Cardioselective antiischemic ATP-sensitive potassium channel openers. 4. Structure-activity studies on benzopyranylcyanoguanidines: Replacement of the benzopyran portion

Article abstract of DOI:10.1021/jm950646f

The results of our efforts aimed at the replacement of the benzopyran ring of the lead cardiac selective antiischemic ATP-sensitive potassium channel (K(ATP)) opener (4) are described. Systematic modification of the benzopyran ring of 4 resulted in the discovery of a structurally simpler acyclic analog (8) with slightly lower antiischemic potency than the lead compound 4. Further structure-activity studies on the acyclic analog 8 provided the 2- phenoxy-3-pyridylurea analog 18 with improved antiischemic potency and selectivity compared to the benzopyran-based compound 4. These data demonstrate that the benzopyran ring of 4 and its congeners is not mandatory for antiischemic activity and cardiac selectivity. The results described in this paper also show that, as for the benzopyran class of compounds, the structure-activity relationships for the antiischemic and vasorelaxant activities of K(ATP) openers are distinct. The mechanism of action of the acyclic analogs (e.g., 18) still appears to involve K(ATP) opening as their cardioprotective effects are abolished by pretreatment with the K(ATP) blocker glyburide.

Full text of DOI:10.1021/jm950646f

304
J . Med. Chem. 1996, 39, 304-313
Ca r d ioselective An tiisch em ic ATP -Sen sitive P ota ssiu m Ch a n n el Op en er s. 4.
Str u ctu r e-Activity Stu d ies on Ben zop yr a n ylcya n ogu a n id in es: Rep la cem en t of
th e Ben zop yr a n P or tion
Karnail S. Atwal,* Francis N. Ferrara, Charles Z. Ding, Gary J . Grover, Paul G. Sleph, Steven Dzwonczyk,
Anne J . Baird, and Diane E. Normandin
The Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New J ersey 08543-4000
Received August 30, 1995X
The results of our efforts aimed at the replacement of the benzopyran ring of the lead cardiac
selective antiischemic ATP-sensitive potassium channel (KATP) opener (4) are described.
Systematic modification of the benzopyran ring of 4 resulted in the discovery of a structurally
simpler acyclic analog (8) with slightly lower antiischemic potency than the lead compound 4.
Further structure-activity studies on the acyclic analog 8 provided the 2-phenoxy-3-pyridylurea
analog 18 with improved antiischemic potency and selectivity compared to the benzopyran-
based compound 4. These data demonstrate that the benzopyran ring of 4 and its congeners
is not mandatory for antiischemic activity and cardiac selectivity. The results described in
this paper also show that, as for the benzopyran class of compounds, the structure-activity
relationships for the antiischemic and vasorelaxant activities of KATP openers are distinct. The
mechanism of action of the acyclic analogs (e.g., 18) still appears to involve KATP opening as
their cardioprotective effects are abolished by pretreatment with the KATP blocker glyburide.
In tr od u ction
We have been interested in the role of KATP in
myocardial ischemia. Accordingly, we have shown that
KATP openers have direct cardioprotective properties
which do not require contribution from vasodilation.3
Although effective as cardioprotective agents when
given directly into the coronary artery, the potent
vasorelaxant properties of the first generation agents
can compromise the tissue already at risk by causing
hypotension and coronary artery steal.4 Previous re-
ports from our laboratories have shown that the struc-
ture-activity relationships for the antiischemic and
vasorelaxant potencies of the benzopyran-based KATP
openers are distinct.5 Our efforts to find cardioprotec-
tive KATP openers with a lower degree of vasorelaxant
potency relative to the first generation agents (i.e.,
cardiac selective agents) resulted in the identification
of BMS-180448 (3).5 We have recently published de-
tailed structure-activity relationships on the lead
compound (4) that led to the discovery of the clinical
candidate BMS-180448 (3).6,7 The results of those
studies helped us understand the minimum structural
requirements for the antiischemic activity of 4 and its
congeners. The present publication describes our stud-
ies aimed at the replacement of the core benzopyran ring
of 4 with simpler surrogates.
The major clinical utility of the ATP-sensitive potas-
sium channel (KATP) openers (e.g., cromakalim) was
originally thought to be for the treatment of hyperten-
sion, primarily due to their potent peripheral vasodi-
lating properties.1 However, the clinical studies with
the first generation agents (e.g., 1 and 2) have failed to
demonstrate any clear advantages of these compounds
over the more established antihypertensive agents such
as the angiotensin-converting enzyme inhibitors and
calcium channel blockers. Therefore, additional indica-
tions need to be explored for these drugs to be successful
as pharmaceuticals. Although experimental studies
show that the first generation agents may be effective
for the treatment of a variety of diseases (asthma,
urinary incontinence, ischemia, etc.) besides hyperten-
sion, their clinical utility is limited due to lack of tissue
selectivity. For example, cromakalim (1) and pinacidil
(2) can open KATP in a variety of tissues.2 Tissue-
selective agents are desired to explore the full potential
of KATP openers for various indications.
Design Str a tegy
The objective of this work was to discover simpler
molecules with a similar or improved pharmacological
profile (e.g., increased potency and selectivity) compared
to the lead benzopyran derivative 4. The simpler
analogs were expected to be more amenable to rapid
development of structure-activity relationships for the
optimization of antiischemic potency and selectivity. The
design strategy beginning with the lead structure 4 is
outlined in Scheme 1. We concentrated on modification
of the benzopyran portion of 4 since it is the most
complex area of the molecule with two adjacent chiral
centers at C3 and C4. A summary of the structure-
activity relationships for antiischemic activity of 4 is
given in Figure 1. The cyanoguanidine moiety can be
X Abstract published in Advance ACS Abstracts, December 1, 1995.
0022-2623/96/1839-0304$12.00/0 © 1996 American Chemical Society

ATP-Sensitive Potassium Channel Openers
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 305
Ta ble 1. Vasorelaxant and Antiischemic Potencies of
Compounds 4-8
F igu r e 1. A summary of the structure-activity relationships
for antiischemic potency of the lead benzopyranylcyanoguani-
dine 4.
Sch em e 1
a
Antiischemic potency was determined by measurement of
EC25, concentration necessary for increase in time to contracture
by 25%, in the globally ischemic rat hearts. Time to contracture
was defined as the time (in minutes) necessary during total global
ischemia to increase end diastolic pressure by 5 mmHg. Each
value is an average of three or four determinations and is within
b
approximately (20%. Vasorelaxant potency was assessed by
measurement of IC50 for inhibition of methoxamine contracted rat
aorta. IC50 is presented as a mean with 95% confidence interval
in parentheses, n ) 4 or higher. c Data presented previously in
ref 6.
replaced with a urea.5 Neither the benzopyran oxygen
nor the C3 hydroxyl group is required for antiischemic
activity of 4 (Figure 1).6 These changes, when combined
in a single molecule, provided the indan analog 5 with
antiischemic potency comparable to the starting mol-
ecule 4 (Table 1).6 The indan analog 5 contains a single
chiral center compared to the two chiral centers usually
present in benzopyran derivatives (e.g., 4). Further
simplification of the structure of 5 was envisioned to
arise from the inclusion of the benzylic nitrogen of 5
into the indan ring (5 f 6) (Scheme 1). Unlike the
indan analog 5, quinoline 6 has no chiral centers. If
sufficiently active, the relatively rigid framework of 6
was expected to provide the incentive to explore its
simplified acyclic analogs (e.g., 8). Compounds related
to 8 are synthetically more easily accessible than the
benzopyran-based compounds (4) for rapid development
of structure-activity relationships. The successful
realization of this strategy is described in this publica-
tion.
reduction with diisobutylaluminum hydride underwent
the reductive Beckmann rearrangement9 to provide the
desired quinoline 24 as a major product. A small
amount of the isoquinoline which could have been
formed due to migration of the alkyl group during the
Beckmann rearrangement (23 f 24) was not isolated.
The bromide in 24 was smoothly converted to the nitrile
25 by treatment with copper(I) cyanide in hot N-
methylpyrrolidone. Replacement of the nitro group in
19 with a bromine 21 was necessitated due to the failure
of the Beckmann rearrangement in the presence of a
nitro group. The phenylurea analog 6 was prepared by
treatment of 25 with phenyl isocyanate.
The synthesis of the dihydroindole analog 7 is sum-
marized in Scheme 3. The starting lactam 28 was
prepared from 3-methylindole (26) via the dibromide
27.10a The nitrogen of the lactam (28) was protected as
an acetate (29), and the second methyl group (30) was
introduced by alkylation with methyl iodide in the
presence of sodium hydride.10b We were unable to
accomplish C-methylation of 28 without prior protection
of the lactam nitrogen. Saponification of the acetate in
30 followed by reduction of 31 with sodium bis(2-
methoxyethoxy)aluminum hydride gave the dihydroin-
dole 32 in good yield. Attempts to replace the bromine
in 32 with a nitrile failed, partly due to the susceptibility
of 32 to oxidation under forcing conditions. Thus, the
amine in 32 had to be reprotected as an acetate (33)
before replacement of the bromine with a cyano group
(34). Deprotection of 34 to 35 was carried out in 91%
yield by heating 34 with aqueous hydrochloric acid. The
3-pyridylurea (7) was formed from 35 by heating with
Ch em istr y
The synthesis of the quinoline nucleus of 6 started
with the previously described indanone 198 (Scheme 2).
The nitro group of 19 was reduced to the amine 20 by
catalytic hydrogenation. The amine 20 was converted
to the bromide 21 by a two-step process which involves
conversion of 20 to the corresponding diazonium salt
followed by treatment with copper(I) bromide. The
ketone in 21 was converted to a mixture of oximes (22)
under standard conditions (hydroxylamine hydrochlo-
ride, sodium acetate). Treatment of 22 with p-toluene-
sulfonyl chloride provided the tosylate 23 which upon

306 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Atwal et al.
