjected to the
The sulfonyl(thio)ureas 19a -d with a chromane
framework instead of the central aromatic ring were
synthesized according to Scheme 5. Starting material
was 7-methoxy-4-chromanone (14)33 which was sub-
jected to Wittig reaction with phosphonoacetic acid
trimethyl ester to yield the carboxy derivative 15 after
hydrogenation and alkaline hydrolysis. This acid 15 was
converted to a racemic mixture of amine 16 as described
for phenethylamines 3f,h -j in Scheme 1 using azido-
diphenylphosphate in tert-butanol which provides 16 via
its tert-butoxycarbonyl-protected derivative. Enantio-
meric separation was achieved via fractional crystal-
lization following salt formation with either (S)-(+)- or
(R)-(-)-mandelic acid. The further transformation into
thioureas 18a -b follows nearly the same pattern as
given by steps d, f, g, k of Scheme 1. In step k the base
used to introduce the thiourea moiety from isothiocy-
anate was K2CO3 in DMSO. In contrast to phenylethyl-
amine-derived sulfonylureas 7, the chromane sulfonyl-
ureas 19c-d were directly obtained from the sulfamoyl-
chromanes 18 using N-methyltrichloroacetamide in
DMSO/NaOH. During the whole sequence from 16 to
19 a (+)-educt yielded allways a (+)-product whereas
(-)-educts gave consistently (-)-products. As checked
by HPLC, enantiomeric purity was >98% at the stage
of the amine 16 and >99% at the stage of the final
products 19a -d .
specific KATP channel opener rilmakalim (HOE 23434,35
)
can be taken as an indirect measure of the antifibril-
latory the potency on the cardiac KATP channel. How-
ever, HMR1883, inducing a 71% reversal of the short-
ening at 2 µM (Table 1), significantly reduced the
incidence of VF by 50% already at 0.1 µM.14 This
indicates that already slight effects on action potential
shortening are sufficient to completely prevent VF.
Therefore, results from our screening assay may un-

1090 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Englert et al.
Ta ble 1. Physical Data and Effects on KATP Channels for Sulfonylthioureas and Sulfonylureas
compd
X
R, R′
mp (°C)
formula
anal.
pancreaticc KATP (% inhib)
cardiace KATP (% inhib)
gliba
HB985
7c
24, 73.3, 92.7d
-0.7, 62.8, 86.3
65.5, 92.8, 81.7
-2.8, -1.3, 43.9
-3.6, -3.2, 25.0
5, 24.3, 83.8
0.0, 76, 87f
nd,g 31, 96
nd, 45, 77
nd, 35, 68
nd, 0, nd
3, 71, 117
nd, 29, nd
nd, 60, nd
O
O
O
S
S
S
H, c-C6H11
H, CH3
CH3, CH3
H, CH3
H, H
H, c-C6H11
164-167
201-203
205-208
190-193
177-178
167-169
C24H30ClN3O6S
C19H22ClN3O6S
C20H24ClN3O6S
C19H22ClN3O5S2
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
7a
7b
6a b
6y
C
18H20ClN3O5S2
1.6, 11.2, 64.7
20.5, 87.6, 121.5
6x
C24H30ClN3O5S2
a
glib, glibenclamide. bHMR1883. ch-SUR1/Kir6.2 activated by diazoxide; test compound concentrations 0.1, 1, and 10 µM. dGlibenclamide
concentrations 1, 3, and 10 nM. eGuinea pig papillary muscle, % reversal of action potential shortening due to rilmakalim; test compound
concentrations 0.2, 2, and 20 µM. Glibenclamide concentrations 0.02, 0.2, and 2 µM. gnd, not determined.
f
Ta ble 2. Physical Data and Effects on KATP Channels for Sulfonylthioureas: Variations of the Oxo Substituent
compd
R
mp (°C)
formula
anal.
pancreaticc KATP (% inhib)
cardiace KATP (% inhib)
gliba
6a b
6k
6p
6q
6r
6s
6u
6v
24, 73.3, 92.7d
5, 24.3, 83.8
0.8, 6.0, 64.9
-2.7, 16.3, 75.4
-4.7, 27.4, 81.1
4.2, 63.6, 103.26
1.7, 31.8, 94.0
12.5, 26.2, 49.5
1,0, 45.5, 96.4
0.0, 76, 87f
3, 71, 117
nd,g 58, nd
14, 100, nd
24, 95, nd
40, 114, nd
nd, 79, 96
61, 98, nd
14, 97, nd
CH3
CF3
C2H5
i-C3H7
C3H7
C3H5
180-182
185-187
164-166
179-182
170-173
134-135
105-108
C19H19ClF3N3O5S2
C20H24ClN3O5S2
C21H26ClN3O5S2
C21H26ClN3O5S2
C21H24ClN3O5S2
C21H26ClN3O6S2
C23H30ClN3O7S2
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C2H4-O-CH3
C2H4-O-C2H4-OCH3
a
glib, glibenclamide. bHMR1883. ch-SUR1/Kir6.2 activated by diazoxide; test compound concentrations 0.1, 1, and 10 µM. dGlibenclamide
concentrations 1, 3, and 10 nM. eGuinea pig papillary muscle, % reversal of action potential shortening due to rilmakalim; test compound
concentrations 0.2, 2, and 20 µM. Glibenclamide concentrations 0.02, 0.2, and 2 µM. gnd, not determined.
f
derestimate antifibrillatory potency of our compounds.
With glibenclamide and HMR1883, two compounds are
available that allow correlation of effects in our screen-
ing models with the in vivo situation measuring anti-
fibrillatory potency and insulin release. As already
mentioned HMR1883 in rats is antifibrillatory at a dose
range of 1-10 mg/kg iv without having significant
effects on plasma insulin.19 This correlates perfectly
with approximately 70% inhibition of the action poten-
tial shortening at 2 µM (Table 1) with almost no effect
(<30% inhibition) on the pancreatic â-cell membrane
potential at this concentration. In the rat only at 30 mg/
kg iv did HMR1883 increase serum insulin, which has
to be correlated with a 80% inhibition at 10 µM of
pancreatic KATP channels (Table 1). Vice versa, glib-
enclamide is antifibrillatory at doses of 0.1-1 mg/kg iv,
while it already induces significant insulin secretion at
0.01 mg/kg iv without having any effect on VF. Again,
this is completely in line with the data of our screening
assays showing no effect at 20 nM in the cardiac
preparation whereas the pancreatic KATP channel was
almost completely inhibited already at 10 nM (see Table
1). Using these two marker compounds, glibenclamide
and HMR1883, for comparison the amount of cardiose-
lectivity achieved with any other compound of our series
can be easily estimated.
central aromatic ring, was considered to be an attractive
lead compound since pancreatic activity, despite an
intact cyclohexyl substituent, was already reduced by
approximately 2 orders of magnitude whereas cardiac
activity was much less affected. When we replaced its
cyclohexyl moiety by the much smaller methyl group of
HB985 we identified for the first time a KATP blocker,
7a , with a greater inhibitory effect in heart than in the
pancreatic system. However, the moderate potency of
7a rendered this compound less attractive in terms of
drug development. This shortcoming could be overcome
by replacement of the sulfonylurea group by a sulfo-
nylthiourea moiety. Starting from compound 7a , this
important structural change increased activity in the
heart as well as in the pancreas, to a similar extent,
thereby providing HMR1883 (6a ) with sufficient cardiac
potency and an acceptable cardioselectivity profile. In
an attempt to further improve the cardiac potency, a
cyclohexyl moiety was reintroduced. However, the re-
sulting compound 6x was found to have less cardiac
potency than HMR1883, indicating that in the series
of sulfonylthioureas cardiac activity benefits from a
small substituent and is less compatible with larger
alkyl substituents. Regarding pancreatic activity 6x
behaved “normal” since the large c-hexyl moiety in-
creased activity by more than 1 order of magnitude. In
7b a further methyl group was attached to the terminal
N of 7a . Since this variation resulted in a complete loss
Compound 7c (Table 1), a meta-derivative of glib-
enclamide with an adjacent methoxy group in the

Cardioselective KATP Channel Blockers
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1091
Ta ble 3. Physical Data and Effects on KATP Channels of Sulfonylthioureas: Influence of Various Substituents
compd
R
mp (°C)
formula
anal.
pancreaticc KATP (% inhib)
cardiace KATP (% inhib)
gliba
6a b
6w
6b
6c
6d
6e
6g
6h
6i
24, 73.3, 92.7d
5, 24.3, 83.8
-4.1, 1.9, 52.7
-3.9, -1.3, 18.1
2.3, 2.8, 40.1
0.0, 76, 87f
3, 71, 117
nd,g 11, nd
nd, 7, nd
nd, 14, nd
nd, 37, nd
nd, 22, nd
nd, 34, nd
nd, 0, nd
OCH3
H
F
Cl
Br
J
SCH3
SOCH3
SO2CH3
N-morpholinyl
CH3
C2H5
C3H7
i-C3H7
ethynyl
C6H5
2-furanyl
2-pyridyl
3-pyridyl
173-175
197-199
194-196
amorph
181
186-187
174-176
205-207
195
183
155
156-160
180
C
18H20ClN3O4S2
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
C18H19ClFN3O4S2
C
C
C
18H19Cl2N3O4S2
18H19BrClN3O4S2
18H19ClIN3O4S2
3.3, 2.2, 67.7
1.7, 19.2, 89.2
-2.1, 15.2, 81.4
1.9, 2.4, 17.6
C19H22ClN3O4S3
C9H22ClN3O5S3
C19H22ClN3O6S3
1.8, 1.1, 16.4
nd, 0, nd
6f
6j
C
22H27ClN4O5S2
-1.6, 26.7, 89.1
1.9, 21.0, 74.8
1.3, 20.5, 92.9
2.3, 41.5, 97.1
12.01, 29.3, 92.4
3.3, 3.4, 27.6
9.4, 33.0, 67.7
-2.6, 16.0, 82.7
6.6, 24.4, 91.4
4.4, 10.2, 62.3
30, 92, nd
nd, 22, nd
nd, 29,nd
nd, 52, nd
nd, 30, nd
nd, 10, nd
nd, 52, nd
nd, 33, nd
43, 80, nd
nd, 20, nd
C19H22ClN3O4S2
C20H24ClN3O4S2
C21H26ClN3O4S2
C21H26ClN3O4S2
C20H20ClN3O4S2
C24H24ClN3O4S2
13a
13b
13c
13d
13e
13f
13g
13h
225
192-194
144-145
85-86
amorph
C
C
22H22ClN3O5S2
23H23ClN4O4S2
C23H23ClN4O4S2
a
glib, glibenclamide. bHMR1883. ch-SUR1/Kir6.2 activated by diazoxide; test compound concentrations 0.1, 1, and 10 µM. dGlibenclamide
concentrations 1, 3, and 10 nM. eGuinea pig papillary muscle, % reversal of action potential shortening due to rilmakalim; test compound
concentrations 0.2, 2, and 20 µM. Glibenclamide concentrations 0.02, 0.2, and 2 µM. gnd, not detemined.
f
of activity this structural pattern was not further
explored. Attempts to further improve cardioselectivity
by removing the N-methyl group of 6a leading to
compound 6y were not successful.
