Synthesis and structure-activity relationships of a novel series of 2,3,5,6,7,9-hexahydrothieno[3,2-b]quinoline-8(4H)-one 1,1-dioxide K ATP channel openers: Discovery of (-)-(9S)-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-b] quinolin-8(4H)-one 1,1-dioxide (A-278637), a potent KATP opener that selectively inhibits spontaneous bladder contractions

Article abstract of DOI:10.1021/jm030356w

Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-containing K_ATP openers. Ring sizes, absolute stereochemistry, and aromatic substitution were evaluated for K _ATP activity in guinea pig bladder cells using a fluorescence-based membrane potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder contractions in vitro was also examined for a select group of compounds. All compounds studied showed greater potency to inhibit spontaneous bladder contractions relative to their potencies to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than 1 in vivo and supports the concept that bladder-selective K_ATP channel openers may have utility in the treatment of overactive bladder.

Full text of DOI:10.1021/jm030356w

J . Med. Chem. 2004, 47, 3163-3179
3163
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of a Novel Ser ies of
2,3,5,6,7,9-Hexa h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e KATP Ch a n n el
Op en er s: Discover y of (-)-(9S)-9-(3-Br om o-4-flu or op h en yl)-2,3,5,6,7,9-
h exa h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (A-278637), a P oten t KATP
Op en er Th a t Selectively In h ibits Sp on ta n eou s Bla d d er Con tr a ction s
William A. Carroll,* Robert J . Altenbach, Hao Bai, J orge D. Brioni, Michael E. Brune, Steven A. Buckner,
Christopher Cassidy, Yiyuan Chen, Michael J . Coghlan, Anthony V. Daza, Irene Drizin, Thomas A. Fey,
Michael Fitzgerald, Murali Gopalakrishnan, Robert J . Gregg, Rodger F. Henry, Mark W. Holladay,
Linda L. King, Michael E. Kort, Philip R. Kym, Ivan Milicic, Rui Tang, Sean C. Turner, Kristi L. Whiteaker,
Lin Yi, Henry Zhang, and J ames P. Sullivan
Abbott Laboratories, Neuroscience Research, Global Pharmaceutical Research and Development,
Abbott Park, Illinois 60064-6101
Received J uly 24, 2003
Structure-activity relationships were investigated on a novel series of sulfonyldihydropyridine-
containing KATP openers. Ring sizes, absolute stereochemistry, and aromatic substitution were
evaluated for KATP activity in guinea pig bladder cells using a fluorescence-based membrane
potential assay and in a pig bladder strip assay. The inhibition of spontaneous bladder
contractions in vitro was also examined for a select group of compounds. All compounds studied
showed greater potency to inhibit spontaneous bladder contractions relative to their potencies
to inhibit contractions elicited by electrical stimulation. In an anesthetized pig model of
myogenic bladder overactivity, compound 14 and (-)-cromakalim 1 were found to inhibit
spontaneous bladder contractions in vivo at plasma concentrations lower than those that affected
hemodynamic parameters. Compound 14 showed approximately 5-fold greater selectivity than
1 in vivo and supports the concept that bladder-selective KATP channel openers may have utility
in the treatment of overactive bladder.
In tr od u ction
Overactive bladder (OAB) is defined by the occurrence
of spontaneous detrusor contractions during bladder
filling.1 Clinically, OAB is manifested by the symptoms
of urgency, frequency, and incontinent episodes. The
origin of spontaneous contractions has been linked to
the hyperexcitability of diseased bladder smooth muscle
cells.1-4 Whereas normal human micturition is pri-
marily mediated by the parasympathetic nervous sys-
tem, there is evidence that diseased bladder contractile
activity has both cholinergic and noncholinergic compo-
nents.5-7 Thus, evidence showing efficacy of anticholin-
ergic drugs against urodynamically proven involuntary
contractions is limited.2,7,8 Ideally, pharmacotherapy for
OAB would suppress disease-related bladder contrac-
F igu r e 1. KATP Opener Standards.
tions while leaving normal voiding function intact, since
excessive inhibition of the latter could lead to undesir-
able urinary retention.
Due to the ability of KATP channel openers9 to dampen
smooth muscle excitability by lowering cellular mem-
brane potential and inhibiting calcium influx, there has
been considerable interest in exploring KATP openers as
therapeutic agents in the treatment of OAB.3,10 Cro-
makalim (1) (Figure 1) entered a small pilot trial for
OAB where promising results were seen; however, its
further development was terminated due to unspecified
animal toxicity in long-term studies.11 Although defini-
tive clinical data is lacking, it is a widely held notion
that 1 possesses insufficient bladder selectivity relative
to its KATP-mediated cardiovascular (CV) effects to be
useful for OAB. Since KATP channel openers relax both
bladder and vascular smooth muscle, the primary
objective of recent efforts in this area has been the
identification of KATP openers with improved bladder/
CV selectivity.
The more recent KATP openers ZD6169 (2), ZM244085
(4), and WAY-133537 (5) have been reported to possess
varying degrees of bladder selectivity on oral dosing in
rat and dog models12-16 Interestingly, none of these
* Address for correspondence: Abbott Laboratories, Neuroscience
Research, R4PM, AP10, 100 Abbott Park Road, Abbott Park, IL
60064-6101. Tel: (847)-938-6041. Fax: (847)-935-5466. E-mail:
william.a.carroll@abbott.com.
10.1021/jm030356w CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/04/2004

3164 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
Sch em e 1a
F igu r e 2.
agents has demonstrated any intrinsic selectivity for
bladder over cardiovascular tissues in vitro. Although
ancillary pharmacology17 and pharmacokinetic consid-
erations15 on oral dosing have emerged as potential
explanations, the true basis for the reported in vivo
selectivities of these agents remains to be completely
elucidated.
a
Conditions: (i) EtOH, 80 °C; (ii) EtOH, Et3N, 80 °C; (iii) HCl,
EtOH, 80 °C.
Sch em e 2a
The reported bladder-selective actions of 4 make it
an attractive lead from which to design novel KATP
openers. Compared to the benzopyran class of KATP
opener like 1,18,19 far less is known about what struc-
tural features influence the KATP activity of acridinedi-
ones such as 4. It has been reported that optimal
potency in this series is achieved with meta and para
disubstitution of electron-withdrawing groups or halo-
gens on the aromatic ring.20 Monosubstitution in the
meta or para positions does retain KATP opening activity,
however with reduced potency. Surprisingly, little ad-
ditional SAR information has appeared on this ring
system, despite the exhaustive studies that have been
carried out on structurally related dihydropyridine
calcium channel antagonists. We were interested there-
fore in investigating the KATP opening activity of novel
ring systems containing the dihydropyridine nucleus
imbedded within. It had previously been shown in SAR
studies around 2 that replacement of the benzophenone
carbonyl by a sulfonyl group resulted in an improvement
in KATP potency in vitro.13 As a starting point for our
own SAR studies, this switch was applied to the
acridinedione system of 4 (Figure 2). Indeed, the
3,4,6,7,8,10-hexahydro-2H-thiopyrano[3,2-b]quinolin-
9(5H)-one 1,1-dioxide ring system (compound 6) was
found to possess potent in vitro KATP opening activity
a
Conditions: (i) NH3, EtOH, 80 °C; (ii) NH3, EtOH, 80 °C;
toluene 110 °C; (iii) HCl, EtOH, 80 °C.
under conditions of heating in ethanol. In the cases
where n ) 1 and p ) 2, this reaction was complicated
by the formation of up to 10% of the corresponding
acridinedione as an impurity. Addition of triethylamine
to the reaction mixture suppressed the formation of the
acridinedione impurity and allowed isolation of an
intermediate hemiaminal 9. For other ring sizes, vary-
ing amounts of the hemiaminal intermediate were
observed either with or without added triethylamine.
Dehydration of the hemiaminal was accomplished by
heating in the presence of acid.
Synthesis of the symmetrical tricyclic bis-sulfones was
carried out in a similar fashion with the exception that
2 equiv of 7 was heated with the aldehyde and ammonia
in the Hantzsch reaction (Scheme 2). Where n ) 1, an
intermediate hemiaminal 10 was produced that could
be dehydrated with acid treatment. Where n ) 2,
Hantzsch conditions similar to those above provided a
complex reaction mixture that appeared to consist of the
desired product plus other double bond isomers. The
appearance of such double bond regioisomers has previ-
ously been observed in the Hantzsch reaction with
larger ring ketosulfones.21 Fortunately, simply heating
the crude reaction product in toluene was sufficient to
convert all the reaction constituents to the desired
product.
in guinea pig bladder smooth muscle cells (pEC50
)
6.42), when substituted by a 3-bromo-4-fluorophenyl
in the 10 position. In this paper, we describe extensive
SAR investigations around the core ring system exam-
ining ring size effects, ring-opening effects, stereochem-
istry, and aromatic ring substitution. In addition,
several compounds were profiled for effects on sponta-
neous versus electrically stimulated bladder contrac-
tions.(-)-(9S)-9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexa-
hydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (14,
A-278637) and 1 were further examined for their ability
to inhibit spontaneous contractions in vivo in the pig.
The results of these studies have led us to offer an
hypothesis for the bladder-selective actions of KATP
openers observed in animal studies.
The above-described methods were also used for the
preparation of most of the bicyclic analogues investi-
gated (see the Experimental Section for details). The
trifluoromethyl-substituted analogue 38, however, was
synthesized in a stepwise manner starting with the
aldol condensation of trifluoroacetone with 3-bromo-4-
fluorobenzaldehyde followed by condensation of the
resultant enone 35 with 3-oxotetrahydrothiophene 1,1-
dioxide 36 and ammonia (Scheme 3). Two diastereo-
Ch em istr y
Unsymmetrical tricyclic analogues were assembled
using the modified Hantzsch reaction of Scheme 1,
wherein a cyclic ketosulfone 7 was condensed with a
3-amino-2-cycloalken-1-one 8 and an aromatic aldehyde

Sulfonyldihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3165
Sch em e 3a
by HPLC invariably possessed a negative rotation and
was assigned the (S)-stereochemistry.
Biologica l Assa ys
Gu in ea P ig Bla d d er (GP B) Assa y.22 Membrane
potential changes elicited by test compounds were
measured using a fluorometric imaging plate reader
(FLIPR). Dose-response curves were generated for
changes in fluorescence with the membrane potential
sensitive dye DiBAC4(3). Potencies are expressed as the
negative logarithm of the EC50 (pEC50), and efficacies
were determined relative to the standard P1075 (3).
F ield -Stim u la ted La n d r a ce P ig Detr u sor (F S-
LP D) Assa y.23 Compounds were evaluated for bladder
KATP activity using tissue strips from Landrace pig
bladders. Low-frequency stimulation (0.05 Hz, 0.5 ms
at 20 V) produced a stable twitch response, the ampli-
tude of which was reduced by increasing concentrations
of test agents. These field-stimulated contractions have
both cholinergic and noncholinergic components and are
partially sensitive to muscarinic blockers such as toltero-
dine.
a
Conditions: (i) NH3, EtOH, reflux; (ii) p-TsOH, toluene, reflux.
Sch em e 4a
a
Conditions: (i) Bu3SnR, Pd(PPh3)4, DMF, 110 °C.
Sch em e 5a
Sp on t a n eou s La n d r a ce P ig Det r u sor (SLP D)
Assa y.24 Spontaneously contracting bladder strips were
obtained from the area closer to the trigonal region of
the bladder in Landrace pigs. The reduction of the area
under the curve (AUC) by increasing concentrations of
test agents was measured. These spontaneous contrac-
tions are purely of myogenic origin, have no cholinergic
component, and thus are insensitive to the effects of
muscarinic blockers such as tolterodine.
a
Conditions: (i) (-)-8-phenylmenthylchloroformate, KtOBu,
THF; (ii) silica gel chromatography; (iii) NaOMe, MeOH.
Concentration-response curves were generated for
each agent with the potency expressed as the pEC50.
Confirmation of a KATP mechanism was demonstrated
for all compounds by reversal of the bladder relaxant
effect following addition of glyburide at the end of each
experiment. In both tissue strip models, the test com-
pounds were fully efficacious when compared to the
control 3. Because of the different sensitivities of the
two assays to muscarinic antagonists, each may model
bladder overactivity of distinct etiology.
Obstr u cted P ig Ur od yn a m ics.25 Compounds were
tested in vivo in a disease model of overactive bladder.
Female Landrace/Yorkshire swine (∼12 weeks old; 14-
20 kg) were obstructed with a 7.5 mm silver omega ring
placed around the proximal urethra. Seventeen to 20
weeks later, the pigs were instrumented with telemetry
transducer/transmitters for the measurement of carotid
arterial pressure and intravesical (bladder) pressure.
Animals were allowed to recover for 10-14 days before
testing.
For urodynamic testing, pigs were anesthetized with
telazol/xylazine, intubated, and maintained on isoflu-
rane/oxygen in the supine position. Anesthesia level and
bladder volume were adjusted to establish a regular
pattern of unstable bladder contractions. The isoflurane/
oxygen mixture inhibits normal parasympathetically
mediated voiding contractions but not disease-related
spontaneous contractions of myogenic origin. The anti-
cholinergic tolterodine is not efficacious in this model.
After a 30 min baseline data acquisition period, two
increasing doses of test compounds were administered
intravenously (3 min infusion) at 30 min intervals.26
Blood samples were obtained from the opposite ear at
meric hemiaminals 37 were isolated and subjected to
dehydration with p-TsOH to obtain the final product 38.
A number of novel aromatic ring substituents were
introduced using palladium-mediated coupling reactions
on the Boc-protected intermediate 39 or the correspond-
ing (S)-enantiomer (Scheme 4). Typical conditions for
effecting this transformation consisted of heating 39
with an organostannane reagent in DMF to 110 °C in
the presence of Pd(PPh3)4. The Boc protecting group was
also removed by the conditions of the coupling reaction.
Single enantiomers of the target compounds were
prepared by two different methods: (i) resolution with
a chiral auxiliary (Scheme 5) or (ii) preparative chiral
HPLC. Several different chiral auxiliaries, attached at
the dihydropyridine nitrogen, were investigated, but
chromatographically separable diastereomers were ob-
tained only through the carbamates of commercially
available (-)-8-phenylmenthol. Once the diastereomers
were separated, the carbamate group was cleaved with
catalytic NaOMe in MeOH to provide the single enan-
tiomer. Chiral chromatographic separation of the enan-
tiomers was accomplished using Regis (R,R)-Whelk-O1
or Whelk-O2 columns. Although both methods were
comparable with regard to the enantiomeric purity
achievable, the HPLC method proved more efficient
than the auxiliary method in terms of substrate gener-
ality and scalability. The absolute stereochemistries
were determined for several different ring systems by
X-ray crystal analysis. The stereochemistries of ana-
logues with simple variations of the aromatic ring
substitution (Table 5) were assigned on the basis of
rotation and/or elution order in analogy with compounds
13 and 14. In this ring system, the less polar enantiomer