Sch em e 2a
a
Reagents: (a) 5% Pd-C, methanol, H2, 15 psi, 100%; (b) EtOH, 48% HBr, NaNO2, 0 °C; (c) CuBr, 48% HBr, 95 °C, 79% from 20; (d)
NH2OH‚HCl, NaOAc, EtOH, heat, 100%; (e) p-toluenesulfonyl chloride, pyridine, 99%; (f) diisobutylaluminum hydride, CH2Cl2, -78 to 0
°C, 49%; (g) CuCN, N-methylpyrrolidone, 185-190 °C, 53%; (h) phenyl isocyanate, 4-(dimethylamino)pyridine, acetonitrile, heat, 83%.
Sch em e 3a
a
Reagents: (a) N-bromophthalimide, benzene, 51%; (b) H2SO4, dioxane, 98%; (c) Ac2O, xylene, reflux, 78%; (d) NaH, MeI, THF, 100%;
(e) NaOH, EtOH, 98%; (f) sodium bis(2-methoxyethoxy)aluminum hydride, toluene, 85 °C, 73%; (g) AcCl, triethylamine, CH2Cl2, 99%; (h)
CuCN, N-methylpyrrolidone, 83%; (i) 5 N HCl, 91%; (j) nicotinyl azide, toluene, 85 °C, 80%.
Sch em e 4a
nicotinyl azide in toluene. The mild basicity of the
amine in 35 obviates the need for the prior formation
of 3-pyridyl isocyanate from nicotinoyl azide.
For the preparation of acyclic urea analog 8, tert-
butylbenzene 36 was converted to the amino compound
38 by the published procedure (Scheme 4).11 The less
hindered nitro group of 37 was selectively reduced to
compound 38 (86%) with sodium sulfide-sulfur mixture.
The amino group in 38 was changed to a nitrile (39)
via the diazonium salt, prepared from 38 by treatment
with sodium nitrite in hydrochloric acid. The nitro
group of 39 was reduced with stannous chloride and the
corresponding amine 40 was converted to the phenyl-
urea 8 by treatment with phenyl isocyanate.
The additional urea analogs (9, 11-15) of 8 were
prepared from the amine 40 via the phenyl carbamate
41, readily obtained by treatment of 40 with phenyl
chloroformate in pyridine (94%). The phenyl carbamate
41 on heating with the appropriate amines provided the
desired products in good yields (Scheme 5). The cyano-
guanidine analog 10 of 9 was prepared from the amine
40 via the phenoxy intermediate 42 by the published
procedure (Scheme 6).7
a
Reagents: (a) H2SO4, HNO3, 70%; (b) water, sodium sulfide-
sulfur, 86%; (c) HCl, NaNO2; (d) CuCN, KCN, water, 42% from
38; (e) stannous chloride, ethanol, 100%; (f) phenyl isocyanate,
heat, 86%.

ATP-Sensitive Potassium Channel Openers
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 307
Sch em e 5a
The sulfonamide analog 17 was prepared from
4-amino-3-nitrobenzonitrile (48) in a straightforward
manner (Scheme 8). The sulfonamide 49 was prepared
in a low yield (16%) by successive treatment of 48 with
sodium hydride and p-toluenesulfonyl chloride in di-
methyl sulfoxide. The nitro group (49) was reduced
with stannous chloride, and the resulting amine (50)
was converted to the 3-pyridylurea analog 19 under
standard conditions (nicotinoyl azide, toluene, heat).
The synthesis of the phenoxy analog 18 is sum-
marized in Scheme 9. The phenoxy group (52) was
introduced by heating 4-chloro-3-nitrobenzonitrile (51)
with phenol in the presence of potassium carbonate.
Reduction of the nitro group of 52 with stannous
chloride followed by treatment of the resulting amine
53 with nicotinoyl azide in hot toluene furnished the
desired product (18) in 62% overall yield from 52.
a
Reagents: (a) pyridine, phenyl chloroformate, 94%; (b) Het-
NH2, DMF, 4-(dimethylamino)pyridine, heat.
Sch em e 6a
Resu lts a n d Discu ssion
a
Reagents: (a) NaH, THF, diphenyl cyanocarbonimidate, 77%;
The vasorelaxant potencies were determined by mea-
surement of IC50 values for relaxation of the methox-
amine contracted rat aorta, as described previously.13
Antiischemic potencies in vitro were determined by
measurement of EC25 values for increase in time to the
onset of contracture in globally ischemic isolated per-
fused rat hearts.14 Time to contracture is defined as
the time necessary during total global ischemia to
increase end diastolic pressure by 5 mmHg compared
to the baseline value.14 Contracture develops due to
rigor bond formation, presumably due to lack of ATP.
The ratio of EC25 value for time to contracture and IC50
value for vasorelaxant potency indicates selectivity in
vitro for the ischemic myocardium. Validity of these in
vitro test systems to predict antiischemic selectivity in
vivo has been previously demonstrated by detailed
studies with BMS-180448 (3).15
(b) 3-aminopyridine, DMF, 100 °C, 58%.
Sch em e 7a
For initial studies, some analogs (e.g., 7) had to be
evaluated as pyridylureas because of poor aqueous
solubilities of the corresponding phenylureas. The
higher aqueous solubility of pyridylurea analogs is
presumably due to a combination of factors which
include solvation, hydrogen-bonding capability, and the
potential for protonation. Previous studies have shown
that the 3-pyridylurea and phenylurea analogs of 4 have
comparable antiischemic potencies.7 The cyano group,
usually present at C6 of the benzopyran-based com-
pounds (e.g., 4), was kept constant throughout these
studies. As shown in Table 1, the quinoline analog 6 is
about 2-fold less active as an antiischemic agent com-
pared to the corresponding benzopyran and indan
derivatives, 4 and 5, respectively. By virtue of having
lower vasorelaxant potency relative to 4 and 5, the
quinoline derivative 6 shows slightly improved cardiac
selectivity over 4 and 5. The indoline analog 7 offered
a
Reagents: (a) AcOH, Br2, 68%; (b) AcOH, sodium nitrite then
NaOAc, benzene, 38%; (c) Cu(I)CN, N-methylpyrrolidone, 180 °C,
56%; (d) stannous chloride dihydrate, EtOH, 89%; (e) nicotinyl
azide, toluene, heat, 73%.
The synthesis of the biphenyl analog 16 is outlined
in Scheme 7. The biphenyl intermediate 45 was pre-
pared from 2-nitroaniline (43) by the literature proce-
dure.12 The bromine in 45 was replaced with a nitrile
(46) by heating 45 with copper(I) cyanide in hot N-
methylpyrrolidone. Reduction of the nitro group in 46
and derivatization of the resulting amine 47 by the
standard procedure provided the desired 3-pyridylurea
16.
Sch em e 8a
a
Reagents: (a) NaH, DMSO, p-toluenesulfonyl chloride, 16%; (b) stannous chloride dihydrate, EtOAc, 84%; (c) nicotinyl azide, toluene,
heat, 75%.

308 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Atwal et al.
Sch em e 9a
a
Reagents: (a)PhOH, K2CO3, DMF, 63%; (b) SnCl2, EtOAc, 88%; (c) nicotinyl azide, toluene, 95 °C, 70%.
Ta ble 2. Vasorelaxant and Antiischemic Potencies of Biaryl
Urea 8 and Its Analogs
cyanoguanidine analog 10 offers no improvement over
the corresponding urea 9. Although the 2-pyridylurea
analog 11 has antiischemic potency similar to 9, the
4-pyridylurea (12) appears to be less potent than 9.
Introduction of an additional nitrogen atom into the
pyridine ring of 9 has a variable effect on antiischemic
potency. While the pyrimidine analog 13 has a reduced
antiischemic potency relative to that of 9, the pyrazine
derivative 14 shows a slight improvement in anti-
ischemic potency over 9. Substitution of the pyridine
ring of 9 with a chlorine atom (15) is slightly beneficial
to both antiischemic and vasorelaxant potencies. The
changes on the pyridine ring of 9 indicate that, although
some qualitative trends in structure-activity relation-
ships can be noted, the antiischemic potency of 9 largely
remains constant. These observations are similar to
those previously reported for the arylurea portion of the
benzopyran-based antiischemic KATP openers (e.g., 4).7
We have previously reported that the antiischemic
potency of the benzopyran-based KATP openers (e.g., 4)
is extremely sensitive to the presence of a gem-dimethyl
group at C2 of the benzopyran ring.6 Assuming that
compounds 4 and 9 are expressing their biological effects
by binding in a similar manner, we expected a more
profound effect of changes to the tert-butyl group of 9.
As it turned out, replacement of the tert-butyl group of
9 with a more rigid phenyl group (16) has a deleterious
effect on antiischemic potency. Increasing the distance
between the two phenyl groups of 16 via a sulfonamide
linker (17) causes complete abolition of antiischemic
potency. The best compound of this series was obtained
by inserting an oxygen atom (18) between the phenyl
rings of compound 16. Compound 18 shows a 5-fold
improvement in antiischemic potency over the starting
benzopyran 4. Further, the phenoxy analog 18 shows
slightly improved cardiac selectivity relative to 4.
Comparison among 9 and 16-18 indicates that the size
of the lipophilic substituent is important for anti-
ischemic potency. The tert-butyl and phenyl groups of
9 and 16, respectively, may not be able to access the
presumed lipophilic pocket occupied by the gem-dimeth-
yl group of the benzopyran series of compounds (4).