If the 4-methoxy group and the aminoethyl group of
6n were incorporated into a ring system, an almost
inactive compound was transformed to the rather potent
enatiomeric chromane derivatives 19a ,b with the (+)-
compound being more cardioselective, the (-)-enanti-
omer being more potent. Rather unexpected, compound
19c, the sulfonylurea derivative of 19a , displayed a
highly favorable cardioselectivity associated with a
slightly better potency than the parent sulfonylthiourea
19a . In this case the enantiomeric counterpart 19d is
much less potent on both channels. It is tempting to
speculate that in particular 19c interacts with a differ-
ent binding site of the cardiac KATP channel as compared
to “open chain” sulfonylthioureas such as HMR1883.
These results promoted us also to investigate the “des-
3-C” analogue of 19c, 7n . Again, much to our surprise,
7n had almost no activity in the dose range investigated
(Table 4), indicating that in the “open chain” series a
4-methoxy group cannot restore activity as might be
expected from 19c. Hence, we speculated that it is not
the additional electron-donating group introduced by the
chromane oxygen to the central aromatic ring, rather
it is the overall changed geometry that causes chro-
manes such as 19 to target a different binding site on
the cardiac KATP channel.
P h a r m a cologica l P r ofile of HMR1883. As already
mentioned HMR1883 was shown to have potent anti-
fibrillatory effects in a canine model of sudden cardiac
death without the untoward side effects of a nonselective
KATP channel blocker such as glibenclamide.15 In con-
trast to the present investigations the opening of KATP
channels was induced in this canine model by ischemia
due to coronary ligation in the presence of exercise
instead of rilmakalim. As shown by Go¨gelein et al.
HMR1883 has significant effects at 2 µmol on action
potential shortenings due to either hypoxia or ril-
makalim in papillary muscles of guinea pigs17 suggest-
Table 2 shows the influence of alkoxy substituents
adjacent to the N-methylsulfonylthiourea moiety. All
compounds in this subseries showed excellent cardiose-
lectivity. Apparently, trifluoromethyl (6k ) displayed a
slightly less pronounced cardiac potency than HMR1883
whereas ethoxy, propoxy, and isopropoxy (6p -r ) all had
increased cardiac potency while cardioselectivity was
roughly not changed. A double bond is well-tolerated
as indicated by allyloxy derivative 6s. A highly potent
compound with excellent cardioselectivity was obtained
using methoxyethoxy substitution (6u ). This compound
is apparently superior to HMR1883, whereas its homo-
logue 6v was found to be slightly less potent than
HMR1883.
Table 3 shows the effect of further variations in the
2-position of the central aromatic ring. Halogen (6b-e)
instead of alkoxy is usually associated with less cardiac
activity as compared to the methoxy derivative 6a . The
same is true for hydrogen in the 2-position (6w ) and
for the thioether (6g). The sulfoxide (6h ) and sulfone
(6i) showed almost no cardiac activity at 2 µM indicating
that electron-withdrawing groups are less favorable in
this position. In contrast, excellent cardioselectivity and
cardiac potency were found for the electron-donating
N-morpholinyl residue (6f). Among various substituents
attached via a C atom to the central aromatic system
(6j, 13a -h ), only the 2-pyridyl derivative (13g), despite
its electron-withdrawing properties, turned out to have
a HMR1883-like profile.
As can be seen from Table 4, the central aromatic ring
does not tolerate additional substituents in positions 3
and 4 of the central aromatic ring as exemplified by
methyl and methoxy groups (compounds 6l-o).

1092 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Englert et al.
Ta ble 4. Physical Data and Effects on KATP Channels for Sulfonylthioureas: Influence of Additional Substituents
compd
R1, R2
H, H
OCH3, H
H, OCH3
H, OCH3
CH3, OCH3
CH3, CH3
X
mp (°C)
formula
anal.
pancreaticc KATP (% inhib)
cardiace KATP (% inhib)
gliba
6a b
6o
6n
7n
24, 73.3, 92.7d
5, 24.3, 83.8
-3.8, -2.12, -2.34
-1.0, 0.7, 30.5
-0.6, 2.8, 13.5
-2.0, 6.7, 47.8
0.8, 6.1, 64.9
0, 76, 87f
3, 71, 117
nd,h 0, nd
nd, 7, nd
nd, 0, nd
nd, 12, nd
nd, 2, nd
S
S
S
O
S
S
166-168
105-107
128
C20H24ClN3O6S2
C20H24ClN3O6S2
C20H24ClN3O7S
C21H26ClN3O6S2
C21H26ClN3O5S2
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N
6m
6l
75-80g
202-204
a
glib, glibenclamide. bHMR1883. ch-SUR1/Kir6.2 activated by diazoxide; test compound concentrations 0.1, 1, and 10 µM. dGliben-
clamide concentrations 1, 3, and 10 nM. eGuinea pig papillary muscle, % reversal of action potential shortening due to rilmakalim;
test compound concentrations 0.2, 2, and 20 µM. Glibenclamide concentrations 0.02, 0.2, and 2 µM. gDecomposition point. hnd, not
f
determined.
Ta ble 5. Physical Data and Effects on KATP Channels for Chromane-Derived Sulfonylthioureas
compd
opt. rotation
X
mp (°C)
formula
anal.
pancreaticc KATP (% inhib)
cardiace KATP (% inhib)
gliba
6a b
19a
19c
19b
19d
24, 73.3, 92.7d
5, 24.3, 83.8
6.8, 63.0, 75.7
2.5, 14.2, 105.4
-3.9, 3.6, 70.7
2.0, 1.0, 0.3
0, 76, 87f
3, 71, 117
27, 86, ndg
32, 116, nd
nd, 52, 98
nd, nd, 14
(-)
(-)
(+)
(+)
S
O
S
201-203
238-240
200-202
241-243
C
21H24ClN3O6S2
C, H, N
C, H, N
C, H, N
C, H, N
C21H24ClN3O7S
C
C
21H24ClN3O6S2
21H24ClN3O7S
O
a
glib, glibenclamide. bHMR1883. ch-SUR1/Kir6.2 activated by diazoxide; test compound concentrations 0.1, 1, and 10 µM. dGlibenclamide
e
concentrations 3 and 10 nM. Guinea pig papillary muscle, % reversal of action potential shortening due to rilmakalim; test compound
concentrations 0.2, 2, and 20 µM. Glibenclamide concentrations 0.02, 0.2, and 2 µM. gnd, not determined.
f
ing that both protocols of channel opening are equiva-
lent to predict antifibrillatory potency of a blocker.
A more recent study in rats shed some light on the
amount of cardioselectivity that can be achieved with
HMR1883 in vivo. Wirth et al. showed in a rat model
that doses of 1, 3, and 10 mg/kg iv dose-dependently
reduced VFs following an ischemia reperfusion protocol
without significantly affecting insulin secretion.29 Glib-
enclamide, though 1 order of magnitude more potent
in this model, increased insulin at all antiarrhythmic
doses. This suggests that a therapeutic width of roughly
10 for HMR1883, as estimated from our in vitro data,
translates into an acceptable in vivo cardioselectivity.
Glibenclamide has been used to demonstrate that
blockade of myocardial KATP channels interferes with
ischemic preconditioning of the hearts.16 However, the
channel responsible for ischemic preconditioning differs
from the channel being connected with VF and is located
within the mitochondria while plasmalemmal KATP
channels account for action potential shortening and
subsequently for VF. HMR1883 specifically adresses the
plasmalemmal channel20,36 and hence does not bear the
risk of interfering with ischemic preconditioning. Of
course, this unique property of HMR1883 could not be
predicted from our data. It is tempting to speculate that
the reduction of effects on pancreatic KATP channels
might run in parallel with the decreased potency on the
cardiac mitochondrial channels. In this regard, other
members of our series have to be investigated for their
potency on the cardiac mito-KATP channel.
Con clu sion
We could demonstrate that by structural modifica-
tions of the antidiabetic glibenclamide, a predominant
blocker of pancreatic KATP channels, new compounds
with selectivity for the cardiac plasmalemmal KATP
channel can be obtained. The following key modifica-
tions were identified: meta-arrangement of the sulfo-
nylurea group and the ethylamino side chain in the
central aromatic ring and size reduction of the lipophilic
substituent attached to the terminal sulfonylurea ni-
trogen. In addition it could be demonstrated that cardiac
inhibitory potency and/or cardioselectivity is further
increased by replacement of the sulfonylurea by a
sulfonylthiourea moiety and by an additional substitu-
ent adjacent to the sulfonylthiourea group, the chemical
nature of which may vary to a considerable extent.
These structural modifications led to the new class of
m-anisamidoethylbenzenesulfonylthioureas, among which
HMR1883 was selected for development as a new and
preventive therapeutic agent against malignant ar-
rhythmias and sudden cardiac death.

Cardioselective KATP Channel Blockers
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1093
was acylated with 5-chloro-2-methoxybenzoic acid chloride (4.3
g, 21.0 mmol) using method ii. The product was extracted with
ethyl acetate and 6.4 g (99%) of 4a was obtained: mp 83-84
°C; 1H NMR (CDCl3) δ 2.86 (t, 2H, J ) 6.0 Hz), 3.64-3.83 (m,
8H) 6.81-6.94 (m, 3H), 7.15-7.21 (m, 2H), 7.35-7.40 (m, 1H)
7.79 (bs, 1H), 8.19 (d, 1H); MS (DCI) m/e 320 (M + H+).
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 was carried out on TLC glass sheets with
silica gel 60 F 254, 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 apparatus B-540 and are not corrected. Enan-
tiomeric purity was determined by a ThermoQuest-HPLC
device, using chiral DNBPG-Bakerbond following Mosher
derivatization of enantiomeric 16a or 16b in the presence of
N-ethylmorpholine or using a CSP S Whelk-01 column from
Daicel for enantiomeric 19a -d .
