Synthesis and structure-activity relationships of a novel series of tricyclic dihydropyridine-based KATP openers that potently inhibit bladder contractions in vitro

Article abstract of DOI:10.1021/jm030357o

Structure-activity relationships were investigated on a novel series of tricyclic dihydropyridine-containing K_ATP openers. This diverse group of analogues, comprising a variety of heterocyclic rings fused to the dihydropyridine nucleus, was des

Full text of DOI:10.1021/jm030357o

3180
J . Med. Chem. 2004, 47, 3180-3192
Syn th esis a n d Str u ctu r e-Activity Rela tion sh ip s of a Novel Ser ies of Tr icyclic
Dih yd r op yr id in e-Ba sed KATP Op en er s Th a t P oten tly In h ibit Bla d d er
Con tr a ction s in Vitr o
William A. Carroll,* Konstantinos A. Agrios, Robert J . Altenbach, Steven A. Buckner, Yiyuan Chen,
Michael J . Coghlan, Anthony V. Daza, Irene Drizin, Murali Gopalakrishnan, Rodger F. Henry, Michael E. Kort,
Philip R. Kym, Ivan Milicic, J amie C. Smith, Rui Tang, Sean C. Turner, Kristi L. Whiteaker, 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 tricyclic dihydropyridine-
containing KATP openers. This diverse group of analogues, comprising a variety of heterocyclic
rings fused to the dihydropyridine nucleus, was designed to determine the influence on activity
of hydrogen-bond-donating and -accepting groups and their stereochemical disposition.
Compounds 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 subset 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 tr od u ction
definitive proof of efficacy in a placebo-controlled trial
has not been demonstrated for either agent.8 Cro-
makalim was dropped from further study due to un-
specified animal toxicity, and 2 was also reportedly
discontinued from development in favor of another KATP
opener, ZD0947.9 Thus, it remains to be established
whether the KATP-opening mechanism can ameliorate
the symptoms of OAB. Also, given the initial interest
in KATP openers as antihypertensives, it is expected that
hypotensive effects may limit dosing.
ATP-sensitive potassium (KATP) channels play a criti-
cal role in linking cellular energy metabolism to mem-
brane potential and cellular excitability.1,2 Opening of
KATP channels results in an efflux of potassium ions
from the cell and an accompanying reduction in mem-
brane potential (hyperpolarization) that restricts cal-
cium entry through L-type calcium channels and damp-
ens cellular excitability. KATP channels are heteroocta-
meric complexes composed of four inwardly rectifying
potassium channel (Kir) subunits that form the pore and
four regulatory sulfonylurea receptor (SUR) subunits.3,4
KATP channels are located in the pancreas, central
nervous system, heart, skeletal muscle, and diverse
smooth muscle tissues such as the bladder and periph-
eral vasculature. Recent molecular biological advances
have resulted in the subclassification of the Kir and
SUR subunits, with distinct combinations found in
different tissues. For example, the pancreatic â-cell KATP
that regulates insulin release is composed of the com-
bination of SUR1 with Kir6.2. The SUR2A/Kir6.2 com-
bination has been identified as the cardiac KATP, whereas
the smooth muscle KATP consists of SUR2B with either
Kir6.1 or Kir6.2. Additional splice variants of SUR1 and
SUR25 have also been described.
Preclinically, the focus continues to be directed toward
identifying agents with selective actions on the bladder
and minimal cardiovascular effects. The arylsquarate
KATP openers WAY-133537 (3)10 and WAY-151616 (4)11
have been reported to inhibit spontaneous, diseased
bladder contractions in rats and to have improved
therapeutic indexes (TIs) with respect to hypotensive
effects compared to 2. The acridinedione ZM244085 (5)
has also been reported to inhibit bladder function in rats
without effects on blood pressure.12
The reported bladder selective actions of 5 make it
an attractive lead from which to design novel KATP
openers. In our accompanying paper we describe initial
SAR studies in this area that led to the discovery of 6
(A-278637). Those efforts focused on extensive modifica-
tions of the aromatic ring substitution as well as an
examination of ring sizes and stereochemistry. The
present studies greatly extend the SAR of the tricyclic
dihydropyridine (DHP) core structure in the form of
diverse heterocyclic ring combinations. The SAR studies
described herein were conducted exclusively with the
3-bromo-4-fluoro substitution pattern on the aromatic
ring as this had previously been found to impart high
potency. The primary focus of these investigations was
to examine the effect of insertion of hydrogen-bond-
donating or -accepting groups in the rings flanking the
There has been considerable interest in exploring
KATP openers as therapeutic agents in the treatment of
bladder overactivity, a condition that may be associated,
in part, with the hyperexcitability of diseased bladder
smooth muscle cells.6,7 Although the KATP openers
cromakalim (1, Figure 1) and ZD6169 (2) have both been
studied in clinical trials for overactive bladder (OAB),
* 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/jm030357o CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/04/2004