Whatever the reasons, these results indicate that the
antiischemic potency of the acyclic analogs (e.g., 8) is
most sensitive to changes at the group that mimics the
gem-dimethyl group at C2 of the benzopyran-based
compounds (e.g., 4).
a
Antiischemic potency was determined by measurement of
EC25, concentration necessary for increase in time to contracture
by 25%, in the globally ischemic rat hearts. Time to contracture
was defined as the time (in minutes) necessary during total global
ischemia to increase end diastolic pressure by 5 mmHg. Each
value is an average of three or four determinations and is within
b
approximately (20%. Vasorelaxant potency was assessed by
measurement of IC50 for inhibition of methoxamine contracted rat
aorta. IC50 is presented as a mean with 95% confidence interval
in parentheses, n ) 4 or higher.
no improvement in the antiischemic potency of 6. At
this stage, we were far from meeting our objective, as
the syntheses of 6 and 7 were much more complicated
than those of the benzopyran-based analogs (e.g., 4).5-7
Further structural simplification was achieved by the
carbon-nitrogen bond scission in 6 (Scheme 1). The
resulting acyclic urea 8 has antiischemic potency com-
parable to 6 (Table 1). Although slightly less potent
than the benzopyran analog 4, the structural simplicity
of 8 made it attractive for further structure-activity
work. The results of those studies are summarized in
Table 2.
As expected, the 3-pyridylurea analog 9 of 8 has
antiischemic potency comparable to 8. Since the py-
ridylurea analogs show better aqueous solubilities than
the corresponding phenylurea derivatives, further work
was concentrated on the heterocyclic analogs of 8. The
As shown by the comparison of ratios between anti-
ischemic and vasorelaxant potencies, the most potent
compound (18, EC25 ) 2 µM) of this series is over 100-
fold more cardiac selective than the reference agent
cromakalim (EC25 ) 9.8 µM). Thus, in addition to
having a simplified structure, compound 18 shows an
improved pharmacological profile compared to the ben-
zopyran-based compounds (e.g., cromakalim). Further,
it offers the opportunity to explore structure-activity

ATP-Sensitive Potassium Channel Openers
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 309
Ta ble 3. Physical Properties of Compounds 6-18
compd
molecular formula
microanalysis
physical characterization
mp (°C)a
4
5
see ref 6
see ref 6
6
7
8
9
10
11
12
13
14
15
16
17
18
C
C
C
C
C
C
C
C
C
C
C
C
C
19H19N3O
17H16N4O
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
off-white solid
white solid
174-5 (A)
220-2 (B)
225-6 (C)
194-6 (D)
219-21 (C)
198-200 (B)
125-30 (B)
208-9 (B)
203-5 (B)
233-4 (B)
180-2 (C)
221-3 (E)
208-9 (F)
18H19N3O‚0.19H2O
17H18N4O‚0.43H2O
18H18N6‚0.3C3H8O
17H18N4O‚0.2EtOAc
17H18N4O‚1.2H2O
16H17N5O
16H17N5O‚0.02H2O
17H17ClN4O‚0.12H2O
19H14N4O‚0.07H2O
20H17N4O3S‚0.11H2O
19H14N4O2‚0.09H2O
off-white solid
off-white solid
off-white solid
off-white solid
amorphous solid
colorless solid
colorless solid
colorless solid
off-white solid
colorless powder
colorless solid
a
Solvent for crystallization: A, trituration with isopropyl ether; B, unrecrystallized material; C, 2-propanol; D, EtOAc/2-propanol/
hexanes; E, DMF/EtOAC/hexanes; F, EtOAc/MeOH/hexanes.
relationships for the discovery of KATP openers with
improved antiischemic potency and cardiac selectivity.
The cardiac selectivity, as determined by the ratio of
vasorelaxant and antiischemic potencies, varies 25-fold
(Table 2). These data support our earlier results,
demonstrating that, regardless of the structural class,
the structure-activity relationships for antiischemic
and vasorelaxant activities of KATP openers are distinct.
We have no clear explanation for these differences at
the present time other than the hypothesis that the
antiischemic and vasorelaxant actions of KATP openers
may be mediated via different receptor subtypes. To
ensure that the mechanism of antiischemic activity of
8 and its derivatives is similar to that of the benzopyran-
based compounds, we studied the effect of the KATP
blocker glyburide on the cardioprotective actions of the
most potent compound 18 of this series. This is espe-
cially important since minor changes in the structure
of the benzopyran-based KATP openers can have a
dramatic effect on their mechanism of action.16 Previ-
ous studies have shown that the cardioprotective effects
of structurally different KATP openers are abolished by
pretreatment with glyburide.14,17 Glyburide is relatively
selective in abolishing the cardioprotective effects of
KATP openers as it has no effect on the cardioprotective
actions of agents working via other mechanisms.18
The effect of glyburide (0.3 µM) on the increase in time
to contracture induced by 10 µM of 18 in isolated
globally perfused rat hearts is shown in Figure 2. This
concentration of glyburide has been shown to be without
an effect on the time to contracture in the isolated
perfused rat hearts.14,17 Compound 18 was given in the
perfusion medium 10 min prior to the onset of total
global ischemia. The development of contracture is
measured as the time necessary to increase end diastolic
pressure by 5 mmHg compared to baseline value.14 The
pyridylurea analog 18 (10 µM) caused a significant
increase in the time (22 min) to the onset of contracture
compared to the vehicle-controlled hearts (17 min). This
increase in time to contracture was completely abolished
by pretreatment with glyburide (0.3 µM), indicating that
the cardioprotective effects of 18 are in some fashion
related to the opening of KATP in the myocardium.
Further, the combination of glyburide (0.3 µM) and
compound 18 (10 µM) was found to be proischemic as
shown by a decrease (30%) in the time to the onset of
contracture compared to the vehicle-treated hearts. This
proischemic effect of glyburide in combination with a
KATP opener previously has been shown for several
F igu r e 2. The effect of glyburide (gly, 0.3 µM) on the increase
in time to contracture induced by 10 µM of the pyridylurea 18
(n ) 4). While having no effect of its own on the increase in
time to contracture (data not shown), glyburide completey
abolished the increase in time to contracture seen with
compound 18. The combination of 18 (10 µM) and glyburide
(0.3 µM) is proischemic as shown by the decrease in time to
contracture compared to vehicle treated hearts. ) signifi-
*
cantly different from vehicle treated hearts; # ) significantly
different from hearts treated with compound 18.
structurally different KATP openers.14,17 These data are
consistent with the profile of antiischemic activity of 18
being similar to that of other KATP openers.5-7
Con clu sion
We have shown that the simplified acyclic analog 18
retains the antiischemic potency and selectivity of its
predecessor benzopyran-based compounds (e.g., 4). The
substituent at the ortho-position of 18, which presum-
ably mimics the gem dimethyl group at the C2 position
of the benzopyran ring of 4, is the most sensitive group
to structural changes. The phenoxy group of 18 appears
to be optimum as the corresponding tert-butyl (8) and
biphenyl (16) analogs are less potent than 18 as anti-
ischemic agents. The results described herein also
demonstrate that the benzopyran ring of 4 is not
mandatory for antiischemic activity and cardiac selec-
tivity. The phenoxy analog 18 is both more potent and
cardioselective compared to the reference agent cro-
makalim. Being structurally simpler compared to the
benzopyran-based KATP openers, compound 18 offers the
opportunity to further explore structure-activity rela-
tionships for the discovery of novel antiischemic KATP
openers with an improved pharmacological profile (e.g.,

310 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Atwal et al.
slowly solidified on standing. The compound was used in the
next step without further purification: 1H NMR (CDCl3) δ 7.93
(d, J ) 8.21 Hz, 2 H), 7.74 (d, J ) 2.35 Hz, 1 H), 7.54 (dd, J )
2.35 and 8.80 Hz, 1 H), 7.37 (d, J ) 8.21 Hz, 2 H), 7.16 (d, J
) 8.21 Hz, 1 H), 2.87 (s, 2 H), 2.45 (s, 3 H), 1.29 (s, 6 H).
E. 7-Br om o-1,2,3,4-tetr a h yd r o-4,4-d im eth ylqu in olin e
(24). To a solution of 23 (7.74 g, 19.0 mmol) in methylene
chloride (95.0 mL) at -78 °C was added diisobutylaluminum
hydride (1 M solution in hexane, 95.0 mL). The reaction
mixture was stirred for 30 min at -78 °C followed by 5 h at 0
°C. The reaction mixture was diluted with methylene chloride
(200 mL) and quenched (while stirring vigorously) by the
addition of sodium fluoride (16.0 g) and water (5 mL). The
reaction mixture was filtered, and the filtrate was dried over
MgSO4. The solvent was evaporated, and the residue was
purified by flash chromatography on silica gel, eluting with
15% ethyl acetate in hexane to obtain the title compound (2.23
g, 49%) as a light yellow oil: 1H NMR (CDCl3) δ 6.93 (d, J )
8.21 Hz, 1 H), 6.63 (dd, J ) 2.34 and 8.20 Hz, 1 H), 6.50 (d, J
) 1.76 Hz, 1 H), 3.85 (broad s, 1 H), 3.21 (dt, J ) 2.93 and
5.86 Hz, 2 H), 1.62 (t, J ) 5.86 Hz, 2 H), 1.18 (s, 6 H); 13C
NMR (CDCl3) δ 144.9, 128.9, 127.8, 119.8, 119.5, 116.2, 38.3,
36.7, 31.5, 30.6, 30.4.
increased potency and cardiac selectivity). The mech-
anism of action of compounds 18 and its analogs still
appears to involve KATP opening as the increase in time
to contracture caused by 18 is abolished by pretreatment
with the KATP blocker glyburide.