Typ ica l P r oced u r e for th e P r ep a r a tion of P h en eth -
yla m in es 3. 4-(Meth ylm er ca p to)p h en yleth yla m in e Hy-
d r och lor id e (3f). 4-(Methylmercapto)benzaldehyde (2a ; 1.52
g, 10.0 mmol), 2,2-dimethyl-1,3-dioxane-4,6-dione (Meldrum’s
acid; 1.44 g, 10.0 mmol) and tetraethylammonium formiate
(5 mL) were combined and the solution stirred at 95-100 °C
for 5 h. After adding of ice-water (50 mL) and acidification to
pH 1 by 2 N HCl crystals were obtained, removed by suction
and dried. The material was crystallized from petroleum ether
to yield 3-(4-(methylmercapto)phenyl)propionic acid (1.23 g,
The following compounds were prepared accordingly.
5-Ch lor o-2-m e t h oxy-N -(2-(4-m e t h ylm e r ca p t op h e n -
yl)eth yl)ben za m id e (4g), 5-Ch lor o-2-m eth oxy-N-(2-(4-tr i-
flu or om eth oxyp h en yl)eth yl)ben za m id e (4i), N-(2-(4-Br o-
m oph en yl)eth yl)-5-ch lor o-2-m eth oxyben zam ide (4d), an d
5-C h lo r o -N -(2-(4-io d o p h e n y l)e t h y l)-2-m e t h o x y b e n z-
a m id e (4f). A suspension of the nitro derivative 4e (13.7 g,
46.1 mmol) and SnCl2‚2H2O (60.0 g, 0.27 mmol) in EtOAc (400
mL) was refluxed for 2 h. 10% aqueous NaHCO3 (400 mL) was
added to the reaction mixture and the resulting white pre-
cipitate was filtered off. The filtrate was extracted with EtOAc,
the combined extracts dried over Na2SO4 and the solvent
evaporated to give 12.1 g (86%) of the intermediate N-(2-(4-
aminophenyl)ethyl)-5-chloro-2-methoxybenzamide as an amor-
phous foam: Rf ) 0.23 (EtOAc/n-heptane 4:1); 1H NMR
(CDCl3) δ 2.80 (t, 2H, J ) 7.0 Hz), 3.68 (dt, 2H, J ) 7.0 Hz),
3.78 (s, 3H), 6.70 (m, 2H), 6.85 (m, 1H), 7.05 (m, 2H), 7.35 (m,
1H), 7.78 (br t, 1H), 8.18 (m, 1H); MS (ESI) m/e 305 (M + H+).
To a cooled (0 °C) suspension of the thus obtained interme-
diate (9.0 g, 29.6 mmol) in concentrated HCl (7.5 mL) and
water (30 mL) a solution of NaNO2 (2.1 g, 30.6 mmol) in water
(6 mL) was added. After 5 min of stirring at 0 °C a solution of
KI (5.0 g, 30.6 mmol) in water (7.5 mL) was added dropwise
and the reaction mixture was stirred for 2 h at room temper-
ature. Extraction with CH2Cl2, drying over Na2SO4, and
evaporation of the solvent gave a residue which was purified
by chromatography on silica gel (EtOAc/n-heptane 1:2) to yield
5.9 g (48%) of 4f as a pale yellow foam: Rf ) 0.48 (EtOAc/n-
1
63%) as a white solid: mp 97-98 °C; H NMR (DMSO-d6) δ
2.44 (s, 3H), 2.77 (t, 2H, J ) 6 Hz), 3.33 (br s, 2H, 7.17 (s, 4H);
MS (DCI) m/e 197 (M + H+). This material (1.2 g, 6.0 mmol)
was added to azidodiphenylphosphate (1.7 g, 6.1 mmol) and
triethylamine (0.62 g, 6.1 mmol) in tert-butanol (20 mL) and
refluxed for 24 h. The solvent was removed in vacuo and the
residue was purified by flash chromatography (silica gel, ethyl
acetate/methanol) to give N-(tert-butoxycarbonyl)-4-(methyl-
mercapto)phenylethylamine, mp 97-98 °C, which was refluxed
in methanol and 2 N HCl (1:1) for 2 h. Following removal of
the solvent in vacuo, the residue was crystallized from diethyl
ether to give 3a as its hydrochloride (0.61 g, 50%): mp 243-
248 °C; 1H NMR (DMSO-d6) δ 2.44 (s, 3H), 2.82-3.05 (m, 4H),
7.15-7.25 (m, 4H); MS (DCI) m/e 204 (M + H+).
1
heptane 2:1); H NMR (DMSO-d6) δ 2.80 (t, 2H, J ) 7.0 Hz),
3.52 (dt, J ) 7.0 Hz), 3.82 (s, 3H), 7.05-7.18 (m, 3H), 7.44-
7.72 (m, 3H), 8.22 (br t, 1H); MS (DCI) m/e 415 (M + H+).
Typ ica l P r oced u r e for th e P r ep a r a tion of 2-Su bsti-
t u t ed 5-[2-(5-Ch lor o-2-m et h oxyb en za m id o)et h yl]b en -
zen esu lfon a m id es 5. The benzamide derivative 4 (1.00
mmol) was added in small portions to cooled (0-5 °C) chloro-
sulfonic acid (3.5 mL). After stirring at ambient temperature
for 3 h the reaction mixture was poured on crushed ice (15
mL). The precipitated sulfochloride was filtered off and taken
up in acetone (10 mL). Concentrated NH4OH (2 mL) was added
to the cooled (0-5 °C) solution and the reaction mixture stirred
at ambient temperature for 1 h. The precipitate was filtered
off and the filtrate was concentrated under reduced pressure.
The product was isolated by extraction with EtOAc, drying of
the extracts over Na2SO4, evaporation of the solvent, and
purification either by crystallization or by chromatography on
silica gel.
The phenylethylamines 3b,c were prepared in a similar
manner.
Typ ica l P r oced u r e for th e P r ep a r a tion of N-(2-P h en -
yleth yl)-5-ch lor o-2-m eth oxyben za m id es 4 by Acyla tion
of P h en eth yla m in es 3. Meth od i: A solution of the 5-chlo-
ro-2 methoxybenzoic acid (1.00 mmol) and N,N′-carbonyldi-
imidazole (1.10 mmol) in dry THF (5 mL) was stirred at
ambient temperature for 2h. Amine 3 (1.05 mmol) and tri-
ethylamine (1.00 mmol) was added and the reaction mixture
stirred at ambient temperature for 12 h. After addition of 1 N
HCl solution (20 mL) the product precipitated and was isolated
by filtration, washing with water and drying under reduced
pressure. Alternatively, the product was obtained by extraction
of the reaction mixture with EtOAc, drying of the combined
extracts over Na2SO4, evaporation of the solvent and purifica-
tion of the residue by chromatography on silica gel.
5-[2-(5-Ch lor o-2-m eth oxyben za m id o)eth yl]-2-m eth oxy-
ben zen esu lfon a m id e (5a ). The amide 4a (6.6 g, 20.6 mmol)
was treated with chlorosulfonic acid and afterward with
aqueous ammonium hydroxide via the general procedure
described above to yield 6.64 g (81%) of 5a as a white solid:
1
mp 220-221; H NMR (DMSO-d6) δ 2.82 (t, 2H, J ) 6.0 Hz),
3.41-3.49 (m, 2H), 3.82 (s, 3H), 3.88 (s, 3H), 7.01 (bs, 2H),
7.09-7.17 (m, 2H), 7.41-7.56 (m, 2H), 7.62-7.70 (m, 2H), 8.25
(br t, 1H); MS (DCI) m/e 399 (M + H+).
The following compounds were prepared accordingly.
Meth od ii: The hydrochloride of amine 3 (10.0 mmol) was
dissolved in pyridine (10 mL) and 5-chloro-2-methoxybenoic
acid chloride (11.0 mmol) was added. After stirring for 1 h at
ambient temperature. The solution was poored into ice-water
(80 mL) and was slowly neutralized with concentrated HCl.
The product precipitated and was isolated by filtration, wash-
ing with water and drying under reduced pressure. Alterna-
tively, the product was obtained by extraction of the reaction
mixture with ethyl acetate, drying of the combined extracts
over Na2SO4, evaporation of the solvent and purification of the
residue by chromatography on silica gel.
5-[2-(5-Ch lor o-2-m et h oxyb en za m id o)et h yl]-2-(m et h -
ylm er ca p to)ben zen esu lfon a m id e (5g), 5-[2-(5-Ch lor o-2-
m e t h oxyb e n za m id o)e t h yl]-2-(t r iflu or om e t h oxy)b e n -
zen esu lfon a m id e (5k ), 2-Br om o-5-[2-(5-ch lor o-2-m eth -
oxyben za m id o)eth yl]ben zen esu lfon a m id e (5d ), a n d 5-[2-
(5-Ch lor o-2-m eth oxyben zam ido)eth yl]-2-(m eth ylsu lfin yl)-
ben zen esu lfon a m id e (5h ). The sulfonamide 5g (0.41 g, 1.0
mmol) was added to 0.2 mL 30% H2O2 (0.2 mL) in acetic acid
(4 mL) and the resulting solution was allowed to stand at 0
°C for 2 days. The mixture was diluted with ice-water (20
mL) and the crystallized material was removed by suction to
give 280 mg (65%) of 5h as a white solid: mp 241-242 °C; 1H
5-Ch lor o-2-m eth oxy-N-(2-(4-m eth oxyph en yl)eth yl)ben -
za m id e (4a ). 4-Methoxyphenylethylamine (3.02 g, 20.0 mmol)

1094 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Englert et al.
NMR (DMSO-d6) δ 2.76 (s,3H) 2.98 (t, 2H, J ) 6.5 Hz), 3.58
(dt, 2H, J ) 6.5 Hz), 3.82 (s, 3H), 7.16 (d, 1H, J ) 8 Hz), 7.48-
7.84 (m, 5H), 8.10 (d, 1H, J ) 8 Hz), 8.35 (br t, 1H); MS (DCI)
m/e 431 (M + H+).
ben za m id o)eth yl]-2-(3-p yr id yl)ben zen esu lfon yl-3-m eth -
ylth iou r ea (13h ).