3166 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
15 min after each dose for subsequent determination of
plasma concentrations by liquid chromatography/mass
spectroscopy. Bladder contraction AUC was averaged
over each 30 min postdosing period and expressed as
percent change from baseline. From the concentration-
response relationship, an EC50 to inhibit bladder con-
tractions was determined.
Con sciou s P ig Hem odyn am ics. For conscious mean
arterial pressure (MAP) and heart rate (HR) evaluation,
pigs obstructed and telemeterized as described above
were placed into a stainless steel restraint cage, and
20 gauge venous catheters were placed in both ears to
provide vascular access for dosing and blood sampling.
Drug administration and plasma sampling were con-
ducted as above. Arterial pressure and heart rate data
were averaged in 5 min bins for each 30 min postdosing
period and expressed as percent change from baseline.
essentially equivalent to the most potent tricyclic com-
pounds. The KATP opening activity of 30 was somewhat
surprising, since ester groups are more known for
imparting calcium channel blocking activity. However,
this result was not totally unexpected, since the pre-
ferred aromatic ring substitution patterns for Ca2+
channel blocking (ortho and/or meta)27 and KATP opening
(meta and/or para) activities were known to be diver-
gent. Increasing the size of the ester to ethyl, however,
did diminish the potency by 10-fold (31). Replacement
of the methyl by CF3 in the case of the ethyl ester served
to reduce the potency still further (32). The carboxylic
acid analogue 33 also showed weak potency relative to
the esters. Interestingly, removal of the ester group with
retention of the CF3 in the 2-position increased the
potency significantly (38).
Using the tricyclic core of compound 14, extensive
SAR investigations were conducted on the aromatic ring
substitution (Table 4). At the meta position, a clear
preference was found for the larger halogens. Groups
such as 3-CF3 (55), 3-NO2 (49), 3-CN (53), and 3-(2-furyl)
(60) were similar to 3-Cl, whereas other substituents
such as 3-F (43, 52), 3-Me (54), 3-MeS (56), 3-MeSO2
(57), 3-acetyl (58), and 3-vinyl (59) were less potent.
Aromatic groups other than 2-furyl attached at the
3-position were essentially inactive up to 10 µM (61-
63). At the para position the following substituents gave
very comparable potencies: F, Me, Cl, Br, CF3. A larger
alkyl group like Et was less well tolerated (50). The
benzoxadiazole (64) was found to be a suitable replace-
ment for a 3,4-dichlorophenyl group; however, the
benzothiadiazole 65 was substantially less active. Sur-
prisingly, addition of an ortho hydroxy group as in
examples 66 and 67 did not reduce potency relative to
the des-hydroxy analogues. These are the first examples
of substitution in a position other than meta or para
providing KATP opening activity. These are also the first
examples of active dihydropyridine analogues possess-
ing an electron-donating group on the aromatic ring.
Chain extension of the hydroxyl to a benzylic alcohol
(68), however, resulted in a complete loss in activity.
In agreement with the previous literature, the mono-
substituted analogues 69-71 were significantly less
active. Parallel synthesis techniques were used to
prepare 130 additional aromatic substitutions from
diverse commercially available aromatic aldehydes.
With the exception of the discovery of the novel 2-OH
5-Br substitution, this exercise served to confirm earlier
findings that electron-donating groups and substitution
patterns other than those already discussed eliminate
KATP activity. Heterocyclic aromatic replacements for
the substituted phenyl were also investigated (Table 5).
In general these gave disappointing results. Unsubsti-
tuted pyridines, thiophenes, and furans all showed poor
activity (data not shown). With the exception of example
75 (potency similar to the carbocylic analogue 69), none
of the substituted pyridines possessed a pEC50 greater
than 5. Substitution with either bromo or nitro on either
thiophene regioisomer improved activity relative to 61
as anticipated (76-79).20
Resu lts a n d Discu ssion
In Vitr o KATP SAR. SAR investigations around
compound 6 first focused on ring size effects and
stereochemistry, and the data are summarized in Table
1. In three of the four pairs of enantiomers, one
enantiomer possessed at least 10-fold greater potency
than the antipode. In two of these three cases, the more
potent analogue had the (R)-stereochemistry (11 and
15). For the third case, a suitable crystal was not
obtained for X-ray analysis; however, the more active
enantiomer 17 displayed the same sign of rotation as
compound 15, the other analogue containing a six-
membered ring sulfone. For 13 and 14, the difference
in potency between the enantiomers was only 3-fold,
presumably due to the pseudosymmetrical nature of
these compounds where the five-membered sulfur-
containing ring and the six-membered carbocyclic ring
have similar steric properties. Among the analogues
with the (R)-configuration, there were no major differ-
ences in potency in GPB, although there appeared to
be some preference for the five-membered sulfone ring
analogues 11 and 13 in FSLPD. Compounds 11 and 13
are highly potent KATP openers, essentially equivalent
with the standard 3. Larger ring sizes such as in
examples 19 and 20 markedly reduced the potency. Of
the two symmetrical bis-sulfone analogues 21 and 22,
the five-membered rings provided the greater potency.
Both 21 and 22, however, were less potent than the
most potent unsymmetrical analogues in Table 1,
indicating that the sulfonyl and carbonyl groups are not
totally interchangeable.
Dimethyl substitution was investigated on the car-
bocyclic ring of the 2,3,5,6,7,9-hexahydrothieno[3,2-b]-
quinolin-8(4H)-one 1,1-dioxide ring system (Table 2).
The gem-dimethyl group adjacent to the dihydropyridine
nitrogen (5-position) reduced the potency for both enan-
tiomers (23 and 24), with the (S)-enantiomer being the
more potent of the two. On the other hand, substitution
adjacent to the carbonyl at the 7-position had little effect
on potency (27 and 28) in GPB; however, the potency
was significantly reduced in FSLPD. Installation of the
gem-dimethyl at the 6-position greatly attenuated po-
tency (25 and 26).
In Vitr o a n d in Vivo Selectivity. Compounds 13,
14, 1, 2, 5, and 3 were evaluated for KATP opening
activity in vitro in both spontaneously contracting
(SLPD) and electrically stimulated (FSLPD) pig bladder
A number of bicyclic variations of the core structure
were investigated (Table 3). The cyano 29 and methyl
ester 30 analogues proved to be the most potent,

Sulfonyldihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3167
Ta ble 1
a
b
d
GPB ) guinea pig bladder cells. FSLPD ) field-stimulated Landrace pig detrusor strips. c Number of determinations ) 2. Number
of determinations g 3. e Standard deviation in parentheses. f Number of determinations g 4; standard error shown. NT ) not tested.
strips (Table 6). All of the compounds displayed greater
tractions than to inhibit those elicited by electrical
potency (5-10-fold) to relax spontaneous bladder con-
stimulation. Both 13 and 14 were more potent than 1,

3168 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
Ta ble 2
Ta ble 4
pEC50
compd
R
stereochem
GPBa,e
FSLPDb,f
23
24
25
26
27
28
5,5-diMe
5,5-diMe
6,6-diMe
6,6-diMe
7,7-diMe
7,7-diMe
R
S
R
S
R
S
<5c
NT
5.57 ( 0.18
NT
NT
6.01 ( 0.07
5.25 ( 0.12
6.20(0.09)c
4.75(0.36)c
5.15(0.01)c
6.97(0.30)d
7.08(0.32)d
a
b
GPB ) guinea pig bladder cells. FSLPD ) field-stimulated
Landrace pig detrusor strips. c Number of determinations ) 2.
Number of determinations g 3. e Standard deviation in paren-
d
theses. f Number of determinations g 4; standard error shown.
NT ) not tested.
Ta ble 3
pEC50
compd
n
R1
R2
CN
CO2Me
CO2Et
CO2Et
CO2H
COMe
H
GPBa,e
FSLPDb,f
29
30
31
32
33
34
38
1
1
1
1
1
2
1
Me
Me
Me
CF3
Me
Me
CF3
7.56(0.24)d
7.27(0.20)d
6.30(0.32)d
<5d
NT
NT
NT
NT
5.74(0.20)d
6.67(0.17)c
6.35(0.19)c
5.06 ( 0.21
6.10 ( 0.13
5.65 ( 0.29
a
b
GPB ) guinea pig bladder cells. FSLPD ) field-stimulated
Landrace pig detrusor strips. c Number of determinations ) 2.
Number of determinations g 3. e Standard deviation in paren-
d
theses. f Number of determinations g 4; standard error shown.
NT ) not tested.
2, and 5. The in vitro selectivity for spontaneous
contractions may be relevant to potential clinical selec-
tivity for diseased bladder contractions of purely myo-
genic origin.
Since 14 showed the most selectivity to inhibit
spontaneous contractions in vitro, it was chosen for
evaluation in the obstructed pig assay, and its properties
were compared to those of 1 (Figure 3). The pig was
employed as the anatomy, physiology, and pharmacol-
ogy of the lower urinary tract are considered similar to
humans.28 Both compounds inhibited spontaneous blad-
der contractions in a dose- and concentration-dependent
fashion, while 14 showed greater potency than 1.
To assess selectivity for bladder versus cardiovascular
in vivo, the effects of 14 and 1 on MAP and HR were
evaluated and compared. Since the anesthesia isoflu-
rane is known to affect cardiovascular function and act
additively with KATP openers such as 1 to lower blood
pressure,29 MAP and HR were determined in conscious
pigs similar to those used for the measurement of
bladder function. Both compounds reduced MAP in a
dose- and concentration-dependent fashion over a simi-
a
b
GPB ) guinea pig bladder cells. FSLPD ) field-stimulated
Landrace pig detrusor strips. c Number of determinations ) 2.
Number of determinations g 3. e Standard deviation in paren-
d
theses. f Number of determinations g 4; standard error shown.
NT ) not tested. *racemate.

Sulfonyldihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3169
Ta ble 5
F igu r e 3. Reductions in AUC (area under the curve) and
MAP (mean arterial pressure) with ascending concentrations.
9, 14 AUC (doses: 3, 10 and 30 nmol/kg); 0, 14 MAP (doses:
1, 3, 10 and 30 nmol/kg); 2, 1 AUC (doses: 10 and 30 nmol/
kg); 4, 1 MAP (doses: 10, 30 and 100 nmol/kg). Plasma
concentrations are the average of 2-4 experiments. 14 AUC
EC50 ) 8 nM. (-)-1 AUC EC50 ) 39 nM.
Ta ble 7. Cardiovascular Effects of 14 and 1
compound 14
compound 1
plasma
concna
(nM)
plasma
concna
(nM)
%∆ MAPb %∆ HRc
%∆ MAPb %∆ HRc
1.9
24
95
-5.4 ( 2.8 6.2 ( 8.2
-6.9 ( 1.9 3.5 ( 8.6
12
44
167
-6.3 ( 0.5 13 ( 22
-12 ( 2.4 38 ( 10
-33 ( 8.4 47 ( 14
-27 ( 2.5
56 ( 14
a
b
Average plasma concentration (n ) 2-4). MAP ) mean
arterial pressure. Percent MAP change from baseline in mmHg
is shown. c HR ) heart rate. Percent HR change from baseline in
beats per minute is shown.
selectivity than 1 due to its approximately 5-fold greater
potency to reduce AUC and equivalent potency to affect
MAP (Figure 3). For 14, bladder AUC was reduced up
to 75% at plasma concentrations that were without
significant effects (<10%) on MAP in conscious pigs.
Since the compounds were administered intravenously
and the AUC and CV effects were measured over the
same time period, these results are less dependent on
pharmacokinetic considerations such as nonlinear ef-
fects that can occur on oral dosing.
a
b
GPB ) guinea pig bladder cells. FSLPD ) field-stimulated
Landrace pig detrusor strips. c Number of determinations ) 2.
Number of determinations g 3. e Standard deviation in paren-
d
theses. f Number of determinations g 4; standard error shown.
NT ) not tested.
Ta ble 6. In Vitro Bladder Relaxationa
pEC50
selectivity
compd
FSLPDa,c
SLPDb,c
SLPD:FSLPD
In what appears to be a general property of KATP
openers, all compounds examined in this study showed
selectivity for spontaneous over electrically stimulated
bladder contractions in vitro. Although in vivo selectiv-
ity for diseased versus normal bladder function was not
measured in this study, the in vitro selectivity for
spontaneous contractions suggests that this may be a
property of KATP openers. Similar to results from other
studies,13,15 all agents from Table 1 showed no absolute
selectivity in vitro against vascular tissue preparations
such as the rat aorta or portal vein31 (data not shown).
Nonetheless, the in vivo data suggests an inherent
selectivity of KATP openers for disease-related bladder
contractions as both 1 and 14 inhibited spontaneous
bladder contractions over concentration ranges that had
minimal effects on cardiovascular parameters. Com-
pound 14 displayed improved selectivity relative to 1;
however, it remains to be determined whether its
efficacy at nonhypotensive concentrations would trans-
late to symptom relief.
13
14
1
2
5
7.16 ( 0.09
6.63 ( 0.15
6.59 ( 0.19
5.56 ( 0.13
6.17 ( 0.13
7.07 ( 0.10
7.90 ( 0.11
7.64 ( 0.08
7.46 ( 0.20
6.53 ( 0.32
6.99 ( 0.06
7.66 ( 0.16
5.5
10
7.4
9.3
6.6
3.9
3
a
FSLPD ) field-stimulated Landrace pig detrusor strips.
SLPD ) spontaneous Landrace pig detrusor strips. c Number of
b
determinations g 4; standard error shown.
lar concentration range (Figure 3). Reflex HR increases
were observed for both compounds in parallel with the
reductions in MAP, although the magnitude of the HR
effects were considerably more variable (Table 7).
Importantly, the correlation of plasma concentration
with HR effects observed here is in accord with pub-
lished clinical results for 1.30
Both 14 and 1 inhibited spontaneous bladder contrac-
tions at plasma concentrations lower than those that
affected blood pressure. Compound 14 displayed greater

3170 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
(-)-(9R)-(3-Br om o-4-flu or op h en yl)-3,4,5,6,7,9-h exa h y-
d r ocyclop en ta [b]th iop yr a n o[2,3-e]p yr id in -8(2H)-on e 1,1-
Dioxid e (15) a n d (+)-(9S)-9-(3-Br om o-4-flu or op h en yl)-
3,4,5,6,7,9-h e x a h y d r o c y c lo p e n t a [b ]t h io p y r a n o [2,3-
e]p yr id in -8(2H)-on e 1,1-Dioxid e (16). A solution of dihydro-
2H-thiopyran-3(4H)-one 1,1-dioxide (888 mg, 6.00 mmol),
3-bromo-4-fluorobenzaldehyde (1.2 g, 6.0 mmol), and 3-ami-
nocyclopent-2-en-1-one (583 mg, 6.0 mmol) in EtOH (10 mL)
was heated to reflux for 72 h and cooled. The solid that
precipitated was collected, washed with EtOH, and dried to
provide 1.476 g of the racemic title compound as a white
solid: 1H NMR (DMSO-d6) δ 2.25 (m, 4H), 2.60 (m, 4H), 3.20
(m, 2H), 4.83 (s, 1H), 7.25 (m, 2H), 7.41 (dd, 1H), 9.96 (br s,
1H); MS (APCI) m/e 412 (M + H)+, 414 (M + H)+.
Con clu sion
In conclusion, these SAR studies have significantly
expanded the understanding of the dihydropyridine
pharmacophore as it relates to KATP opening activity.
Specifically, we examined the effects of absolute ster-
eochemistry, ring sizes, and novel aromatic substitu-
tions. The analogues 11 and 13 displayed equivalent
potency to the standard 3. We have also demonstrated
novel methods for the preparation of single enantiomers
in this structural class. In addition, we found that
compound 14 potently inhibited spontaneous bladder
contractions in the pig both in vitro and in vivo in
addition to demonstrating greater selectivity than 1.
Since the spontaneous contractions measured in this
study lack a cholinergic component, compound 14 may
have utility in the treatment of diseased bladder con-
tractions that are resistant to antimuscarinic drugs.
Meth od B. The racemic product from above (1.476 g, 3.58
mmol) as a slurry in THF (20 mL) under N2 at 5 °C was treated
dropwise with a solution of 1.0 M KOtBu in THF (3.9 mL),
allowed to warm to room temperature over 20 min, treated
with a solution of (-)-8-phenylmenthylchloroformate (1.17 g,
3.97 mmol) in THF (5 mL), stirred at room temperature
overnight, quenched in aqueous NaHCO3, extracted with Et2O
(2×). The organics were dried with Na2SO4 and filtered, and
solvent was evaporated to provide a mixture of diastereomeric
carbamates. This mixture was flash chromatographed over a
6 × 36 cm column of silica gel, eluting with Et2O:hexane (85/
15) to provide 746 mg of the less polar diastereomer. This
material, as a slurry in MeOH (10 mL) under N2, was treated
with catalytic NaOMe, stirred at room temperature for 24 h,
and treated with glacial AcOH (3 drops). The solid precipitate
was collected, washed with EtOH, and dried to provide 227
mg of compound 16 as a white solid (see Supporting Informa-
tion for X-ray structure report): [R]23D +63.9 (MeCN); 1H NMR
(DMSO-d6) δ 2.15-2.35 (m, 4H), 2.46-2.70 (m, 4H), 3.23 (m,
2H), 4.83 (s, 1H), 7.25 (m, 2H), 7.42 (dd, 1H), 9.96 (br s, 1H);
MS (APCI-) m/z 410 (M - H)-. Anal. (C17H15BrFNO3S) C, H,
N. From the chromatography of diastereomers described above
was obtained 824 mg of the impure more polar diastereomer.
This material was flash chromatographed over a 6 × 36 cm
column of silica gel, eluting with Et2O:hexane (9/1) to provide
695 mg of the more polar diastereomer. This diastereomer, as
a slurry in MeOH (10 mL) under N2, was treated with catalytic
NaOMe, stirred at room temperature for 5 d, and treated with
glacial AcOH (3 drops). The solid precipitate was collected,
washed with EtOH, and dried to provide 120 mg of the title
compound as a white solid. The filtrate was flash chromato-
graphed (5-15% EtOH/CH2Cl2) and the product triturated
with EtOAc to provide an additional 186 mg of compound 15.
[R]23D -60.8 (MeCN); 1H NMR (DMSO-d6) δ 2.15-2.30 (m, 4H),
2.47-2.70 (m, 4H), 3.20 (m, 2H), 4.83 (s, 1H), 7.25 (m, 2H),
7.41 (dd, 1H), 9.96 (br s, 1H); MS (APCI-) m/z 410 (M - H)-.
Anal. (C17H15BrFNO3S) C, H, N.
Exp er im en ta l Section
Ch em istr y. Gen er a l. Proton NMR spectra were obtained
on a General Electric QE 300 or QZ 300 MHz instrument with
chemical shifts (δ) reported relative to tetramethylsilane as
internal standard. Melting points were determined on a
Thomas-Hoover capillary melting point apparatus and are
uncorrected. Unless otherwise indicated in the individual
experimentals, melting points of final compounds were all
greater than 260 °C. Elemental analyses were performed by
Robertson Microlit Laboratories. Column chromatography was
carried out on silica gel 60 (230-400 mesh). Thin-layer
chromatography (TLC) was performed using 250 mm silica gel
60 glass-backed plates with F254 as indicator. HPLC separa-
tions were done using a Gilson system with a 215 liquid
handler and a UV detector. Optical rotations were measured
with a Perkin-Elmer 541 polarimeter. X-ray crystal structures
were obtained on a Bruker SMART system.
(+)-(9R)-9-(3-Br om o-4-flu or op h en yl)-2,3,5,6,7,9-h exa h y-
d r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (13) a n d
(-)-(9S )-9-(3-Br om o-4-flu or op h e n yl)-2,3,5,6,7,9-h e xa -
h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (14).
(Meth od A). A solution of dihydrothiophen-3(2H)-one 1,1-
dioxide (4.82 g, 36 mmol), 3-bromo-4-fluorobenzaldehyde (4.00
g, 36 mmol), Et3N (2.5 mL, 18 mmol), and 3-aminocyclohex-
2-en-1-one (7.67 g, 37.8 mmol) in EtOH (50 mL) was heated
to reflux for 72 h and cooled, and 11.6 g of the intermediate
hemiaminal was collected as a white precipitate. The precipi-
tate in EtOH (120 mL) was heated to reflux, treated with 1.0
M HCl/Et2O (2 mL), reacted for 15 min, and cooled, and the
solid precipitate was collected to provide 10.56 g of the racemic
title compound as a white solid: mp >260 °C; 1H NMR
(DMSO-d6) δ 1.88 (m, 2H), 2.23 (m, 2H), 2.56 (m, 2H), 2.83
(dtd, 1H), 3.03 (dt, 1H), 3.33 (t, 2H), 4.85 (s, 1H), 7.22 (m, 2H),
7.40 (dd, 1H), 9.78 (br s, 1H); MS (APCI) m/e 410 (M - H)-,
412 (M - H)-.
(-)-(9S )-(3,4-D ic h lo r o p h e n y l)-2,3,5,6,7,9-h e x a h y -
d r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (51). 3,4-
Dichlorobenzaldehyde (1.05 g, 6.00 mmol) was treated accord-
ing to method A to provide 1.72 g of the racemic title
compound: 1H NMR (DMSO-d6) δ 1.75-2.0 (m, 2H), 2.23 (m,
2H), 2.57 (m, 2H), 2.85 (dt, 1H), 3.03 (dt, 1H), 3.38 (m, 2H),
4.84 (s, 1H), 7.17 (dd, 1H), 7.35 (d, 1H), 7.50 (d, 1H), 9.85 (br
s, 1H); MS (APCI) m/e 384 (M + H)+.
Meth od C. The racemic title compound (1.65 g, 4.30 mmol)
as a slurry in THF (20 mL) under nitrogen at 5 °C was treated
dropwise with a solution of 1.0 M KOtBu in THF (3.9 mL),
allowed to warmed to room temperature over 20 min, treated
9-(3-Bromo-4-fluorophenyl)-2,3,5,6,7,9-hexahydrothieno[3,2-
b]quinolin-8(4H)-one 1,1-dioxide (0.50 g), obtained from method
A above, was chromatographed on a 5 × 25 cm Regis WhelkO
2 chiral column with 280 g of packing, eluting with hexane:
MeOH:CH2Cl2 (77.5/15/7.5) as the mobile phase with a flow
rate of 117 mL/min to provide 220 mg of compound 13 as the
more polar enantiomer, the absolute stereochemistry of which
was determined by X-ray crystal structure analysis (see
Supporting Information): [R]23 +50.24° (CH3CN); 1H NMR
with
a solution of (-)-8-phenylmenthylchloroformate (4.3
D
mmol) in THF (5 mL), stirred at room temperature overnight,
quenched in aqueous NaHCO3, and extracted with Et2O (3×).
The organics were dried (Na2SO4) and filtered, and solvent was
evaporated to provide a mixture of diastereomeric carbamates.
This mixture was flash chromatographed (2×) over a 6 × 40
cm column of silica gel, eluting with CHCl3:hexane:Et2O(7:2:
1) to provide 628 mg of the pure more polar diastereomer. This
diastereomer, as a slurry in MeOH (10 mL) under N2, was
treated with catalytic NaOMe, stirred at room temperature
overnight, and treated with glacial AcOH (2 drops). The solid
(DMSO-d6) δ 1.72-1.98 (m, 2H), 2.22 (m, 2H), 2.55 (m, 2H),
2.8 (m, 1H), 3.1 (m, 1H), 3.32 (m, 2H), 4.82 (s, 1H), 7.2 (m,
2H), 7.4 (m, 1H), 9.8 (s, 1H); MS (APCI+) m/z 414 (M + H)+.
Anal. (C17H15BrFNO3S) C, H, N. From the chiral chromatog-
raphy described above was obtained 210 mg of compound 14
as the less polar enantiomer: [R]23 -48.8 (CH3CN);1H NMR
D
(DMSO-d6) δ 1.72-1.98 (m, 2H), 2.22 (m, 2H), 2.52 (m, 2H),
2.8 (m, 1H), 3.1 (m, 1H), 3.31 (m, 2H), 4.82 (s, 1H), 7.2 (m,
2H), 7.4 (m, 1H), 9.8 (s, 1H); MS (APCI+) m/z 414 (M + H)+.
Anal. (C17H15BrFNO3S) C, H, N.

Sulfonyldihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3171
precipitate was collected, washed with EtOH, and dried to
the racemic title compound as a white solid. The filtrate was
evaporated to dryness, redissolved in EtOH, treated with 1.0
M HCl/Et2O (1.5 mL), heated to reflux for 2 h, and cooled. The
solid precipitate was collected, washed with EtOH, and dried
to provide an additional 548 mg of the racemic title com-
pound: mp >260 °C; 1H NMR (DMSO-d6) δ 1.75 (m, 1H), 1.90
(m, 1H), 2.20 (m, 4H), 2.55 (m, 4H), 3.20 (m, 2H), 5.01 (s, 1H),
7.20 (m, 2H), 7.40 (dd, 1H), 9.35 (br s, 1H); MS (APCI) m/e
426 (M + H)+, 428 (M + H)+. The racemic product from above
(1.646 g, 3.86 mmol) was processed by method B to provide
223 mg of compound 18 as a white solid: [R]23D +7.3 (DMSO);
1H NMR (DMSO-d6) δ 1.75 (m, 1H), 1.88 (m, 1H), 2.20 (m,
4H), 2.50 (m, 4H), 3.20 (m, 2H), 5.01 (s, 1H), 7.15-7.28 (m,
2H), 7.88 (dd, 1H), 9.39 (br s, 1H); MS (APCI-) m/z 424 (M -
H)-. Anal. (C18H17BrFNO3S) C, H, N. Also obtained was 148
provide 228 mg of compound 51 as a white solid: [R]23D -68.8°
1
(DMSO); H NMR (DMSO-d6) δ 1.75-1.95 (m, 2H), 2.23 (m,
2H), 2.55 (m, 2H), 2.73 (dt, 1H), 3.03 (dt, 1H), 3.35 (m, 2H),
4.84 (s, 1H), 7.17 (dd, 1H), 7.35 (d, 1H), 7.50 (d, 1H), 9.85 (br
s, 1H); MS (APCI-) m/z 382 (M - H)-. Anal. (C17H15Cl2NO3S)
C, H, N.
(9S )-(3-E t h e n y l-4-flu o r o p h e n y l)-2,3,5,6,7,9-h e x a -
h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (59).
(9S)-1,1-Dim eth yleth yl 9-(3-br om o-4-flu or oph en yl)-8-oxo-
3,5,6,7,8,9-h exa h yd r ot h ien o[3,2-b]q u in olin e-4(2H )-ca r -
boxyla te 1,1-Dioxid e. A solution of compound 14 (1.0 g, 2.4
mmol), Boc2O (1.0 g, 24 mmol), and DMAP (29 mg, 0.1 mmol)
in MeCN was heated to reflux for 1 h, cooled to room
temperature, and concentrated, and the residue was purified
by flash chromatography on silica gel eluting (EtOAc/hexane
1:1) to provide 900 mg of the title compound: 1H NMR (DMSO-
d6) δ 1.56 (s, 9H), 1.90-2.02 (m, 2H), 2.3-2.5 (m, 2H), 3.00
(m, 2H), 3.45 (m, 2H), 3.50 (m, 2H), 4.83 (s, 1H), 7.20 (m, 1H),
7.32 (t, 1H), 7.37 (dd, 1H).
mg of compound 17 as a white solid: [R]23 -5.2 (DMSO); 1H
D
NMR (DMSO-d6) δ 1.73 (m, 1H), 1.88 (m, 1H), 2.20 (m, 4H),
2.50 (m, 4H), 3.20 (m, 2H), 5.01 (s, 1H), 7.15-7.27 (m, 2H),
7.38 (dd, 1H), 9.40 (br s, 1H); MS (APCI-) m/z 424 (M - H)-.
Anal. (C18H17BrFNO3S) C, H, N.
10-(3-Br om o-4-flu or oph en yl)-2,3,4,5,6,7,8,10-octa h yd r o-
9H-cyclop en ta [b]th iep in o[2,3-e]p yr id in -9-on e (19). A so-
lution of 3-bromo-4-fluorobenzaldehyde (639 mg, 3.14 mmol),
3-aminocyclopent-2-en-1-one (305 mg, 3.14 mmol), and thia-
cycloheptan-3-one 1,1-dioxide (510 mg, 3.14 mmol) in EtOH
(10 mL) was heated to 80 °C in a sealed tube for 3 d and cooled.
The solid precipitate was collected, washed with EtOH, and
dried to provide 700 mg of compound 19 as a white solid: mp
210 °C;1H NMR (DMSO-d6) δ 1.60 (m, 1H), 1.82 (m, 1H), 2.05
(m, 2H), 2.32 (m, 2H), 2.62 (m, 3H), 2.92 (m, 2H), 3.20 (m,
1H), 4.75 (s, 1H), 7.25 (dd, 1H, J ) 3 Hz), 7.32 (m, 1H), 7.45
(dd, 1H, J ) 3 Hz), 10.02 (s, 1H);MS (ESI+) m/z 427 (M + H)+.
Anal. (C18H17BrFNO3S) C, H, N.
11-(3-Br om o-4-flu or op h en yl)-2,3,4,5,7,8,9,11-oct a h y-
d r oth iep in o[3,2-b]qu in olin -10(6H)-on e 1,1-Dioxid e (20).
A solution of 3-bromo-4-fluorobenzaldehyde (1.22 g, 6.00
mmol), 3-aminocyclohex-2-en-1-one (667 mg, 6.00 mmol), and
thiacycloheptan-3-one 1,1-dioxide (973 mg, 6.00 mmol) in
EtOH (10 mL) with Et3N (0.4 mL) was heated to 80 °C in a
sealed tube for 3 d and cooled. The solid precipitate was
collected, washed with EtOH, and dried to provide 1.8 g of
compound 20 as a white solid: 1H NMR (DMSO-d6) δ 1.65 (m,
1H), 1.75 (m, 2H), 1.90 (m, 1H), 2.02 (m, 2H), 2.52 (m, 2H),
2.75 (m, 3H), 3.15 (m, 1H), 4.95 (s, 1H), 7.20 (m, 1H), 7.25 (m,
1H), 7.40 (dd, 1H, J ) 3 Hz), 9.44 (s, 1H); MS (ESI+) m/z 441
(M + H)+. Anal. (C19H19BrFNO3S) C, H, N.
Meth od D. A solution of the above intermediate (150 mg,
0.29 mmol) and Pd(PPh3)4 (10 mol %) in DMF (0.1 M) was
treated with vinyl tributylstannane (0.45 mL, 1.4 mmol),
heated to 110 °C for 24 h, cooled to room temperature, treated
with saturated KF, and extracted with EtOAc. The extract was
washed with brine, dried (Na2SO4), filtered, concentrated, and
purified by flash chromatography on silica gel (MeOH:CH2Cl2
5:95). Recrystallization from EtOH provided 82 mg of com-
pound 59 as a white solid: 1H NMR (DMSO-d6) δ 1.99-1.82
(m, 2H), 2.25-2.20 (m, 2H), 2.5 (m, 2H), 2.79-2.73 (m, 1H),
3.32-3.30 (m, 4H), 3.25-2.81 (m, 1H), 4.86 (s, 1H), 5.40 (dd,
1H, J ) 11.53, 1.35 Hz), 5.80 (dd, 1H, J ) 18.0, 1.35 Hz), 6.77
(dd, 1H, J ) 17.63, 11.20 Hz), 7.08-7.01 (m, 2H), 7.35 (dd,
1H, J ) 7.46, 2.04 Hz), 9.74 (S, 1H); MS (ESI-) m/z 358 (M -
H)-. Anal. (C19H18FNO3S‚0.3H2O) C, H, N.
(+)-(8R)-8-(3-Br om o-4-flu or op h en yl)-2,3,4,5,6,8-h exa -
h yd r o-7H -cyclop en t a [b]t h ien o[2,3-e]p yr id in -7-on e 1,1-
Dioxid e (11) a n d (-)-(8S)-8-(3-Br om o-4-flu or op h en yl)-
2,3,4,5,6,8-h exa h yd r o-7H -cyclop en t a [b]t h ien o[2,3-e]p y-
r id in -7-on e 1,1-Dioxid e (12). A solution of dihydrothiophen-
3(2H)-one 1,1-dioxide (166 mg, 1.24 mmol), 3-bromo-4-fluo-
robenzaldehyde (250 mg, 1.23 mmol), and 3-aminocyclopent-
2-en-1-one (120 mg, 1.24 mmol) in EtOH (4 mL) was heated
to reflux for 72 h and cooled. The precipitate was collected,
washed with ethanol, and dried to provide 241 mg of the
1
racemic title compound: mp >260 °C; H NMR (DMSO-d6) δ
2.30 (t, 2H), 2.63 (m, 2H), 2.85 (dt, 1H), 3.06 (dt, 1H), 3.40 (t,
2H), 4.72 (s, 1H), 7.27 (m, 2H), 7.47 (d, 1H), 10.33 (br s, 1H);
MS (APCI-) m/z 396 (M - H)-. The racemic product above
(0.80 g) was chromatographed on a 5 × 25 cm Regis WhelkO
2 chiral column with 280 g of packing, eluting with hexane:
MeOH:CH2Cl2 (70/15/15) as the mobile phase at a flow rate of
117 mL/min to provide 264 mg of compound 11 as the more
polar enantiomer (see Supporting Information for X-ray crystal
analysis): [R]23D +4.8° (CH3CN); 1H NMR (DMSO-d6) δ 2.3 (m,
2H), 2.62 (m, 2H), 2.85 (m, 1H), 3.05 (m, 1H), 3.4 (m, 2H), 4.72
(s, 1H), 7.25 (m, 2H), 7.48 (d, 1H), 10.35 (s, 1H); MS (ESI+)
m/z 400 (M + H)+. Anal. (C16H13BrFNO3S) C, H, N. From the
above chiral chromatography was obtained 250 mg of com-
pound 12 as the less polar enantiomer: [R]23D -4.5° (CH3CN);
1H NMR (DMSO-d6) δ 2.3 (t, 2H), 2.63 (m, 2H), 2.85 (m, 1H),
3.06 (m, 1H), 3.4 (m, 2H), 4.71 (s, 1H), 7.25 (d, 2H), 7.47 (d,
8 -(3 -B r o m o -4 -fl u o r o p h e n y l )-2 ,3 ,4 ,5 ,6 ,8 -h e x a h y -
d r od ith ien o[3,2-b:2′,3′-e]p yr id in e 1,1,7,7-Tetr a oxid e (21).
3-Bromo-4-fluorobenzaldehyde (305 mg, 1.5 mmol), dihy-
drothiophen-3(2H)-one 1,1-dioxide (402 mg, 3.00 mmol), and
2.0 M NH3 in EtOH (1.1 mL, 2.2 mmol) were heated in EtOH
(3 mL) to 80 °C for 3 d in a sealed tube and cooled. The
intermediate hemiaminal precipitate was collected and washed
with EtOH. The solid was heated to reflux overnight in EtOH
with 1.0 M HCl/Et2O (1 mL) and cooled, and the solid was
collected, washed with EtOH, and dried to provide 185 mg of
compound 21 as an off-white solid: 1H NMR (DMSO-d6) δ 2.80
(m, 2H), 3.01 (dt, 2H), 3.35 (m, 4H), 4.97 (s, 1H), 7.30 (m, 2H),
7.53 (dd, 1H), 9.19 (br s, 1H); MS (APCI-) m/z 432 (M - H)-.
Anal. (C15H13BrFNO4S2) C, H, N.
10-(3-Br om o-4-flu or op h en yl)-3,4,6,7,8,10-h exa h yd r o-
2H,5H-d ith iop yr a n o[3,2-b:2′,3′-e]p yr id in e 1,1,9,9-Tetr a ox-
id e (22). 3-Bromo-4-fluorobenzaldehyde (202 mg, 1.0 mmol),
dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide (305 mg, 2.06
mmol), and 2.0 M NH3 in EtOH (0.70 mL, 1.4 mmol) were
heated in EtOH (3 mL) to 80 °C for 5 d in a sealed tube and
cooled. The solid precipitate was collected and washed with
ethanol. The solid in toluene (10 mL) was then heated to reflux
overnight and cooled, and the solid was collected, washed with
ethanol, and dried to provide 129 mg of compound 22 as a
white solid: 1H NMR (DMSO-d6) δ 2.17 (m, 4H), 2.50 (m, 4H),
3.18 (m, 4H), 5.09 (s, 1H), 7.24 (m, 2H), 7.38 (dd, 1H), 9.11 (s,
1H); MS (APCI-) m/z 460 (M - H)-. Anal. (C17H17BrFNO4S2)
C, H, N.
1H) 10.35 (s, 1H); MS (ESI+) m/z 400 (M + H)+. Anal. (C16H13
-
BrFNO3S) C, H, N.
(-)-10-(3-Br om o-4-flu or oph en yl)-3,4,6,7,8,10-h exah ydr o-
2H-th iop yr a n o[3,2-b]qu in olin -9(5H)-on e 1,1-Dioxid e (17)
a n d (+)-10-(3-Br om o-4-flu or op h en yl)-3,4,6,7,8,10-h exa h y-
d r o-2H-th iop yr a n o[3,2-b]qu in olin -9(5H)-on e 1,1-Dioxid e
(18). A solution of dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide
(888 mg, 6.00 mmol), 3-bromo-4-fluorobenzaldehyde (1.22 g,
6.00 mmol), Et3N (0.42 mL, 3 mmol), and 3-aminocyclohex-2-
en-1-one (666 mg, 6 mmol) in EtOH (10 mL) was heated to
reflux for 72 h and cooled. The solid that precipitated was
collected, washed with EtOH, and dried to provide 1.098 g of

