Cardioselective antiischemic ATP-sensitive potassium channel (K(ATP)) openers. 5. Identification of 4-(N-aryl)-substituted benzopyran derivatives with high selectivity

Article abstract of DOI:10.1021/jm9605905

This paper describes our studies aimed at the discovery of structurally distinct analogs of the cardioprotective K(ATP) opener BMS-180448 (2) with improved selectivity for the ischemic myocardium. The starting compound 6, derived from the indole analog 4, showed good cardioprotective potency and excellent selectivity compared to 2 and the first-generation K(ATP) opener cromakalim (1). The structure-activity studies indicate that increasing the size of the alkyl ester leads to diminished potency as does its replacement with a variety of other groups (nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its predecessor 6. The results described in this publication further support that there is no correlation between vasorelaxant and cardioprotective potencies of K(ATP) openers. Compound 3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim (1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim (1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the K(ATP) blocker glyburide, indicating that the K(ATP) opening is involved in its mechanism of cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3 h) in rats, compound 3 offers an excellent candidate to investigate the role of residual vasorelaxant potency of 2 toward its cardioprotective activity in vivo.

Full text of DOI:10.1021/jm9605905

24
J . Med. Chem. 1997, 40, 24-34
Ca r d ioselective An tiisch em ic ATP -Sen sitive P ota ssiu m Ch a n n el (KATP ) Op en er s.
5. Id en tifica tion of 4-(N-Ar yl)-Su bstitu ted Ben zop yr a n Der iva tives w ith High
Selectivity
George C. Rovnyak, Syed Z. Ahmed, Charles Z. Ding, Steven Dzwonczyk, Francis N. Ferrara,
W. Griffith Humphreys, Gary J . Grover, Dinos Santafianos, Karnail S. Atwal,* Anne J . Baird,
Lee G. McLaughlin, Diane E. Normandin, Paul G. Sleph, and Sarah C. Traeger
The Bristol-Myers Squibb Pharmaceutical Research Institute, P.O. Box 4000, Princeton, New J ersey 08543-4000
Received August 15, 1996X
This paper describes our studies aimed at the discovery of structurally distinct analogs of the
cardioprotective KATP opener BMS-180448 (2) with improved selectivity for the ischemic
myocardium. The starting compound 6, derived from the indole analog 4, showed good
cardioprotective potency and excellent selectivity compared to 2 and the first-generation KATP
opener cromakalim (1). The structure-activity studies indicate that increasing the size of the
alkyl ester leads to diminished potency as does its replacement with a variety of other groups
(nitrile, methyl sulfone). Replacement of the ethyl ester of 6 with an imidazole gave the best
compound 3 (BMS-191095) of this series which maintains the potency and selectivity of its
predecessor 6. The results described in this publication further support that there is no
correlation between vasorelaxant and cardioprotective potencies of KATP openers. Compound
3 is over 20- and 4000-fold more selective for the ischemic myocardium than 2 and cromakalim
(1), respectively. The selectivity for the ischemic myocardium is achieved by reduction of
vasorelaxant potency rather than enhancement in antiischemic potency. As for cromakalim
(1) and 2, the cardioprotective effects of compound 3 are inhibited by cotreatment with the
KATP blocker glyburide, indicating that the KATP opening is involved in its mechanism of
cardioprotection. With its good oral bioavailability (47%) and plasma elimination half-life (3
h) in rats, compound 3 offers an excellent candidate to investigate the role of residual
vasorelaxant potency of 2 toward its cardioprotective activity in vivo.
In tr od u ction
We have shown that no correlation exists between
cardioprotective and vasorelaxant potencies of KATP
openers.10 Further work aimed at the discovery of KATP
openers selective for the ischemic myocardium led to the
discovery of BMS-180448 (2) which shows enhanced
selectivity compared to the first-generation agents (e.g.,
cromakalim). Unlike cromakalim which had to be given
directly into the coronary artery to observe cardiopro-
tection in vivo, 2 shows excellent cardioprotection on iv
The ATP-sensitive potassium channel (KATP) openers
have been found to have direct cardioprotective proper-
ties independent of their vasodilating actions.1 The
cardioprotection afforded by these agents is inhibited
by structurally different KATP blockers, indicating that
KATP opening is involved in their protective actions.2 The
KATP openers show cardioprotective activity at concen-
trations that cause little cardiodepression, unlike, for
example, calcium channel blockers (e.g., diltiazem).3
However, in order to show efficacy in whole animal
models, the first-generation compounds (e.g., cro-
makalim) have to be given directly into the coronary
artery4 to avoid peripheral vasodilation which can cause
underperfusion of the tissue already at risk.5 Thus, they
have a narrow window of safety for the treatment of
myocardial ischemia. The interest in KATP openers as
cardioprotective agents is also highlighted by recent
studies indicating that the KATP openers might mimic
the beneficial effects of myocardial preconditioning.6
Using the KATP blocker glyburide as a tool, a number of
invesitigators have shown that the opening of the KATP
is involved in mediating the cardioprotective actions of
preconditioning in animal models7 and humans.8 The
protective effects of KATP openers are not unique to the
myocardium as they also mimic the neuronal protective
effects of cerebral ischemic preconditioning in hippo-
campal neurons.9 Thus, opening of the KATP may be
part of an endogenous protective mechanism to mini-
mize injury following ischemia.
administration.11 Although more selective for the is-
chemic myocardium compared to the reference agents
(e.g., cromakalim), compound 2 retains some degree of
vasorelaxant activity (Table 1). To delineate the role
X Abstract published in Advance ACS Abstracts, December 15, 1996.
S0022-2623(96)00590-0 CCC: $14.00 © 1997 American Chemical Society

Cardioselective Antiischemic KATP Openers
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 25
Sch em e 2
Sch em e 1
of the residual vasorelaxant activity of 2 toward its
cardioprotective efficacy, we set out to find agents that
were nearly devoid of vasorelaxant activity. This pub-
lication details the results of those studies. We identi-
fied a structurally distinct analog, 3 (BMS-191095), of
2 which is over 20-fold more selective for the ischemic
myocardium than compound 2.
The benzoxazole derivative 16 was prepared according
to the procedure outlined in Scheme 3. The amino
alcohol 3610 was subjected to reductive amination with
ethyl glyoxalate in the presence of sodium cyanoboro-
hydride to provide the ester 37 in 48% yield. The ester
37 was treated with 2-chlorobenzoxazole in the presence
of sodium hydride, and the resulting O-alkylated mate-
rial 38 was treated with acetic acid to provide the
desired product 16. Details of this method which
involves the intramolecular O- to N-migration (38 f 16)
of the benzoxazole moiety are published.15
The N-acetyl analog 22 was prepared according to the
method outlined in Scheme 4. The phthalamido-
protected compound 39, prepared from the epoxide 32
in the usual manner (magnesium perchlorate, acetoni-
trile, heat, 67%), was deprotected by treatment with
methylhydazine to give the amine 40 in a quantitative
yield. The amine 40 was acetylated under standard
conditions (AcCl, pyridine) to provide 22 in 85% yield.
The synthesis of the oxalate derivative 23 is sum-
marized in Scheme 5. The amino alcohol 41 was
prepared by treatment of the epoxide 3212 with 4-fluo-
roaniline in the presence of magnesium perchlorate. The
hydroxyl group in 41 was protected as a 4-methoxyben-
zyl ether, and the resulting product 42 was acylated
(ethyl oxalyl chloride, 4-(dimethylamino)pyridine) to
provide the oxalate derivative 43 in 76% yield. The
4-methoxybenzyl ether was cleaved by treatment with
trifluoroacetic acid to provide the desired product 23 in
55% yield. The protection of the hydroxyl group in 41
was necessitated due to the competing O-acylation of
41 which we were unable to suppress.
Ch em istr y
Most of the analogs (5-8, 10-14, 18-20, 24, 25, 29)
were prepared by opening the known epoxide 3212 with
appropriately substituted aniline derivatives 33 in the
presence of magnesium perchlorate in acetonitrile
(Scheme 1).13 The yield of this reaction is critically
dependent on the concentration of the reaction mixture.
The reaction proceeds in a high yield (96%) when the
reactants are mixed in the presence of a minimum
amount of acetonitrile (i.e., paste). Dilution of the reac-
tion mixture usually results in longer reaction times and
a reduction of yield. Lower yields of some of the prod-
ucts reflect reactions performed under dilute conditions
prior to noticing the effect of concentration (Table 3).
While the magnesium perchlorate-induced opening of
the epoxide 32 with aniline derivatives 33 was success-
ful for the preparation of a wide variety of compounds
(Table 3), it failed to provide the imidazole analogs 3,
28, 30, and 31. The use of cobalt chloride in place of
magnesium perchlorate provided the requisite imidazole
derivatives 3, 28, 30, and 31 in modest yields (24-55%)
(Scheme 1).14 The success of this reaction is dependent
on the quality of cobalt chloride. We usually dried the
commercially available cobalt chloride prior to its use,
as the use of material directly out of a bottle gave lower
yields of the products.
The synthesis of 9, 17, and 26 from the ester 6 is
outlined in Scheme 6. The acid analog 9 was obtained
in excellent yield by simple saponification (LiOH, THF)
of the ester 6. The ethylamide analog 17 was obtained
in 70% yield by treatment of the ester 6 with ethyl-
amine. The oxadiazole derivative 26 was prepared in
61% yield by treatment of the ester 6 with N-hydroxy-
acetamidine in the presence of sodium hydride.