Syn th esis of In ter m ed ia tes. 4-(2-(Tr iflu or oa ceta m id o)-
e t h y l)-2-N ,N -d im e t h y la m in o m e t h y le n e a m in o s u lfo -
n yla n isol (8b). The sulfonamide 8a (32.6 g, 100 mmol) was
dissolved in DMF (70 mL) and N,N-dimethylformamide dim-
ethylacetal (16 mL, 14.3 g, 120 mmol) was added. After 3 h
stirring at room temperature the mixture was poured into an
ice/NaHSO4 solution (5%). The precipitate was filtered, washed
with water and dried. 32.5 g (85%) of 8b was obtained as a
white solid: mp 143-144 °C; 1H NMR (DMSO-d6) δ 2.75-2.82
(m, 2H), 2.88 (s, 3H), 3.11 (s, 3H), 3.12-3.24 (m, 2H), 3.79 (s,
3H), 7.05-7.11 (m, 1H), 7.26-7.31 (m, 1H), 7.40-7.45 (m, 1H),
8.18 (s, 1H), 9.45 (br t, 1H); MS (ESI) m/e 382 (M + H+).
4-(2-(T r i flu o r o a c e t a m i d o )e t h y l)-2-d i m e t h y la m i -
n om eth yla m in osu lfon ylp h en ol‚HBr (9). 4-(2-(Trifluoro-
a cet a m ido)et h yl)-2-N,N-dim et h yla m in om et h ylen ea m in o-
sulfonylanisol (8b; 32.5 g, 85 mmol) was dissolved in CH2Cl2
(450 mL) and BBr3 solution (100 mL, 100 mmol, 1 M in CH2-
Cl2) was added slowly. After additional 5 h stirring at room
temperature the mixture was diluted with methanol (150 mL).
The mixture was poured into diisopropyl ether (2 L) and the
precipitate was filtered off. 36.0 g (95%) of the hydrobromide
9 was obtained as a colorless solid: mp 160-161 °C; 1H NMR
(DMSO-d6) δ 2.73 (t, 2H, J ) 7.0 Hz), 2.90 (s, 3H), 3.16 (s,
3H), 3.38 (q, 2H, J ) 7.0 Hz), 3.79 (s, 3H), 6.79-6.84 (m, 1H),
7.17-7.23 (m, 1H), 7.55-7.60 (m, 1H), 8.21 (s, 1H), 9.43 (br t,
1H); 10.0-10.4 (m, 1H); MS (ESI) m/e 368 (M + H+).
5-[2-(5-Ch lor o-2-m eth oxyben za m id o)eth yl]-2-(m eth yl-
su lfon yl)ben zen esu lfon a m id e (5i). The sulfonamide 5g
(0.41 g, 1 mmol) was added to 30% H2O2 (0.4 mL) in acetic
acid (4 mL) and the resulting solution was kept at 80 °C for 8
h. The mixture was diluted with ice-water (20 mL) and the
crystallized material was removed by suction to give 310 mg
(69%) of 5i as a white solid: mp 241-242 °C; 1H NMR (DMSO-
d6) δ 2.76 (s, 3H), 2.98 (t, 2H, J ) 6.5 Hz), 3.54 (dt, 2H, J )
6.5 Hz), 3.83 (s, 3H), 7.17 (d, 1H, J ) 8 Hz), 7.48-7.95 (m,
5H), 8.10 (d, 1H, J ) 8 Hz), 8.35 (br t, 1H); MS (DCI) m/e 447
(M + H+).
5-[2-(5-Ch lor o-2-m et h oxyb en za m id o)et h yl]-2-N-m or -
p h olin ylben zen esu lfon a m id e (5f). The sulfonamide 5b (500
mg, 1.29 mmol) was dissolved in 4.0 mL DMF and 0.11 mL
morpholine (112 mg, 1.29 mmol). After addition of 357 mg (2.58
mmol) potassium carbonate the mixture was heated to reflux
for 3h. The reaction was poured on ice/water and extracted
with ethyl acetate followed by cromatography (EtOAc/n-
heptane 2:1-4:1). The product (59 mg, 10%) was isolated as a
1
colorless solid: mp 236 °C; H NMR (DMSO-d6) δ 2.81-2.98
(m, 6H), 3.42-3.58 (m, 2H), 3.71-3.84 (m, 7H), 6.92 (bs, 2H),
7.14-7.20 (m, 1H), 7.48-7.57 (m, 3H), 7.62-7.66 (m, 1H), 7.75
(bs, 1H), 8.30 (bt, 1H); MS (DCI) m/e 454 (M + H+).
Typ ica l P r oced u r e for th e P r ep a r a tion of 2-Su bsti-
Typ ica l P r oced u r e for th e P r ep a r a tion of 2-(4-Alk oxy-
3-su lfa m oylp h en yl)eth yla m in e Hyd r och lor id es 10. To a
mixture of the phenol (1 mmol) and 2.5 mmol of potassium
carbonate in dry DMF (40 mL) was added alkyl halide (2.0
mmol). The mixture was heated for 3 h at 80 °C. After dilution
with ethyl acetate, the organic layer was washed with sodium
chloride solution, dried and the solvent evaporated. The
resulting product was chromatographed, if necessary, or
directly used in the next reaction. The alkylated compound (1
mmol) was heated to reflux in a mixture of methanol (10 mL)
and 5.5 N HCl (10 mL) for 8 h. The mixture was concentrated
and the residue stirred with ethanol. The precipitate was
filtered and washed with ethanol.
2-(4-Eth oxy-3-su lfam oylph en yl)eth ylam in e Hydr och lo-
r id e (10a ). Phenol 9 (5.4 g, 12 mmol) was treated with ethyl
iodide and the resulting product was deprotected with HCl as
described in the general procedure above. Precipitation with
ethanol resulted in 2.9 g (86%) of the product as a colorless
solid: mp 254-247 °C; 1H NMR (DMSO-d6) δ 1.39 (t, 3H, J )
7.0 Hz), 2.80-3.06 (m, 4H), 4.22 (q, 2H, J ) 7.0 Hz), 6.90 (bs,
2H), 7.13-7.22 (m, 1H), 7.40-7.49 (m, 1H), 7.61-7.65 (m, 1H),
8.11 (bs, 3H); MS (ESI) m/e 245 (M + H+).
2-(4-Allyloxy-3-su lfa m oylp h en yl)et h yla m in e H yd r o-
ch lor id e (10d ). Phenol 9 (4.5 g, 10 mmol) was alkylated with
allyl bromide and the resulting product deprotected with HCl
as described in the general procedure given above. The
precipitated compound (2.4 g, 82%) was filtered and dried: mp
247-248 °C; 1H NMR (DMSO-d6) δ 2.81-3.04 (m, 4H), 4.71-
4.82 (m, 2H), 5.19-5.45 (m, 2H), 5.96-6.17 (m, 1H), 7.00 (bs,
2H), 7.10-7.20 (m, 1H), 7.39-7.43 (m, 1H), 7.61- - 7.65 (m,
1H), 8.05 (bs, 3H); MS (ESI) m/e 257 (M + H+).
2-(4-Meth oxyeth oxy-3-su lfam oylph en yl)eth ylam in e Hy-
d r och lor id e (10f). Phenol 9 (2.7 g, 6 mmol) was alkylated
with bromoethyl methyl ether and the resulting product
deprotected with HCl as given in the general procedure
described above. Precipitation with ethanol resulted in 1.2 g
(65%) of the desired product as a colorless solid: mp 195-197
°C; 1H NMR (DMSO-d6) δ 2.81-3.10 (m, 4H), 3.36 (s, 3H),
3.64-3.78 (m, 2H), 4.21-4.30 (m, 2H), 6.81 (bs, 2H), 7.10-
7.16 (m, 1H), 7.41-7.52 (m, 1H), 7.61- - 7.64 (m, 1H), 8.08
(bs, 3H); MS (ESI) m/e 275 (M + H+).
tu ted
5-[2-(5-Ch lor o-2-m eth oxyben za m id o)eth yl]ben -
zen esu lfon yl-N-m et h ylt h iou r ea s fr om Ben zen esu lfon -
a m id es. A solution of the sulfonamide (1.00 mmol) and KOtBu
(1.20 mmol) was stirred at ambient temperature for 15 min.
A 1 M solution of the isothiocyanate in dry DMF (1.10 mmol)
was added and stirring was continued at 80 °C for 1 h. The
reaction mixture was acidified by addition of 1 N HCl and the
product was isolated either by filtering off the precipitate or
extraction with CH2Cl2.
2-Br om o-5-[2-(5-ch lor o-2-m eth oxyben zam ido)eth yl]ben -
zen esu lfon yl-3-m eth ylth iou r ea (6d ). The sulfonamide 5d
(184 mg, 0.41 mmol) was treated with methyl isothiocyanate
via general procedure described above. Chromatography with
EtOAc/methanol (20:1) yielded 152 mg (71%) of 6d as an
1
amorphous white foam: Rf ) 0.13 (EtOAc/n-heptane 2:1); H
NMR (DMSO-d6) δ 2.85 (d, 3H, J ) 4.0 Hz), 2.92 (t, 2H, J )
7.0 Hz), 3.55 (dt, 2H, J ) 7.0 Hz), 3.80 (s, 3H), 7.16 (m, 1H),
7.42-7.80 (m, 4H), 8.02 (m, 1H), 8.26 (br t, 1H); MS (ESI) m/e
520/522 (M + H+).
5-[2-(5-Ch lor o-2-m eth oxyben za m id o)eth yl]-2-m eth oxy-
ben zen esu lfon yl-3-m eth ylth iou r ea (6a ). The sulfonamide
5a (1.2 g, 3.0 mmol) was treated with methyl isothiocyanate
via the typical procedure described above. Trituration with 1
N HCl yielded 1.3 g (92%) of 6a as a white solid: mp 190-
1
193 °C; H NMR (DMSO-d6) δ 2.85 (t, 2H, J ) 5.0 Hz), 2.93
(d, 3H, J ) 5.0 Hz), 3.49 (q, 2H, J ) 5.0 Hz), 3.85 (s, 3H), 3.88
(s, 3H), 7.11-7.25 (m, 2H), 7.45-7.61 (m, 2H),), 7.63-7.75 (m,
2H), 8.25 (br t, 1H); 8.40 (q, 1H, J ) 5.0 Hz), 11.21 (s, 1H);
MS (ESI) m/e 472 (M + H+).