Exp er im en ta l Section
Ch em istr y. All melting points were taken on a capillary
melting point apparatus and are uncorrected. The infrared
spectra were recorded with a Perkin-Elmer 983 spectropho-
tometer in KBr pallets. 1H NMR and 13C NMR spectra were
measured on J EOL GX-400 and FX-270 spectrometers with
tetramethylsilane as an internal standard. Mass spectra were
obtained with a Finnigan TSQ-4600 spectrometer. Flash
chromatography was run with Whatman LPS-1 silica gel and
Merck kieselgel 60 (230-400 mesh ASTM). All compounds
were characterized by 1H-, 13C-NMR, and mass spectra.
Microanalysis of all crystalline compounds is consistent with
the structures assigned. The amount of solvent present in the
molecular formula was determined by 1H NMR spectra and
microanalysis. Karl Fisher analysis was performed in selected
cases to confirm the amount of water present.
F . 1,2,3,4-Tetr a h yd r o-4,4-d im eth ylqu in olin e-7-ca r bo-
n itr ile (25). A mixture of 24 (2.24 g, 9.33 mmol) and CuCN
(1.67 g, 18.7 mmol) in N-methylpyrrolidinone (22.5 mL) was
heated at 185-190 °C for 3 h. The reaction mixture was
diluted with ethyl acetate and filtered. The filtrate was
evaporated, and the residue was purified by flash chromatog-
raphy on silica gel, eluting with 15% ethyl acetate in hexane
to obtain the desired product (0.92 g, 53%) as a light yellow
oil: 1H NMR (CDCl3) δ 7.21 (d, J ) 7.62 Hz, 1 H), 6.86 (dd, J
) 1.76 and 8.21 Hz, 1 H), 6.67 (d, J ) 1.75 Hz, 1H), 4.12 (broad
s, 1 H), 3.34 (t, J ) 5.86 Hz, 2 H), 1.72 (t, J ) 5.86 Hz, 2 H),
1.28 (s, 6 H); 13C NMR (CDCl3) δ 143.9, 134.9, 126.8, 119.9,
119.6, 116.5, 109.9, 38.0, 36.0, 32.05, 30.2; mass spectrum (CI),
m/ z 187.
G. 7-Cya n o-3,4-d ih yd r o-4,4-d im eth yl-N-p h en yl-1(2H)-
qu in olin eca r boxa m id e (6). A solution of 25 (0.20 g, 1.07
mmol), phenyl isocyanate (0.13 g, 1.07 mmol), and 4-(dimeth-
ylamino)pyridine (50 mg) in acetonitrile (4.5 mL) was heated
at reflux temperature for 1 h. The solvent was recovered
under vacuum, and the residue was triturated with isopropyl
ether to afford the title compound (0.27 g, 83%) as an off-white
solid: 1H NMR (DMSO-d6) δ 9.11 (s, 1 H), 7.80 (s, 1 H), 7.54
(m, 3 H), 7.40 (dd, J ) 1.76 and 8.21 Hz, 1 H), 7.29 (m, 2 H),
7.02 (m, 1 H), 3.79 (t, J ) 5.86 Hz, 2 H), 1.78 (t, J ) 5.86 Hz,
2 H), 1.30 (s, 6 H); 13C NMR (DMSO-d6) δ 154.5, 142.7, 139.6,
138.4, 128.4, 127.3, 126.6, 125.3, 122.6, 120.0, 118.8, 108.4,
42.0, 37.1, 32.9, 29.1.
7-Cyan o-3,4-dih ydr o-4,4-dim eth yl-N-ph en yl-1(2H)-qu in -
olin eca r boxa m id e (6). A. 6-Am in o-2,3-d ih yd r o-3,3-d i-
m eth yl-1H-in d en -1-on e (20). A solution of 198 (6.5 g, 31.7
mmol) in methanol (150 mL) was hydrogenated at 15 psi using
5% palladium over charcoal catalyst. The catalyst was filtered
off, and the solvent was removed under vacuum to give an off-
white solid (5.72 g, 100%) which was used in the next reaction
without purification: 1H NMR (CDCl3) δ 7.26 (d, J ) 8.2 Hz,
1 H), 6.95 (m, 2 H), 3.82 (br s, 2 H), 2.55 (s, 2 H), 1.34 (s, 6 H);
13C NMR (CDCl3) δ 206.3, 154.5, 146.1, 136.3, 124.0, 123.0,
107.1, 53.4, 37.7, 30.0.
B. 6-Br om o-2,3-d ih yd r o-3,3-d im eth yl-1H-in d en -1-on e
(21). To a solution of compound 20 (6.02 g, 34.4 mmol) in 48%
aqueous hydrobromic acid (9.7 mL) and ethanol (30 mL) at 0
°C was added sodium nitrite until a positive starch iodide test
was obtained. The resulting diazonium salt solution at 0 °C
was added via a pipette to a mixture of CuBr (5.42 g, 18.9
mmol) and 48% aqueous hydrobromic acid at 95 °C. The
reaction mixture was heated at reflux temperature for 15 min,
cooled to room temperature, and partitioned between ethyl
acetate and water. The organic phase was washed with
saturated sodium bicarbonate and brine, dried over MgSO4,
and evaporated in vacuo to obtain an orange solid (7.33 g).
The crude product was purified by flash chromatography on
silica gel, eluting with hexane/ethyl acetate (4:1) to obtain the
title compound (6.52 g, 79%) as a yellow solid: mp 117-118
1
°C; H NMR (CDCl3) δ 7.74 (d, J ) 1.76 Hz, 1 H), 7.64 (dd, J
) 2.34 and 8.21 Hz, 1 H), 7.32 (d, J ) 8.21 Hz, 1 H), 2.53 (s,
2H), 1.34 (s, 6H); 13C NMR (CDCl3) δ 204.7, 162.8, 138.2, 137.7,
126.79, 125.8, 122.1, 53.4, 38.9, 30.3; mass spectrum (CI), m/ z
239.
6-Cya n o-2,3-d ih yd r o-3,3-d im eth yl-N-(3-p yr id yl)-1H-in -
d ole-1-ca r boxa m id e (7). A. 1-Acetyl-6-br om o-3-m eth yl-
1H-in d ol-2(3H)-on e (29). A solution of compound 2810a (9.31
g, 41.2 mmol) in xylene (100 mL) containing acetic anhydride
(10 mL) was heated at reflux for 7 h. The reaction mixture
was cooled to room temperature and diluted with ethyl acetate.
The crude product solution was washed with distilled water
followed by saturated sodium bicarbonate solution and brine.
The solvent was removed under vacuum, and the residue was
purified by flash chromatography on silica gel, eluting with
hexane/ethyl acetate (3:1) to obtain an off-white solid (9.18 g,
C. 6-Br om o-2,3-d ih yd r o-3,3-d im eth yl-1H-in d en -1-on e
Oxim e (22). A solution of compound 21 (6.52 g, 27.3 mmol)
in ethanol (130 mL) containing hydroxylamine hydrochloride
(3.79 g, 54.5 mmol) and sodium acetate (4.03 g, 49.1 mmol)
was heated at reflux temperature for 2.5 h. The solvent was
removed under vacuum, and the residue was partitioned
between ethyl acetate and water. The organic phase was
washed with brine, dried over anhydrous MgSO4, and evapo-
rated in vacuo to obtain the title compound (6.94 g, 100%) as
a yellow solid, mp 115-117 °C. The crude product was used
in the next step without further purification: 1H NMR (CDCl3)
δ 7.85 (s, 1H), 7.48 (dd, J ) 1.76 and 8.21 Hz, 1 H), 7.16 (d, J
) 8.21 Hz, 1 H), 2.89 (s, 2 H), 1.34 (s, 6 H); 13C NMR (CDCl3)
δ 161.0, 155.9, 136.2, 133.6, 124.5, 121.1, 42.7, 41.0, 30.1.
D. 6-Br om o-2,3-d ih yd r o-3,3-d im eth yl-1H-in d en -1-on e
Oxim e, 4-Meth ylben zen esu lfon a te (23). To a solution of
22 (5.30 g, 20.9 mmol) in pyridine (50 mL) at 0 °C was added
p-toluenesulfonyl chloride (4.77 g, 25.0 mmol). The reaction
mixture was warmed to room temperature and stirred for 18
h. It was diluted with ethyl acetate, washed with cold dilute
hydrochloric acid, water, saturated NaHCO3 solution and
brine, and dried over MgSO4. The solvent was removed under
vacuum to obtain an orange residue (8.74 g, 100%) which
1
78%): mp 102-104 °C; H NMR (CDCl3) δ 8.34 (s, 1 H), 7.26
(d, J ) 8.21 Hz, 1 H), 7.04 (d, J ) 8.21 Hz, 1 H), 3.49 (q, 1 H),
2.58 (s, 3H), 1.45 (d, J ) 7.62 Hz, 3 H); 13C NMR (CDCl3) δ
178.9, 171.2, 141.4, 128.8, 128.5, 124.9, 122.1, 120.2, 41.1, 27.0,
16.2; mass spectrum (CI), m/ z 268.
B. 1-Acetyl-6-br om o-3,3-d im eth yl-1H-in d ol-2(3H)-on e
(30). To a solution of 29 (8.98 g, 33.5 mmol) in dry tetrahy-
drofuran (115 mL) at 0 °C under argon was added sodium
hydride (1.41 g, 35.2 mmol, 60% dispersion in mineral oil).10b
After stirring for 10 min, methyl iodide (4.75 g, 35.2 mmol)
was added dropwise. The reaction mixture was stirred for 2
h at room temperature, quenched by the addition of saturated
ammonium chloride solution, and extracted with ethyl acetate.