The aniline derivatives 33 used for the opening of
epoxide 3212 can be readily obtained from suitably
substituted anilines by either reductive amination with
aldehydes or alkylation with suitable electrophiles.
Selective procedures are described in the Experimental
Section.
A more convergent approach for the preparation of
analogs of 6 which involves the alkylation of the protio
derivative 8 was somewhat less successful, presumably
due to the low reactivity of the aniline nitrogen in 8 and
potential interference by the C3-hydroxyl. The only
compound prepared by this method was the thiazole
analog 15 (Scheme 2) which could not be obtained by
the route outlined in Scheme 1. The intermediate 35,
obtained by opening of the epoxide 32 with 2-amino-4-
methylthiazole (34), was alkylated with ethyl bromoac-
etate to provide the desired product 15 in a low overall
yield.
The oxazole analog 27 was obtained from the ester 6
in three steps (Scheme 7). The ester 6 was heated with
2,2-dimethoxyethylamine to give the amide 44 in 96%
yield. The dimethyl acetal in 44 was cleaved (aqueous
HCl, THF), and the resulting aldehyde 45 was im-
mediately cyclized to the oxazole 27 in low (12%) overall
yield.
1
The H and 13C NMR spectra of most of the analogs
show broad signals at room temperature due to a
restricted rotation around the C4-N bond. Heating the

26 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Rovnyak et al.
Sch em e 3
Sch em e 4
Sch em e 5
Sch em e 6a
the rat aorta preconstricted with methoxamine.17 De-
tails of these assays are described.18 The ratio of the
EC25 value for time to contracture and IC50 value for
vasorelaxant potency indicates selectivity in vitro for the
ischemic myocardium. Since the two in vitro tests are
different from each other (isolated rat heart vs agonist-
constricted rat aorta), the ratio does not indicate abso-
lute selectivity. It only serves as a useful index to select
compounds for evaluation in vivo. Validity of these in
vitro test systems to predict antiischemic selectivity in
vivo has been demonstrated by detailed studies with 2
and cromakalim (1).11
a
Reaction conditions: (a) for 9, lithium hydroxide, THF, water,
80%; (b) for 17, ethylamine, methanol, 70%; (c) for 26, N-
hydroxyacetamidine, NaH, THF, heat, molecular sieves, 61%.
sample up to 100 °C in dimethyl sulfoxide usually gave
a well-resolved spectrum.
The starting point for the identification of a lead
compound was the indole analog 4 which showed modest
antiischemic potency with excellent cardiac selectivity
(Table 1).19 Although 4 had all the desirable features
to serve as a lead compound, the synthesis of 4 and its
analogs presented a major synthetic challenge. For
example, the formation of the desired product 4 from
epoxide 32 is accompanied by the dehydration product.19
Therefore, efforts were undertaken to prepare simplified
analogs of this compound by breaking various indole
bonds (Scheme 8).20 That exercise led to the identifica-
tion of compound 5 with slightly superior cardioprotec-
tive potency relative to compound 4 (Table 1). Since 5
possesses little vasorelaxant activity (IC50 > 30 µM), it
is more selective than 2 for the ischemic myocardium.
Most of the antiischemic activity of 5 resides in the
3R,4S-enantiomer 6, as the 3S,4R-enantiomer 7 is
significantly less potent than 6 as an antiischemic agent.
Resu lts a n d Discu ssion
Discover y of th e Lea d Com p ou n d . The cardio-
protective (also referred to as antiischemic) potencies
in vitro were determined by measurement of EC25
values for increase in time to the onset of contracture
in globally ischemic isolated perfused rat hearts.16 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.16 Contrac-
ture develops due to rigor bond formation resulting from
depletion of ATP. Compounds were initially screened
at 10 µM concentration. Those showing greater than
25% increase in time to the onset of contracture were
subjected to concentration-response studies to deter-
mine EC25 values. Vasorelaxant potencies were deter-
mined by measurement of IC50 values for relaxation of

Cardioselective Antiischemic KATP Openers
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 27
Sch em e 7
Ta ble 1. Vasorelaxant and Antiischemic Potencies of
Compounds 1, 2, and 4-7
Sch em e 8
antiischemic
potencya
EC25 (µM) or %
incorp @ 10 µM
vasorelaxant
ratio
EC25/IC50
compd
potencyb IC50 (µM)
1 (racemic)
2 (3S,4R)
4 (racemic)
5 (racemic)
6 (3R,4S)
7 (3S,4R)
8.9
2.5
8.1
4.7
2.2
5%
0.032 (0.021, 0.04)
1.8 (0.78, 4.25)
33 (19.0, 58.6)
278
1.4
0.25
<0.17
<0.07
>30c
>30c
>30c
a
EC25 for antiischemic (cardioprotective) potency is determined
by measurement of increase in time to contracture in globally
ischemic isolated perfused rat hearts. Time to contracture is
defined as the time necessary during total global ischemia to
increase end diastolic pressure by 5 mmHg. Each point on the
concentration-response curve is an average of three to four
antiischemic activity. Lack of antiischemic activity in
16 compared to 15 and 6 indicates that there are
restrictions as to the size of the pendant aryl/heterocy-
clic ring of 6.
Since the ethyl ester of 6 was expected to be meta-
bolically labile (the acid 9 being inactive), a major
portion of our effort was devoted to preparing stable
surrogates for the ester group of 6. Replacement of the
ester with an amide (17), ether (18), or nitrile (19) led
to a reduction in cardioprotective potency. The phos-
phonate analog 20 has cardioprotective potency similar
to the ethyl ester 6. Although a direct sulfone analog
of 6 could not be prepared due to synthetic difficulty,
the homologous sulfone 21 is less potent than 6. The
N-acetyl analog 22 also shows reduced cardioprotective
potency relative to 6. These results indicate that
narrow structure-activity relationships exist in this
portion of the molecule. This conclusion is also sup-
ported by the lower cardioprotective potency of the
carbonyl (23) replacement for the side chain methylene
group of 6. Comparison between 6, 23, and 24 also
suggests that an sp3 carbon and nitrogen atoms adjacent
to the aniline nitrogen are preferred.
The most gratifying results for replacing the ethyl
ester of 6 with potentially metabolically stable sur-
rogates were obtained with heterocyclic analogs. While
the furan analog 25 has cardioprotective potency similar
to the ester 6, the oxadiazole 26 is slightly less potent
than 6. Both the oxazole (27) and imidazole (28)
analogs retain the cardioprotective potency of 6. The
isoxazole analog 29 shows diminished potency relative
to the parent ester 6. Based on its potency and
selectivity, the imidazole analog 28 was selected for
further modifications. The 4-fluorophenyl- and 4-chlo-
rophenyl-substituted imidazoles 30 and 3, respectively,
prepared to suppress potential hydroxylation in vivo of
the pendant phenyl ring, retain the full antiischemic
potency of their parent 28. The 4-chlorophenyl imida-
zole analog 3 is the most potent compound of this series.
Similar to the prototype ester 6, most of the cardiopro-
tective activity resides in the 3R,4S-enantiomer 3, as
the 3S,4R-enantiomer (31) of 3 has little antiischemic
activity up to a concentration of 10 µM. Thus, changing
the ester (6) to an imidazole (3) does not affect the
absolute stereochemical requirements for the cardio-
protective activity of this series of compounds. By virtue
b
determinations, and the IC50 value is within (20%. IC50 for
vasorelaxant potency is determined by relaxation of rat aorta
precontracted with methoxamine. IC50 value is presented as a
mean with 95% confidence interval in parentheses; n ) 4 or higher.
c Concentrations higher than 30 µM could not be tested due to
limitation of solubility.
It is of interest to note that the absolute stereochemistry
of 6 is opposite to that of 2 and cromakalim (1). The
reasons for this reversal of absolute stereochemical
requirements for 6 are not known at the present time.
They may be related to its different mode of binding to
the receptor site(s) compared to 2 and cromakalim (1).
The higher cardiac selectivity of 6 and its significantly
altered structure (opposite stereochemistry, no cyan-
oguanidine) compared to 2 made it attractive for further
structure-activity work.
Str u ctu r e-Activity Rela tion sh ip s. Since cardio-
protective and vasorelaxant potencies define selectivity,
we studied the effect of structural changes on both
parameters. We concentrated on making changes to the
structural moiety (PhNCH2COOEt) attached to C4 of
the benzopyran ring in 6 (Table 2). The detailed
structure-activity relationships for the benzopyran
portion of 2 are published.18 Comparison between 6
(3R,4S) and the protio analog 8 (racemate) indicates
that the second substituent on the aniline nitrogen
contributes little to antiischemic potency although it
enhances cardiac selectivity by reducing vasorelaxant
potency. The carboxylic acid analog 9, a putative
metabolite of 6, is devoid of antiischemic activity.
Chain-extended esters 10 and 11 offer no further
improvement in the antiischemic potency of 6. Further
increase in the size of the ester group, as in the n-butyl
analog 12, causes attenuation of antiischemic potency.