The following compounds were prepared accordingly:
5-[2-(5-ch lor o-2-m e t h oxyb e n za m id o)e t h yl]-2-isop r o-
poxyben zen esu lfon yl-3-m eth ylth iou r ea (6q), 5-[2-(5-ch lo-
r o-2-m e t h oxyb e n za m id o)e t h yl]-2-(m e t h ylm e r ca p t o)-
ben zen esu lfon yl-3-m eth ylth iou r ea (6g), 5-[2-(5-ch lor o-2-
m e t h oxyb e n za m id o)e t h yl]-2-(t r iflu or om e t h oxy)b e n -
zen esu lfon yl-3-m eth ylth iou r ea (6k ), 5-[2-(5-ch lor o-2-
m e t h oxyb e n za m id o)e t h yl]-2-(2-m e t h oxye t h oxy)b e n -
zen esu lfon yl-3-m eth ylth iou r ea (6u ), 2-(a llyloxy)-5-[2-(5-
ch lor o-2-m et h oxyb en za m id o)et h yl]b en zen esu lfon yl-3-
m eth ylth iou r ea (6s), 5-[2-(5-ch lor o-2-m eth oxyben zam ido)-
eth yl]-2-p h en ylben zen esu lfon yl-3-m eth ylth iou r ea (13e),
5-[2-(5-ch lor o-2-m eth oxyben za m id o)eth yl]-2-eth yn ylben -
zen esu lfon yl-3-m eth ylth iou r ea (13d ), 5-[2-(5-ch lor o-2-
m eth oxyben za m id o)eth yl]-2-(2-p yr id yl)ben zen esu lfon yl-
3-m et h ylt h iou r ea (13g), and 5-[2-(5-ch lor o-2-m et h oxy-
Typ ica l P r oced u r e for th e P r ep a r a tion of N-(2-P h en -
yleth yl)-5-ch lor o-2-m eth oxyben za m id es 12a -h by P d (0)-
Ca ta lyzed Cr oss-Cou p lin g Rea ction s a n d Rem ova l of th e
P r otectin g Gr ou p . 5-[2-(5-Ch lor o-2-m eth oxyben za m id o)-
eth yl]-2-n -p r op ylben zen esu lfon a m id e (12b). Under an

Cardioselective KATP Channel Blockers
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1095
argon atmosphere a 0.5 M solution of ZnCl2 in THF (5.5 mL)
were added dropwise to a suspension of the iodide 11b (500
mg, 0.91 mmol), Pd(dppf)Cl2 (37.5 mg, 0.05 mmol) and CuI
(10.2 mg, 0.05 mmol) in THF (5 mL). A 2 M solution of n-pro-
pylmagnesium chloride (1.2 mL) in diethyl ether was added
slowly and the reaction mixture was refluxed for 6 h. After
cooling to room temperature and evaporation of the solvents
and the obtained residue was dissolved in a solution of EtOAc
and 1 N HCl. The separated organic layer was washed with 1
N HCl, aqueous NaHCO3 and dried over Na2SO4. Evaporation
of the solvent and purification of the obtained residue by
chromatography on silica gel with EtOAc/n-heptane (3:1) gave
307 mg (73%) of 5-[2-(5-chloro-2-methoxybenzamido)ethyl]-2-
n-propyl-N-(dimethylaminomethylene)benzenesulfonamide as
an amorphous foam: Rf ) 0.40 (EtOAc/n-heptane 8:1); 1H NMR
(DMSO-d6) δ 0.95 (t, 3H, J ) 7.5 Hz), 1.60 (m, 2H), 2.84 (t,
2H, J ) 6.5 Hz), 2.90 (s, 3H), 2.95 (t, 2H, J ) 7.0 Hz), 3.10 (s,
3H), 3.50 (dt, 2H, J ) 7.0 Hz), 3.82 (s, 3H), 7.14 (m, 1H), 7.35
(m, 2H), 7.50 (m, 1H), 7.64 (m, 1H), 7.72 (m, 1H), 8.14 (m,
1H), 8.25 (br t, 1H); MS (DCI) m/e 466 (M + H+).
6.0 Hz), 3.85 (s, 3H), 7.00 (s, 1H), 7.12-7.26 (m, 5H), 7.38 (m,
2H), 7.50 (m, 2H), 7.66 (m, 1H), 7.96 (m, 1H), 8.30 (br t, 1H);
MS (DCI) m/e 500 (M + H+).
This amidine (1.43 g, 2.88 mmol) was deprotected applying
the procedure described for compound 12b to yield 1.05 g (82%)
of 12e as a pale yellow solid: mp 134-136 °C; Rf ) 0.73
(EtOAc/n-heptane 5:1); 1H NMR (DMSO-d6) δ 2.95 (t, 2H, J )
7.5 Hz), 3.60 (dt, 2H, J ) 7.5 Hz), 3.84 (s, 3H), 7.10 (m, 1H),
7.26 (m, 1H), 7.38 (m, 5H), 7.50 (m, 2H), 7.68 (m, 1H9, 7.95
(m, 1H), 8.35 (br t, 1H); MS (FAB) m/e 445 (M + H+).
5-[2-(5-Ch lor o-2-m eth oxyben zam ido)eth yl]-2-(2-pyr idyl-
)ben zen esu lfon a m id e (12g). A suspension of the iodide 11b
(400 mg, 0.73 mmol), freshly prepared 2-(trimethylstannyl)-
pyridine (199 mg, 0.82 mmol), 10 mg LiCl, 10 mg CuI and Pd-
(PPh3)2Cl2 (32 mg, 0.004 mmol) in dry THF (10 mL) was
refluxed for 10 h. After cooling to ambient temperature EtOAc
(10 mL) was added to reaction mixture. Filtration, evaporation
of the solvents and subsequent purification of the obtained
residue by chromatography on silica gel with CH2Cl2/EtOAc
(4:1) yielded 265 mg (73%) of 5-[2-(5-chloro-2-methoxybenz-
amido)ethyl]-2-(2-pyridyl)-N-(dimethylaminomethylene)ben-
zenesulfonamide as an amorphous white foam: Rf ) 0.05 (CH2-
Cl2/EtOAc 4:1); 1H NMR (DMSO-d6) δ 2.66 (s, 3H), 2.90 (s,
3H), 3.00 (t, 2H, J ) 6.5 Hz), 3.58 (dt, 2H, J ) 6.5 Hz), 3.84 (s,
3H), 7.15 (m, 1H), 7.30-7.58 (m, 6H), 7.66 (m, 1H), 7.82 (m,
1H), 7.95 (m, 1H), 8.32 (br t, 1H), 7.58 (m, 1H); MS (DCI) m/e
501 (M + H+).
This amidine (250 mg, 0.50 mmol) was deprotected applying
the procedure described for compound 12b to give 161 mg
(72%) of 12g as a white solid: mp 202-203 °C; Rf ) 0.29 (CH2-
Cl2/EtOAc 4:1); 1H NMR (DMSO-d6) δ 2.96 (t, 2H, J ) 7.0 Hz),
3.58 (dt, 2H, J ) 7.0 Hz), 3.84 (s, 3H), 7.16 (m, 1H), 7.42-
7.70 (m, 6H), 7.94 (m, 2H), 8.35 (br t, 1H), 8.65 (m, 1H); MS
(DCI) m/e 446 (M + H+).
5-[2-(5-Ch lor o-2-m eth oxyben zam ido)eth yl]-2-(3-pyr idyl)-
ben zen esu lfon a m id e (12h ). The iodide 11b (200 mg, 0.36
mmol) was coupled with freshly prepared 3-(trimethylstannyl)-
pyridine (100 mg, 0.41 mmol) following the procedure described
for compound 12g to yield 60 mg (32%) of 5-[2-(5-chloro-2-
methoxybenzamido)ethyl]-2-(3-pyridyl)-N-(dimethylamino-
methylene)benzenesulfonamide as an amorphous solid: Rf )
0.26 (CH2Cl2/EtOAc/methanol 8:4:1); 1H NMR (DMSO-d6) δ
2.66 (s, 3H), 2.84 (s, 3H), 2.98 (t, 2H, J ) 6.5 Hz) 3.56 (dt, 2H,
J ) 6.5 Hz), 3.84 (s, 3H), 7.18 (m, 1H), 7.30 (m, 2H), 7.50 (m,
4H), 7.65 (m, 1H), 7.70 (m, 1H), 7.96 (m, 1H), 8.16 (m, 1H),
8.34 (br t, 1H); MS (ESI) m/e 501 (M + H+).
This amidine (55 mg, 0.11 mmol) was deprotected applying
the procedure described for compound 12b to give 34 mg (65%)
of 12h as an amorphous solid; Rf ) 0.32 (CH2Cl2/EtOAc/
methanol 8:4:1); 1H NMR (DMSO-d6) δ 3.00 (t, 2H, J ) 6.5
Hz) 3.52 (dt, 2H, J ) 6.5 Hz), 3.84 (s, 3H), 7.20 (m, 1H), 7.34
(m, 2H), 7.44-7.52 (m, 3H), 7.60 (m, 1H), 7.72 (m, 1H), 7.92
(m, 1H), 8.16 (m, 1H), 8.30 (br t, 1H); MS (ESI) m/e 446 (M +
H+).
A solution of the amidine (300 mg, 0.56 mmol) in methanol
(10 mL) and concentrated HCl (1.7 mL) was refluxed for 3 h.
After evaporation of the methanol the pH of the remaining
aqueous solution was adjusted to 5, the precipitate filtered off
and dried under reduced pressure to yield 237 mg (89%) of
12b as a white solid: mp 177-181 °C; Rf ) 0.76 (EtOAc/n-
1
heptane 8:1); H NMR (DMSO-d6) δ 0.96 (t, 3H, J ) 7.0 Hz),
1.64 (m, 2H), 2.88 (m, 4H), 3.50 (dt, 2H, J ) 6.5 Hz), 3.82 (s,
3H), 7.15 (m, 1H), 7.35 (m, 2H), 7.50 (m, 1H), 7.68 (m, 1H),
7.75 (m, 1H), 8.28 (br t, 1H); MS (DCI) m/e 411 (M + H+).
According to this procedure using a Nigishi-Kumada-type
cross-coupling reaction as the key step, also the sulfonamides
12a ,c were synthesized.
5-[2-(5-Ch lor o-2-m eth oxyben za m id o)eth yl]-2-eth yn yl-
ben zen esu lfon a m id e (12d ). A solution of the iodide 11b (800
mg, 1.46 mmol), ethynyl tri-n-butylstannane (477 µL, 1.65
mmol) and Pd(PPh3)2Cl2 (80 mg, 0.01 mmol) in dry THF (15
mL) was refluxed for 20 h. After cooling to ambient temper-
ature EtOAc (20 mL) was added to to reaction mixture.