The organic phase was washed with water and brine and dried
over magnesium sulfate. The solvent was removed under
vacuum to obtain the desired product (9.67g, 100%) as an off-

ATP-Sensitive Potassium Channel Openers
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 311
white solid which was used in the next step without further
purification: 1H NMR (CDCl3) δ 8.45 (d, J ) 1.76 Hz, 1 H),
7.35 (dd, J ) 2.05 and 7.90 Hz, 1 H), 7.11 (d, J ) 8.20 Hz, 1
H), 2.68 (s, 3 H), 1.43 (s, 6 H); 13C NMR (CDCl3) δ 181.3, 170.8,
139.5, 133.5, 128.2, 123.3, 121.4, 119.8, 44.4, 26.5, 25.1; mass
spectrum (CI), m/ z 282.
eluting with hexane/ethyl acetate (3:2) to obtain the desired
compound (3.16 g, 91%) as a light yellow solid: 1H NMR
(CDCl3) δ 7.06 (d, J ) 7.63 Hz, 1 H), 7.00 (dd, J ) 1.76 and
7.62 Hz, 1 H), 6.78 (s, 1 H), 3.42 (s, 2 H), 1.31 (s, 6 H); 13C
NMR (CDCl3) δ 150.5, 143.7, 123.0, 122.5, 119.8, 111.2, 110.5,
61.3, 41.8, 27.2; mass spectrum (CI), m/ z 173.
C. 6-Br om o-3,3-d im eth yl-1H-in d ol-2(3H)-on e (31).
A
H . 6-Cya n o-2,3-d ih yd r o-3,3-d im et h yl-N-(3-p yr id yl)-
1H-in d ole-1-ca r boxa m id e (7). The reaction mixture con-
taining 35 (0.30 g, 1.74 mmol) and nicotinoyl azide (0.32 g,
2.18 mmol) in toluene (6 mL) was heated at 85 °C for 1 h. It
was cooled to room temperature and partitioned between ethyl
acetate and water. The organic phase was washed with
saturated sodium bicarbonate solution followed by brine. The
product solution was dried over magnesium sulfate and
evaporated under vacuum to obtain a yellow solid. The crude
material was purified by flash chromatography on silica gel,
eluting with ethyl acetate to afford the title compound (0.41
g, 80%) as a white solid: 1H NMR (DMSO-d6) δ 8.84 (s, 1 H),
8.32 (d, J ) 4.11 Hz, 1 H), 8.22 (s, 1 H), 8.08 (d, J ) 8.21 Hz,
1 H), 7.53 (m, 3 H), 7.43 (dd, J ) 4.69 and 8.21 Hz, 1 H), 4.07
(s, 2 H), 1.44 (s, 6 H); 13C NMR (DMSO-d6) δ 152.9, 146.2,
144.0, 143.2, 142.4, 136.3, 127.6, 126.8, 123.9, 123.6, 119.5,
117.5, 110.2, 61.8, 42.0, 28.2; mass spectrum (CI), m/ z 293.
N-[5-Cya n o-2-(1,1-d im et h ylet h yl)p h en yl]-N′-p h en yl-
u r ea (8). A. 4-(1,1-Dim eth yleth yl)-3-n itr oben zon itr ile
(39). To a solution of 3811 (10.0 g, 51.5 mmol) in ethanol (50
mL) at 0 °C was added a solution of concentrated hydrochloric
acid (12.5 mL) in ethanol (87.5 mL) followed by a solution of
sodium nitrite (3.91g, 56.6 mmol) in water (25 mL). The
reaction mixture was stirred at 0 °C for 10 min and added in
portions to a solution of copper(I) cyanide (18.45 g) and
potassium cyanide (13.41 g) in water (200 mL) at 100 °C. After
the addition was finished, the reaction mixture was stirred
for 15 min at 100 °C, cooled to room temperature, and
partitioned between water and ethyl acetate. The organic
fraction was washed with brine, dried over magnesium sulfate,
and evaporated in vacuo. The crude product was purified by
flash chromatography on silica gel, eluting with hexane/ethyl
acetate (9:1) to afford the desired compound (3.74 g, 42%) as
solution of compound 30 (9.61 g, 34.1 mmol) in ethanol (80
mL) and 1 N sodium hydroxide (20 mL) was stirred at room
temperature for 1 h. The reaction mixture was partitioned
between water and diethyl ether. The organic phase was
washed with distilled water and brine and dried over magne-
sium sulfate. The solvent was recovered under vacuum to
obtain the desired compound (8.03 g, 98%) as an off-white
solid: mp 183-185 °C; 1H NMR (CDCl3) δ 9.05 (broad s, 1 H),
7.18 (dd, J ) 1.76 and 8.20 Hz, 1 H), 7.13 (d, J ) 1.76 Hz, 1
H), 7.05 (d, J ) 7.62 Hz, 1 H), 1.39 (s, 6 H); 13C NMR (CDCl3)
δ 183.0, 141.1, 135.0, 125.3, 123.9, 121.0, 113.3, 44.5, 24.1.
D. 6-Br om o-2,3-d ih yd r o-3,3-d im eth yl-1H-in d ole (32).
To a solution of 31 (8.0 g, 33.3 mmol) in toluene (185 mL) at
85 °C was added sodium bis(2-methoxyethoxy)aluminum hy-
dride (14.7 mL, 50 mmol, 3.4 M in toluene) over the course of
15 min. After the addition was finished, heating was contin-
ued for an additional 15 min at 85 °C. The reaction mixture
was cooled to 0 °C and quenched by the addition of 1 N sodium
hydroxide solution. The organic phase was separated and
washed with 1 N sodium hydroxide and brine. The crude
product solution was dried over magnesium sulfate and
evaporated in vacuo to obtain a tan solid. This material was
purified by flash chromatography on silica gel, eluting with
hexane/ethyl acetate (9:1) to obtain the desired product (5.48
g, 73%) as an off-white solid: mp 100-102 °C; 1H NMR (CDCl3)
δ 6.85, (s, 1 H), 6.83 (d, J ) 1.76 Hz, 1 H), 6.73 (d, J ) 1.76
Hz, 1 H), 3.75 (broad s, 1 H), 3.31 (s, 2 H), 1.28 (s, 6 H); 13C
NMR (CDCl3) δ 152.0, 137.7, 123.50, 121.5, 120.9, 112.6, 62.0,
41.6, 27.8; mass spectrum (CI), m/ z 226.
E. 1-Acetyl-6-br om o-2,3-d ih yd r o-3,3-d im eth yl-1H-in -
d ole (33). A solution of compound 32 (5.45 g, 24.1 mmol) in
methylene chloride (55 mL) and triethylamine (2.68 g, 26.5
mmol) was cooled to 0 °C and treated with acetyl chloride (2.1
g, 26.5 mmol) dropwise over 5 min. The reaction mixture was
stirred for 45 min at room temperature and partitioned
between 1 N hydrochloric acid and ethyl acetate. The organic
phase was washed with saturated sodium bicarbonate solution
and brine, dried over magnesium sulfate, and evaporated in
vacuo to obtain a pale yellow solid (6.42 g, 99%): mp 95-96
1
a yellow solid: mp 67-69 °C; H NMR (CDCl3) δ 7.72 (m, 2
H), 7.62 (m, 1 H), 1.58 (s, 9 H); 13C NMR (CDCl3) δ 151.2, 146.8,
133.8, 130.1, 127.3, 116.5, 111.2, 36.4, 30.3.
B. 3-Am in o-4-(1,1-d im eth yleth yl)ben zon itr ile (40). A
mixture of 39 (3.74 g, 18.3 mmol) and stannous chloride
dihydrate (20.6 g, 91.6 mmol) in ethanol (25 mL) was heated
at reflux temperature for 45 min. The reaction mixture was
poured into ice-cold water and neutralized with solid sodium
bicarbonate. The pH was adjusted to approximately 12 with
50% NaOH solution, and the reaction mixture was extracted
with diethyl ether. The combined extracts were washed with
brine, dried over magnesium sulfate, and evaporated in vacuo
to obtain the desired compound (3.20 g, 100%) as a brown solid.
The crude product was used in the next step without further
purification: 1H NMR (CDCl3) δ 7.34 (d, J ) 8.20 Hz, 1 H),
7.04 (dd, J ) 1.76 and 8.21 Hz, 1 H), 6.94 (d, J ) 1.76 Hz, 1
H), 4.16 (broad s, 2 H), 1.47 (s, 9 H); 13C NMR (CDCl3) δ 145.3,
138.4, 127.2, 121.6, 119.7, 119.2, 110.1, 34.5, 29.0; mass
spectrum (CI), m/ z 175.
C. N-[5-Cya n o-2-(1,1-d im eth yleth yl)p h en yl]-N′-p h en -
ylu r ea (8). A solution of 40 (0.40 g, 2.29 mmol) and phenyl
isocyanate (0.27 g, 2.29 mmol) in chloroform (4 mL) was heated
at reflux temperature for 16 h. The solvent was removed
under vacuum, and the residue was crystallized from 2-pro-
panol to obtain an off-white solid (0.46 g, 86%): 1H NMR
(CDCl3) δ 9.33 (s, 1 H), 7.90 (s, 1 H), 7.79 (s, 1 H), 7.64 (s, 2
H), 7.56 (d, J ) 7.62 Hz, 2 H), 7.37 (m, 2 H), 7.06 (m, 1 H),
1.47 (s, 9 H); 13C NMR (CDCl3) δ 153.1, 149.2, 139.8, 137.0,
132.4, 128.8, 128.4, 127.8, 121.9, 118.5, 118.1, 109.0, 35.1, 29.9.
N-[(2-Ch lor o-5-p yr id yl)-N′-[5-cya n o-2-(1,1-d im et h yl-
eth yl)p h en yl]u r ea (15). A. N-Cya n o-N′-[5-cya n o-2-(1,1-
d im eth yleth yl)p h en yl]ca r ba m ic Acid , P h en yl Ester (41).