3172 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
(+)-(9R )-(3-B r o m o -4-flu o r o p h e n y l)-5,5-d im e t h y l-
2,3,5,6,7,9-h exa h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-
Dioxid e (23) a n d (-)-(9S)-(3-br om o-4-flu or op h en yl)-5,5-
dim eth yl-2,3,5,6,7,9-h exah ydr oth ien o[3,2-b]qu in olin -8(4H)-
on e 1,1-Dioxide (24).3-Meth oxy-4,4-dim eth yl-2-cycloh exen -
1-on e. A stirred solution of 4,4-dimethyl-1,3-cyclohexanedione
(3.04 g, 21.7 mmol) and p-TsOH‚H2O (413 mg, 2.17 mmol) in
MeOH (40 mL) was heated at reflux for 2 h. The reaction
mixture was cooled and concentrated to give an oily residue.
The residue was purified by flash chromatography (elution
with 3% MeOH/EtOAc) to provide 805 mg of 3-methoxy-4,4-
dimethyl-2-cyclohexen-1-one as a colorless liquid: 1H NMR
(DMSO-d6) δ 1.12 (s, 6H), 1.83 (t, 3H, J ) 7.1 Hz), 2.42 (t, 3H,
J ) 7.1 Hz), 3.68 (s, 3H), 5.26 (s, 1H); MS (DCI/NH3) m/z 155
(M + H)+.
3-Am in o-4,4-d im eth yl-2-cycloh exen -1-on e. 3-Methoxy-
4,4-dimethyl-2-cyclohexen-1-one in condensed anhydrous NH3
(50 mL) was heated at 100 °C (850 psi) for 34 h. Ammonia
was removed by evaporation, and the residue was dissolved
in EtOAc (5 mL) and filtered through Florisil to provide 1.14
g of 3-amino-4,4-dimethyl-2-cyclohexen-1-one as a pale tan
oil: 1H NMR (DMSO-d6) δ 1.11 (s, 3H), 1.18 (s, 3H), 1.67 (t,
3H, J ) 7.1 Hz), 2.15 (t, 3H, J ) 7.1 Hz), 4.83 (s, 1H), 6.59 (br
s, 2H); MS (DCI/NH3) m/z 139 (M + H)+.
drothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide (534 mg, 34%)
as an off-yellow solid. The racemic material was resolved by
chiral HPLC using an (R,R)-Whelk-O 1 column (2.1 cm × 25
cm), with gradient elution with 3% MeOH-CH2Cl2 (2:1)/
hexanes to 25% MeOH-CH2Cl2 (2:1)/hexanes to provide 26
as the less polar enantiomer (149 mg, tR ) 44 min): [R]23
)
D
1
-42.2° (c ) 0.1, DMSO); mp 251-252 °C; H NMR (DMSO-
d6) δ 9.74 (br s, 1H), 7.39 (dd, 1H, J ) 6.7, 2.0 Hz), 7.26-7.17
(m, 2H), 4.80 (s, 1H), 3.12-2.99 (m, 2H), 2.90-2.88 (m, 2H),
2.50 (br s, 2 H), 2.14 (br s, 2 H), 2.13 (AB q, 2H, J AB ) 12.2
Hz, ∆νAB ) 28.9 Hz), 1.03 (s, 3H), 0.92 (s, 3H); MS (DCI/NH3)
m/z 440 (M + H)+. Anal. (C19H19BrFNO3S) C, H, N. Also
obtained was 25 as the more polar enantiomer (163 mg, tR
)
56 min): [R]23 ) +39.9° (c ) 0.2, DMSO); mp 250-252 °C;
D
1H NMR (DMSO-d6) δ 9.74 (br s, 1H), 7.39 (dd, 1H, J ) 6.7,
2.0 Hz), 7.26-7.17 (m, 2H), 4.80 (s, 1H), 3.12-2.99 (m, 2H),
2.90-2.88 (m, 2H), 2.50 (br s, 2 H), 2.14 (br s, 2 H), 2.13 (AB
q, 2H, J AB ) 12.2 Hz, ∆νAB ) 28.9 Hz), 1.03 (s, 3H), 0.92 (s,
3H); MS (DCI/NH3) m/z 440 (M + H)+. Anal. (C19H19BrFNO3S)
C, H, N.
(+)-(9R )-(3-B r o m o -4-flu o r o p h e n y l)-7,7-d im e t h y l-
2,3,5,6,7,9-h exa h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-
Dioxid e (27) a n d (-)-(9S)-(3-Br om o-4-flu or op h en yl)-7,7-
dim eth yl-2,3,5,6,7,9-h exah ydr oth ien o[3,2-b]qu in olin -8(4H)-
on e 1,1-Dioxid e (28). A stirred solution of 3-bromo-4-
fluorobenzaldehyde (725 mg, 3.57 mmol), 4,4-dimethyl-1,3-
cyclohexanedione (500 mg, 3.57 mmol), and dihydrothiophen-
3(2H)-one 1,1-dioxide (479 mg, 3.57 mmol) in EtOH (40 mL)
was treated with anhydrous NH4OAc (330 mg, 4.29 mmol),
and the mixture was heated at reflux for 60 h. The reaction
mixture was cooled to room temperature, and the white solid
that precipitated was isolated by filtration. The solid was
triturated sequentially with 10% EtOAc/EtOH, Et2O, and then
25% Et2O/EtOH to provide 543 mg of the racemic title
compound as a white solid: mp >270 °C; 1H NMR (DMSO-d6)
δ 0.89 (s, 3H), 0.98 (s, 3H), 1.75 (t, 2H, J ) 6.1 Hz), 2.50-
2.640 (m, 2H), 2.68-3.07 (m, 3H), 3.29-3.41 (m, 1H), 4.80 (s,
1H), 7.13-7.32 (m, 2H), 7.38 (dd, 1H, J ) 6.7, 2.0 Hz), 9.69
(br s, 1H); MS (DCI/NH3) m/z 457 (M + NH4)+. The racemic
product from above was chromatographed on an (R,R)-Whelk-
O1 column (2.1 cm × 25 cm), with gradient elution with 3%
MeOH-CH2Cl2 (2:1)/hexanes to 25% MeOH-CH2Cl2 (2:1)/
9-(3-b r om o-4-flu or op h en yl)-5,5-d im et h yl-2,3,5,6,7,9-
h exa h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e.
A stirred solution of 3-bromo-4-fluorobenzaldehyde (725 mg,
3.57 mmol), 3-amino-4,4-dimethyl-2-cyclohexen-1-one (496 mg,
3.57 mmol), and tetrahydrothiophene-3-oxo-1,1-dioxide (473
mg, 3.57 mmol) in EtOH (30 mL) was heated at reflux for 96
h. The reaction mixture was cooled and concentrated to give
a yellow residue which was redissolved in EtOH (30 mL) and
treated with 2 M HCl in Et2O (2.0 mL). The solution was
heated at reflux for 9 h and then cooled to ambient tempera-
ture, and the white solid that precipitated was triturated with
EtOAc. The solid was purified by flash chromatography
(elution with 8% MeOH/CH2Cl2) to provide 267 mg of the title
compound as an off-yellow solid: mp >270 °C; 1H NMR
(DMSO-d6) δ 1.30 (s, 3H), 1.34 (s, 3H), 1.83-1.92 (m, 2H),
2.14-2.21 (m, 1H), 2.36-2.45 (m 1H), 2.89-2.97 (m, 1H),
3.03-3.11 (m, 1H), 3.29-3.44 (m, 2H), 4.85 (s, 1H), 7.13-7.26
(m, 2H), 7.35-7.39 (m, 1H), 9.40 (br s, 1H); MS (DCI/NH3)
m/z 457 (M + NH4)+. The racemic product from above was
chromatographed on an (R,R)-Whelk-O1 column (2.1 cm × 25
cm), with gradient elution with 3% MeOH-CH2Cl2 (2:1)/
hexanes to 25% MeOH-CH2Cl2 (2:1)/hexanes, to provide
hexanes to provide compound 27: tR ) 47 min. [R]23 +30.5°
D
1
(c ) 0.6, DMSO); mp >270 C; H NMR (DMSO-d6) δ 1.30 (s,
3H), 1.34 (s, 3H), 1.83-1.92 (m, 2H), 2.14-2.21 (m, 1H), 2.36-
2.45 (m 1H), 2.89-2.97 (m, 1 H), 3.03-3.11 (m, 1 H), 3.29-
3.44 (m, 2H), 4.85 (s, 1H), 7.13-7.26 (m, 2H), 7.35-7.39 (m,
1H), 9.40 (br s, 1H); MS (DCI/NH3) m/z 457 (M + NH4)+. Anal.
(C19H19BrFNO3S) C, H, N. Also obtained was compound 28:
tR ) 41 min; [R]23D -21.6° (c 0.5, DMSO); mp >270 °C; 1H NMR
(DMSO-d6) δ 1.30 (s, 3H), 1.34 (s, 3H), 1.83-1.92 (m, 2H),
2.14-2.21 (m, 1H), 2.36-2.45 (m 1H), 2.89-2.97 (m, 1 H),
3.03-3.11 (m, 1 H), 3.29-3.44 (m, 2H), 4.85 (s, 1H), 7.13-
7.26 (m, 2H), 7.35-7.39 (m, 1H), 9.40 (br s, 1H); 13C NMR
(DMSO-d6) δ 199.2, 157.9, 155.5, 151.4, 144.4, 143.3, 142.2,
132.6, 128.7, 116.2, 113.0, 107.1, 48.8, 33.9, 33.4, 24.7, 24.1,
compound 23: tR ) 53 min; [R]23 +17.6° (c 0.4, DMSO); mp
D
> 270 °C; 1H NMR (DMSO-d6) δ 0.89 (s, 3H), 0.98 (s, 3H), 1.75
(t, 2H, J ) 6.1 Hz), 2.50-2.64 (m, 2H), 2.68-3.07 (m, 3H),
3.29-3.41 (m, 1H), 4.80 (s, 1H), 7.13-7.32 (m, 2H), 7.38 (dd,
1H, J ) 6.7, 2.0 Hz), 9.69 (br s, 1H); MS (DCI/NH3) m/z 457
(M + NH4)+. Anal. (C19H19BrFNO3S) C, H, N. Also obtained
was compound 24: tR ) 49 min; [R]23D -19.9° (c ) 0.6, DMSO);
mp >270 °C; 1H NMR (DMSO-d6) δ 0.89 (s, 3H), 0.98 (s, 3H),
1.75 (t, 2H, J ) 6.1 Hz), 2.50-2.64 (m, 2H), 2.68-3.07 (m, 3H),
3.29-3.41 (m, 1H), 4.80 (s, 1H), 7.13-7.32 (m, 2H), 7.38 (dd,
1H, J ) 6.7, 2.0 Hz), 9.69 (br s, 1H); MS (DCI/NH3) m/z 457
(M + NH4)+. Anal. (C19H19BrFNO3S) C, H, N.
23.4, 22.8; MS (DCI/NH3) m/z 457 (M + NH4)+. Anal. (C19H19
BrFNO3S) C, H, N.
-
7-(3-Br om o-4-flu or op h en yl)-5-m et h yl-2,3,4,7-t et r a h y-
d r oth ien o[3,2-b]p yr id in e-6-ca r bon itr ile 1,1-Dioxid e (29).
3-Bromo-4-fluorobenzaldehyde (1.02 g, 5.00 mmol), dihy-
drothiophen-3(2H)-one 1,1-dioxide (0.67 g, 5.0 mmol), and
3-aminocrotononitrile (0.41 g, 5.0 mmol) in MeOH (10 mL)
were heated at 65 °C for 2 d and cooled. The solvent was
evaporated and the crude product purified by flash chroma-
tography over silica gel eluting with MeOH:CH2Cl2 (5:95) to
provide 520 mg of compound 29 as a white solid: 1H NMR
(DMSO-d6) δ 2.07 (s, 3H), 2.72-3.04 (m, 2H), 3.31-3.40 (m,
2H), 4.78 (s, 1H), 7.34 (m, 2H), 7.59 (d, 1H), 9.84 (s, 1H); MS
(ESI-) m/z 383 (M - H)-. Anal. (C15H12BrFN2O2S) C, H, N.
(+)-(9R )-(3-B r o m o -4-flu o r o p h e n y l)-6,6-d im e t h y l-
2,3,5,6,7,9-h exa h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-
Dioxid e (25) a n d (-)-(9S)-(3-Br om o-4-flu or op h en yl)-6,6-
dim eth yl-2,3,5,6,7,9-h exah ydr oth ien o[3,2-b]qu in olin -8(4H)-
on e 1,1-Dioxid e (26). A stirred solution of 3-bromo-4-
fluorobenzaldehyde (725 mg, 3.57 mmol), 5,5-dimethyl-1,3-
cyclohexanedione (501 mg, 3.57 mmol), and dihydrothiophen-
3(2H)-one 1,1-dioxide (473 mg, 3.57 mmol) in EtOH (30 mL)
was heated at reflux for 48 h. The reaction mixture was cooled
and concentrated. The resulting yellow residue was redissolved
in ethanol (30 mL) and treated with 2 M HCl in Et2O (2.0 mL).
The solution was then heated at reflux for 9 h and cooled to
ambient temperature, and the white solid that precipitated
was triturated with EtOAc. The solid was purified by flash
chromatography (elution with 8% MeOH/CH2Cl2) to provide
9-(3-bromo-4-fluorophenyl)-6,6-dimethyl-2,3,5,6,7,9-hexahy-
Met h yl 7-(3-Br om o-4-flu or op h en yl)-5-m et h yl-2,3,4,7-
tetr a h yd r oth ien o[3,2-b]p yr id in e-6-ca r boxyla te 1,1-Diox-
id e (30). 3-Bromo-4-fluorobenzaldehyde (2.03 g, 10.0 mmol),
methyl 3-aminocrotonate (1.15 g, 10.0 mmol), and dihy-

Sulfonyldihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3173
drothiophen-3(2H)-one 1,1-dioxide (1.29 g, 9.60 mmol) in
MeOH (30 mL) were heated at 65 °C overnight. The white
precipitate was collected, washed with acetone, dried, and then
heated to reflux in MeOH (30 mL) with 1.0 M HCl in Et2O (10
mL) for 2 h. The reaction was cooled and solvent evaporated.
The solid was triturated with Et2O, collected, washed with
Et2O, and dried to provide 2.88 g of compound 30 as a white
solid: mp 232-234 °C; 1H NMR (DMSO-d6) δ 2.28 (s, 3H),
2.75-3.05 (m, 2H), 3.28-3.35 (m, 2H), 3.52 (s, 3H), 4.87 (s,
1H), 7.19 (m, 1H), 7.26 (t, 1H), 7.48 (d, 1H), 9.50 (s, 1H); MS
(ESI-) m/z 416 (M - H)-. Anal. (C16H15BrFNO4S) C, H, N.
Eth yl 7-(3-Br om o-4-flu or op h en yl)-5-m eth yl-2,3,4,7-tet-
r a h yd r oth ien o[3,2-b]p yr id in e-6-ca r boxyla te 1,1-Dioxid e
(31). Ethyl 3-aminocrotonate was treated according to the
procedure of compound 30 to provide compound 31: 1H NMR
(DMSO-d6) δ 1.07 (t, 3H), 2.28 (s, 3H), 2.80 (m, 1H), 2.96 (m,
1H), 3.35 (m, 2H), 3.95 (m, 2H), 4.87 (s, 1H), 7.20 (ddd, 1H),
7.28 (t, 1H), 7.39 (dd, 1H), 9.49 (s, 1H); MS (ESI-) m/z 428 (M
- H)-. Anal. (C17H17BrFNO4S) C, H, N.
Eth yl 7-(3-Br om o-4-flu or op h en yl)-5-(tr iflu or om eth yl)-
2,3,4,7-tetr ah ydr oth ien o[3,2-b]pyr idin e-6-car boxylate 1,1-
Dioxid e (32). Ethyl 4,4,4-trifluoroacetoacetate (368 mg, 2.0
mmol), 3-bromo-4-fluorobenzaldehyde (406 mg, 2 mmol), di-
hydrothiophen-3(2H)-one 1,1-dioxide (268 mg, 2.0 mmol), and
2 M NH3/EtOH (2 mL) were heated in EtOH to 80 °C overnight
in a sealed tube and cooled, and an intermediate hemiaminal
was collected as a solid precipitate (370 mg). The intermediate
was heated to reflux in toluene with catalytic p-TsOH for 6 h
and cooled, and the solvent was evaporated and the crude flash
chromatographed (5% MeOH/CH2Cl2) to provide 125 mg of
compound 32: mp 200-202 °C; 1H NMR (DMSO) δ 1.05 (t,
3H), 2.88-3.08 (m, 2H), 3.37 (t, 2H), 4.01 (q, 2H), 4.96 (s, 1H),
7.28 (m, 1H), 7.34 (t, 1H), 7.50 (d, 1H), 9.98 (s, 1H); MS (ESI+)
m/z 482 (M + H)+ Anal. (C17H14BrF4NO4S) C, H, N.
7-(3-Br om o-4-flu or op h en yl)-5-m et h yl-2,3,4,7-t et r a h y-
d r oth ien o[3,2-b]p yr id in e-6-ca r boxylic Acid 1,1-Dioxid e
(33). Compound 30 (416 mg, 1.00 mmol) in CH2Cl2 (4 mL) at
0 °C was treated with 1.0 M BCl3 in CH2Cl2 (6 mL), allowed
to warm to room temperature, stirred 4 h, diluted with ice-
water (50 mL), and extracted with EtOAc (4×). The organic
extracts were dried (MgSO4) and filtered, and solvent was
evaporated. The crude material was triturated with EtOAc,
and the solid precipitate collected, washed with EtOAc, and
dried to provide 271 mg of compound 33 as a yellow solid: mp
220-223 °C; 1H NMR (DMSO-d6) δ 2.28 (s, 3H), 2.23-3.02
(m, 2H), 3.30-3.40 (m, 2H), 4.84 (s, 1H), 7.18 (m, 1H), 7.28 (t,
1H), 7.37 (d, 1H), 9.39 (s, 1H), 11.97 (s, 1H); MS (ESI-) m/z
400 (M - H)-. Anal. (C15H13BrFNO4S) C, H, N.
were heated to reflux overnight. The solvent was evaporated,
and the residue was dissolved in toluene, treated with p-TsOH
(cat.), and heated to reflux for 1 h. The solvent was evaporated
and the crude product flash chromatographed over silica gel
eluting with MeOH:CH2Cl2 (5:95) to provide 630 mg of 38 as
a white solid: 1H NMR (DMSO-d6) δ 2.84 (m, 1H), 2.98 (m,
1H), 3.3 (m, 2H), 4.81 (s, 1H), 5.42 (s, 1H), 7.33 (m, 2H), 7.56
(d, 1H), 9.57 (br s, 1H); MS (APCI+) m/z 429 (M + NH4)+. Anal.
(C14H10BrF4NO2S) C, H, N.
(9S )-(4-F lu o r o -3-i o d o p h e n y l)-2,3,5,6,7,9-h e x a h y -
drothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (41).3-Amino-
4-fluorobenzoic acid (15 g, 97 mmol) in THF at 0 °C was treated
with 1.0 M BH3‚THF (50 mL), stirred overnight at room
temperature, treated with an additional 130 mL of 1.0 M BH3‚
THF, stirred 10 h, quenched by the addition of MeOH, and
stirred for 3 h at room temperature. The solvent was evapo-
rated, the product was partitioned between aqueous NaHCO3/
CH2Cl2, and the organic layer was dried (Na2SO4) and filtered.
The solvent was evaporated and the product was purified by
flash chromatography over silica gel (EtOAc/hexane 1:1) to
provide 7.0 g of 3-amino-4-fluorobenzyl alcohol. 1H NMR
(CDCl3) δ 4.58 (s, 2H), 6.67 (br m, 1H), 6.81 (d, 1H), 6.95 (t,
1H). 3-Amino-4-fluorobenzyl alcohol (7.0 g, 50 mmol) in water
(100 mL) at 0 °C was treated slowly with concentrated H2SO4
(30 mL) at a rate to maintain the temperature below 10 °C
and then treated dropwise with an aqueous solution of NaNO2
(3.45 g, 50 mmol). This solution was then added to a solution
of KI (8.13 g, 50 mmol) in water (15 mL). The reaction was
heated to 60 °C for 2 h, cooled, and extracted with CH2Cl2.
The organics were washed with 10% NaOH, 1 M Na2S2O3, 10%
HCl, and aqueous NaHCO3, dried (Na2SO4), and filtered, and
solvent was evaporated. The material was purified by flash
chromatography over silica gel (EtOAc/hexane 7:3) to provide
6.4 g of 4-fluoro-3-iodobenzyl alcohol: 1H NMR (CDCl3) δ 1.69
(t, 1H), 4.66 (d, 2H), 7.05 (t, 1H), 7.60 (d, 1H), 7.78 (dd, 1H).
4-Fluoro-3-iodobenzyl alcohol (6.4 g, 26 mmol) in CHCl3 (300
mL) was treated with MnO2 (4.5 g, 50 mmol), stirred overnight,
treated with an additional portion of MnO2 (2.25 g), stirred
overnight, and filtered, and the solvent was evaporated. The
material was purified by flash chromatography over silica gel
(EtOAc/hexane 1:4) to provide 1.9 g of 4-fluoro-3-iodobenzal-
dehyde: 1H NMR (CDCl3) δ 7.23 (t, 1H), 7.89 (m, 1H), 8.32
(dd, 1H), 9.91 (s, 1H). 4-Fluoro-3-iodobenzaldehyde (0.25 g, 1.0
mmol) was processed according to method A to provide 0.20 g
of the title compound as the racemate: mp >250 °C; 1H NMR
(DMSO-d6) δ 1.88 (m, 2H), 2.22 (m, 2H), 2.62 (m, 2H), 2.7 (m,
1H), 3.02 (m, 1H), 3.45 (m, 2H),4.81 (s, 1H), 7.12 (m, 1H), 7.18
(m, 1H), 7.55 (dd, 1H), 9.81 (s, 1H); MS (ESI+) m/z 460 (M +
H)+. Anal. Calcd for C17H15FINO3S: C, 44.45; H, 3.29; N, 3.04.
Found: C, 44.51; H, 3.31; N, 2.97. (312678) The racemic
1-[8-(3-Br om o-4-flu or op h e n yl)-3,4,5,8-t e t r a h yd r o-6-
m et h yl-1,1-d ioxid o-2H -t h iop yr a n o[3,2-b]p yr id in -7-yl)]-
eth a n -1-on e (34). A solution of dihydro-2H-thiopyran-3(4H)-
one 1,1-dioxide (179 mg, 1.21 mmol), 3-bromo-4-fluorobenz-
aldehyde (246 mg, 1.21 mmol), and 4-amino-3-penten-2-one
(120 mg, 1.21 mmol) in EtOH (4 mL) was heated to reflux for
24 h and cooled. The solid that precipitated was collected,
washed with ethanol, and dried to provide 325 mg of compound
compound (110 mg) was chromatographed over
a Regis
WhelkO-1 2 × 25 cm chiral column eluting with hexane:
MeOH:CH2Cl2 (60:27:13) at a flow rate of 10 mL/min to provide
45 mg of the less polar enantiomer, compound 41, as an off-
white solid: [R]20 -47.3° (DMSO); 1H NMR (DMSO-d6) δ
D
1.80-1.95 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.75-3.08 (m,
2H), 3.30-3.35 (m, 2H), 4.81 (s, 1H), 7.12 (t, 1H), 7.18 (m, 1H),
7.54 (d, 1H), 9.79 (s, 1H); MS (ESI+) m/z 460 (M + H)+; MS
(ESI-) m/z 458 (M - H)-. Anal. (C17H15FINO3S 0.1C6H14) C,
H, N.
1
34 as a white solid: mp >260 °C; H NMR (DMSO-d6) δ 2.17
(m, 2H), 2.20 (s, 3H), 2.30 (s, 3H), 2.50 (m, 2H), 3.20 (m, 2H),
5.06 (s, 1H), 7.20 (m, 2H), 7.40 (dd, 1H), 9.11 (s, 1H); MS
(APCI-) m/z 412 (M - H)-. Anal. (C17H17BrFNO3S) C, H, N.
(-)-(9S)-(3-Ch lor o-4-flu or op h en yl)-2,3,5,6,7,9-h exa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (42).3-Chlo-
ro-4-fluorobenzaldehyde (264 mg, 1.66 mmol) was treated
according to method A to provide 317 mg of the racemic title
7-(3-Br om o-4-flu or op h en yl)-5-(tr iflu or om eth yl)-2,3,4,7-
tetr a h yd r oth ien o[3,2-b]p yr id in e 1,1-Dioxid e (38). 4-(3-
Br om o-4-flu or op h en yl)-1,1,1-tr iflu or o-3-bu ten -2-on e (35).
To 3-bromo-4-fluorobenzaldehyde (406 mg, 2.0 mmol) in
benzene (10 mL) with piperidine (0.08 mL), and AcOH (0.01
mL) was added 1,1,1-trifluoroacetone (1.8 mL, 20 mmol) to the
bottom of the vessel by syringe. The reaction vessel was sealed
and heated to 50 °C overnight. The solvents were evaporated,
and the residue was flash chromatographed over silica gel
eluting with hexane:EtOAc (4:1) to provide 226 mg of the title
compound: 1H NMR (CDCl3) δ 6.95 (d, 1H), 7.21 (t, 1H), 7.58
(m, 1H), 7.85 (d, 1H), 7.87 (dd, 1H). Compound 35 (800 mg,
2.69 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (361 mg,
2.69 mmol), and 2.0 M NH3/EtOH (2.1 mL) in EtOH (5 mL)
1
compound as a white solid: mp >260 °C H NMR (DMSO-d6)
δ 1.73-1.96 (m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.82 (dt, 1H),
3.02 (dt, 1H), 3.46 (m, 2H), 4.85 (s, 1H), 7.17 (m, 1H), 7.28 (m,
2H), 9.75 (br s, 1H); MS (APCI-) m/z 366 (M - H)-. Anal. Calcd
for C17H15ClFNO3S: C, 55.51; H, 4.11; N, 3.80. Found: C,
55.24; H, 3.97; N, 3.85. The racemic compound was processed
according to method C to provide compound 42: mp >250 °C;
1
[R]23 -49.57 (c ) 0.56, DMSO); H NMR (DMSO-d6) δ 1.86
D
(m, 2H), 2.22 (m, 2H), 2.56 (m, 2H), 2.85 (m, 1H), 3.05 (m,
1H), 3.35 (m, 2H), 4.85 (s, 1H), 7.18 (m, 1H), 7.28 (m, 2H),

3174 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
9.88 (s, 1H); MS (ESI+) m/z 368 (M + H)+. Anal. (C17H15
-
cooled to 5 °C and treated with a solution of sodium dithionite
(15.0 g, 86.0 mmol) and K2CO3 (13.4 g, 87.0 mmol) in water
(45 mL). The cooling bath was removed and the biphasic
mixture stirred vigorously at 23 °C for 4 h. The mixture was
partitioned between additional CH2Cl2 (75 mL) and water (50
mL) and the aqueous layer was extracted with CH2Cl2 (75 mL).
The organic portions were washed with brine (75 mL) and
dried (Na2SO4). The residue was treated with EtOAc (25 mL)
and silica gel (75 g) and the suspension was filtered through
a small pad of Celite, rinsing with 10% EtOAc/CH2Cl2 (15 mL).
The filtrate was concentrated to provide 3-amino-4-chlorobenz-
aldehyde as an off-yellow powder (3.44 g, 22%): MS (DCI/NH3)
m/e 218 (M + NH4)+.
3-Br om o-4-ch lor oben za ld eh yd e. The product from above
(3.4 g, 22 mmol) in concentrated 48% aqueous HBr (20 mL) at
0 °C was treated with a 0 °C solution of NaNO2 (1.5 g, 22
mmol) in water (30 mL). The reaction mixture was stirred for
30 min and then transferred cold to a stirred solution of CuBr
(4.44 g, 31 mmol) in 48% aqueous HBr (20 mL) at 23 °C
(significant frothing!). Water (40 mL) was added, the solution
was heated at 60 °C for 45 min, cooled, diluted with EtOAc
(200 mL) and water (50 mL), and the layers were separated.
The aqueous layer was extracted with EtOAc (2×, 50 mL). The
organic layers were combined, washed with 1 M HCl (2×, 100
mL) and brine (50 mL), dried (Na2SO4), filtered, and concen-
trated to provide 3-bromo-4-chlorobenzaldehyde as a pale
yellow powder (3.9 g, 82%). 3-Bromo-4-chlorobenzaldehyde
(650 mg, 2.96 mmol) was treated according to method A to
provide 842 mg of the title compound as a racemate. Resolution
of this material by chiral HPLC using an (R,R)-Whelk-O 1
column (2.1 cm × 25 cm), eluting with 40% MeOH-CH2Cl2
(2:1)/hexanes (10 mL/min), afforded compound 46, the less
polar enantiomer (t ) 31 min): mp >270 C; [R]23D ) -26.1° (c
) 0.3, DMSO); 1H NMR (DMSO-d6) δ 1.70-1.91 (m, 2H), 2.14-
2.23 (m, 2H), 2.43-2.55 (m, 3H), 3.32-3.40 (m, 1H), 2.78 (dt,
1H, J ) 17.0, 6.6 Hz), 2.98 (dt, 1H, J ) 17.0, 6.6 Hz), 4.78 (s,
1H), 7.15 (dd, 1H, J ) 8.1, 2.2 Hz), 7.22 (d, 1H, J ) 2.4 Hz),
7.24 (d, 1H, J ) 8.0 Hz), 9.80 (br s, 1H); MS (DCI/NH3) m/z
445 (M + NH4)+. Anal. (C17H15BrClNO3S) C, H, N.
ClFNO3S) C, H, N.
(-)-(9S )-(3,4-D iflu o r o p h e n y l)-2,3,5,6,7,9-h e x a h y -
d r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (43). 3,4-
Difluorobenzaldehyde (110 µL, 1.00 mmol) was treated ac-
cording to method A to provide 151 mg of the racemic title
compound as an off-white solid: 1H NMR (DMSO-d6) δ 1.90
(m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.82 (dt, 1H), 3.02 (dt,
1H), 3.35 (m, 2H), 4.86 (s, 1H), 7.02 (m, 1H), 7.15 (ddd, 1H),
7.29 (dt, 1H), 9.79 (br s, 1H); MS (APCI) m/e 352 (M + H)+.
Anal. Calcd for C17H15F2NO3S: C, 58.11; H, 4.30; N, 3.99.
Found: C, 57.90; H, 3.96; N, 3.88. The racemic compound (1.2
g, 3.4 mmol) was processed according to method C to provide
200 mg of compound 43. mp >250; [R]23 -34.0 (c ) 0.70,
D
DMSO); 1H NMR (DMSO-d6) δ 1.88 (m, 2H), 2.25 (m, 2H), 2.55
(m, 2H), 2.82 (m, 1H), 3.02 (m, 1H), 3.35 (m, 2H), 4.85 (s, 1H),
7.03 (m, 1H), 7.15 (m, 1H), 7.28 (m, 1H), 9.82 (s, 1H); MS
(ESI+) m/z 352 (M + H)+. Anal. (C17H15F2NO3S) C, H, N.
(-)-(9S)-(3-Iod o-4-m et h ylp h en yl)-2,3,5,6,7,9-h exa h y-
d r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-d ioxid e (44). To
a slurry of 3-iodo-4-methylbenzoic acid (1.0 g, 3.96 mmol) in
1:1 CH2Cl2-THF (200 mL) was added oxalyl chloride (1 mL,
11.9 mmol) and several drops of DMF. The reaction was heated
to 65 °C for 30 min, cooled to room temperature, and
concentrated to form a light yellow solid that was dissolved
in THF (200 mL), treated with a solution of LiAlH(OtBu) (4.1
mL, 4.1 mmol) at -78 °C, stirred 30 min, and treated with a
solution of saturated Rochelle’s salt to quench the reaction at
-78 °C. The mixture was warmed to room temperature, the
layers were separated, the organic layer was washed with 1
N HCl, sat. NaHCO3 and brine, dried (Na2SO4), and concen-
trated, and the resulting residue was purified by flash chro-
matography (hexane/EtOAc 4:1) to yield 3-iodo-4-methylbenz-
aldehyde as a white solid (300 mg, 18%). 3-Iodo-4-methyl-
benzaldehyde (300 mg, 1.63 mmol) was treated according to
method A to provide 314 mg of the racemic title compound as
a white solid: 1H NMR (DMSO-d6) δ 1.75-1.94 (m, 4H), 2.20-
2.24 (m, 2H), 2.28 (s, 3H), 2.83-2.86 (m, 1H), 2.96-3.06 (m,
1H), 3.2-3.5 (m, 2H), 4.76 (s, 1H), 7.08 (dd, 1H, J ) 7.67,1.47
Hz), 7.17 (d, 7.67H), 7.56 (d, 1.47H), 9.76 (s, 1H); MS (ESI-)
m/z 454 (M - H)-. The racemate was chromatographed on a
Regis Whelk-O1 chiral column eluting with hexane:MeOH:
CH2Cl2 (50:34:16) to provide compound 44 as the less polar
(-)-(9S )-(3,4-D ib r o m o p h e n y l)-2,3,5,6,7,9-h e x a h y -
d r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (47). 3,4-
Dibromobenzaldehyde (1.58 g, 6.00 mmol) was treated accord-
ing to method A to provide 1.8 g of the racemic title compound.
mp >250 °C; 1H NMR (DMSO-d6) δ 1.90 (m, 2H), 2.25 (m, 2H),
2.60 (m, 2H), 2.85 (m, 1H), 3.02 (m, 1H), 3.38 (m, 2H), 4.80 (s,
1H), 7.12 (dd, 1H, J ) 3, 9 Hz), 7.48 (d, 1H, J ) 3 Hz), 7.62 (d,
1H, J ) 9 Hz), 9.85 (s, 1H); MS (ESI+) m/z 474 (M + H)+. The
racemic title compound (180 mg) was separated into the
individual enantiomers using the HPLC conditions of com-
pound 53 to provide 44 mg of compound 47, the less polar
enantiomer: [R]20 -53.6° (DMSO); 1H NMR (DMSO-d6) δ
D
1.75-1.94 (m, 4H), 2.20-2.24 (m, 2H), 2.28 (s, 3H), 2.83-2.86
(m, 1H), 2.96-3.06 (m, 1H), 3.2-3.5 (m, 2H), 4.76 (s, 1H), 7.08
(dd, 1H, J ) 7.67,1.47 Hz), 7.17 (d, 7.67H), 7.56 (d, 1.47H),
9.76 (s, 1H); MS (ESI-) m/z 454 (M - H)-. Anal. (C18H18INO3S
0.5H2O) C, H, N.
(-)-(9S)-(3-Br om o-4-m eth ylp h en yl)-2,3,5,6,7,9-h exa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (45). 3-Bro-
mo-4-methylbenzaldehyde (0.70 g, 3.5 mmol) was treated
according to method A to provide 0.87 g of the racemic title
compound: 1H NMR (DMSO-d6) δ 1.76-1.94 (m, 2H), 2.17-
2.24 (m, 2H), 2.26 (s, 3H), 2.49-2.57 (m, 2H), 2.78-2.85 (m,
1H), 2.98-3.04 (m, 1H), 3.25-3.35 (m, 2H), 4.80 (s, 1H), 7.07
(dd, 1H, J ) 8.0, 1.5 Hz), 7.19 (d, 1H, J ) 8.0 Hz), 7.30 (d, 1H,
J ) 1.5 Hz); MS (ESI+) m/z 410, 408 (M + H)+. The racemate
(600 mg) was chromatographed on a 2 × 25 cm Regis Whelk-
O1 column, eluting with hexane:MeOH:CH2Cl2 (65:24:11) as
the mobile phase at a flow rate of 10 mL/min to provide 250
mg of compound 45, the less polar enantiomer, as a white
enantiomer: mp >250 °C; [R]20 -50.1° (DMSO); 1H NMR
D
(DMSO-d6) δ 1.90 (m, 2H), 2.25 (m, 2H), 2.60 (m, 2H), 2.86
(m, 1H), 3.02 (m, 1H), 3.38 (m, 2H), 4.80 (s, 1H), 7.12 (dd, 1H,
J ) 3, 9 Hz), 7.48 (d, 1H, J ) 3 Hz), 7.62 (d, 1H, J ) 9 Hz),
9.85 (br, s, 1H); MS (ESI+) m/z 474 (M + H)+. Anal. (C17H15
Br2NO3S) C, H, N.
-
(-)-(9S)-(3-Br om o-4-tr iflu or om eth ylp h en yl)-2,3,5,6,7,9-
h exa h yd r ot h ien o[3,2-b]q u in olin -8(4H )-on e 1,1-Dioxid e
(48). [3-Nitr o-4-(tr iflu or om eth yl)p h en yl]m eth a n ol. R,R,R-
Trifluoromethyl-p-toluic acid (15 g, 78.9 mmol) in 90 mL of
concentrated H2SO4 was treated dropwise with a mixture of
fuming HNO3 (2 mL) and H2SO4 (24 mL). The reaction mixture
was stirred at room temperature for 48 h and quenched into
ice-water, and the precipitate (12 g) was collected (mixture
of nitration products and unreacted starting material), washed
with water, and dried under reduced pressure. The resulting
dry solid was dissolved in THF (300 mL), cooled to 0 °C, treated
with 1 M BH3‚THF complex (80 mL), and stirred at room
temperature overnight. The mixture was treated carefully with
MeOH (5 mL) and then concentrated HCl (5 mL), refluxed for
1 h, evaporated to dryness, and partitioned between water and
Et2O. The organic layer was dried (MgSO4) and concentrated
under reduced pressure. The residue was chromatographed
on silica gel eluting with 30% EtOAc /hexanes to provide
solid: [R]20 -73.66° (DMSO); 1H NMR (DMSO-d6) δ 1.76-
D
1.94 (m, 2H), 2.17-2.24 (m, 2H), 2.26 (s, 3H), 2.49-2.57 (m,
2H), 2.78-2.85 (m, 1H), 2.98-3.04 (m, 1H), 3.25-3.35 (m, 2H),
4.80 (s, 1H), 7.07 (dd, 1H, J ) 8.0, 1.5 Hz), 7.19 (d, 1H, J )
8.0 Hz), 7.30 (d, 1H, J ) 1.5 Hz); MS (ESI+) m/z 410, 408 (M
+ H)+. Anal. (C18H18BrNO3S‚0.75H2O) C, H, N.
(-)-(9S)-(3-Br om o-4-ch lor op h en yl)-2,3,5,6,7,9-h exa h y-
drothieno[3,2-b]quinolin-8(4H)-one 1,1-Dioxide (46).3-Amino-
4-ch lor oben za ld eh yd e. 4-Chloro-3-nitrobenzaldehyde (4.00
mg, 21.6 mmol) in CH2Cl2 (150 mL) at 23 °C was treated with
water (50 mL) and N,N′-diheptyl-4,4′-bipyridinium dibromide
(220 mg, 10 mg/mmol of substrate). The biphasic mixture was

Sulfonyldihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3175
[3-nitro-4-(trifluoromethyl)phenyl]methanol (3.6 g, 20% yield):
1H NMR (CDCl3) δ 4.9 (s, 2H), 7.7 (d, 1H), 7.8 (d, 1H), 7.9 (s,
1H).
(-)-(9S)-(4-Ch lor o-3-flu or op h en yl)-2,3,5,6,7,9-h exa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (52).4-Chlo-
ro-3-fluorobenzaldehyde (0.95 g, 6.0 mmol) was treated ac-
cording to method A to provide the racemic title compound:
[3-Am in o-4-(tr iflu or om eth yl)ph en yl]m eth an ol. The prod-
uct from above (3.6 g, 16.28 mmol) in MeOH (100 mL) was
hydrogenated in the presence of a catalytic amount of Pd/C
for 4 h. The catalyst was filtered off, and the volatiles were
evaporated to yield 2.7 g of [3-amino-4-(trifluoromethyl)phenyl]-
methanol: 1H NMR (CDCl3) δ 4.62 (s, 2H), 6.75 (m, 2H), 7.5
(d, 1H).
1
mp >250; H NMR (DMSO-d6) δ 1.90 (m, 2H), 2.26 (m, 2H),
2.54 (m, 2H), 2.86 (m, 1H), 3.02 (m, 1H), 3.38 (m, 2H), 4.86 (s,
1H), 7.05 (dd, 1H, J ) 1.5,9.0 Hz), 7.14 (dd, 1H, J ) 1.5;9.0
Hz), 7.48 (t, 1H, J ) 9.0 Hz), 9.85 (s, 1H); MS (ESI+) m/z 368
(M + H)+. The racemate was chromatographed on a 2 × 25
cm Regis Whelk-O1 column, eluting with hexane:MeOH:CH2-
Cl2 (60:27:13) as the mobile phase at a flow rate of 10 mL/min
to provide compound 52, the less polar enantiomer: mp > 250;
[3-Br om o-4-(tr iflu or om eth yl)ph en yl]m eth an ol.[3-Amino-
4-(trifluoromethyl)phenyl]methanol (0.76 g, 4 mmol) in water
(8 mL) at 0 °C was treated with concentrated H2SO4 (3 mL)
and then treated dropwise with an aqueous solution of NaNO2
(0.41 g, 6 mmol), and the temperature was kept below 10 °C.
After stirring for 1 h, this solution was added to a solution of
CuBr (0.85 g, 5 mmol) in 48% HBr (50 mL). The reaction
mixture was heated at 60 °C for 3 h, cooled to room temper-
ature, and partitioned between water and EtOAc. The organic
layer was washed with aqueous Na2CO3, dried (MgSO4), and
concentrated to provide [3-bromo-4-(trifluoromethyl)phenyl]-
methanol contaminated with approximately 30% of 2-bromo-
4-(bromomethyl)-1-(trifluoromethyl)benzene.
[R]20 -77.1° (DMSO); 1H NMR (DMSO-d6) δ 1.90 (m, 2H),
D
2.26 (m, 2H), 2.54 (m, 2H), 2.86 (m, 1H), 3.02 (m, 1H), 3.38
(m, 2H), 4.86 (s, 1H), 7.05 (dd, 1H, J ) 1.5, 9.0 Hz), 7.14 (dd,
1H, J ) 1.5;9.0 Hz), 7.48 (t, 1H, J ) 9.0 Hz), 9.85 (s, 1H); MS
(ESI+) m/z 368 (M + H)+. Anal. (C17H15ClFNO3S) C, H, N.
(9S )-(3-C y a n o -4-flu o r o p h e n y l)-2,3,5,6,7,9-h e x a h y -
d r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (53). 1,1-
Dim eth yleth yl9-(3-Br om o-4-flu or oph en yl)-8-oxo-3,5,6,7,8,9-
h exa h yd r oth ien o[3,2-b]qu in olin e-4(2H)-ca r boxyla te 1,1-
Dioxid e (40). A solution of 9-(3-bromo-4-fluorophenyl)-
2,3,5,6,7,9-hexahydrothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide
(racemic 14, 1.0 g, 2.4 mmol), Boc2O (1.0 g, 24 mmol), and
DMAP (29 mg, 0.1 mmol) in MeCN was heated to reflux for 1
h, cooled to room temperature, concentrated, and purified by
flash chromatography on silica gel (1:1 EtOAc/hexane) to
provide 900 mg of compound 40: 1H NMR (DMSO-d6) δ 1.57
(s, 9H), 1.90-2.00 (m, 2H), 2.3-2.5 (m, 2H), 3.00 (m, 2H), 3.45
(m, 2H), 3.50 (m, 2H), 4.83 (s, 1H), 7.20 (m, 1H), 7.32 (t, 1H),
7.37 (dd, 1H). Compound 40 (200 mg, 0.390 mmol) and ZnCN2
were reacted according to method D to provide the racemic
compound 53 that was chromatographed (60 mg) on a 2 × 25
cm Regis Whelk-O1 column, eluting with hexane:MeOH:CH2-
Cl2 (60:27:13) as the mobile phase at a flow rate of 10 mL/min
to provide 18 mg of the less polar enantiomer, compound 53,
as a white solid: 1H NMR (DMSO-d6) δ 1.8-2.0 (m, 2H), 2.19-
2.30 (m, 2H), 2.51 (m, 2H), 2.85 (m, 2H), 2.9-3.1 (m, 2H), 4.91
(s, 1H), 7.40 (t, 1H, J ) 8.83 Hz), 7.60-7.76 (m, 2H), 9.98 (s,
1H); MS (ESI+) m/z 359 (M + H)+. Anal. (C18H15FN2O3S‚
0.5H2O) C, H, N.
9-(4-F lu o r o -3-m e t h y lp h e n y l)-2,3,5,6,7,9-h e x a h y -
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (54).3-Meth-
yl-4-fluorobenzaldehyde34 (77 mg, 0.56 mmol), dihydrothiophen-
3(2H)-one 1,1-dioxide (68 mg, 0.51 mmol), 3-aminocyclohex-
2-en-1-one (55 mg, 0.50 mmol), and Et3N (35 µL) were heated
in EtOH (2 mL) to 80 °C in a sealed tube for 48 h and cooled,
and the solvent was evaporated. The crude reaction product
was flash chromatographed over silica gel (MeOH:CH2Cl2 7:93)
to provide 92 mg of an intermediate hemiaminal that was
heated to reflux in EtOH (6 mL), treated with 1.0 M HCl/Et2O
(0.5 mL), heated for 1 h, and cooled, and the solid precipitate
was collected, washed with EtOH, and dried to provide 55 mg
of compound 54 as a white solid: mp >260 °C; 1H NMR
(DMSO-d6) δ 1.70-1.98 (m, 2H), 2.22 (m, 2H), 2.54 (m, 2H),
2.80 (dt, 1H), 2.99 (dt, 1H), 3.33 (t, 2H), 4.80 (s, 1H), 6.91-
7.07 (m, 3H), 9.74 (br s, 1H); MS (APCI-) m/z 346 (M - H)-.
Anal. (C18H18FNO3S) C, H, N.
3-Br om o-4-(tr iflu or om eth yl)ben za ld eh yd e. The crude
product from above in CHCl3 (100 mL) was treated with MnO2
(1.1 g, 12.6 mmol), stirred overnight, filtered, and concentrated.
The residue was chromatographed on silica gel (15% EtOAc/
hexanes) to provide 0.28 g of 3-bromo-4-(trifluoromethyl)-
benzaldehyde: 1H NMR (CDCl3) δ 7.9 (m, 2H), 8.2 (s, 1H),
10.02 (s, 1H). 3-Bromo-4-trifluoromethyl-benzaldehyde (0.35
g,1.5 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide (0.2 g, 1.5
mmol), and 3-amino-2-cyclohexene-1-one (0.17 g, 1.5 mmol)
were heated in EtOH (4 mL) to 80 °C in a sealed tube for 2 d.
The reaction mixture was cooled, solvent evaporated, and the
residue flash chromatographed on silica gel (10% EtOH/CH2-
Cl2 to give a hemiaminal (0.37 g) that was suspended in EtOH
(30 mL) and heated to reflux for 3 h with 1 M HCl/Et2O (1
mL). The reaction mixture was concentrated and chromato-
graphed on silica gel (10% EtOH/CH2Cl2) to yield 0.27 g of the
title compound as a racemate. Separation of enantiomers was
accomplished on a Welk-O1 column, eluting with CH2Cl2:
MeOH:hexane (5:10:85) to yield 0.09 g of compound 48 as the
less polar enantiomer: [R]20D -34.0° (DMSO); 1H NMR (DMSO)
δ 1.9 (m, 2H), 2.23 (m, 2H), 2.58 (m, 2H), 2.85 (m, 2H), 3.0.5
(m, 2H), 4.9 (s, 1H), 7.49 (d, 1H), 7.6 (s, 1H), 7.72 (d, 1H), 9.89
(s, 1H); MS (ESI-) m/z 462 (M - 1)- Anal. (C18H15NBrF3O3S)
C, H, N.
(-)-(9S)-(4-Meth yl-3-n itr oph en yl)-2,3,5,6,7,9-h exah ydr o-
[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e (49). 4-Methyl-3-
nitrobenzaldehyde (165 mg, 1.00 mmol) was treated according
to method A to provide 196 mg of the racemic title compound:
1H NMR (DMSO-d6) δ 1.88 (m, 2H), 2.23 (m, 2H), 2.45 (s, 3H),
2.56 (m, 2H), 2.85 (dtd, 1H), 3.03 (dt, 1H), 3.35 (m, 2H), 4.93
(s, 1H), 7.36 (d, 1H), 7.45 (dd, 1H), 7.72 (d, 1H), 9.83 (br s,
1H); MS (APCI) m/e 375 (M + H)+. Anal. Calcd for C18H18N2O5S‚
0.25H2O: C, 57.06; H, 4.92; N, 7.39. Found: C, 57.24; H, 4.77;
N, 7.23. The racemic title compound (1.24 g, 3.32 mmol) was
separated into the individual enantiomers using the HPLC
conditions for compound 14 to provide 63 mg of compound 49,
(-)-(9S)-[4-Flu or o-3-(tr iflu or om eth yl)ph en yl]-2,3,5,6,7,9-
h exa h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e
(55). 4-Fluoro-3-trifluoromethylbenzaldehyde (1.9 g, 5.4 mmol)
was treated according to methods A and C to provide 312 mg
of compound 55: mp >250 °C; [R]23D -50.26 (c ) 0.59, DMSO);
1H NMR (DMSO-d6) δ 1.90 (m, 2H), 2.23 (m, 2H), 2.56 (m,
2H), 2.88 (m, 1H), 3.05 (m, 1H), 3.35 (t, 2H, J ) 9 Hz), 4.92 (s,
1H), 7.38 (m, 1H), 7.51 (m, 2H), 9.95 (s, 1H); MS (ESI+) m/z
402 (M + H)+. Anal. (C18H15F4NO3S) C, H, N.
9-[4-Me t h y l-3-(m e t h y ls u lfa n y l)p h e n y l]-2,3,5,6,7,9-
h exa h yd r ot h ien o[3,2-b]q u in olin -8(4H )-on e 1,1-Dioxid e
(56). 2-(3-Br om o-4-m eth ylp h en yl)-1,3-d ioxola n e. To a so-
lution of 3-bromo-4-methylbenzaldehyde (10.0 g, 50.5 mmol)
in benzene (100 mL) was added ethylene glycol (10 mL) and
p-TsOH (0.05 g). The reaction was heated at reflux for 4 h
and water was removed as an azeotrope with benzene using a
the less polar enantiomer, as a white solid: [R]20 -39.3°
D
(DMSO); 1H NMR (DMSO-d6) δ 1.82 (m, 1H), 1.90 (m, 1H),
2.23 (m, 2H), 2.45 (s, 3H), 2.54 (m, 2H), 2.84 (dt, 1H), 3.03 (dt,
1H), 3.35 (m, 2H), 4.91 (s, 1H), 7.37 (d, 1H), 7.45 (dd, 1H),
7.71 (d, 1H), 9.87 (br s, 1H); MS (APCI-) m/z 373 (M - H)-.
Anal. (C18H18N2O5S) C, H, N.
9-(4-Eth yl-3-n itr op h en yl)-2,3,5,6,7,9-h exa h yd r oth ien o-
[3,2-b]qu in olin -8(4H) -on e 1,1-Dioxid e (50). 4-Ethyl-3-
nitrobenzaldehyde33 (0.165 g, 1.00 mmol) was treated according
to method A to provide 0.145 g of compound 50: 1H NMR
(DMSO-d6) δ 1.18 (t, 3H),1.88 (m, 2H), 2.25 (m, 2H), 2.53 (m,
2H),2.75 (q, 2H),2.85 (m, 1H), 3.0 (m, 1H), 4.91 (s, 1H), 7.39
(d, 1H), 7.47 (dd, 1H), 7.62 (d, 1H), 9.84 (s, 1H); MS (ESI-)
m/z 387 (M - H)-. Anal. (C19H20N2O5S) C, H, N.