Filtration, evaporation of the solvents and finally purification
of the obtained residue by chromatography on silica gel with
EtOAc/n-heptane (4:1) yielded 420 mg (64%) of 5-[2-(5-chloro-
2-methoxybenzamido)ethyl]-2-ethynyl-N-(dimethylaminometh-
ylene)benzenesulfonamide as an amorphous foam: Rf ) 0.10
(EtOAc/n-heptane 4:1); 1H NMR (DMSO-d6) δ 2.88 (s, 3H), 2.92
(t, 2H, J ) 6.0 Hz), 3.15 (s, 3H), 3.54 (dt, 2H, J ) 6.0 Hz), 7.14
(m, 1H), 7.44-7.64 (m, 4H), 7.86 (m, 1H), 8.24 (m, 1H), 8.28
(br t, 1H); MS (FAB) m/e 448 (M + H+).
This amidine (210 mg, 0.47 mmol) was deprotected applying
the procedure described for compound 12b to yield 90 mg (48%)
of 12d as an amorphous solid: Rf ) 0.23 (EtOAc/n-heptane
1
4:1); H NMR (DMSO-d6) δ 3.05 (t, 2H, J ) 6.5 Hz), 3.60 (dt,
2H, J ) 6.5 Hz), 3.84 (s, 3H), 7.12 (m, 1H), 7.48 (m, 1H), 7.58
(m, 1H), 7.75 (m, 1H), 7.95 (m, 1H), 8.05 (m, 1H), 8.28 (br t,
1H); MS (DCI) m/e 393 (M + H+).
According to this procedure using a Stille-type cross-
coupling reaction as the key step, the sulfonamide 12f was
synthesized.
Gen er a l P r oced u r e for P r otection of a Su lfa m oyl
Gr ou p. 5-[2-(5-Ch lor o-2-m eth oxyben zam ido)eth yl]-2-iodo-
N-(d im eth yla m in om eth ylen e)ben zen esu lfon a m id e (11b).
A solution of the sulfonamide 5e (4.3 g, 8.70 mmol) and N,N-
dimethylformamide dimethylacetal (1.4 mL, 10.4 mmol) in dry
DMF (32 mL) was stirred at room temperature for 1 h. The
reaction mixture was concentrated, the obtained residue
dissolved in water and in aqueous NaHSO4 (100 mL) and the
precipitate was filtered off. Chromatography of the precipitate
on silica gel with EtOAc/n-heptane (2:1) yielded 3.4 g (70%) of
11b as a white solid: mp 183-186 °C; Rf ) 0.13 (EtOAc/n-
5-[2-(5-Ch lor o-2-m et h oxyb en za m id o)et h yl]-2-p h en yl-
ben zen esu lfon a m id e (12e). A solution of benzeneboronic
acid (488 mg, 3.98 mmol) in ethanol (20 mL) was added to a
suspension of the bromide 11a (2.0 g, 3.98 mmol) and Pd(PPh)4
(142 mg, 0.11 mmol) in toluene (20 mL). After 15 min of
stirring at ambient temperature a 2 M Cs2CO3 solution (4.6
mL) was added and the reaction mixture refluxed for 6 h. The
mixture was concentrated under reduced pressure and the
remaining residue taken up in CH2Cl2 (50 mL). Washing with
water, drying over Na2SO4, evaporation of the solvent and
purification of the residue by chromatography on silica gel with
EtOAc/toluene (8:1) gave 1.44 g (72%) of 5-[2-(5-chloro-2-
methoxybenzamido)ethyl]-2-phenyl-N-(dimethylaminomethyl-
ene)benzenesulfonamide as a white amorphous foam: Rf )
0.40 (CH2Cl2/methanol 20:1); 1H NMR (DMSO-d6) δ 2.64 (s,
3H), 2.72 (s, 3H), 2.96 (t, 2H, J ) 6.0 Hz), 3.58 (dt, 2H, J )
1
heptane 4:1); H NMR (DMSO-d6) δ 2.88 (t, 2H, J ) 7.0 Hz),
2.95 (s, 3H), 3.18 (s, 3H), 3.50 (dt, 2H, J ) 7.0 Hz), 3.82 (s,
3H), 7.15 (m, 2H), 7.50 (m, 1H), 7.64 (m, 1H), 7.96 (m, 2H),
8.26 (m, 2H); MS (DCI) m/e 550 (M + H+).
Gen er a l P r oced u r e for Oxid a tion of Su lfon ylth iou r ea
to Su lfon ylu r ea . 1 mmol of sulfonythiourea 6 was dissolved
in 3 mL 1 N NaOH and 0.6 mL hydrogen peroxide (30%) was

1096 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Englert et al.
added. After 1 h stirring at room temperature the mixture was
acidified with 2 N HCl and the precipitate filtered off and
dried.
(+)-N-[[4-[(5-Ch lor o-2-m et h oxyben za m id o)m et h yl]-7-
m eth oxy-6-ch r om a n yl]su lfon yl]-N′-th iou r ea (19b). This
urea was prepared in the same manner as the (-)-derivative
19a from (+)-5-chloro-2-methoxy-N-[(7-methoxy-6-sulfamoyl-
5-[2-(5-Ch lor o-2-m eth oxyben za m id o)eth yl]-2-m eth oxy-
ben zen esu lfon yl-3-m eth ylu r ea (7a ). 470 mg (1.0 mal) of 6a
was oxidized according to the general procedure described
above and the sulfonylurea 7a , 420 mg (92%), was obtained
as colorless solid: mp 201-203 °C; 1H NMR (DMSO-d6) δ
2.88-2.91 (m, 2H), 3.42-3.58 (m, 2H), 3.83 (s, 3H), 3.88 (s,
3H), 7.12-7.24 (m, 2H), 7.41-7.73 (m, 4H), 8.21-8.33 (m, 1H),
10.38 (s, 1H); MS (ESI) m/e 456 (M + H+).
5-[2-(5-Ch lor o-2-m eth oxyben za m id o)eth yl]-2-m eth oxy-
ben zen esu lfon ylth iou r ea (6y). The sulfonamide 5a (2.0 g,
5.0 mmol) was dissolved in DMF (15 mL) and carbon disulfide
(0.4 mL) and powdered KOH (280 mg, 5.0 mmol) were added.
After stirring at room temperature for 20 h, ethyl acetate (25
mL) was added. The precipitated intermediate was filtered,
dried and directly used in the following step. 550 mg (1.0
mmol) of the intermediate was suspended in CH2Cl2 and ethyl
chloroformate (0.18 mL, 2.2 mmol) was added. After stirring
for 48 h ammonia gas was bubbled through the mixture for
30 min. The solvent was evaporated, the residue dissolved in
DMF and 1 N HCl added. The product 6y precipitated as
colorless solid and was recrystallized from methanol to yield
100 mg (22%): mp 177-178 °C; 1H NMR (DMSO-d6) δ 2.78-
2.93 (m, 2H), 3.41-3.56 (m, 2H), 3.85 (s, 3H), 3.91 (s, 3H),
7.11-7.28 (m, 2H), 7.32-7.78 (m, 5H), 8.28 (t, 1H, J ) 5.0
Hz), 8.95 (bs, 1H), 11.33 (s, 1H); MS (ESI) m/e 458 (M + H+).
5-[2-(5-Ch lor o-2-m eth oxyben za m id o)eth yl]-2-m eth oxy-
ben zen esu lfon yl-3,3-d im eth ylu r ea (7b). The title com-
pound was prepared by oxidation (see general method for 7a )
with H2O2 in 1 N NaOH following the procedure described
above for thiourea 6y using 40% aqueous dimethylamine
instead of aqueous ammonia. 7b was obtained in an overall
yield of 18% from 2.0 g (5.0 mmol) sulfonamide 5a as colorless
solid: mp 205-208 °C; 1H NMR (DMSO-d6) δ 2.93 (s, 6H), 2.95
(t, 2H, J ) 6.0 Hz), 3.73 (q, 2H, J ) 5.0 Hz), 3.88 (s, 3H), 3.96
(s, 3H), 6.83-7.03 (m, 2H), 7.30-7.53 (m, 3H), 7.82-7.96 (m,
2H), 8.11-8.19 (m, 1H); MS (ESI) m/e 470 (M + H+).
Syn th esis of Ch r om a n es 19a -d . (-)-N-[[4-[(5-Ch lor o-
2-m eth oxyben za m id o)m eth yl]-7-m eth oxy-6-ch r om a n yl]-
su lfon yl]-N′-m eth ylth iou r ea (19a ). (-)-5-Chloro-2-methoxy-
N-[(7-methoxy-6-sulfamoylchroman-4-yl)methyl]benzamide (18a;
1.76 g, 4.0 mmol), K2CO3 (1.65 g) and methyl isothiocyanate
(0.35 g, 4.8 mmol) were heated in DMSO (15 mL) at 80 °C for
2 h. The reaction mixture was poured into ice-water and
acidified with 2 N HCl. The resulting precipitate was removed,
dried at ambient temperature and recrystallized from ethanol
containing traces of DMF to give 0.62 g (30%) of 19a : mp 202
°C; [R]D20 ) -64.5° (c ) 1, DMF); 1H NMR (DMSO-d6) δ 1.84-
1.99 (m, 2H), 2.93 (d, 3H), 3.04, (m, 1H), 3.40-3.65 (m, 2H),
3.80 (s, 3H), 3.88 (s, 3H), 4.18-4.35 (m, 2H), 6.62 (s, 1H), 7.18
(d, 1H, J ) 10 Hz), 7.55 (dd, 1H, J 1 ) 10 Hz, J 2 ) 2 Hz), 7.70-
7.78 (m, 2H), 8.36 (br q, 1H), 8.46 (br t, 1H), 11.04 (s, 1H); MS
(ESI) m/e 515 (M + H+); HPLC (CSP S, S-Whelk-0 1, n-hexane/
ethanol/CH2Cl2 4:1:1.1% AcOH) ee 97.9%.
20
chroman-4-yl)methyl]benzamide (18b): mp 201 °C; [R]D
)
+59.1° (c ) 1, DMF); HPLC (CSP S, S-Whelk-01, n-hexane/
ethanol/CH2Cl2 4:1:1.1% AcOH) ee 98.0%.