A solution of 40 (1.5 g, 8.61 mmol) in methylene chloride (15
mL) and pyridine (1 mL) at 0 °C was treated with phenyl
chloroformate (1.42 g, 9.0 mmol). The reaction mixture was
stirred for 1 h at ambient temperature and partitioned
between ethyl acetate and 1 N hydrochloric acid. The organic
phase was washed with saturated sodium bicarbonate solution
1
°C; H NMR (CDCl3) δ 8.29, (s, 1 H), 7.07 (d, J ) 8.21 Hz, 1
H), 6.89 (d, J ) 8.21 Hz, 1 H), 3.68 (s, 2 H), 2.11 (s, 3H), 1.25
(s, 6 H); 13C NMR (CDCl3) δ 168.9, 142.7, 139.4, 126.7, 123.0,
121.1, 119.9, 63.7, 40.0, 28.3, 24.1; mass spectrum (CI), m/ z
268.
F . 1-Acetyl-2,3-d ih yd r o-3,3-d im eth yl-1H-in d ole-6-ca r -
bon itr ile (34). The reaction mixture containing 33 (6.56 g,
24.5 mmol) and copper(I) cyanide (4.38 g, 48.9 mmol) in
N-methylpyrrolidone (70 mL) was heated at 175 °C under
argon for 3 h. It was cooled to room temperature, diluted with
diethyl ether, and filtered. The filtrate was washed with
water, 1 N aqueous hydrochloric acid, saturated sodium
bicarbonate, and brine. The product solution was dried over
magnesium sulfate and evaporated in vacuo to obtain an off-
white solid (4.37 g, 83%) which was used for the next reaction
without purification: 1H NMR (CDCl3) δ 8.47 (s, 1 H), 7.34
(d, J ) 6.45 Hz, 1 H), 7.22 (d, J ) 7.62 Hz, 1 H), 3.85 (s, 2 H),
2.24 (s, 3 H), 1.39 (s, 6 H); 13C NMR (CDCl3) δ 169.2, 145.6,
141.9, 128.1, 122.6, 119.8, 119.0, 111.2, 63.3, 40.6, 28.2, 24.0;
mass spectrum (CI), m/ z 215.
G. 2,3-Dih yd r o-3,3-d im eth yl-1H-in d ole-6-ca r bon itr ile
(35). A solution of 34 (4.33 g, 20.2 mmol) in a mixture of
acetonitrile (120 mL) and 5 N hydrochloric acid (40 mL) was
heated at reflux temperature for 2 h. The reaction mixture
was cooled to room temperature and carefully neutralized with
saturated sodium bicarbonate solution. The oily layer was
separated, and the aqueous layer was extracted with ethyl
acetate. The combined organic layers were washed with
saturated sodium chloride solution, dried over sodium sulfate,
and evaporated in vacuo to obtain a brown oil. The crude
material was purified by flash chromatography on silica gel,

312 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1
Atwal et al.
and brine and dried over magnesium sulfate. The solvent was
removed under vacuum, and the residue was purified by flash
chromatography on silica gel eluting with hexane/ethyl acetate
(4:1) to afford the desired compound (2.38 g, 94%) as a colorless
thick oil: 1H NMR (CDCl3) δ 8.10 (broad s, 1 H), 7.52-7.38
(m, 5 H), 7.28-7.18 (m, 3 H), 1.49 (s, 9 H); 13C NMR (CDCl3)
δ 152.0, 150.3, 135.9, 129.4, 128.8, 127.6, 125.9, 121.5, 118.2,
110.9, 35.0, 30.3.
B. N-[(2-Ch lor o-5-p yr id yl)-N′-[5-cya n o-2-(1,1-d im eth -
yleth yl)p h en yl]u r ea (15). A solution of 41 (0.60 g, 2.04
mmol), 5-amino-2-chloropyridine (0.29 g, 2.24 mmol), and
(N,N-dimethylamino)pyridine (50 mg) in N,N-dimethylforma-
mide (6 mL) was heated at 100 °C for 45 min. The reaction
mixture was partitioned between ethyl acetate and saturated
sodium bicarbonate solution. The organic phase was washed
with saturated sodium bicarbonate solution and brine, dried
over magnesium sulfate, and evaporated. The residue was
purified by flash chromatography on silica gel, eluting with
ethyl acetate/hexane (2:1) to obtain a colorless solid (0.63 g,
73%): 1H NMR (DMSO-d6) δ 9.57 (s, 1 H), 8.55 (d, J ) 2.35
Hz, 1 H), 8.09 (dd, J ) 2.34 and 8.20 Hz, 1 H), 7.99 (s, 1 H),
7.88 (s, 1 H), 7.66 (m, 2 H), 7.49 (d, J ) 8.21 Hz, 1 H), 1.46 (s,
9 H); 13C NMR (DMSO-d6) δ 153.1, 149.9, 142.3, 139.4, 136.7,
136.1, 132.8, 129.0, 128.8, 127.9, 124.1, 118.3, 109.2, 35.2, 30.0.
and 8.21 Hz, 1 H), 7.68 (d, J ) 8.80 Hz, 1 H), 7.45 (m, 2 H),
7.33-7.23 (m, 3 H), 1.42 (s, 9 H); 13C NMR (DMSO-d6) δ 153.0,
151.1, 135.2, 135.1, 132.2, 129.7, 129.0, 126.5, 121.5, 117.9,
109.8, 35.8, 30.4.
B. N′′-Cya n o-N-[5-cya n o-2-(1,1-d im eth yleth yl)p h en yl]-
N′-(3-p yr id yl)gu a n id in e (10). A solution of 42 (0.40 g, 1.26
mmol) and 3-aminopyridine (0.14g, 1.51 mmol) in N,N-dimeth-
ylformamide (8 mL) was heated at 100 °C under argon for 4
h. The reaction mixture was partitioned between water and
ethyl acetate. The organic phase was washed with water and
brine, dried over magnesium sulfate, and evaporated. The
crude material was purified by flash chromatography on silica
gel, eluting with hexane/ethyl acetate (7:3), and the product
was crystallized from 2-propanol to give an off-white solid (0.23
g, 58%): 1H NMR (DMSO-d6) δ 9.21 (s, 1 H), 8.94 (s, 1 H),
8.50 (d, J ) 2.35 Hz, 1 H), 8.35 (d, J ) 3.52 Hz, 1 H), 7.84 (s,
1 H), 7.78 (m, 2 H), 7.66 (d, J ) 8.21 Hz, 1 H), 7.38 (dd, J )
4.69 and 8.21 Hz, 1 H), 1.39 (s, 9 H); 13C NMR (DMSO-d6) δ
157.7, 153.9, 146.2, 145.7, 136.0, 134.6, 132.2, 132.0, 129.3,
123.8, 118.5, 116.1, 110.9, 36.1, 30.7.
N-[4-Cyan o-(1,1′-biph en yl)-2-yl]-N′-(3-pyr idyl)u r ea (16).
A. 2-Nitr o-(1,1′-bip h en yl)-4-ca r bon itr ile (46). The reac-
tion mixture containing 4512 (4.56 g, 16.4 mmol) and copper-
(I) cyanide (2.94 g, 9.12 mmol) in N-methylpyrrolidone (45 mL)
was heated at 175-180 °C for 2.5 h. It was cooled to room
temperature and diluted with diethyl ether. The precipitated
solids were filtered, and the filtrate was washed with water,
1 N hydrochloric acid, saturated sodium bicarbonate solution,
and brine. The extract was dried over magnesium sulfate and
evaporated. The residue was purified by flash chromatography
on silica gel, eluting with hexane/ethyl acetate (4:1) to obtain
the desired compound as a pale yellow solid (2.08 g, 56%): mp
Compounds 9 and 11-14 were prepared in
manner.
a similar
N-[5-Cya n o-2-(1,1-d im et h ylet h yl)p h en yl]-N′-(3-p yr i-
d yl)u r ea (9): 1H NMR (CD3OD) δ 8.71 (d, J ) 2.35 Hz, 1 H),
8.28 (dd, J ) 1.18 and 4.69 Hz, 1 H), 8.13 (m, 1 H), 7.86 (d, J
) 1.76 Hz, 1 H), 7.72 (d, J ) 8.21 Hz, 1 H), 7.62 (dd, J ) 1.76
and 8.21 Hz, 1 H), 7.46 (dd, J ) 4.69 and 8.21 Hz, 1 H), 1.55
(s, 9 H); 13C NMR (CD3OD) δ 155.8, 152.1, 144.0, 141.03, 138.2,
137.8, 134.5, 130.7, 129.3, 128.1, 125.3, 119.2, 111.5, 36.4, 30.8.
1
117-119 °C; H NMR (CDCl3) δ 8.13 (d, J ) 1.17 Hz, 1 H),
7.89 (dd, J ) 1.76 and 7.62 Hz, 1 H), 7.60 (d, J ) 8.20 Hz, 1
H), 7.45 (m, 3 H), 7.29 (m, 2 H); 13C NMR (CDCl3) δ 149.3,
140.7, 135.5, 135.1, 133.1, 129.4, 129.0, 128.6, 127.6, 116.5,
112.4; mass spectrum (CI), m/ z 242.
N-[5-Cya n o-2-(1,1-d im et h ylet h yl)p h en yl]-N′-(2-p yr i-
d yl)u r ea (11): 1H NMR (CDCl3) δ 11.94 (broad s, 1 H), 9.69
(broad s, 1 H), 8.17 (m, 2 H), 7.71 (m, 1 H), 7.54 (d, J ) 8.21
Hz, 1 H), 7.42 (dd, J ) 1.76 and 8.21 Hz, 1 H), 6.98 (dd, J )
2.93 and 4.11 Hz, 1 H), 6.94 (s, 1 H), 1.52 (s, 9 H); 13C NMR
(CDCl3) δ 154.5, 152.8, 147.9, 145.5, 139.1, 136.6, 130.9, 128.2,
127.5, 118.8, 117.6, 112.4, 110.3, 35.3, 29.8.