The 4-fluoro (13)- and 4-chloro (14)-substituted ana-
logs of 6 retain antiischemic potency indicating that the
pendant aromatic ring of 6 can be substituted without
adversely affecting antiischemic potency. While re-
placement of the pendant phenyl ring with methyl-
thiazole (15) maintains significant antiischemic activity,
the corresponding benzoxazole analog 16 is devoid of

28 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Rovnyak et al.
of having low vasorelaxant potencies, most compounds
of this series show excellent selectivity for the ischemic
myocardium (Tables 1, 2).
on the vehicle-treated hearts (data not shown).21 As
shown in Figure 1, glyburide has no effect on the
cardioprotective effects of the calcium channel blocker
diltiazem (time to contracture: 23.7 vs 24 min). Thus,
glyburide appears to be specific for abolishing the
cardioprotective actions of 3. We have previously shown
that glyburide does not affect the cardioprotective
benefits of a diverse group of cardioprotectants acting
via mechanisms other than the KATP opening.21 These
data suggest that the cardioprotection afforded by 3 and
its analogs in the isolated perfused rat hearts is most
likely due to the opening of the KATP in the heart.
Although the nature of the molecular interaction be-
tween the KATP openers (e.g., 3) and glyburide is not
known at the present time, it is clear that the glyburide-
binding ABC-type protein (SUR) is part of the KATP
complex.22
Bioa va ila bility a n d P h a r m a cok in etics of Com -
p ou n d 3. Since metabolism and pharmacokinetics can
impact the results of studies in vivo, we evaluated the
oral bioavailability and plasma half-life of 3 in rats.
Male rats were given single intravenous or oral doses
(30 µmol/kg, N ) 4) of compound 3 as a solution in
ethanol:PEG 400:water (2:3:5). Serial plasma samples
were analyzed by a specific LC/MS method developed
for 3. After intravenous administration, 3 was elimi-
nated from plasma with apparent biphasic kinetics
(Figure 2). The apparent terminal elimination half-life
(t1/2â) was 3.0 h. Following an oral dose of compound 3
(30 µmol/kg), the maximal plasma concentration of 3
(Cmax) was 1.3 µM and was observed at a Tmax of 1.9 h.
Based upon AUC values, bioavailability of 3 after oral
doses was estimated to be about 47%. Thus, 3 has a
modest half-life (3 h) and good oral bioavailability (47%)
in rats.
Compound 3 is slightly more potent than 2 as a
cardioprotectant. Having very little vasorelaxant activ-
ity up to a concentration of 30 µM, it is at least 20-fold
more cardiac selective than 2. Compound 3 is over
4000-fold more selective than the first-generation agent
cromakalim (1). The selectivity for the ischemic myo-
cardium is achieved by reduction of vasorelaxant po-
tency as the cardioprotective potency remains relatively
constant (Tables 1, 2). These results indicate that the
structure-activity relationships for the vasorelaxant
and antiischemic potencies are distinct. We have no
explanation for these differences except that the va-
sorelaxant and cardioprotective effects of KATP openers
might be mediated via different receptors. We need to
understand the molecular mechanism of action of KATP
to explain our experimental observations.
With the identification of compound 3, we achieved
our objective of finding a more cardiac selective agent
than 2. We further characterized 3 for its mechanism
of action and metabolic stability before evaluating its
efficacy in vivo. Both these factors can potentially
impact the results of studies in vivo.
Since there are significant differences (absolute ster-
eochemistry, C4 moiety) between the structures of 2 and
3, it was important to confirm the KATP-opening mech-
anism for the cardioprotective activity of 3. This is
especially important as our assay measuring cardiopro-
tective potency in isolated rat hearts is not based on
the mechanism of action of KATP openers. The receptor
site(s) relevant to cardioprotection being unknown, the
biochemical tools to carry out the mechanism studies
on cardioprotective KATP openers are limited at the
present time. The mechanistic work is usually carried
out through pharmacological and electrophysiological
studies. The currently available tools for pharmacologi-
cal studies are the sulfonylurea class of KATP blockers
(e.g., glyburide) which abolish the cardioprotective ef-
fects of KATP openers in isolated perfused hearts.21 The
concentrations of KATP blockers that abolish the cardio-
protective effects of KATP openers have no effects in the
isolated hearts when given alone.21
Con clu sion
The objective of our work was to find a structurally
distinct analog of BMS-180448 (2) with enhanced car-
diac selectivity. We have shown that the modest
selectivity of 2 for the ischemic myocardium can be
further increased by structural modifications of 6 which
was derived from the indole analog 4. The structure-
activity studies indicate that increasing the size of the
alkyl ester leads to diminished potency as does its
replacement with a variety of other groups such as
acetonitrile and methyl sulfone. The ester can be
successfully replaced with some heterocycles (e.g., imi-
dazole, oxazole). The best compound of this series is
the 4-chlorophenyl imidazole analog 3 (BMS-191095)
which shows enhanced selectivity for the ischemic
myocardium compared to its predecessor 2. Notably,
the biological stereoselectivity of 3 (3R,4S) and its
congeners is opposite to that of 2 (3S,4R). The results
described in this publication further support that there
is no correlation between vasorelaxant and cardiopro-
tective potencies of KATP openers. While compounds 2
and 3 show greater than 20-fold separation in their
vasorelaxant potencies, the two compounds show similar
“glyburide-sensitive” cardioprotective potencies. The
improved cardiac selectivity of 3, as measured by the
ratio of cardioprotective and vasorelaxant potencies,
might translate into a wider window of safety for the
treatment of myocardial ischemia. With its good oral
bioavailability (47%) and plasma elimination half-life
(3 h), compound 3 offers an excellent candidate to probe
Effect of th e KATP Block er Glybu r id e on Ca r d io-
p r otection by Com p ou n d 3. We studied the effect
of the KATP blocker glyburide on the cardioprotective
effects of 3 as measured by the increase in time to the
onset of ischemic contracture in isolated rat hearts. The
globally perfused rat hearts were divided into five
groups: vehicle, 3 (6 µM), 3 (6 µM) + glyburide (0.3 µM),
diltiazem (1 µM), and diltiazem (1 µM) + glyburide (0.3
µM). The calcium channel blocker diltiazem was in-
cluded in this study to ensure the specificity of the KATP
blocker glyburide. The test agents were given in the
perfusion medium 10 min prior to the cessation of flow.
The 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.
In control hearts, the contracture develops in ap-
proximately 17 min which is significantly enhanced (23
min) by pretreatment with 6 µM 3 (Figure 1). This
increase in time to the onset of contracture is abolished
by cotreatment with 0.3 µM glyburide (22.8 ( 0.3 vs 17.6
( 0.5 min). This concentration of glyburide has no effect

Cardioselective Antiischemic KATP Openers
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 29
Ta ble 2. Vasorelaxant and Antiischemic Potencies of Analogs of 6 (All compounds except 8, 9 (racemic), and 31 (3S,4R) have
3R,4S-stereochemistry)
a
EC25 for antiischemic (cardioprotective) potency is determined by measurement of increase in time to contracture in globally ischemic
isolated perfused rat hearts. Time to contracture is defined as the time necessary during total global ischemia to increase end diastolic
pressure by 5 mmHg. Each point on the concentration-response curve is an average of three to four determinations, and the IC50 value
b
is within (20%. IC50 for vasorelaxant potency is determined by relaxation of rat aorta precontracted with methoxamine. IC50 value is
presented as a mean with 95% confidence interval in parentheses; n ) 4 or higher. c For some analogs, concentrations higher than 30 µM
could not be tested due to solubility limitations.

30 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Ta ble 3. Physical Properties of Compounds 3 and 5-31
Rovnyak et al.
compd
conditions
yield (%)
mol formula
mp (°C)a
microanal.
3
5
6
7
8
CoCl2
55
53
31
20
84
C22H21ClN4O2‚HCl
C22H24N2O4
226-228 (A)
140-144 (B)
182-183 (B)
182-183 (B)
195-197 (B)
163-165 (B)
62-63
C, H, N, Cl
C, H, N
C, H, N
C, H, N
C, H, N, Cl
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N, F
C, H, N, Cl
C, H, N
C, H, N
C, H, N
C, H, N,
C, H, N,
C, H, N, F, P
C, H, N, S
C, H, N
C, H, N, F
C, H, N
C, H, N
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
C22H24N2O4‚0.37H2O
C22H24N2O4‚0.24H2O
C18H18N2O2‚HCl‚0.13Et2O
9
C20H20N2O4‚0.1H2O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
96
96
65
37
47
C23H26N2O4‚0.1H2O
C24H29N2O4‚0.1H2O
C24H28N2O4
109-110
82-85
C22H23FN2O4
C22H23ClN2O4
195-197 (C)
172-173 (B)
83
C
C
C
20H23N3SO4‚1.3H2O
23H23N3O5‚0.3H2O
22H25N3O3
90
213-214 (B)
Mg(ClO4)2
Mg(ClO4)2
Mg(ClO4)2
77
39
35
C21H24N2O3
C20H19N3O2‚0.27H2O
C23H28FN2O5P
119-124
85-90 (B)
55-56
C
C
C
21H24N2O4S‚0.6H2O
22H25N3O3‚0.21H2O
22H21FN2O5‚0.25C6H14
75-85
217-218 (D)
122-123 (E)
161-162
Mg(ClO4)2
Mg(ClO4)2
25
72
C21H23N3O4
C23H22N2O3
134-135
C
C
22H22N4O3
22H21N3O3‚1.0H2O‚0.14EtOAc
148-149 (B)
207-208
C, H, N
C, H, N
C, H, N
C, H, N
C, H, N, F, Cl
C, H, N, Cl
CoCl2
Mg(ClO4)2
CoCl2
24
60
41
50
C22H22N4O2‚0.94H2O
C23H23N3O3
259-260 (F)
80-90
C22H21FN4O2‚HCl‚1.4H2O
C22H21ClN4O2‚HCl
lyophilate
224-226 (A)
CoCl2
a
Solvents for crystallization: A, acetonitrile-toluene; B, hexanes trituration; C, EtOAc-hexanes; D, triturated with isopropyl ether;
E, triturated with hexanes-ether; F, CHCl3-hexanes.