(-)-N-[[4-[(5-Ch lor o-2-m et h oxyben za m id o)m et h yl]-7-
m eth oxy-6-ch r om a n yl]su lfon yl]-N′-u r ea (19c). This urea
was prepared in the same manner as the (+)-derivative from
(-)-5-chloro-2-methoxy-N-[(7-methoxy-6-sulfamoylchroman-4-
20
yl)methyl]benzamide (18a ): mp 239 °C; [R]D ) -59.8° (c )
1, DMF); HPLC (CSP S, S-Whelk-01, n-hexane/ethanol/CH2-
Cl2 4:1:1.1% AcOH) ee 98.5%.
(+)-5-Ch lor o-2-m et h oxy-N-[(7-m et h oxy-6-su lfa m oyl-
ch r om a n -4-yl)m eth yl]ben za m id e (18b) a n d (-)-5-Ch lor o-
2-m e t h oxy-N -[(7-m e t h oxy-6-su lfa m oylch r om a n -4-yl)-
m et h yl]b en za m id e (18a ). This compounds were prepared
from
(+)-5-chloro-2-methoxy-N-[(7-methoxychroman-4-yl)-
methyl]benzamide (17b) and (-)-5-chloro-2-methoxy-N-[(7-
methoxychroman-4-yl)methyl]benzamide (17a ), respectively,
according to the procedure described for benzenesulfonamides
5 (Scheme 1) using chlorosulfonic acid at ambient temperature
and subsequently aqueous ammonia in acetone.
(+)-5-Ch lor o-2-m eth oxy-N-[(7-m eth oxych r om a n -4-yl)-
m eth yl]ben za m id e (17b) a n d (-)-5-Ch lor o-2-m eth oxy-N-
[(7-m eth oxych r om a n -4-yl)m eth yl]ben za m id e (17a ). These
compounds were prepared from (+)- and (-)-4-aminomethyl-
7-methoxychromanes 16b,a , respectively, according to method
i for the preparation of amides 4 in Scheme 1.
(-)-4-Am in om eth yl-7-m eth oxych r om a n e (16a ). En a n -
tiom er ic Sep a r a tion of 16. (R)-(-)-Mandelic acid (82.1 g,
0.54 mol) and 4-aminomethyl-7-methoxychromane (16; 103.1
g, 0.534 mol) were fractionally crystallized from absolute
ethanol (1200 mL) at ambient temperature. After 3 crystal-
lizations 29.8 g of the (R)-(-) mandelic acid salt of 16a were
20
obtained with [R]D ) -59.5° (c ) 1, H2O); mp 147-148 °C;
HPLC ee >99%. From this salt the free base of 4-aminomethyl-
7-methoxychromane was obtained by treatment with aqueous
NaOH and extraction with CH2Cl2 as a viscous oil.
(+)-4-Am in om eth yl-7-m eth oxych r om a n e (16b) was ob-
tained in the same manner as the (-)-enantiomer 16a using
(S)-(+)-mandelic acid instead of the R-(-)-isomer. The purity
of the (S)-(+)-mandelic salt 16b was >98.2%.
4-Am in om eth yl-7-m eth oxych r om a n e (16). To NaH (30
g, 95% in oil, 1.2 mol) in THF (1 L) was added phosphonoacetic
acid trimethyl ester (240 mL, 1.2 mol) dropwise under a N2
atmosphere. The mixture was cooled to 0 °C and 7-methoxy-
chroman-4-one (14; 116 g, 0.65 mol) in THF (200 mL) was
added dropwise. The mixture was allowed to stand overnight.
After removal of the solvent, the residue was taken up with
water (2 L) and CH2Cl2 (1 L). The organic layer was washed
with water and dried over Na2SO4. The solvent was evaporated
and the resulting gum purified by column chromatography
with silica gel (petroleum ether/ethyl acetate 5:1) to give a pale
yellow oil, 98 g, (61%) consisting of a mixture of steroisomeric
7-methoxychromanylideneacetic acid methyl esters. This oil
was completely dissolved in acetic acid (800 mL) and subjected
to hydrogenation at ambient temperature with 12 g Pd/C
(10%). The catalyst was filtered off and the solvent removed
in vacuo to give the crude 7-methoxy-4-chromaneacetic acid
ethyl ester as an oil which was dissolved in 2 N NaOH (320
mL) and ethanol (120 mL). After reflux for 1.5 h ethanol was
removed in vacuo and the resulting clear aqueous solution was
acidified to pH 1-2 (concentrated HCl). The precipitate was
removed by suction and air-dried to give 7-methoxy-4-chro-
maneacetic acid: 71.6 g (61%); mp 82-83 °C; MS (DCI) m/e
223 (M + H+). This material (18.9 g, 85 mmol) was added to
azidodiphenylphosphate (18.88 mL, 85 mmol) and triethyl-
amine (11.96 mL, 85 mmol) in tert-butanol (200 mL) and
refluxed for 24 h. The solvent was removed in vacuo, the
residue was purified by flash chromatography on silica gel
(ethyl acteate/CH2Cl2 1:19) to give N-(tert-butoxycarbonyl)-4-
aminomethyl-7-chromane: 23.3 g (95%); mp 83-85 °C; 1H
(+)-N-[[4-[(5-Ch lor o-2-m et h oxyb en za m id o)m et h yl]-7-
m eth oxy-6-ch r om an yl]su lfon yl]-N′-m eth ylu r ea (19d). (+)-
5-Chloro-2-methoxy-N-[(7-methoxy-6-sulfamoylchroman-4-yl)-
methyl]benzamide (18b; 3.5 g, 8.0 mmol), powdered NaOH (0.8
g) and N-methyltrichloracetamide (2.1 g, 12.0 mmol) were
heated in DMSO for 0.5 h. The mixture was poured into ice-
water and acidified with 2 N HCl. The resulting precipitate,
dried at ambient temperature, was purified by chromatogra-
phy with CH2Cl2/acetic acid (29:1). Recrystallization from
ethanol yielded 1.12 g (28%) of 19d : mp 242 °C; [R]D20 ) +63.4°
(c ) 1, DMF); HPLC ee ) 100%; 1H NMR (DMSO-d6) δ 1.85-
1.96 (m, 2H), 2.53 (s, 3H), 3.03, (m, 1H), 3.40-3.57 (m, 2H),
3.82 (s, 3H), 3.87 (s, 3H), 4.18-4.34 (m, 2H), 6.22, (br q, 1H,
J ) 2,5 Hz), 7.58, (s, 1H), 7.18 (d, 1H, J ) 10 Hz), 7.55 (dd,
1H, J 1) 10 Hz, J 2 ) 2 Hz) 7.68-77.4, m, 2H), 8.46 (br t, 1H),
11.2 (s, 1H); MS (ESI) m/e 498 (M + H+); HPLC (CSP S,
S-Whelk-0 1, n-hexane/ethanol/CH2Cl2 4:1:1.1% AcOH) ee
99.0%.

Cardioselective KATP Channel Blockers
J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7 1097
(4) Pratt, C. M.; Moye, L. A. The Cardiac Arrhythmia Suppression
Trial: background, interim results and implications. Am. J .
Cardiol. 1990, 65, 20B-29B.
(5) Hohnloser, S. H. Proarrhythmia with class III antiarrhythmic
drugs: types, risks, and management. Am. J . Cardiol. 1997, 80,
82G-89G.
(6) J anse, M. J .; Wit, A. S. Electrophysiological mechanisms of
ventricular arrhythmias resulting from myocardial ischemia and
infarction. Physiol. Rev. 69, 1049-1169.
(7) Nakaya, H.; Takeda, Y.; Tohse, N.; Kanno, M. Effects of ATP-
sensitive K+ channel blockers on the action potential shortening
in hypoxic and ischaemic myocardium. Br. J . Pharmacol. 1991,
103, 1019-1026.
(8) Nichols, C. G.; Ripoll, C.; Lederer, W. J . ATP-sensitive potassium
channel modulation of the guinea pig ventricular action potential
and contraction. Circ. Res. 1991, 68, 280-287.
(9) Venkatesh, N.; Lamp, S. T.; Weiss, J . N. Sulfonylureas, ATP-
sensitive K+ channels, and cellular K+ loss during hypoxia,
ischemia, and metabolic inhibition in mammalian ventricle. Circ.
Res. 1991, 69, 623-637.
(10) Kantor, P. F.; Coetzee, W. A.; Carmeliet, E. E.; Dennis, S. C.;
Opie, L. H. Reduction of ischemic K+ loss and arrhythmias in
rat hearts. Effect of glibenclamide, a sulfonylurea. Circ. Res.
1990, 66, 478-485.
(11) Billman, G. E.; Avendano, C. E.; Halliwill, J . R.; Burroughs, J .
M. The effects of the ATP-dependent potassium channel antago-
nist, glyburide, on coronary blood flow and susceptibility to
ventricular fibrillation in unanesthetized dogs. J . Cardiovasc.
Pharmacol. 1993, 21, 197-204.
NMR (DMSO-d6) δ 1.38 (s, 9H), 1.70-1.97 (m, 2H), 2.70-2.82
(m, 1H), 2.88-3.06 (m, 1H), 3.14-3.30 (m, 1H), 3.68 (s, 3H),
3.97-4.20 (m, 2H), 6.30 (d, 1H, J ) 2 Hz), 6.42 (dd, 1H, J 1
)
10 Hz, J 2 ) 2 Hz), 7.02 (br d, 2H, J ) 10 Hz); MS (DCI) m/e
294 (M + H+), which was refluxed in methanol and 2 N HCl
(1:1) for 2 h. Following removal of the solvent in vacuo, the
residue was titurated with ether to give 4-aminomethyl-7-
methoxychromane 16 as its hydrochloride (15 g, 82%): mp
191-193 °C; MS (DCI) m/e 194 (M + H+).
II. P h a r m a cologica l Meth od s. Mem br a n e P oten tia l
Mea su r em en t of CHO Cells Exp r essin g SUR1 a n d Kir 6.2.
CHO cells stably expressing SUR1/Kir6.2 and SUR2A/Kir 6.2,
respectively, were seeded in black-walled 96-well microtiter
plates the day before measurement. On the experimental day
plates were washed three times with PBS. The final washing
step left 90 µL in each well. Cells were loaded with DiBAC4
(3) (Molecular Probes, Portland, OR) by adding 90 µL of a 10
µM DiBAC4 (3) solution in PBS and 90 µL of a 400 µM
diazoxide solution in PBS into each well; cells were incubated
for 30 min at 37 °C before transfer to the fluorescent microtiter
plate reader (FLIPR, Molecular Devices, Sunnyvale, CA).