N-[5-Cya n o-2-(1,1-d im et h ylet h yl)p h en yl]-N′-(4-p yr i-
d yl)u r ea (12): 1H NMR (DMSO-d6) δ 9.70 (s, 1 H), 8.44 (broad
s, 2 H), 8.04 (s, 1 H), 7.87 (s, 1 H), 7.67 (m, 2 H), 7.53 (m, 2 H),
1.45 (s, 9 H); 13C NMR (DMSO-d6) δ 152.9, 150.2, 150.1, 146.6,
136.5, 133.2, 129.2, 128.0, 118.4, 112.3, 109.2, 35.2, 30.0.
N-[5-Cya n o-2-(1,1-d im eth yleth yl)p h en yl]-N′-(5-p yr im -
id in yl)u r ea (13): 1H NMR (DMSO-d6) δ 9.58 (s, 1 H), 9.01
(s, 2 H), 8.89 (s, 1 H), 8.14 (s, 1 H), 7.90 (d, J ) 1.76 Hz, 1 H),
7.68 (m, 2 H), 1.47 (s, 9 H); 13C NMR (DMSO-d6) δ 153.2, 151.9,
150.2, 146.2, 136.6, 135.2, 133.2, 129.2, 128.0, 118.37, 109.2,
35.2, 30.0.
N-[5-Cya n o-2-(1,1-d im et h ylet h yl)p h en yl]-N′-(2-p yr a -
zin yl)u r ea (14): 1H NMR (CDCl3) δ 11.11 (broad s, 1 H), 10.14
(s, 1 H), 8.42 (s, 1 H), 8.25 (d, J ) 2.35 Hz, 1 H), 8.10 (s, 1 H),
8.03 (s, 1 H), 7.57 (d, J ) 8.21 Hz, 1 H), 7.48 (d, J ) 8.21 Hz,
1 H), 1.49 (s, 9 H); 13C NMR (CDCl3) δ 154.2, 148.9, 148.6,
138.8, 137.7, 136.2, 135.7, 131.6, 129.2, 127.7, 118.4, 110.5,
35.3, 29.9.
N′′-Cya n o-N-[5-cya n o-2-(1,1-d im eth yleth yl)p h en yl]-N′-
(3-p yr id yl)gu a n id in e (10). A. N-Cya n o-N′-[5-cya n o-2-
(1,1-d im et h ylet h yl)p h en yl]ca r b a m im id ic Acid , P h en yl
Ester (42). To a solution of 40 (0.25 g, 1.43 mmol) in dry
tetrahydrofuran (5 mL) was added sodium hydride (91 mg, 2.3
mmol, 60% oil dispersion). After stirring at room temperature
for 15 min, diphenyl cyanocarbonimidate (0.51 g, 2.15 mmol)
was added and the reaction mixture was heated at reflux
temperature for 4 h. The reaction was quenched by the
addition of saturated ammonium chloride solution; the layers
were separated, and the aqueous layer was extracted with
ethyl acetate. The combined organic layers were washed with
saturated sodium bicarbonate solution and brine, dried over
magnesium sulfate, and evaporated. The crude material was
purified by flash chromatography on silica gel, eluting with
hexane/ethyl acetate (7:3) to obtain the desired compound (0.35
g, 77%) as an off-white solid: mp 179-181 °C; 1H NMR
(DMSO-d6) δ 8.10 (d, J ) 1.76 Hz, 1 H), 7.82 (dd, J ) 1.76
B. 2-Am in o-(1,1′-bip h en yl)-4-ca r bon itr ile (47). A mix-
ture of 46 (1.82 g, 8.12 mmol) and stannous chloride dihydrate
(9.16 g, 40.6 mmol) in ethanol (20 mL) was heated at reflux
temperature for 45 min. The reaction mixture was poured
onto ice/water and neutralized with solid sodium bicarbonate.
The pH was adjusted to 12 by the addition of 5 N sodium
hydroxide, and the aqueous mixture was extracted with ethyl
acetate. The combined extracts were washed with brine and
dried over magnesium sulfate. The solvent was removed
under vacuum, and the residue was triturated with cold
pentane to yield an off-white solid (1.40 g, 89%): mp 53-55
1
°C; H NMR (CDCl3) δ 7.44 (m, 5 H), 7.17 (d, J ) 8.21 Hz, 1
H), 7.07 (dd, J ) 1.76 and 9.38 Hz, 1 H), 6.99 (s, 1 H); 13C
NMR (CDCl3) δ 144.2, 137.6, 131.7, 131.0, 129.1, 128.6, 128.1,
121.9, 119.2, 118.0, 111.8.
C. N-[4-Cya n o-(1,1′-bip h en yl)-2-yl]-N′-(3-p yr id yl)u r ea
(16). Compound 47 was converted (nicotinoyl azide, toluene,
heat, 73%) to the desired product 16 by the same procedure
as used for the preparation of 7 from 35. The product was
crystallized from 2-propanol to obtain an off-white solid: 1H
NMR (DMSO-d6) δ 9.45 (s, 1 H), 8.60 (s, 1 H), 8.50 (s, 1 H),
8.27 (d, J ) 4.69 Hz, 1 H), 8.18 (s, 1 H), 7.99 (d, J ) 8.21 Hz,
1 H), 7.67-7.47 (m, 7 H), 7.37 (dd, J ) 4.69 and 8.79 Hz, 1 H);
13C NMR (DMSO-d6) δ 152.6, 143.2, 140.0, 136.9, 136.7, 136.1,
131.8, 129.2, 129.0, 128.6, 126.5, 125.2, 124.8, 123.7, 118.8,
110.5.
N-[5-Cya n o-2-[[(4-m eth ylp h en yl)su lfon yl]a m in o]p h en -
yl]-N′-(3-p yr id yl)u r ea (17). A. N-(4-Cya n o-2-n itr op h en -
yl)-4-m eth ylben zen esu lfon a m id e (49). To a solution of
4-amino-3-nitrobenzonitrile (48) (1.90 g, 11.6 mmol) in dimeth-
yl sulfoxide (50 mL) was added sodium hydride (0.56 g, 14
mmol). The resulting red solution was stirred for 5 min and
treated with p-toluenesulfonyl chloride (2.45 g, 12.8 mmol) in
one portion. The reaction mixture was stirred for 30 min,
poured into water (200 mL), and basified to pH 12 by the
addition of 10% potassium hydroxide. The precipitate (starting
material) was filtered off, and the mother liquor was acidified
to pH 2 with 10% hydrochloric acid. The precipitate was
collected to give the desired product as a light yellow solid (0.6

ATP-Sensitive Potassium Channel Openers
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 1 313
g, 16%). This material was employed in the next reaction
without further purification: 1H NMR (CDCl3) δ 2.35 (s, 3 H),
2.56 (s, 1 H), 7.25 (d, J ) 8 Hz, 2 H), 7.69 (dd, J 1 ) 2 Hz, J 2
) 8 Hz, 1 H), 7.64 (d, J ) 8 Hz, 2 H), 7.89 (d, J ) 8 Hz, 1 H),
8.40 (d, J ) 2 Hz, 1 H); 13C NMR (CDCl3) δ 146.5, 138.9, 138.6,
135.9, 131.5, 131.1, 128.2, 120.8, 117.0, 107.6, 22.4.
B. N-(2-Am in o-4-cya n op h en yl)-4-m eth ylben zen esu l-
fon a m id e (50). To the reaction mixture containing 49 (330
mg, 1.04 mmol) in ethyl acetate (10 mL) was added stannous
chloride dihydrate (940 mg, 4.16 mmol) at room temperature.
The mixture was stirred at room temperature for 3 h and
quenched with saturated NaHCO3 solution (3 mL). The
resulting solution was treated with excess MgSO4 and stirred
at room temperature for 2 h. The suspension was filtered
through a pad of Celite, and the filtrate was concentrated. The
residue was crystallized from hexane/ethyl acetate to give a
colorless solid (250 mg, 84%): mp 167-168 °C; 1HNMR
(DMSO-d6) δ 2.35 (s, 3 H), 6.80 (dd, 1 H), 6.93 (d, J ) 2 Hz, 1
H), 6.99 (d, J ) 8.2 Hz, 1 H), 7.35 (d, J ) 8 Hz, 2 H), 7.62 (d,
J ) 8.2 Hz, 2 H).
C. N-[5-Cya n o-2-[[(4-m eth ylp h en yl)su lfon yl]a m in o]-
p h en yl]-N′-(3-p yr id yl)u r ea (17). The desired product (17)
was prepared in 75% yield from 50 and nicotinoyl azide by
the same procedure as described for the synthesis of 7 from
35. The product was crystallized from DMF/ethyl acetate/
hexanes to give a colorless powder (170 mg, 75%): 1H NMR
(DMSO-d6) δ 9.78 (s, 1 H), 8.61 (d, 2 H), 8.37 (d, J ) 2 Hz, 1
H), 8.25 (d, 1 H), 7.61 (d, J ) 8 Hz, 2 H), 7.35 (m, 4 H), 6.75
(d, J ) 8 Hz, 1 H), 2.34 (s, 3 H).
N-(5-Cya n o-2-p h en oxyp h en yl)-N′-(3-p yr id yl)u r ea (18).