F igu r e 2. Mean plasma concentrations of (3R)-trans-4-[(4-
chlorophenyl)-N-(1H-imidazol-2-ylmethyl)amino]-3,4-dihydro-
3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile, mono-
hydrochloride (3) after intravenous and oral doses to rats.
Merck Kieselgel 60 (230-400 mesh ASTM). All compounds
were characterized by 1H and 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.
Rep r esen ta tive P r oced u r e for th e Ma gn esiu m P er -
ch lor a te-P r om oted Rea ction : P r ep a r a tion of (3R)-tr a n s-
3-[N-(6-Cya n o-3,4-d ih yd r o-3-h yd r oxy-2,2-d im eth yl-2H-1-
b en zop yr a n -4-yl)p h en yla m in o]p r op a n oic Acid , E t h yl
Ester (10). A mixture of 3-(N-phenylamino)propanoic acid,
ethyl ester23 (0.44 g, 2.3 mmol), epoxide 3212 (0.30 g, 1.5 mmol),
and magnesium perchlorate (0.33 g, 1.5 mmol) in acetonitrile
(0.3 mL) was allowed to stand at room temperature for 24 h.
The solvent was evaporated, and the residue was purified by
flash chromatography on silica gel eluting with EtOAc/hexanes
(1:12) to give a colorless solid (0.57 g, 96%): 1H NMR (CDCl3)
δ 7.3-7.4 (m, 4H), 6.8-7.2 (m, 4H), 4.8 (d, J ) 10.0 Hz, 1H),
4.0-4.1 (m, 3H), 3.6 (s, 2H), 3.2 (s, 1H), 2.7-2.8 (m, 1H), 2.5-
2.6 (m, 1H), 1.6, 1.3 (s, 3H each), 1.2 (t, J ) 7.0 Hz, 3H); 13C
NMR (CDCl3) δ 172.9, 157.2, 148.6, 132.6, 131.9, 129.6, 123.2,
119.7, 119.1, 118.6, 116.5, 103.5, 80.3, 70.0, 62.9, 60.9, 41.0,
F igu r e 1. Effect of the KATP blocker glyburide on the cardio-
protective effects of 3 (6 µM) and the calcium channel blocker
diltiazem (1 µM) in isolated perfused globally ischemic rat
hearts. While glyburide (0.3 µM) has no effect on the cardio-
protective effects of diltiazem, it abolishes the cardioprotective
actions of 3 as measured by the time to the onset of contrac-
ture. *Significantly different from vehicle-treated hearts.
the role of residual vasorelaxant potency of 2 toward
its cardioprotective activity in vivo. The results of those
studies will be reported in future publications.
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 pellets. 1H and 13C NMR spectra were
measured on J OEL 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

Cardioselective Antiischemic KATP Openers
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 31
32.2, 27.1, 18.8, 14.0. Compounds 5-8, 11-14, 18-20, 24,
25, and 29 were prepared in a similar manner.
aniline derivatives 33 prepared by this method were those used
for the preparation of compounds 5-7, 12-14, and 18.
3. 5-Meth yl-3-[(N-p h en yla m in o)m eth yl]isoxa zole, 33
(R1 ) P h , R 2 ) CH 2-3-isoxa zolyl). A solution of 5-meth-
yl-3-(bromomethyl)isoxazole24 (500 mg, 2.84 mmol) in aceto-
nitrile (3 mL) under argon at ambient temperature was treated
with aniline (530 mg, 5.68 mmol). After stirring overnight,
precipitated solids were filtered and washed with acetoni-
trile. The concentrated filtrate was flash chromatographed
on silica gel (ethyl acetate/hexane, 1:4) to give the desired
product (411 mg, 75%). This material was used in the next
step (for 29) without further purification. The aniline deriva-
tive (R1 ) Ph, R2 ) CH2CH2SO2Me) for 21 was prepared in an
analogous manner from aniline and 2-chloroethyl methyl
sulfide followed by oxidation (3-chloroperoxybenzoic acid) to
the sulfone.
Rep r esen ta tive P r oced u r e for th e Coba lt Ch lor id e-
P r om oted Rea ction : P r ep a r a tion of (3R)-tr a n s-4-[(4-
Ch lor op h en yl)-N-(1H -im id a zol-2-ylm et h yl)a m in o]-3,4-
d ih yd r o-3-h yd r oxy-2,2-d im e t h yl-2H -1-b e n zop yr a n -6-
ca r bon itr ile, Mon oh yd r och lor id e (3). A mixture of epoxide
3212 (40.0 g, 198.79 mmol), N-(4-chlorophenyl)-1H-imidazole-
2-methanamine (41.3 g, 198.79 mmol), and anhydrous cobalt
chloride (25.8 g, 198.79 mmol) in dry acetonitrile (160 mL)
under argon was heated at 60 °C (oil bath temperature) for
28 h. The deep blue reaction mixture was allowed to cool to
room temperature and treated with saturated sodium bicar-
bonate followed by ethyl acetate (1600 mL). The mixture was
shaken and filtered through a sintered glass filter to remove
solids. The organic layer was separated, washed with satu-
rated sodium bicarbonate, and filtered through a short pad of
Celite to remove additional solids. The aqueous layer was
removed, and the yellow organic layer was washed with brine.
It was dried (sodium sulfate), and the solvent was removed.
The residue was heated with hexanes (∼1000 mL)/ethyl
acetate (100 mL) and the colorless solid was collected. The
solid was heated with methanol (2000 mL) for 15 min, cooled
to room temperature, and filtered to provide the desired
product as a white solid (44.72 g, 55%). This material was
converted to its hydrochloride salt by treatment with ethereal
HCl and crytallized from acetonitrile-toluene to provide 3 as
a colorless powder: 1H NMR (CD3OD, 60 °C) δ 7.73 (d, J )
1.2 Hz, 1H), 7.67 (dd, J ) 1.2, 8.8 Hz, 1H), 7.35 (d, J ) 8.8 Hz,
2H), 7.12 (d, J ) 8.8 Hz, 1H), 7.02 (d, J ) 8.8 Hz, 2H), 5.15 (d,
J ) 10.0 Hz, 1H), 5.05 (d, J ) 1.8 Hz, 2H), 4.71 (br s, 1H),
4.22 (d, J ) 10.0 Hz, 1H), 1.68, 1.47 (s, 3H each); 13C NMR
(CD3OD, 60 °C) 158.9, 147.6, 147.4, 134.5, 133.1, 130.4, 126.8,
124.5, 120.5, 120.1, 119.8, 118.9, 105.3, 82.1, 71.4, 63.4, 46.0,
27.3, 19.1. Compounds 28, 30, and 31 were prepared in a
similar manner.
Rep r esen ta tive P r oced u r es for th e P r ep a r a tion of
Com p ou n d s 33. 1. N-(4-Ch lor op h en yl)-1H-im id a zole-2-
m eth a n a m in e, 33 (R1 ) 4Cl-P h , R2 ) CH2-2-im id a zolyl).
A mixture of 4-chloroaniline (66.65 g, 522.43 mmol) and
2-imidazolecarboxaldehyde (50.2 g, 522.43 mmol) in MeOH
(1000 mL) was stirred at 55-60 °C for 16 h. The reaction
mixture was cooled in an ice bath, treated with sodium
borohydride (21.74 g, 574.67 mmol), and allowed to warm to
ambient temperature. It was stirred for 2 h and concentrated
to give a white emulsion. It was diluted with water (∼500
mL) and ethyl acetate (1200 mL). The organic layer was
removed and the aqueous mixture reextracted with ethyl
acetate (3 × 200 mL). The combined organic layers were
washed with brine, dried (sodium sulfate), and concentrated
to ∼500 mL of a brown solution containing some solid. The
mixture was treated with hexane (∼200 mL) and stored in the
freezer (-5 to 0 °C) for 2 h. The desired product was collected
by filtration to give a colorless solid (83.36 g, 77%). 1H NMR
(DMSO-d6, 50 °C) δ 11.80 (br s, 1H), 7.07 (ABq, J ) 8.8 Hz,
2H), 6.91 (s, 2H), 6.65 (ABq, J ) 8.8 Hz, 2H), 6.11 (br m, 1H),
4.22 (d, J ) 5.3 Hz, 2H); 13C (DMSO-d6, 50 °C) 147.3, 145.5,
128.3, 121.5, 119.5, 113.7, 41.1. This material was used for
the preparation of compounds 3 and 31. Other aniline
derivatives 33 prepared by this method were those used for
the preparation of compounds 28 and 30.