Excitation was at 488 nm with an argon laser (Innova 90,
Coherent, Santa Clara, CA) and fluorescence emission was
monitored by a CCD camera. The membrane potential mea-
surement was initiated after 4 min by the addition of 20 µL
compound or control solution to each well and measurements
were taken for 20 min every 20 s. Data are the mean of at
least four experiments.
Meth od Ca r d ia c Action P oten tia l. Exp er im en ts w ith
p a p illa r y m u scles: Guinea pigs of either sex (Marioth,
animal breeding Hoechst, Frankfurt/Main, Germany), weigh-
ing 300-500 g, were killed by cervical dislocation and exsan-
guination. The hearts were rapidly removed and the right or
left papillary muscles were excised and mounted in an organ
bath which contained the following bathing solution (in mM):
136 NaCl, 3.3 KCl, 2.5 CaCl2, 1.2 KH2PO4, 1.1 MgSO4, 5
glucose, 10 HEPES, pH adjusted to 7.4 with NaOH, gassed
with 100% O2.
The muscles were stimulated with rectangular pulses of 1
V and 1 ms duration at a rate of 1 Hz. The following
parameters were determined: the cell’s resting potential, the
action potential duration at 90% repolarization (APD90), the
upstroke velocity, and the amplitude of the action potential.
To obtain the action potential, a standard microelectrode
technique was used. Briefly, a glass microelectrode containing
3 M KCl was inserted into the cell, and the obtained signal
was amplified (microelectrode amplifier type 309, Hugo Sachs,
March-Hugstetten, Germany) and recorded with a computer
system. When the right muscle was used, the contractile force
was recorded by means of a strain-gage (GIC, Bodenheim,
Germany) and the signal was displayed on a chart recorder.
E xp er im en t s w it h t h e ch a n n el op en er r ilm a k a lim :
(12) Sturgess, N. C.; Ashford, M. L.; Cook, D. L.; Hales, C. N. The
sulphonylurea receptor may be an ATP-sensitive potassium
channel. Lancet 1985, 2, 474-475.
(13) Schmid-Antomarchi, H.; de-Weille, J .; Fosset, M.; Lazdunski, M.
The antidiabetic sulfonylurea glibenclamide is a potent blocker
of the ATP-modulated K+ channel in insulin secreting cells.
Biochem. Biophys. Res. Commun. 1987, 146, 21-25.
(14) Daut, J .; Maier-Rudolph, W.; von Beckerath, N.; Mehrke, G.;
Gunther, K.; Goedel-Meinen, L. Hypoxic dilation of coronary
arteries is mediated by ATP-sensitive potassium channels.
Science 1990, 247, 1341-1344.
(15) Schulz, R.; Rose, J .; Heusch, G. Involvement of activation of ATP-
dependent potassium channels in ischemic preconditioning in
swine. Am. J . Physiol. 1994, 267, H1341-1352.
(16) J aburek, M.; Yarov-Yarovoy, V.; Paucek, P.; Garlid, K. State-
dependent inhibition of the mitochondrial KATP channel by
glyburide and 5-hydroxydecanoate. J . Biol. Chem. 1998, 273,
13578-13582.
(17) Go¨gelein, H.; Hartung, J .; Englert, H. C.; Scho¨lkens, B. A. HMR
1883, a novel cardioselective inhibitor of the ATP-sensitive
potassium channel. Part I: Effects on cardiomyocytes, coronary
flow and pancreatic â-cells. J . Pharmacol. Exp. Ther. 1998, 286,
1453-1464.
(18) Billman, G. E.; Englert, H. C.; Scho¨lkens, B. A. HMR 1883, a
novel cardioselective inhibitor of the ATP-sensitive potassium
channel. Part II: Effect on suceptibility to ventricular fibrillation
induced by myocardial ischemia in conscious dogs. J . Pharmacol.
Exp. Ther. 1998, 286, 1465-1473E.
(19) Wirth, K. J .; Klaus, E.; Englert, H.; Scho¨lkens, B.; Linz, W.
HMR1883, a cardioselective KATP channel blocker inhibits is-
chemia and reperfusion induced ventricular fibrillations in rats.
Naunyn-Schmiedbergs Arch. Phamacol. 1999, 360, 295-300.
(20) Sato, T.; Sasaki, N.; Seharaseyon, J .; O’Rourke, B.; Marban, E.
Selective pharmacological agents implicate mitochondrial but
not sarcolemmal K(ATP) channels in ischemic cardioprotection.
Circulation 2000, 101, 2418-2423.
(21) J ung, O.; Englert, H. C.; J ung, W.; Go¨gelein, H.; Scho¨lkens, B.
A.; Busch, A. E.; Linz, W. The K(ATP) channel blocker HMR
1883 does not abolish the benefit of ischemic preconditioning
on myocardial infarct mass in anesthetized rabbits. Naunyn-
Schmiedebergs Arch. Pharmacol. 2000, 361, 445-451.
(22) Wirth,-K. J .; Rosenstein, B.; Uhde, J .; Englert, H. C.; Busch, A.
E.; Scho¨lkens, B. A. ATP-sensitive potassium channel blocker
HMR 1883 reduces mortality and ischemia-associated electro-
cardiographic changes in pigs with coronary occlusion. J . Phar-
macol. Exp. Ther. 1999, 291, 474-481.
After
a 30-min equilibration period, the channel opener
rilmakalim (HOE234)27,28 was applied. The test compound was
added 30 min after the channel opener, and APD90 was
recorded after an additional 60 min. As the shortening of the
APD90 by rilmakalim and its subsequent prolongation by KATP
channel blockers was highly reproducible, the number of
experiments per concentration was one in most cases.
Ack n ow led gm en t. We thank K.-H. Herget-J u¨rgens,
N. Ho¨rl, F. Roll, P. Voss, P. Lehmann, A. Vo¨lker-Winter,
and R. Rothenba¨cher for their excellent technical as-
sistance.
(23) Gribble, F. M.; Tucker, S. J .; Seino, S.; Ashcroft, F. M. Tissue
specificity of sulfonylureas: studies on cloned cardiac and beta-
cell K(ATP) channels. Diabetes 1998, 47, 1412-1418.
(24) For review see: Glombik, H.; Weyer, R. Orale Antidiabetika.
Progress in Drug Research; Birkha¨user Verlag: Basel, 1986; Vol.
30.
(25) Sturgess, N. C.; Kozlowski, R. Z.; Carrington, C. A.; Hales, C.
N., Ashford, M. L. Effects of sulphonylureas and diazoxide on
insulin secretion and nucleotide-sensitive channels in an insulin-
secreting cell line. Br. J . Pharmacol. 1988, 95, 83-94.
(26) Toth, G.; Ko¨ver, K. E. Simple, safe large scale synthesis of
5-arylmethyl-2,2-dimethyl-1,3-dioxane-4,6-diones and 3-arylpro-
pionic acids. Synth. Commun. 1995, 25, 3067-3074.
Refer en ces
(1) Demirovic, J .; Myerburg, R. J . Epidemiology of sudden coronary
death: an overview. Prog. Cardiovasc. Dis. 1994, 37, 39-48.
(2) Davies, M. J .; Thomas, A. Thrombosis and acute coronary artery
lesions in sudden ischemic death. N. Engl. J . Med. 1984, 310,
1137-1140.
(3) Zehender, M.; Faber, T.; Brunner, M.; Grom, A. Acute myocardial
ischemia and ventricular arrhythmias in the pathogenesis of
sudden cardiac death in coronary disease. Z. Kardiol. 2000, 89,
13-23.

1098 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 7
Englert et al.
(27) Sakurai, S.; Mitani, K.; Hashimoto, S.; Morikawa, K.; Yasuda,
S. Novel phenoxyalkylamine derivatives. VII. Synthesis and
pharmacological activities of 2-alkoxy-5-[(phenoxyalkylamino)-
alkyl]benzenesulfonamide derivatives. Chem. Pharm. Bull. 1992,
40, 1443-1451.
(28) Deprez, P.; Guillaume, J .; Becker, R.; Corbier, A.; Didierlaurent,
S.; Fortin, M.; Frechet, D.; Hamon, G.; Heckmann, B.; Heitsch,
H.; Kleemann, H.-W.; Vevert, J .-P.; Vincent, J .-C.; Wagner, A.;
Zhang, J . Sulfonylureas and sulfonylcarbamates as new non-
tetrazole angiotensin II receptor antagonists. Discovery of a
highly potent orally active (imidazolyl-biphenyl)sulfonylurea (HR
720). J . Med. Chem. 1995, 38, 2357-2377.
(29) Weichert, A.; Bauer, M.; Wirsig, P. Palladium(0)-catalyzed cross-
coupling reactions of hindered, double activated aryl halides with
organozinc reagents - the effect of copper(I) cocatalyst. Synlett
1996, 473-474.
(30) Bailey, T. R. Unsymmetrical heterobiaryl synthesis. A highly
efficient palladium-catalyzed cross-coupling reaction of het-
eroaryl trialkylstannanes with aryl halides. Tetrahedron Lett.
1986, 4407-4410.
(31) Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. A new
convergent synthesis of alpha-substituted beta-carbolines. Tet-
rahedron 1993, 49, 3325-3342.
(32) Miyaura, N.; Yanagi, T.; Suzuki, A. The palladium-catalyzed
cross-coupling reaction of phenylboronic acid with haloarenes
in the presence of bases. Synth. Commun. 1981, 11, 513-519.
(33) Sacquet, M.-C.; Bellassoued-Fargeau, M.-C.; Graffe, B.; Maitte,
P. Synthesis of 2-oxo pyrano[3,2-c]benzopyrans and 2-oxopy-
rano[3,2-d]benzoxepins. J . Heterocycl. Chem. 1985, 22, 757-
760.
(34) Krause, E.; Englert, H.; Gogelein, H. Adenosine triphosphate-
dependent K currents activated by metabolic inhibition in rat
ventricular myocytes differ from those elicited by the channel
opener rilmakalim. Pflu¨gers Arch. 1995, 429, 625-635.
(35) Terzic, A.; J ahangir, A.; Kurachi, Y. HOE-234, a second genera-
tion K+ channel opener, antagonizes the ATP-dependent gating
of cardiac ATP-sensitive K+ channels. J . Pharmacol. Exp. Ther.
1994, 268, 818-825.
(36) Ghosh, S.; Standen, N. B.; Galinanes, M. Evidence for mito-
chondrial KATP channels as effectors of human myocardial
preconditioning. Cardiovasc. Res. 2000, 45, 934-940.
J M000985V