A. 3-Nitr o-4-p h en oxyben zon itr ile (52). To a solution of
4-chloro-3-nitrobenzonitrile (3.6 g, 20 mmol) and phenol (2.8
g, 30 mmol) in dimethylformamide (75 mL) was added solid
potassium carbonate (5 g, 36 mmol), and the suspension was
stirred at room temperature for 8 h and at 50 °C for 18 h. The
reaction mixture was concentrated, and the residue was
diluted with water (500 mL) and extracted with ethyl acetate.
The combined organic extracts were washed with saturated
sodium bicarbonate and dried over MgSO4. The solvent was
removed, and the residue was purified by flash column
chromatography to give an oil (3.0 g, 63%), which solidified
upon standing. The crude product was used in the next
reaction: 1H NMR (CDCl3) δ 7.10 (d, J ) 8.8 Hz, 1 H), 7.24
(m, 2 H), 7.40 (m, 1 H), 7.55 (m, 2 H), 7.82 (dd, J ) 2.4, 8.8
Hz, 1 H), 8.34 (d, J ) 2.4 Hz, 1 H); 13C NMR (CDCl3) δ 155.0
153.0 140.0, 137.2, 130.5, 129.9, 126.3, 120.4, 119.1, 116.5,
115.0, 106.1.
Refer en ces
(1) Cook, N. S. The Pharmacology of Potassium Channels and their
Therapeutic Potential. Trends Pharmacol. Sci. 1988, 9, 21-28.
(2) Atwal, K. S. Modulation of Potassium Channels by Organic
Molecules. Med. Res. Rev. 1992, 12, 569-591.
(3) (a) Grover, G. J .; McCullough, J . R.; Henry, D. E.; Conder, M.
L.; Sleph, P. G. Anti-Ischemic Effects of the Potassium Channel
Activator Pinacidil and Cromakalim and the Reversal of these
Effects with the Potassium Channel Blocker Glyburide. J .
Pharmacol. Exp. Ther. 1989, 251, 98-104.
(4) Grover, G. J .; Dzwonczyk, S.; Parham, C. S.; Sleph, P. G. The
Protective Effects of Cromakalim and Pinacidil on Reperfusion
Function and Infarct Size in Isolated Perfused Rat Hearts and
Anesthetized Dogs. Cardiovasc. Drugs Ther. 1990, 4, 465-474.
(5) Atwal, K. S.; Grover, G. J .; Ahmed, S. Z.; Ferrara, F. N.; Harper,
T. W.; Kim, K. S.; Sleph, P. G.; Dzwonczyk, S.; Russell, A. D.;
Moreland, S.; McCullough, J . R.; Normandin, D. E. Cardiose-
lective anti-ischemic ATP-sensitive potassium channel openers.
J . Med. Chem. 1993, 36, 3971-3974.
(6) Atwal, K. S.; Grover, G. J .; Ferrara, F. N.; Ahmed, S. Z.; Sleph,
P. G.; Dzwonczyk, S.; Normandin, D. E. Cardioselective anti-
ischemic ATP-sensitive potassium channel openers 2. Structure-
Activity Studies on Benzopyranyl Cyanoguanidines; Modification
of the Benzopyran. J . Med. Chem. 1995, 38, 1966-1973.
(7) Atwal, K. S.; Grover, G. J .; Ahmed, S. Z.; Sleph, P. G.; Dzwonc-
zyk, S.; Baird, A. J .; Normandin, D. E. Cardioselective anti-
ischemic ATP-sensitive potassium channel openers 3. Structure-
Activity Studies on Benzopyranyl Cyanoguanidines; Modification
of the Cyanoguanidine Portion. J . Med. Chem. 1995, 38, 3238.
(8) Buckle, D. R.; Arch, J . R. S.; Edge, C.; Foster, K. A.; Houge-
Frydrych, C. S. V.; Pinto, I. L.; Smith, D. G.; Taylor, J . F.; Tedder,
J . M.; Webster, R. A. B. Synthesis and Smooth Muscle Relaxant
Activity of a New Series of Potassium Channel Activators:
3-Amido-1,1-dimethylindan-2-ols. J . Med. Chem. 1991, 34, 919-
926.
(9) (a) Hattori, K.; Matsumura, Y.; Miyazaki, T.; Maruoka, K.;
Yamamoto, H. Successive Beckmann Rearrangement-alkylation
Sequence by Organoaluminum Reagents. A simple Route to dl-
Pumiliotoxin C. J . Am. Chem. Soc. 1981, 103, 7368-7370. (b)
Maruoka, K.; Miyazaki, T.; Ando, M.; Matsumura, Y.; Sakane,
S.; Hattori, K.; Yamamoto, H. Organoaluminum-Promoted Beck-
mann Rearrangement of Oxime Sulfonates. J . Am. Chem. Soc.
1983, 105, 2831-2843. (c) Sasatani, S.; Miyazaki, T.; Maruoka,
K.; Yamamoto, H. Diisobutylaluminum hydride. A Novel Re-
agent for the Reduction of Oximes. Tetrahedron Lett. 1983, 24,
4711-4712.
(10) (a) Lawson, W. B.; Patchornik, A.; Witkop, B. Substitution,
Oxidation and Group Participation in the Bromination of In-
doles. J . Am. Chem. Soc. 1960, 82, 5918-5923. (b) Takayama,
K.; Isobe, M.; Harano, K.; Taguchi, T. A General Synthetic Route
of 3,3-Disubstituted 3H-Indoles and Rearrangement of their Acyl
Chloride Adducts. Tetrahedron Lett. 1973, 365-368.
(11) Biekart, H. J . B.; Dessens, H. B.; Verkade, P. E.; Wepster, B.
M. Preparation and Constitution of Some tert. Butyl-acetyl-
amino-nitrobenzenes. Recueil 1952, 71, 321-339.
B. 3-Am in o-4-p h en oxyben zon itr ile (53). The title com-
pound was prepared (88%) from 52 by the same procedure as
described for the preparation of 50 from 49. The product was
obtained as a colorless solid: mp 74-75 °C; 1H NMR (CDCl3)
δ 4.14 (broad s, 2 H), 6.79 (d, J ) 8 Hz, 1 H), 6.99 (dd, J ) 2,
8 Hz, 1 H), 7.08 (m, 3 H), 7.24 (m, 1 H), 7.42 (m, 2 H); 13C
NMR (CDCl3) δ 155.0, 148.0, 138.0, 130.0, 124.4, 122.8, 119.1,
118.4, 117.6, 106.0.
C. N-(5-Cya n o-2-p h en oxyp h en yl)-N′-(3-p yr id yl)u r ea
(18). The preparation of 18 from 53 was carried out in 70%
yield by the same procedure as described for the synthesis of
7 from 35. The product was crystallized from ethyl acetate/
methanol/hexane to give a colorless solid: 1H NMR (CDCl3) δ
6.55 (d, J ) 8 Hz, 1 H), 6.88-7.28 (m, 7 H), 7.91 (m, 1 H), 8.02
(d, J ) 3.5 Hz, 1 H), 8.33 (d, J ) 2.4 Hz, 1 H), 8.54 (m, 2 H),
9.20 (s, 1 H); 13C NMR (CDCl3) δ 154.0, 152.0, 149.0, 142.1,
138.9, 136.0, 130.0, 129.8, 125.7, 125.5, 124.8, 123.3, 122.1,
119.6, 115.7, 106.0.
(12) Badger, G. M.; Sasse, W. F. H. Phenanthridines. Part I. The
Synthesis of Bromophenanthridines. J . Chem. Soc. 1957, 4-8.
(13) Atwal, K. S.; Moreland, S.; McCullough, J . R.; O’Reilly, B. C.;
Ahmed, S. Z.; Normandin, D. E. Aryl Cyanoguanidine Potassium
Channel Openers. Bioorg. Med. Chem. Lett. 1992, 2, 83-86.
(14) Grover, G. J .; Newburger, J .; Sleph, P. G.; Dzwonczyk, S.; Taylor,
S. C.; Ahmed, S. Z.; Atwal, K. S. Cardioprotective Effects of the
Potassium Channel Opener Cromakalim: Stereoselectivity and
Effects on Myocardial Adenine Nucleotides. J . Pharmacol. Exp.
Ther. 1991, 257, 156-162.
(15) Grover, G. J .; McCullough, J . R.; D’Alonzo, A. J .; Sargent, C. S.;
Atwal, K. S. Cardioprotective Profile of the Cardiac-Selective
ATP-Sensitive Potassium Channel Opener BMS-180448. J .
Cardiovasc. Pharmacol. 1994, 25, 40-50.
(16) Atwal, K. S.; McCullough, J . R.; Hedberg, A.; Conder, M. L.;
Ahmed, S. Z.; Cucinotta, G.; Normandin, D. E. The Discovery of
a Novel Calcium Channel Blocker Related to the Structure of
Potassium Channel Opener Cromakalim. Bioorg. Med. Chem.
Lett. 1992, 2, 1475-1478.
(17) Grover, G. J .; Dzwonczyk, S.; Sleph, P. G. Reduction of Ischemic
Damage in Isolated Rat Hearts by the Potassium Channel
Opener RP 52891. Eur. J . Pharmacol. 1990, 69, 571-581.
(18) Sargent, C. A.; Smith, M. A.; Dzwonczyk, S.; Sleph, P. G.; Grover,
G. J . Effect of Potassium Channel Blockade on the Anti-Ischemic
Actions of Mechanistically Diverse Agents. J . Pharmacol. Exp.
Ther. 1991, 259, 97-103.
Biologica l Assa ys. EC25 values for increasing time to
contracture were determined in isolated perfused globally
ischemic rat hearts. To compare the antiischemic vs periph-
eral vasodilator potencies, we determined IC50 values for
relaxation of the methoxamine contracted rat aorta. Experi-
mental details of both methods are described.6
J M950646F