4. An ilin e Der iva t ive 33 (R 1 ) P h , R 2 ) CH 2(CH 2)2-
COOEt) for th e P r ep a r a ion of Com p ou n d 11. A mixture
of 1-phenyl-2-pyrrolidinone (4.00 g, 25.0 mmol), absolute
ethanol (20 mL) ,and concentrated hydrochloric acid (2 mL)
was refluxed for 24 h. The reaction mixture was concentrated
in vacuo, and the residue, diluted with ethyl acetate, was
washed with 5% sodium bicarbonate, water, and brine. The
organic layer was dried over MgSO4 and concentrated in vacuo.
The desired product was separated from the starting material
by flash chromatography on silica gel (hexanes/EtOAc, 1:1) to
give a colorless solid (0.51 g, 10%): mp 40-42 °C.
5. An ilin e Der iva tive 33 (R 1 ) P h , R2 ) NHCOOEt)
for th e P r ep a r a ion of Com p ou n d 24. A solution of phen-
ylhydrazine (5.00 g, 46.24 mmol) in chloroform (40 mL) and
triethylamine (7.1 mL, 50.9 mmol) was cooled to -10 °C and
treated dropwise with ethyl chloroformate (4.4 mL, 46.24
mmol). The cooling bath was removed, and the reaction
mixture was allowed to warm to room temperature and stirred
for 30 min. The solvent was removed, and the residue was
partitioned between ethyl acetate (150 mL) and water (60 mL).
The organic layer was washed with saturated ammonium
chloride solution, water, and brine and dried over sodium
sulfate. The solvent was removed, and the residue was
triturated with hexanes/dichloromethane to give an off-white
solid (4.059 g, 49%) which was used in the next reaction
without further purification.
The aniline derivative 33 (R1 ) Ph, R2 ) CH2PO(OEt)2) used
for the preparation of 20 was prepared according to literature
methods.25 Compound 33 (R1 ) Ph, R2 ) CH2CN) used for
the preparation of analog 19 is commercially available.
tr a n s-[(6-Cya n o-3,4-d ih yd r o-3-h yd r oxy-2,2-d im et h yl-
2H-1-ben zop yr a n -4-yl)p h en yla m in o]a cetic Acid (9).
A
solution of compound 5 (310 mg, 0.81 mmol) in THF (7 mL)
and water (5 mL) at 0-5 °C was treated with 1 M lithium
hydroxide (1 mL) and stirred for 3 h as the temperature rose
to ambient. The mixture was diluted with ethyl acetate and
extracted with water. The combined aqueous fractions were
acidified with 10% citric acid to pH 3 and extracted with ethyl
acetate. The organic fraction was washed with water and
brine, dried (anhydrous magnesium sulfate), and concentrated
to give the product as a foam. Trituration with hexanes-ether
afforded the desired product (230 mg, 80%): 1H NMR (DMSO-
d6/CD3OD, 100 °C) δ 7.66 (s, 1H), 7.52 (dd, J ) 1.3, 8.5 Hz,
1H), 7.14 (d, J ) 8.6 Hz, 1H), 7.12 (d, J ) 7.7 Hz, 1H), 6.93 (d,
J ) 8.5 Hz, 1H), 6.60-6.67 (m, 3H), 4.83 (d, J ) 10.2 Hz, 1H),
4.05 (s, 2H), 3.92 (d, J ) 9.8 Hz, 1H), 1.46 (s, 3H), 1.26 (s,
3H); 13C NMR (CDCl3) δ 178.5, 134.6, 133.1, 131.0, 123.3,
120.8, 120.2, 119.4, 114.2, 114.2, 105.3, 81.6, 68.6, 59.9, 49.0,
28.4, 20.6.
2. N-(2-F u r a n ylm eth yl)p h en yla m in e, 33 (R1 ) P h , R2
) CH2-2-fu r yl). A mixture of aniline (1.93 g, 20.0 mmol) and
2-furaldehyde (2.50 g, 26.8 mmol) in 1,2-dichloroethane (100
mL) under argon at 5 °C was treated with Na(OAc)3BH (5.65
g, 26.8 mmol) and acetic acid (1.5 mL) and stirred at room
temperature overnight. The reaction mixture was concen-
trated, and the residue, diluted with ethyl acetate, was washed
with sodium bicarbonate, water, and brine. The organic layer
was dried over magnesium sulfate and concentrated. The
product was purified by flash chromatography on silica gel
eluting with hexanes/EtOAc (20:1) to give an oil (3.43 g,
99%): 1H NMR (CDCl3) δ 7.4-7.6 (m, 3H), 6.8-7.0 (m, 3H),
6.4-6.6 (m, 2H), 4.5 (s, 2H), 4.2 (s, 1H); 13C NMR (CDCl3) δ
152.6, 147.5, 141.7, 129.1, 117.8, 112.9, 110.2, 106.8, 41.2. This
material was used for the preparation of compound 25. Other
(3R )-t r a n s-[(6-Cya n o-3,4-d ih yd r o-3-h yd r oxy-2,2-d i-
m eth yl-2H-1-ben zop yr a n -4-yl)(4-m eth yl-2-th ia zolyl)a m i-
n o]a cetic Acid , Eth yl Ester (15). A. Com p ou n d 35.
A
solution of 3212 (810 mg, 4.0 mmol), 2-amino-4-methylthiazole
(1.05 g, 9.2 mmol), and magnesium perchlorate (1.15 g, 5.1
mmol) in acetonitrile (1 mL) under argon was stirred at room
temperature for 18 h. The resultant syrup was diluted with
ethyl acetate (15 mL) and poured into saturated ammonium
chloride solution. The aqueous layer was extracted with ethyl
acetate, and the combined organic extracts were dried over
Na2SO4 and concentrated. The residue was purified by flash

32 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Rovnyak et al.
chromatography on silica gel (ethyl acetate/hexanes, 1:2) to
give 35 as a white solid (730 mg, 58%): 1H NMR (CDCl3) δ
1.40 (s, 3H), 1.62 (s, 3H), 2.30 (s, 3H), 3.90 (d, J ) 8.8 Hz,
1H), 4.93 (d, J ) 8.8 Hz, 1H), 5.40 (br s, 1H), 6.19 (s, 1H), 7.0
(d, J ) 8.8 Hz, 1H), 7.58 (dd, J 1 ) 8.8 Hz, J 2 ) 2.0 Hz, 1H),
7.80 (d, J ) 2.0 Hz, 1H); 13C NMR (CDCl3) δ 169.01, 157.17,
147.24, 133.38, 132.58, 122.82, 118.80, 104.15, 102.60, 80.46,
75.99, 55.89, 26.46, 18.40, 16.99.
B. (3R)-tr a n s-[(6-Cya n o-3,4-d ih yd r o-3-h yd r oxy-2,2-
d im et h yl-2H -1-b en zop yr a n -4-yl)(4-m et h yl-2-t h ia zolyl)-
a m in o]a cetic Acid , Eth yl Ester (15). A solution of com-
pound 35 (620 mg, 2.0 mmol) and ethyl bromoacetate (0.24
mL, 2.15 mmol) in DMF (4 mL) was treated with finely
powdered K2CO3 (300 mg, 2.17 mmol). The reaction mixture
was stirred at room temperature overnight, poured into
saturated NaHCO3 (10 mL), and extracted with ethyl acetate.
The combined organic extracts were dried over Na2SO4 and
concentrated. The residue was purified by flash chromatog-
raphy on silica gel (hexane/ethyl acetate, 4:1) to give a colorless
solid (110 mg, 14%): 1H NMR (CDCl3) δ 7.58 (d, J ) 8.2 Hz,
1H), 7.46 (s, 1H), 7.00 (d, J ) 8.2 Hz, 1H), 6.27 (s, 1H), 5.20
(d, J ) 10 Hz, 1H), 4.97 (br s, 1H), 4.20-4.50 (m, 3H), 3.70 (d,
J ) 10 Hz, 1H), 3.65 (d, J ) 12.3 Hz, 1H), 2.35 (s, 3H), 1.67 (s,
3H), 1.43 (s, 3H), 1.40 (t, 3H).
(3R)-tr a n s-[(2-Ben zoxa zolyl)(6-cya n o-3,4-d ih yd r o-3-h y-
d r oxy-2,2-d im eth yl-2H-1-ben zop yr a n -4-yl)a m in o]a cetic
Acid , Eth yl Ester (16). A. Com p ou n d 36. To a solution
of epoxide 3212 (2.5 g, 12.4 mmol) in THF (5 mL) was added
ammonium hydroxide solution (2 mL), and the reaction
mixture was heated at 75 °C in a sealed tube for 16 h. The
reaction mixture was cooled to room temperature and concen-
trated. The residue in ethyl acetate was washed with brine
and dried over Na2SO4. The solvent was evaporated to give
an oil (2.6 g) which was used for the next step without further
purification.