3176 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
Dean-Stark apparatus. The reaction was cooled to room
temperature, diluted with EtOAc (100 mL), and quenched with
aqueous NaHCO3. The organic layer was dried (Na2SO4),
filtered, and concentrated to provide 11.5 g of 2-(3-bromo-4-
methylphenyl)-1,3-dioxolane as an oil: 1H NMR (DMSO-d6) δ
2.35 (s, 3H), 3.91-4.07 (m, 4H), 5.71 (s, 1H), 7.32-7.39 (m,
2H), 7.60 (d, J ) 1.5 Hz, 1H).
2-[4-Meth yl-3-(m eth ylsu lfa n yl)p h en yl]-1,3-d ioxola n e.
To a solution of the dioxolane product from above (6.95 g, 28.7
mmol) in dry THF (100 mL) at -78 °C was added n-BuLi (19.7
mL of 1.6 M, 31.5 mmol), and the reaction stirred for 30 min
at -78 °C, at which point a solution of Me2S2 (4.05 g, 43.0
mmol) in THF (10 mL) was added dropwise over 10 min. The
reaction was allowed to stir at -78 °C for 30 min and then
warmed to room temperature, quenched with saturated aque-
ous NaHCO3, and extracted with EtOAc (2 × 50 mL). The
organic layer was dried (Na2SO4), filtered, and concentrated
to provide 5.0 g of 2-[4-methyl-3-(methylsulfanyl)phenyl]-1,3-
dioxolane: 1H NMR (DMSO-d6) δ 2.24 (s, 3H), 2.46 (s, 3H),
3.91-4.07 (m, 4H), 5.70 (s, 1H), 7.12 (dd, J ) 7.8, 1.5 Hz, 1H),
7.20 (d, J ) 7.8 Hz, 1H), 7.22 (d, J ) 1.5 Hz, 1H).
4-Meth yl-3-(m eth ylsu lfa n yl)ben za ld eh yd e. To a solu-
tion of the above product (1.4 g, 6.7 mmol) in MeCN (50 mL)
was added 2.0 M HCl (50 mL) and the reaction mixture was
allowed to stir for 2 h at room temperature. The reaction
mixture was poured onto a mixture of ice and saturated
aqueous NaHCO3 and diluted with EtOAc, and the layers were
separated. The organic layer was dried (Na2SO4), concentrated,
and purified by flash chromatography (hexanes/EtOAc 5:1) to
provide 1.1 g of 4-methyl-3-(methylsulfanyl)benzaldehyde: 1H
NMR (DMSO-d6) δ 2.32 (s, 3H), 2.55 (s, 3H), 7.42 (d, J ) 7.8
Hz, 1H), 7.60 (dd, J ) 7.8, 1.5 Hz, 1H), 7.70 (d, J ) 1.5 Hz,
1H), 9.98 (s, 1H). The aldehyde product from above (0.77 g,
4.64 mmol) was treated according to method A to provide 0.725
g compound 56: 1H NMR (DMSO-d6) δ 1.78-1.96 (m, 2H), 2.13
(s, 3H), 2.19-2.25 (m, 2H), 2.39 (s, 3H), 2.48-2.55 (m, 2H),
2.75-2.85 (m, 1H), 2.94-3.04 (m, 1H), 3.25-3.38 (m, 2H), 4.84
(s, 1H), 6.82 (dd, 1H, J ) 7.5,2.0 Hz), 7.00 (d, 1H, J ) 2.0 Hz),
7.01 (d, 1H, J ) 7.5 Hz), 9.71 (s, 1H); MS (ESI+) m/z 376 (M
+ H)+. Anal. (C19H21NO3S2‚0.2H2O) C, H, N.
9-[4-Me t h y l-3-(m e t h y ls u lfo n y l)p h e n y l]-2,3,5,6,7,9-
h exa h yd r ot h ien o[3,2-b]q u in olin -8(4H )-on e 1,1-Dioxid e
(57). 4-Meth yl-3-(m eth ylsu lfon yl)ben za ld eh yd e. To a solu-
tion 2-[4-methyl-3-(methylsulfanyl)phenyl]-1,3-dioxolane (see
previous text) (3.6 g, 17.1 mmol) in CH2Cl2 (100 mL) at 0 °C
was added mCPBA (11.81 g, 68.4 mmol) and the reaction
stirred for 30 min at 0 °C. The reaction was quenched with
saturated aqueous NaHCO3, and the organic layer was dried
(Na2SO4), filtered, and concentrated to provide 3.8 g of an
intermediate sulfone (3.8 g, 15.7 mmol) that was dissolved in
MeCN (50 mL) and treated with 2.0 M HCl (50 mL). The
reaction mixture was stirred for 2 h at room temperature,
quenched in cold, saturated aqueous NaHCO3, extracted with
EtOAc, dried (Na2SO4), filtered, concentrated, and purified by
flash chromatography (hexanes/EtOAc 2:1) to provide 2.2 g of
4-methyl-3-(methylsulfonyl)benzaldehyde: 1H NMR (DMSO-
d6) δ 2.75 (s, 3H), 3.30 (s, 3H), 7.72 (d, J ) 7.8 Hz, 1H), 8.13
(dd, J ) 7.8, 1.7 Hz, 1H), 8.41 (d, J ) 1.7 Hz, 1H), 10.07 (s,
1H). The aldehyde product from above (0.80 g, 4.04 mmol) was
treated according to method A to provide 0.425 g of the title
compound as a white solid: 1H NMR (DMSO-d6) δ 1.83-1.99
(m, 2H), 2.16-2.26 (m, 2H), 2.50-2.60 (m, 2H), 2.56 (s, 3H),
2.78-2.88 (m, 1H), 2.94-3.04 (m, 1H), 3.13 (s, 3H), 3.29-3.39
(m, 2H), 4.90 (s, 1H), 7.32 (d, 1H, J ) 7.8 Hz), 7.39 (dd, 1H, J
) 7.8, 2.0 Hz), 7.73 (d, 1H, J ) 2.0 Hz), 9.81 (s, 1H); MS (ESI+)
m/z 408 (M + H)+. Anal. (C19H21NO5S2‚H2O) C, H, N.
(m, 1H), 3.00 (m, 1H), 3.86 (q, 2H, J ) 7.01 Hz), 4.48 (d, 1H,
J ) 2.5 Hz), 4.55 (d, 1H, J ) 2.5 Hz), 4.83 (s, 1H), 7.03-7.20
(m, 2H), 7.41 (dd, 1H, J ) 7.31, 1.90 Hz), 9.78 (s, 1H); MS
(ESI+) m/z 404 (M + H)+. Anal. Calcd for C21H22FNO4S: C,
62.51; H, 5.50; N, 3.47. Found: C, 59.95; H, 5.28; N, 3.13. The
intermediate enol ether from above (108 mg, 0.27 mmol) in
Et2O at 0 °C was treated with 1.0 M HCl/Et2O (1 mL, 1 mmol),
stirred for 2 h, treated with saturated NaHCO3, and extracted
with EtOAc. The residue was purified by flash chromatography
on silica gel eluting with 5% MeOH/CH2Cl2, followed by
recrystallization from EtOH, to provide 93 mg of compound
58. 1H NMR (DMSO-d6) δ 1.8 (m, 2H), 2.2 (m, 2H), 2.5 (m,
2H), 2.55 (s, 3H), 2.8 (m, 2H), 3.0 (m, 2H), 4.89 (s, 1H), 7.21
(dd, 1H, J ) 8.5, 2.94 Hz), 7.48 (m, 1H), 7.60 (m, 1H), 9.82 (s,
1H); MS (ESI+) m/z 376 (M + H)+. Anal. (C19H18FNO4S‚
0.25H2O) C, H, N.
(-)-(9S)-[4-Flu or o-3-(2-fu r yl)p h en yl]-2,3,5,6,7,9-h exa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (60). Com-
pound 40 (200 mg, 0.39 mmol) and 2-(tributylstannyl)furan
were processed by method D to provide 64 mg of the racemic
title compound: 1H NMR (DMSO-d6) δ 1.96 (m, 2H), 2.2 (m,
2H), 2.5 (m, 2H), 2.8 (m, 2H), 3.0 (m, 2H), 4.88 (s, 1H), 6.6
(dd, 1H, J ) 3.31, 1.47 Hz), 6.81 (t, 1H, J ) 3.68 Hz), 7.15 (m,
2H), 7.58 (dd, 1H, J ) 7.19, 2.21 Hz), 7.85 (d, 1H, J ) 1.8 Hz),
9.80 (s, 1H); MS (ESI+) m/z 400 (M + H)+. The racemic
compound was chromatographed on a 2 × 25 cm Regis Whelk-
O1 column, eluting with hexane:MeOH:CH2Cl2 (78:14:8) as the
mobile phase at a flow rate of 10 mL/min to provide 40 mg of
compound 60, the less polar enantiomer, as a white solid:
1
[R]20 -54.95° (DMSO); H NMR (DMSO-d6) δ 1.96 (m, 2H),
D
2.2 (m, 2H), 2.51 (m, 2H), 2.82 (m, 2H), 3.03 (m, 2H), 4.88 (s,
1H), 6.6 (dd, 1H, J ) 3.31, 1.47 Hz), 6.81 (t, 1H, J ) 3.68 Hz),
7.15 (m, 2H), 7.58 (dd, 1H, J ) 7.19, 2.21 Hz), 7.85 (d, 1H, J
) 1.8 Hz), 9.80 (s, 1H); MS (ESI+) m/z 400 (M + H)+. Anal.
(C21H18FNO4S‚0.5H2O) C, H, N.
9-[4-F lu or o-3-(2-t h ie n yl)p h e n yl]-2,3,5,6,7,9-h e xa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (61). Com-
pound 40 (200 mg, 0.39 mmol) and 2-(tributylstannyl)-
thiophene were processed by method D to provide 119 mg of
compound 61 as a white solid: 1H NMR (DMSO-d6) δ 1.9 (m,
2H), 2.22 (m, 2H), 2.52 (m, 2H), 2.86 (m, 2H), 3.00 (m, 2H),
4.90 (s, 1H), 7.08-7.21 (m, 4H), 7.48-7.51 (m, 2H), 7.66 (d,
1H, J ) 5.15 Hz), 9.81 (s, 1H); MS (ESI+) m/z 333 (M + H)+.
Anal. (C21H18FNO3S2) C, H, N.
9-[4-F lu or o-3-(3-p yr id in yl)p h en yl]-2,3,5,6,7,9-h exa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (62). Com-
pound 40 (200 mg, 0.390 mmol) and 3-(tributylstannyl)pyridine
were processed by method D to provide 89 mg of compound
62 as a white solid: 1H NMR (DMSO-d6) δ 1.8-1.95 (m, 2H),
2.20-2.30 (m, 2H), 2.8 (m, 1H), 3.0 (m, 1H), 4.95 (s, 1H), 7.20-
7.30 (m, 2H), 7.34 (d, 1H, J ) 7.5 Hz), 7.52 (d, 1H, J ) 7.5
Hz), 7.92 (m, 1H), 8.61 (m, 1H), 8.68 (s, 1H), 9.79 (s, 1H); MS
(ESI+) m/z 411 (M + H)+. Anal. (C22H19FN2O3S 0.75H2O) C,
H, N.
9-[6-F lu or o-(1,1′-b ip h e n yl)-3-yl]-2,3,5,6,7,9-h e xa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (63). Com-
pound 40 (200 mg, 0.39 mmol) and tetraphenyltin were
processed by method D to provide 95 mg of compound 63: 1H
NMR (DMSO-d6) δ 1.90 (m, 2H), 2.25 (m, 2H), 2.5 (m, 2H),
2.8 (m, 2H), 3.0 (m, 2H), 4.92 (s, 1H), 7.16 (m, 1H), 7.18 (s,
1H), 7.27 (d, 1H, J ) 6.6 Hz), 7.40 (m, 1H), 7.48 (s, 2H), 7.49
(s, 2H), 9.77 (s, 1H); MS (ESI+) m/z 410 (M + H)+. Anal.
(C23H20FNO3S H2O) C, H, N.
(-)-(9S)-(2,1,3-Ben zoxa d ia zol-5-yl)-2,3,5,6,7,9-h exa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (64). 2,1,3-
Benzoxadiazole-5-carboxaldehyde35 (0.296 g, 2.00 mmol) was
treated according to method A to provide 0.42 g of the racemic
title compound: 1H NMR (DMSO-d6) δ 1.9 (m, 2H), 2.25 (m,
2H), 2.55 (m, 2H), 2.88 (m, 1H), 3.05 (m, 1H), 3.4 (m, 2H), 5.0
(s, 1H), 7.51 (d, 1H), 7.7 (s, 1H), 7.95 (d, 1H), 9.96 (s, 1H); MS
(ESI+) m/z 358 (M + H)+. The racemate (1.34 g) was processed
9-(3-Acetyl-4-flu or oph en yl)-2,3,5,6,7,9-h exah ydr oth ien o-
[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxide (58). 9-[3-(1-Eth oxy-
vin yl)-4-flu or oph en yl]-2,3,5,6,7,9-h exa h ydr oth ien o[3,2-b]-
qu in olin -8(4H)-on e 1,1-Dioxid e. Compound 40 (100 mg,
0.195 mmol) and tributyl(1-ethoxyvinyl)tin were processed by
method D to provide 54.2 mg of the title compound as a white
solid: 1H NMR (DMSO-d6) δ 1.10 (m, 2H), 1.32 (t, 3H, J )
7.01 Hz), 1.60 (m, 2H), 1.80-1.99 (m, 2H), 2.2 (m, 2H), 2.80
according to method C to provide 110 mg of compound 64 as
1
a white solid: [R]23 -41.7° (DMSO); H NMR (DMSO-d6) δ
D
1.9 (m, 2H), 2.25 (m, 2H), 2.57 (m, 2H), 2.9 (m, 1H), 3.05 (m,

Sulfonyldihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3177
1H), 3.4 (m, 2H), 5.0 (s, 1H), 7.51 (d, 1H), 7.7 (s, 1H), 7.95 (d,
1H), 9.95 (s, 1H); MS (ESI-) m/z 356 (M - H)-. Anal.
(C17H15N3O4S) C, H, N.
9-[4,5-Dich lor o-2-(h yd r oxym et h yl)p h en yl]-2,3,5,6,7,9-
h exa h yd r oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-Dioxid e
(68). To 5,6-dichloro-3H-isobenzofuran-1-one37 (6.0 g, 29.5
mmol) in toluene (500 mL) at -78 °C was added DIBAL (42.4
mL, 1.0 M in toluene) dropwise over 30 min. The reaction was
stirred for 4 h and quenched with sat. Rochelle’s salt (150 mL).
After warming to room temperature, the solution was filtered,
the solvent was removed in vacuo, and the residue partitioned
between CH2Cl2 (200 mL) and water (200 mL). The organic
layer was washed twice with water and brine and dried
(MgSO4) before filtration and concentration to give the crude
aldehyde as a white solid (3.75 g, 62%). The lactol:hydroxyal-
dehyde ratio determined by proton NMR was 2:1. The aldehyde
(1.50 g, 7.32 mmol), tetrahydrothiophene-3-oxo-1,1-dioxide
(0.98 g, 7.32 mmol), 3-amino-2-cyclohexene-1-one (0.81 g, 7.32
mmol), and Et3N (1 mL) in EtOH (40 mL) were heated to reflux
for 13 h. The red solution was concentrated in vacuo and the
residue partitioned between EtOAc (100 mL) and water (50
mL). The organic layer was dried (Na2SO4) before filtration
and concentration to give a yellow-white solid that was
dissolved in EtOH (30 mL), treated with 1.0 M HCl/Et2O (1
mL), and stirred for 2 h. The solvent was evaporated to give a
white solid which was washed with EtOAc and MeOH and
dried to give 1.08 g of compound 68: 1H NMR (DMSO) δ 1.86
(m, 2H), 2.21 (m, 2H), 2.50-2.62 (m, 2H), 2.82 (m, 1H), 3.00
(m, 1H), 3.33 (m, 2H), 3.92 (1H, br s), 4.75 (d, 1H), 4.78 (s,
1H), 5.04 (d, 1H), 7.16 (s, 1H), 7.54 (s, 1H), 9.88 (s, 1H); MS
(DCI) m/z 431 (30, M + NH3), 414 (10, M+), 187 (100). Anal.
Calcd for C18H17Cl2NO4S 0.5H2O: C, 50.01; H, 4.43. Found:
C, 50.46; H, 4.27.
(9S )-(2,1,3-Be n zot h ia d ia zol-5-yl)-2,3,5,6,7,9-h e xa h y-
dr oth ien o[3,2-b]qu in olin -8(4H)-on e 1,1-dioxide (65). 5-Br o-
m om et h ylb en zo-2,1,3-t h ia d ia zole. 5-Methylbenzo-2,1,3-
thiadiazole (5.0 g, 33 mmol), NBS (5.92 g, 33.3 mmol), and
catalytic AIBN were heated at reflux for 16 h in CHCl3 (75
mL). The reaction mixture was cooled and the resulting
precipitate was filtered off and discarded. The filtrate was
evaporated and recrystallized from EtOH to provide 4.8 g of
5-bromomethylbenzo-2,1,3-thiadiazole: 1H NMR (CDCl3) 4.65
(s, 2H), 7.65 (dd, 1H), 8.01 (d, 2H).
5-Hyd r oxym eth ylben zo-2,1,3-th ia d ia zole. 5-Bromome-
thylbenzo-2,1,3-thiadiazole (4.8 g) and CaCO3 (10 g) were
heated at reflux in 1:1 dioxane/water (120 mL) for 3 h. The
solvents were evaporated, and the residue was partitioned
between 2 N HCl and CH2Cl2. The organic layers were dried
(MgSO4), evaporated, and chromatographed on silica gel
(EtOAc/hexane) to provide 2.66 g of 5-hydroxymethylbenzo-
2,1,3-thiadiazole: 1H NMR (CDCl3) 1.92 (t, 1H), 4.9 (d, 1H),
7.6 (dd, 1H), 8.0 (m, 2H).
2,1,3-b en zot h ia d ia zole-5-ca r b oxa ld eh yd e. 5-Hydroxy-
methylbenzo-2,1,3-thiadiazole (2.6 g, 16 mmol) and MnO2 (6.0
g, 64 mmol) in CHCl3 (150 mL) were stirred at room temper-
ature overnight. The reaction mixture was filtered and the
filtrate evaporated to provide 1.9 g of 2,1,3-benzothiadiazole-
5-carboxaldehyde: 1H NMR (CDCl3) 8.12 (s, 2H), 8.51 (m, 1H),
10. 21 (s, 1H). 2,1,3-Benzothiadiazole-5-carboxaldehyde (0.33
g, 2 mmol) was treated according to method A to provide 0.35
g of racemic 9-(2,1,3-benzothiadiazol-5-yl)-2,3,5,6,7,9-hexahy-
drothieno[3,2-b]quinolin-8(4H)-one 1,1-dioxide: 1H NMR (DM-
SO-d6) δ 1.87 (m, 2H), 2.22 (m, 2H), 2.56 (m, 2H), 2.87 (m,
1H), 3.05 (m, 1H), 3.32 (m, 2H), 5.06 (s, 1H), 7.61 (dd, 1H),
7.75 (s, 1H), 7.98 (d, 1H), 9.89 (s, 1H); MS (ESI-) m/z 372 (M
- H)-. The racemate (0.14 g) was chromatographed on a Regis
Whelk-O1 chiral column eluting with hexane:MeOH:CH2Cl2
(65:24:11) to provide 0.06 g of compound 65 as the less polar
enantiomer: [R]20D -36.4° (DMSO); 1H NMR (DMSO-d6) δ 1.9
(m, 2H), 2.22 (m, 2H), 2.48 (m, 2H), 2.88 (m, 1H), 3.04 (m,
1H), 5.05 (s, 1H), 7.61 (dd, 1H), 7.75 (s, 1H), 7.98 (d, 1H), 9.9
(s, 1H); MS (ESI) m/z 372 (M - H)-. Anal. (C17H15N3O3S2) C,
H, N.
(-)-(9S)-(3-Cya n op h en yl)-2,3,5,6,7,9-h exa h yd r oth ien o-
[3,2-b]qu in olin -8(4H) -on e 1,1-Dioxid e (69). 3-Cyanobenz-
aldehyde (136 mg, 1.04 mmol) was treated according to the
method A to provide 160 mg of the racemic title compound as
a white solid: 1H NMR (DMSO-d6) δ 1.88 (m, 2H), 2.22 (m,
2H), 2.56 (m, 2H), 2.85 (dtd, 1H), 3.03 (dt, 1H), 3.36 (m, 2H),
4.90 (s, 1H), 7.45 (td, 1H), 7.54 (dd, 1H), 7.56 (d, 1H), 7.61
(dd, 1H), 9.81 (br s, 1H); MS (APCI) m/e 341 (M + H)+. Anal.
Calcd for C18H16N2O3S: C, 63.51; H, 4.73; N, 8.22. Found: C,
63.31; H, 4.61; N, 8.19. Racemate (1.27 g) was processed
according to method C to provide 280 mg of compound 69: mp
1
>250 °C; [R]23 -33.77, (c ) 0.53, DMSO); H NMR (DMSO-
D
d6) δ 1.85 (m, 2H), 2.20 (m, mH, J ) 2 Hz), 2.55 (m, 2H), 2.85
(m, 1H), 3.05 (m, 1H), 3.32 (m, 2H), 4.90 (s, 1H), 7.45 (t, 1H,
J ) 7.5 Hz), 7.55 (d, 2H, J ) 9 Hz), 7.62 (d, 1H, J ) 7.5 Hz),
10.45 (s, 1H); MS (ESI+) m/z 341 (M + H)+. Anal. (C18H16N2O3S)
C, H, N.
9-(5-B r o m o -4-flu o r o -2-h y d r o x y p h e n y l)-2,3,5,6,7,9-
h exa h yd r ot h ien o[3,2-b]q u in olin -8(4H )-on e 1,1-Dioxid e
(66). 4-F lu or o-5-br om o-2-h yd r oxyben za ld eh yd e. 4-Fluoro-
2-hydroxybenzaldehyde36 (2.00 g, 14.3 mmol) in CHCl3 (10 mL)
was treated slowly with a solution of Br2 (0.70 mL, 13 mmol)
in CHCl3 (6 mL) at room temperature. After the free Br2 had
disappeared, the mixture was refluxed with 20% NaOH (20
mL) for 4 h and cooled, the CHCl3 evaporated, and the solid
was dissolved in EtOAc and acidified with 1 N HCl (pH ) 5).
The solvents were evaporated, and the crude product was
purified by flash chromatography over silica gel (hexane:EtOAc
6:1) to provide 1.95 g of 4-fluoro-5-bromo-2-hydroxybenzalde-
hyde: 1H NMR (CDCl3) δ 6.78 (d, 1H, J ) 9 Hz), 7.75 (d, 1H,
J ) 9 Hz), 9.80 (s, 1H), 11.25 (s, 1H); MS (ESI+) m/z 219 (M +
H)+. The aldehyde from above (657 mg, 3.00 mmol) was treated
according to method A to provide 1.1 g of compound 66: mp
9-(3-Br om op h en yl)-2,3,5,6,7,9-h exa h yd r oth ien o[3,2-b]-
qu in olin -8(4H)-on e 1,1-Dioxid e (70). 3-Bromobenzaldehyde
was treated according to method A to provide compound 70:
1H NMR (DMSO) δ 1.89 (m, 2H), 2.21 (m, 2H), 2.55 (m, 2H),
2.82 (m, 1H), 3.0 (m, 1H), 3.32 (m, 2H), 4.81 (s, 1H), 7.18 (m,
1H), 7.3 (m, 2H), 9.8 (s, 1H); MS (ESI-) m/z 394 (M - H)-.
Anal. (C17H16NBrO3S) C, H, N.
9-(4-Br om op h en yl)-2,3,5,6,7,9-h exa h yd r oth ien o[3,2-b]-
qu in olin -8(4H)-on e 1,1-Dioxid e (71). 4-Bromobenzaldehyde
was treated according to method A to provide compound 71:
1H NMR (DMSO) δ 1.88 (m, 2H), 2.2 (m, 2H), 2.52 (m, 2H),
2.81 (m, 1H), 2.97 (m, 1H), 3.32 (m, 2H), 4.8 (s, 1H), 7.12 (d,
2H), 7.4 (d, 2H), 9.78 (s, 1H),; MS (ESI-) m/z 394 (M - H)-.
Anal. (C17H16NBrSO3) C, H, N.
1
>250 °C; H NMR (DMSO-d6) δ 1.90 (m, 2H), 2.25 (m, 2H),
2.55 (m, 2H), 2.80 (m, 1H), 2.92 (m, 1H), 3.26 (t, 2H, J ) 7.5
Hz), 5.10 (s, 1H), 6.6 (d, 1H, J ) 12 Hz), 7.05 (d, 1H, J ) 9
Hz), 9.70 (s, 1H), 10.25 (s, 1H); MS (ESI+) m/z 429 (M + H)+.
Anal. (C17H15BrFNO4S) C, H, N.
8-(6-Cya n o-2-p yr id in yl)-2,3,4,5,6,8-h exa h yd r o-7H -cy-
clop en t a [b]t h ien o[2,3-e]p yr id in -7-on e 1,1-Dioxid e (72).
2-Cyano-6-formylpyridine38 (140 mg, 1.06 mmol) was treated
as in example 75 to provide 40 mg of compound 72 as a gray
powder: 1H NMR (DMSO) δ 2.32 (t, 2H), 2.6-3.1 (m, 4H), 3.4
(m, 2H), 5.77 (s, 1H), 7.65 (d, 1H), 7.88 (d, 1H), 7.95 (t, 1H),
10.37 (s, 1H); MS (APCI) m/z 328 (M + H)+ Anal. (C16H13N3O3S‚
0.25H2O‚0.05HCl) C, H, N.
8-(4-Cya n o-2-p yr id in yl)-2,3,4,5,6,8-h exa h yd r o-7H -cy-
clop en t a [b]t h ien o[2,3-e]p yr id in -7-on e 1,1-Dioxid e (73).
4-Cyano-2-pyridinecarboxaldehyde37 (40 mg, 0.30 mmol) was
treated as in Example 75 with the solvent for the second step
being 15% MeOH/CH2Cl2 to provide 11 mg of compound 73 as
9-(5-B r o m o -2-h y d r o x y p h e n y l)-2,3,5,6,7,9-h e x a h y -
dr oth ien o[3,2-b]qu in olin -8 (4H)-on e 1,1-Dioxide (67). 5-Bro-
mosalicylaldehyde (0.201 g, 1.0 mmol) was treated according
to method A to provide 0.13 g of compound 67 as an orange-
yellow solid: 1H NMR (DMSO-d6) δ 1.74-2.0 (m, 2H), 2.23
(m, 2H), 2.56 (m, 2H), 2.78 (dt, 1H), 2.95 (dt, 1H), 3.28 (t, 2H),
5.11 (s, 1H), 6.63 (d, 1H), 6.97 (d, 1H), 7.07 (dd, 1H), 9.70 (s,
1H), 9.73 (s, 1H); MS (APCI-) m/z 408 (M - H)-. Anal. (C17H16
BrNO4S) C, H, N.
-

3178 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
1
a brown solid: mp 160 °C (dec); H NMR (DMSO) δ 2.31 (m,
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal struc-
ture analysis of compounds 11, 13, and 16. This material is
available free of charge via the Internet at http://pubs.acs.org.
2H), 2.65 (m, 2H), 2.95 (m, 2H), 3.35 (m, 2H), 4.93 (s, 1H),
7.68 (d, 1H), 7.81 (s, 1H), 8.70 (d, 1H), 10.35 (s, 1H); MS
(APCI+) m/ z 328 (M + H)+; MS (APCI-) m/z 326 (M - H)-.
Anal. (C16H13N3O3S‚0.15CH2Cl2‚1.5CH4O) C, H, N.
8-(5-Nitr o-3-p yr id in yl)-2,3,4,5,6,8-h exa h yd r o-7H-cyclo-
p en ta [b]th ien o[2,3-e]p yr id in -7-on e 1,1-Dioxid e (74). 5-Ni-
tronicotinaldehyde38 (120 mg, 0.80 mmol) was treated as in
example 75 to provide 88 mg of compound 74 as a white solid:
Refer en ces
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(2) Brading, A. F. A Myogenic Basis for the Overactive Bladder.
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(3) Turner, W. H.; Brading, A. F. Smooth Muscle of the Bladder in
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(12) Howe, B. B.; Halterman, T. J .; Yochim, C. L.; Do, M. L.;
Pettinger, S. J .; Stow, R. B.; Ohnmacht, C. J .; Russell, K.;
Empfield, J . R.; Trainor, D. A.; Brown, F. J .; Kau, S. T. ZENECA
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Gibson, K. H.; Mayhugh, D. R.; Mclaren, F. M.; Shapiro, H. S.;
Brown, F. J .; Trainor, D. A.; Ceccarelli, C.; Lin, M. M.; Masek,
B. B.; Forst, J . M.; Harris, R. J .; Hulsizer, J . M.; Lewis, J . J .;
Silverman, S. M.; Smith, R. W.; Warwick, P. J .; Kau, S. T.; Chun,
A. L.; Grant, T. L.; Howe, B. B.; Li, J . H.; Trivedi, S.; Halterman,
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1
mp >260 °C; H NMR (DMSO) δ 2.32 (m, 2H), 2.65 (m, 2H),
3.0 (m, 2H), 3.43 (m, 2H), 5.03 (s, 1H), 8.39 (s, 1H), 8.90 (s,
1H), 9.20 (s, 1H), 10.45 (s, 1H); MS (APCI+) m/z 348 (M + H)+;
MS (APCI-) m/z 346 (M - H)-. Anal. (C15H13N3O5S) C, H, N.
8-(2-Cya n o-4-p yr id in yl)-2,3,4,5,6,8-h exa h yd r o-7H -cy-
clop en t a [b]t h ien o[2,3-e]p yr id in -7-on e 1,1-Dioxid e (75).
Dihydrothiophen-3(2H)-one 1,1-dioxide (241 mg, 1.8 mmol),
3-aminocyclopent-2-en-1-one (146 mg, 1.5 mmol), and 2-cyano-
4-pyridinecarboxaldehyde38 (200 mg, 1.5 mmol) were heated
to 40-50 °C in IPA for 3 days. Solvent was evaporated and
the crude material flash chromatographed on silica gel (10%
MeOH/CH2Cl2) to give an intermediate hemiaminal that was
redissolved in IPA, treated with 1.5 mL of 1.0 M HCl/Et2O,
and heated to 50 °C for 10 min. The solvent was evaporated
and the material triturated with Et2O to provide 63 mg of
compound 75 as a light yellow solid: mp 160 °C (dec); 1H NMR
(DMSO) δ 2.30 (t, 2H), 2.65 (m, 2H), 3.02 (m, 2H), 3.45 (t, 2H),
4.85 (s, 1H), 7.64 (d, 1H), 7.94 (s, 1H), 8.65 (d, 1H), 10.48 (s,
1H); MS (APCI); m/ z 326 (M - H)+ Anal. (C16H13N3O3S‚
0.42C4H10O‚0.14HCl) C, H, N.
2,3,4,5,6,8-H exa h yd r o-8-(5-n it r o-3-t h ien yl)-7H -cyclo-
p en ta [b]th ien o[2,3-e]p yr id in -7-on e 1,1-Dioxid e (76). 2-Ni-
trothiophene-4-carboxaldehyde (0.41 g, 2.6 mmol) was treated
according to the procedure described in example 79 to provide
0.423 g of compound 76 as a brown powder: 1H NMR (DMSO-
d6) δ 2.34 (t, 2H), 2.52-2.74 (m, 2H), 2.80-2.92 (m, 1H), 2.98-
3.11 (m, 1H), 3.43 (t, 2H), 4.84 (s, 1H), 7.78 (d, 1H), 7.94 (d,
1H), 10.39 (s, 1H); MS (APCI+) m/z 353 (M + H)+, 370 (M +
NH4)+; MS (APCI-) m/z 351 (M - H)-. Anal. (C14H12N2O5S2)
C, H, N.
8-(5-Br om o-2-th ien yl)-2,3,4,5,6,8-h exa h yd r o-7H-cyclo-
pen ta[b]th ien o[2,3-e]pyr idin -7-on e 1,1-Dioxide (77). 5-Bro-
mothiophene-2-carboxaldehyde (500 mg, 2.6 mmol) was treated
according to the procedure described for compound 79 to
provide 0.297 g of compound 77 as a brown solid: mp 246-
247 °C; 1H NMR (DMSO-d6) δ 2.35 (t, 2H), 2.52-2.73 (m, 2H),
2.78-2.90 (m, 1H), 2.95-3.08 (m, 1H), 3.41 (t, 2H), 4.92 (s,
1H), 6.73 (d, 1H), 6.97 (d, 1H), 10.39 (s, 1H); MS (APCI-) m/z
384 (M - H)-. Anal. (C14H12NO3S2Br) C, H, N.
2,3,4,5,6,8-H exa h yd r o-8-(5-n it r o-2-t h ien yl)-7H -cyclo-
p en ta [b]th ien o[2,3-e]p yr id in -7-on e 1,1-Dioxid e (78). 5-Ni-
trothiophene-2-carboxaldehyde (205 mg, 1.30 mmol) was treated
according to the procedure described for compound 79 to
provide 238 mg of compound 78 as a brown solid: mp 251-
254 °C; 1H NMR (DMSO-d6) δ 2.37 (t, 2H), 2.56-2.78 (m, 2H),
2.83-2.96 (m, 1H), 3.01-3.14 (m, 1H), 3.46 (t, 2H), 5.07 (s,
1H), 7.10 (d, 1H), 7.97 (d, 1H), 10.59 (s, 1H); MS (APCI+) m/z
353 (M + H)+, 370 (M + NH4)+; MS (APCI-) m/z 351 (M -
H)-. Anal. (C14H12N2O5S2) C, H, N.
(14) Pandita, R. K.; Persson, K.; Andersson, K. E. Effects of the K+
channel opener, ZD-6169, on volume- and PGE2-stimulated
bladder activity in conscious rats. J . Urol. 1997, 158, 2300-2304.
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Freeden, C.; Graceffa, R. F.; Hirth, B. H.; J enkins, D.; Lennox,
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Spinelli, W.; Warga, D.; Wojdan, A.; Woods, M. Design and SAR
of Novel Potassium Channel Openers Targeted for Urge Urinary
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Dihydropyridine KATP Channel Activator. Cardiovasc. Drug Rev.
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Conductance Ca2+-Activated K+ Channels by Zeneca ZD6169 in
Guinea Pig Bladder Smooth Muscle Cells. J . Pharmacol. Exp.
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(18) Primeau, J .; Butera, J . A. Potassium Channel Activating Agents;
Emerging Trends. Curr. Pharm. Des. 1995, 1, 391-406.
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Li, J . H.; Ohnmacht, C. J .; Smith, R. W.; Trainor, D. A.; Trivedi,
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(22) Gopalakrishnan, M.; Whiteaker, K. L.; Molinari, E. J .; Davis-
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I.; Cain, J . C.; Postl, S.; Sullivan, J . P.; Brioni, J . D. Character-
ization of the ATP-Sensitive Potassium Channels (KATP) Ex-
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8-(4-Br om o-2-th ien yl)-2,3,4,5,6,8-h exa h yd r o-7H-cyclo-
pen ta[b]th ien o[2,3-e]pyr idin -7-on e 1,1-Dioxide (79). 4-Bro-
mothiophene-2-carboxaldehyde (500 mg, 2.6 mmol), dihy-
drothiophen-3(2H)-one 1,1-dioxide (295 mg, 2.2 mmol), and
3-amino-2-cyclopenten-1-one (215 mg, 2.2 mmol) were heated
in EtOH (5 mL) to 80 °C in a sealed tube for 2 d and cooled,
and the solid precipitate was collected, washed with EtOH,
dissolved in a solution of MeOH/CH2Cl2 1:3, filtered through
cotton, concentrated on a steam bath, and allowed to crystallize
to provide 0.34 g of compound 79 as a light brown solid: mp
254-255 °C; 1H NMR (DMSO-d6) δ 2.35 (t, 2H), 2.53-2.75 (m,
2H), 2.78-2.91 (m, 1H), 2.97-3.10 (m, 1H), 3.42 (t, 2H), 4.95
(s, 1H), 6.88 (d, 1H), 7.46 (d, 1H), 10.43 (bs, 1H); MS (APCI+)
m/z 386 (M + H)+, 403 (M + NH4)+; MS (APCI-) m/z 384 (M
- H)-. Anal. (C14H12NO3S2Br) C, H, N.

Sulfonyldihydropyridine-Containing KATP Openers
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J M030356W