B. Com p ou n d 38. A solution of 36 (2.6 g, 11.9 mmol) and
ethyl glyoxylate (2.5 g, 24.0 mmol) in methanol (30 mL) and
acetic acid (2 mL) at 0 °C under argon was treated with
NaBH3CN (1.5 g, 23.8 mmol). The reaction mixture was
stirred at 0 °C for 30 min and poured into saturated sodium
bicabonate solution (150 mL). The aqueous solution was
extracted with ethyl acetate, and the combined organic ex-
tracts were dried over Na2SO4. The solvent was removed, and
the residue was purified by flash chromatography on silica gel
(ethyl acetate/hexanes, 3:1) to give a colorless solid (1.8 g,
48%): 1H NMR (CDCl3) δ 7.90 (s, 1H), 7.50 (d, J ) 8.8 Hz,
1H), 6.95 (d, J ) 8.8 Hz, 1H), 4.35 (m, 2H), 3.90 (d, J ) 10 Hz,
1H), 3.57 (d, J ) 14 Hz, 2H), 3.54 (d, J )10 Hz, 1H), 1.64 (3,
3H), 1.40 (t, J ) 7 Hz, 3H), 1.34 (s, 3H); 13C NMR (CDCl3) δ
175.02, 157.49, 132.58, 132.23, 124.00, 119.30, 118.18, 103.58,
79.76, 71.41, 61.59, 56.93, 46.07, 26.92, 18.95, 13.99.
yla ceta m id e (17). A mixture of 6 (260 mg, 0.68 mmol) in
methanol (1 mL) was treated with 70% aqueous ethylamine
(1 mL, 15 mmol). After stirring at room temperature for 72
h, volatiles were removed and the residue was dissolved in
ethyl acetate. The solution was washed with dilute sodium
bicarbonate, water, and brine. The dried (anhydrous magne-
sium sulfate) organic fraction was concentrated to give an oil.
Flash chromatography on silica gel (ethyl acetate/hexanes, 2:3)
gave a colorless residue which was triturated with hexanes to
afford the desired product (180 mg, 70%): 1H NMR (DMSO-
d6, 110 °C) δ 8.02 (s, 1H), 7.55 (d, J ) 9.6 Hz, 1H), 7.40 (s,
1H), 7.17 (t, J ) 7.9 Hz, 2H), 6.96 (d, J ) 8.6 Hz, 1H), 6.65-
6.75 (m, 3H), 6.13 (s, 1H), 4.89 (d, J ) 10.2 Hz, 1H), 3.95-
4.00 (m, 1H), 3.80-3.84 (m, 2H), 3.16-3.21 (m, 2H), 1.50 (s,
3H), 1.32 (s, 3H), 1.07 (t, J ) 7.8 Hz, 3H); 13C NMR (CDCl3) δ
172.1, 133.5, 130.1, 123.4, 119.7, 119.5, 119.0, 113.6, 104.1,
81.2, 71.2, 59.5, 50.3, 35.3, 27.8, 20.0, 15.2.
(3R)-tr a n s-4-[[2-(Acetyla m in o)eth yl]p h en yla m in o]-3,4-
d ih yd r o-3-h yd r oxy-2,2-d im eth yl-2H-1-ben zop yr a n -6-ca r -
bon itr ile (22). A. (3R)-tr a n s-4-[N-(2-Am in oeth yl)p h en -
yla m in o]-3,4-d ih yd r o-3-h yd r oxy-2,2-d im eth yl-2H-1-ben -
zop yr a n -6-ca r bon itr ile (40). To a solution of compound 39
(4.50 g, 10.69 mmol), prepared in 67% yield from 32 by the
same procedure as described for 41, in ethanol (100 mL) at
room temperature was added a mixture of methylhydrazine
(50 mL) and ethanol (50 mL). The reaction was stirred at room
temperature for 1.5 h and heated at reflux for 1 h. The
volatiles were removed, and the residue was partitioned
between ethyl acetate and saturated sodium bicarbonate
solution. The organic phase was washed with brine, dried over
magnesium sulfate, and evaporated to obtain an off-white foam
(3.57 g, 100%): 1H NMR (CDCl3) δ 7.44 (dd, J ) 1.75, 8.79
Hz, 1H), 7.30-7.26 (m, 4H), 6.94 (m, 4H), 4.80 (d, J ) 10.55
Hz, 1H), 4.13 (d, J ) 9.38 Hz, 1H), 3.78 (m, 2H), 3.34 (m, 2H),
1.52 (s, 3H), 1.29 (s, 3H); 13C NMR (CDCl3) δ 157.46, 145.62,
133.56, 131.77, 130.19, 122.70, 121.15, 121.44, 119.28, 118.61,
116.91, 116.80, 112.71, 108.51, 103.18, 80.52, 71.13, 62.35,
44.50, 38.04, 26.35, 18.46.
B. (3R)-tr a n s-4-[[2-(Acetyla m in o)eth yl]p h en yla m in o]-
3,4-d ih yd r o-3-h yd r oxy-2,2-d im eth yl-2H-1-ben zop yr a n -6-
ca r bon itr ile (22). To a solution of 40 (0.5 g, 1.48 mmol) in
methylene chloride (5 mL) containing pyridine (0.18 g) at 0
°C was added acetyl chloride (0.12 g, 1.55 mmol). The reaction
mixture was stirred at 0 °C for 30 min followed by 2 h at room
temperature. The reaction mixture was partitioned between
1 N hydrochloric acid and ethyl acetate. The organic phase
was washed with saturated sodium bicarbonate solution and
brine and dried over magnesium sulfate. The solvent was
evaporated, and the residue was triturated with isopropyl
ether to obtain the desired product (0.48 g, 85%) as a white
solid:
1H NMR (DMSO-d6, 100 °C) δ 7.74 (br s, 1H), 7.66 (dd,
J ) 1.76, 8.80 Hz, 1H), 7.45 (s, 1H), 7.32 (m, 2H), 7.08 (m,
3H), 6.84 (m, 1H), 4.91 (d, J ) 9.38 Hz, 1H), 4.05 (d, J ) 9.97
Hz, 1H), 3.44-3.15 (m, 4H), 1.92 (s, 3H), 1.63 (s, 3H), 1.39 (s,
3H); 13C NMR (DMSO-d6) δ 169.53, 157.21, 132.69, 131.86,
129.03, 124.73, 119.08, 118.30, 116.89, 113.74, 102.81, 80.98,
69.35 (broad), 59.75 (broad), 44.40 (broad), 36.90, 26.95, 22.54,
18.70.
C. (3R)-tr a n s-[(2-Ben zoxa zolyl)(6-cya n o-3,4-d ih yd r o-
3-h ydr oxy-2,2-dim eth yl-2H-1-ben zopyr an -4-yl)am in o]ace-
tic Acid , Eth yl Ester (16). To a solution of compound 37
(500 mg, 1.64 mmol) in DMF (5 mL) at 0 °C under argon was
added NaH (60% in oil, 165 mg, 4.1 mmol). The suspension
was stirred at 0 °C for 15 min, and 2-chlorobenzoxazole (230
µL, 2.1 mmol) was added. The reaction mixture was stirred
at 0 °C for 30 min and poured into saturated NH4Cl (10 mL)
and ethyl acetate (100 mL). The organic layer was separated,
and the aqueous solution was extracted with ethyl acetate.
The combined extracts were treated with acetic acid (0.5 mL)
and stirred at room temperature for 16 h. The solution was
washed with sodium bicarbonate and dried over Na2SO4. The
solvent was evaporated, and the residue was purified by flash
chromatography (hexane/ethyl acetate, 4:1) to give a foam (320
mg, 46%): 1H NMR (CDCl3) δ 7.58 (m, 3H), 7.47 (d, J ) 8.2
Hz, 1H), 7.35 (t, J )7.6, 1H), 7.24 (t, J ) 7.6 Hz, 1H), 7.04 (d,
J ) 8.2 Hz, 1H), 5.72 (d, J ) 10.0 Hz, 1H), 4.86 (d, J ) 3.5 Hz,
1H), 4.63 (d, J ) 18 Hz, 1H), 4.45 (m, 2H), 3.70 (m, 2H), 1.72
(s, 3H), 1.55 (s, 3H), 1.46 (t, J ) 7.5 Hz, 3H); 13C NMR (CDCl3)
δ 171.83, 162.41, 157.89, 148.96, 142.42, 133.50, 131.61,
124.37, 121.52, 120.43, 118.81, 118.67, 117.11, 109.25, 104.30,
80.43, 70.15, 62.66, 58.94, 45.78, 26.98, 19.20, 13.96.
(3R)-tr a n s-[N-(6-Cya n o-3,4-d ih yd r o-3-h yd r oxy-2,2-d i-
m eth yl-2H-1-ben zopyr an -4-yl)-N-(4-flu or oph en yl)am in o]-
oxoa cetic Acid , Eth yl Ester (23). A. Com p ou n d 41. The
reaction mixture containing 4-fluoroaniline (1.8 g, 16.4 mmol),
epoxide 3213 (3.0 g, 14.9 mmol), and magnesium perchlorate
(3.3 g, 14.9 mmol) in acetonitrile (3 mL) was allowed to stand
at room temperature for 48 h. The reaction mixture was
diluted with ethyl acetate and washed with water. It was
dried (magnesium sulfate) and concentrated, and the resi-
due was purified by flash chromatography on silica gel
(hexanes/ethyl acetate, 7:3) to give an oil (3.8 g, 82%): 1H
NMR (CDCl3) δ 7.57 (s, 1H), 7.40 (dd, J ) 1.8, 8.2 Hz,
1H), 6.8-6.95 (m, 3H), 6.65 (m, 2H), 4.40 (t, J ) 9.4, 8.8
Hz, 1H), 3.80 (d, J ) 9.4 Hz, 1H), 3.66 (d, J ) 9.4 Hz, 1H),
2.76 (s, 1H), 1.53, 1.33 (s, 3 H each); 13C NMR (CDCl3) 158.3,
156.5, 154.7, 143.4, 132.9, 132.3, 124.8, 119.0, 118.3, 116.4,
116.0, 115.8, 115.4, 114.8, 114.7, 103.9, 79.8, 73.5, 54.6, 26.6,
19.3.
(3R)-tr a n s-2-[N-(6-Cya n o-3,4-d ih yd r o-3-h yd r oxy-2,2-
d im e t h yl-2H -1-b e n zop yr a n -4-yl)p h e n yla m in o]-N -e t h -

Cardioselective Antiischemic KATP Openers
J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1 33
B. Com p ou n d 42. A solution of 41 (1.0 g, 3.2 mmol) in
dimethylformamide (5 mL) under argon at 0 °C was treated
with sodium hydride (0.3 g, 6.4 mmol, 60% oil dispersion) and
stirred for 10 min. The reaction mixture was treated with
4-methoxybenzyl chloride (550 mg, 3.5 mmol) and stirred at
room temperature for 1 h. The reaction mixture was poured
into water (50 mL) and extracted with ethyl acetate, and the
combined extracts were washed with water and brine. After
drying over anhydrous magnesium sulfate, the solvent was
removed to give the desired product (1.3 g, 94%) as an oil. This
material was subjected to the next reaction without further
purification.
C. Com p ou n d 43. The reaction mixture containing 42 (0.5
g, 1.1 mmol) in acetonitrile (2 mL) was treated with ethyl
oxalyl chloride (0.19 g, 1.4 mmol) followed by 4-(dimethylami-
no)pyridine (20 mg). The reaction mixture was stirred at room
temperature for 4 h, diluted with ethyl acetate, and washed
with 10% hydrochloric acid, sodium bicarbonate solution, and
brine. After drying over anhydrous magnesium sulfate, the
solvent was removed to give an oil which was used in the next
step without purification.
D. (3R)-tr a n s-[N-(6-Cya n o-3,4-d ih yd r o-3-h yd r oxy-2,2-
d im eth yl-2H-1-ben zop yr a n -4-yl)-N-(4-flu or op h en yl)a m i-
n o]oxoa cetic Acid , Eth yl Ester (23). To a solution of 43
(0.5 g, 0.88 mmol) in dichloromethane (2 mL) was added
trifluoroacetic acid (2 mL), and the reaction mixture was
stirred at room temperature for 3 h. The solvent was
evaporated, and the residue in ethyl acetate was washed with
saturated sodium bicarbonate solution, water, and brine. After
drying over anhydrous magnesium sulfate, the solvent was
removed and the residue was purified by flash chromatography
on silica gel (hexanes/ethyl acetate, 1:1) to give an oil (0.2 g,
55%). Trituration with hexanes-ether provided the desired
product as a colorless solid: 1H NMR (CDCl3) δ 7.61 (s, 1H),
7.43 (dd, J ) 1.0, 8.2 Hz, 1H), 7.10-6.92 (m, 4H), 6.80 (d, J )
8.2 Hz, 1H), 5.67 (s, 1H), 3.98 (m, 2H), 3.52 (m, 2H), 1.38, 1.22
(s, 3H each); 13C NMR (CDCl3) 165.0, 162.7, 158.1, 134.3, 133.1,
132.3, 132.1, 122.2, 119.9, 117.6, 117.3, 105.4, 81.1, 70.5, 63.1,
27.3, 19.4, 14.5.
(3R)-tr a n s-3,4-Dih yd r o-3-h yd r oxy-2,2-d im et h yl-4-[N-
[(3-m eth yl-1,2,4-oxa d ia zol-5-yl)m eth yl]p h en yla m in o]-2H-
1-ben zop yr a n -6-ca r bon itr ile (26). A solution of N-hydroxy-
acetamidine (0.16 g, 2.1 mmol) in dry tetrahydofuran (3 mL)
under argon was treated with sodium hydride (50%, 0.053 g,
2.2 mmol) and 4 Å molecular sieves (1.8 g) and heated at 50
°C for 1 h. A solution of compound 6 (0.4 g, 1.0 mmol) in
tetrahydrofuran (1 mL) was added, and the reaction mixture
was heated at 50 °C for 4 h. The reaction mixture was cooled
to ambient temperature, diluted with dichloromethane (150
mL), and washed with water. After drying over anhydrous
magnesium sulfate, the solvent was evaporated and the
residue was purified by flash chromatography on silica gel
(hexanes/ethyl acetate, 7:3) to give a colorless solid (0.25 g,
61%): 1H NMR (CDCl3) δ 7.40 (d, J ) 10.0 Hz, 1H), 7.30 (s,
1H), 7.18 (m, 2H), 6.75-6.85 (m, 4H), 5.54 (d, J ) 3.0 Hz, 1H),
5.03 (s, 1H), 4.65 (d, J ) 18.1 Hz, 1H), 4.17 (s, 1H), 3.65 (s,
1H), 2.3 (s, 3H), 1.51 and 1.33 (s, 3H each); 13C NMR (CDCl3)
179.0, 166.9, 158.1, 133.3, 131.8, 129.9, 122.3, 119.6, 119.0,
118.7, 113.1, 104.1, 80.7, 70.6, 27.3, 19.5, 11.5.
B. (3R)-tr a n s-3,4-Dih yd r o-3-h yd r oxy-2,2-d im eth yl-4-
[N-(2-oxa zolylm eth yl)p h en yla m in o]-2H-1-ben zop yr a n -6-
ca r bon itr ile (27). The reaction mixture containing 44 (610
mg, 1.40 mmol) in THF (5 mL) was treated with 6 N
hydrochloric acid (5 mL) and stirred at room temperature until
completion. The solution was diluted with diethyl ether (100
mL), washed with water (until the pH was 6.5-7) and brine,
and dried over MgSO4. The solvent was removed, and the
residue was immediately dissolved in dichloromethane (5 mL)
and treated with
a freshly prepared solution containing
triphenylphosphine (371 mg, 1.414 mmol), iodine (355 mg, 1.40
mmol), and triethylamine (0.4 mL). The dark brown reaction
mixture was stirred at room temperature for 30 min, diluted
with diethyl ether (50 mL), and washed with water, 5% sodium
bisulfite, and brine. After drying over anhydrous MgSO4, the
solvent was removed to give a white foam which was purified
by flash chromatography on silica gel (12% EtOAc in hexanes)
to give a colorless solid (44 mg, 10%): 1H NMR (CDCl3, 55
°C): δ 7.66 (s, 1H), 7.45 (dd, J ) 2.1, 8.4 Hz, 1H), 7.41 (s, 1H),
7.26-7.20 (m, 2H), 7.07 (s, 1H), 6.90 (d, J ) 9.0 Hz, 1H), 6.84-
6.80 (m, 3H), 5.10 (d, J ) 9.7 Hz, 1H), 4.63 (d, J ) 18.2 Hz,
1H), 4.22 (d, J ) 18.2 Hz, 1H), 3.79 (d, J ) 9.9 Hz, 1H), 1.6,
1.43 (s, 3H each); 13C NMR (CDCl3, 60 °C) 163.7, 158.1, 139.1,
132.89, 131.7, 129.5 (2C), 126.8, 123.0, 119.0, 118.8, 118.4,
113.2, 104.1, 80.7, 70.5, 59.5, 44.1, 27.2, 19.4.
Biologica l Assa ys. EC25 values for increasing time to
contracture were determined in isolated perfused globally
ischemic rat hearts. Compounds were initially evaluated at
10 µM concentration. Those demonstrating greater than 25%
increase in time to the onset of contracture were subjected to
concentration-response studies to determine EC25 values. To
compare the antiischemic and peripheral vasodilator potencies,
we determined IC50 values for relaxation of the methoxamine-
contracted rat aorta. Experimental details of both methods
are described.18
For pharmacokinetic studies, the hydrochloride salt of 3 (30
µmol/kg) was administered to male rats as a solution (total
volume: 0.75 mL for both routes) in ethanol:poly(ethylene
glycol)-400:water (2:3:5). Rats were dosed either intravenously
(N ) 4) by injection into the jugular vein or orally (N ) 4) by
gavage. Serial blood samples were obtained at 0, 5, 10, 20,
and 40 min and at 1, 2, 4, 6, 8, 12, 24, and 28 h after dosing.
Plasma was prepared from each blood sample by centrifugation
and analyzed by a specific LC/MS method for compound 3.
Pharmacokinetic parameters were calculated with standard
model-independent methods. Areas under the curve (AUC)
were calculated using Language integration and extrapolated
to infinity with the iv elimination half-life. The systemic oral
bioavailability was estimated by dividing the mean AUC0f∞
value for the oral doses by the mean AUC0f∞ value for the
intravenous doses.
Refer en ces
(1) 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.
(2) 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.
(3) Grover, G. J .; Sleph, P. G.; Dzwonczyk, S. Pharmacological
Profile of Cromakalim in the treatment of Myocardial Ischemia
in isolated rat Hearts and Anesthetized Dogs. J . Cardiovasc.
Pharmacol. 1990, 16, 853-864.
(4) (a) Grover, G. J .; Dzwonczyk, S.; Parham, C. S.; Sleph, P. G.
The Protective Effects of Cromakalim and Pinacidil on Reper-
fusion Function and Infarct Size in Isolated Perfused Rat Hearts
and Anesthetized Dogs. Cardiovasc. Drugs Ther. 1990, 4, 465-
474. (b) Grover, G. J . Protective Effects of ATP Sensitive
Potassium Channel Openers in Models of Myocardial Ischaemia.
Cardiovasc. Res. 1994, 28, 778-782.
(5) Chi, L.; Uprichard, A. C. G.; Lucchesi, B. R. Profibrillatory
Actions of Pinacidil in a Conscious Canine Model of Sudden
Coronary Death. J . Cardiovasc. Pharmacol. 1990, 15, 452-462.
(6) (a) Parratt, J . R.; Kane, K. A. KATP Channels in Ischemic
Preconditioning. Cardiovasc. Res. 1994, 28, 783-787. (b) Parratt,
J . R. Protection of the Heart by Ischemic Preconditioning:
Mechanism and Possibilities for Pharmacological Exploitation.
Trends Pharmacol. Sci. 1994, 15, 19-25.
(3R)-tr a n s-3,4-Dih yd r o-3-h yd r oxy-2,2-d im et h yl-4-[N-
(2-oxazolylm eth yl)ph en ylam in o]-2H-1-ben zopyr an -6-car -
bon itr ile (27). A. Com p ou n d 44. A solution of 6 (1.5 g,
3.94 mmol) in 2-aminoacetaldehyde dimethyl acetal (5 mL) was
heated under reflux for 16 h. The mixture was diluted with
ethyl acetate (100 mL), washed with 10% citric acid and brine,
and dried (MgSO4). The solvent was removed, and the residue
was purified by flash chromatography on silica gel (EtOAc/
hexane, 1:1) to give a white foam (1.66 g, 96%): 1H NMR
(CDCl3, 60 °C) δ 7.43 (d, J ) 7.7 Hz, 1H), 7.31-7.26 (m, 3H),
6.92-6.76 (m, 4H), 6.71 (br s, 1H), 5.03 (d, J ) 9.9 Hz, 1H),
4.95 (d, J ) 4.0 Hz, 1H), 4.38 (t, J ) 4.0 Hz, 1H), 3.99 (d, J )
18.1 Hz, 1H), 3.84-3.63 (m, 1H), 3.54 (d, J ) 18.5, 1H), 3.40
(s, 3H), 3.20 (dt, J ) 14.0, 4.2 Hz, 1H), 1.55, 1.37 (s, 3H each);
13C NMR (CDCl3, 60 °C) 171.5, 158.2, 145.5, 133.2, 132.1, 129.3
(2C), 122.90, 119.31, 118.6, 116.6, 113.2, 104.2, 102.9, 80.6,
70.2, 58.1, 55.1, 54.9, 40.3, 26.9, 19.0.

34 J ournal of Medicinal Chemistry, 1997, Vol. 40, No. 1
Rovnyak et al.
(7) (a) Gross, G. J .; Auchampach, J . A. Blockade of ATP-Sensitive
Potassium Channels Prevents Myocardial Preconditioning in
Dogs. Circ. Res. 1990, 70, 223-233. (b) Auchampach, J . A.;
Grover, G. J .; Gross, G. J . Blockade of Ischemic Preconditioning
in Dogs by the Novel ATP-dependent Potassium Channel
Antagonist Sodium 5-Hydroxydecanoate. Cardiovasc. Res. 1992,
26, 1054-1062. (c) Yao, Z.; Gross, G. J . The ATP-Dependent
Potassium Channel: An Endogenous Cardioprotective mecha-
nism. J . Cardiovasc. Pharmacol. 1994, 24, S28-S34. (d) Yao,
Z.; Mizumura, T.; Mei, D. A.; Gross, G. J . Activation of KATP-
(15) Ding, C. Z.; Miller, A. V. Synthesis of 4-(N-Alkyl-N-heterocyclo)-
amino-3,4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-
carbonitrile Derivatives via an Unusual 1,4-Oxygen to Nitrogen
Migration. Tetrahedron Lett. 1996, 37, 4447-4450.
(16) 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.
(17) 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.
(18) 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.
(19) 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; Modifica-
tion of the Cyanoguanidine Portion. J . Med. Chem. 1995, 38,
3236.
(20) Compounds resulting from scission of other indole bonds had
varying degrees of biological activity (unpublished results).
Compounds 5 had the best profile in terms of cardioprotective
potency and selectivity.
(21) 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.
(22) (a) Inagaki, N.; Gonoi, T.; Clement, J . P., IV; Namba, N.;
Inazawa, J .; Gonzalez, G.; Aguilar-Bryan, L.; Seino, S.; Bryan,
J . Reconstitution of IKATP: An Inward Rectifier Subunit plus the
Sulfonylurea Receptor. Science 1995, 270, 1166. (b) Al-Awqati,
Q. Regulation of Ion Channels by ABC Transporters that Secrete
ATP. Science 1995, 269, 805. (c) Philipson, L. H. ATP-Sensitive
K+ Channels: Paradigm Lost, Paradigm Regained. Science 1995,
270, 1159.
(23) Kano, S.; Ebata, T.; Shibuya, S. Formationb of 2,3-Dihydro-
4(1H)-quinolones and Related Compounds via Frie-type Acid-
catalyzed Rearrangement of 1-Arylazetidin-2-ones. J . Chem.
Soc., Perkin Trans. 1 1980, 2105-2111.
Channels May Play
a Role in the “Memory” of Ischemic
Preconditioning (PC) in Anesthetized Dogs. Circulation 1994,
90 (4 Part 2), I108.
(8) Tomai, F.; Crea, F.; Gaspardone, A.; Versaci, F.; De Paulis, R.;
Pentadepeppo, A.; Chiariello, L.; Gioffre, P. Ischemic Precondi-
tioning During Coronary Artery Angioplasty is Prevented by
Glybenclamide, a Selective ATP-Sensitive K+ channel Blocker.
Circulation 1994, 90, 700-705.
(9) Heurteaux, C.; Lauritzen, I.; Widmann, C.; Lazdunski, M. K+
Channel Openers Prevent Global Ischemia-Induced Expression
of c-fos, c-jun, Heat Shock Protein, and Amyloid â-Protein
Precursor Genes and Neoronal Death in Rat Hippocampus. Proc.
Natl. Acad. Sci. U.S.A. 1995, 92, 4666.
(10) 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.
(11) 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.
(12) (a) Ashwood, V. A.; Buckingham, R. E.; Cassidy, F.; Evans, J .
M.; Faruk, E. A.; Hamilton, T. C.; Nash, D. J .; Stemp, G.;
Willcock, K. Synthesis and Antihypertensive Activity of 4-(Cyclic
amido)-2H-1-benzopyrans. J . Med. Chem. 1986, 29, 2194-2201.
(b) Burrell, G.; Cassidy, F.; Evans, J . M.; Lightowler, D.; Stemp,
G. Variation in the Aromatic Ring of Cromakalim: Antihyper-
tensive Activity of Pyranopyridines and 6-Alkyl-2H-1-benzopy-
rans. J . Med. Chem. 1990, 33, 3023-3027. (c) Arch, J . R. S.;
Buckle, D. R.; Carey, C.; P.-Dobrzanski, H.; Faller, A.; Foster,
K. A.; H.-Frydrych, C. S. V.; Pinto, I. L.; Smith, D. G.; Taylor,
S. G. Relaxant Activity of 6-Cyano-2,2-dimethyl-2H-1-benzopy-
ran-4-carboxamides and -thiocarboxamides and Their Analogs
in Guinea Pig Trachealis. J . Med. Chem. 1991, 34, 2588-2594.
(d) For the synthesis of chiral epoxide 32, see: Lee, N. H.; Muci,
A. R.; J acobsen, E. R. Enantiomerically Pure Epoxychromans
via Asymmetric Catalysis. Tetrahedron Lett. 1991, 32, 5055.
(13) Chini, M.; Crotti, P.; Macchia, F. Metal Salts as New Catalysts
for Mild and Efficient Aminolysis of Oxiranes. Tetrahedron Lett.
1990, 31, 4661-4664.
(24) Pei, Y.; Wickham, B. O. S. Regiospecific Synthesis of 3-Ami-
nomethyl-5-substituted Isoxazoles: A Facile and Chemoselective
Reduction of Azide to Amine by Sodium Borohydride Using 1,3-
Propanedithiol as a Catalyst. Tetrahedron Lett. 1993, 34, 7509-
7512.
(25) Ha, H.; Nam, G.; Park, K. A Facile Synthesis of N-Arylamino-
methyl Phosphonate. Tetrahedron Lett. 1990, 31, 1567-1568.
(14) Iqbal, J .; Pandey, A. An Unusual Chemoselectivity in Cobalt (II)
chloride catalyzed Cleavage of Oxiranes with Anilines: A Highly
Regioselective Synthesis of â-Amino Alcohols. Tetrahedron Lett.
1990, 31, 575-576.
J M9605905