Tricyclic Dihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3181
F igu r e 1.
F igu r e 2.
piperidine-containing compounds (37, 38, 48, 51, 56)
encountered in this discussion were prepared via the
intermediacy of an N-benzyl derivative that was deben-
zylated via the respective vinylchloroformates (see the
Experimental Section for details). In the preparation of
32 and 33, the initial Hantzsch reaction provided an
intermediate that necessitated treatment with HCl to
effect conversion to the racemic dihydropyridine (method
B). Certain symmetrical target compounds (40, 47, 48)
were prepared directly through reaction of 2 equiv of
the cyclic dione with an aldehyde and ammonia source
(see method C in the Experimental Section).
Final compounds containing a γ-lactone were pre-
pared by bromination and cyclization of an intermediate
bicyclic dihydropyridine (Scheme 2, method D). Simi-
larly, γ-lactams were prepared from the same interme-
diates by reacting the bromo intermediate with a
primary amine or ammonia (method E). Final com-
pounds prepared by these methods are shown in Scheme
2. For the preparation of single enantiomers containing
either a γ-lactone or γ-lactam, a bicyclic intermediate
was derivatized as the ester with mandelic acid to
produce a mixture of diastereomers that were separable
through silica gel chromatography (Scheme 3, method
F). Transesterification led to the enantiomerically pure
methyl ester intermediate that was transformed to the
γ-lactones and γ-lactams using methods D and E,
respectively, from Scheme 2. The combination of meth-
ods F and E was utilized in parallel fashion to explore
F igu r e 3.
dihydropyridine but in positions other than the 2-, 3-,
5-, or 6-position of the dihydropyridine. A variety of
unique combinations of heteroatoms either on one or
both sides of the dihydropyridine core (see Figures 2 and
3 and the structures accompanying Tables 1-3 for the
types of ring systems to be discussed) were prepared
and evaluated for KATP activity in both cell- and tissue-
based assays.
Ch em istr y
Final compounds and intermediates containing a
dihydropyridine ring were prepared using the Hantzsch
dihydropyridine synthesis (Scheme 1, method A). An
array of carbonyl (c1-c11) and enamine (e1-e5) mono-
mers (Figure 2) were reacted to create diverse combina-
tions of the core structure, with the final compounds
obtained by this method indicated in Scheme 1. Several

3182 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
Ta ble 1
Ta ble 3
pEC50
ring
fusion
pEC50
GPBa,e FSLPDb,f
compd
n
stereochem
GPBa,e
FSLPDb,f
compd port starboard stereochem
7
8
9
1
A
A
A
A
B
B
C
C
D
D
E
R
S
R
S
rac
rac
rac
rac
R
S
R
S
R
6.94(0.11)d
7.65(0.18)d
6.40(0.39)d
8.20(0.16)d
7.17(0.03)c
7.10(0.01)c
7.50(0.21)d
7.45(0.03)d
6.68(0.27)d
5.96(0.38)c
6.94(0.25)d
5.58(0.41)d
6.85(0.17)d
6.50(0.18)c
6.75(0.41)c
6.16(0.14)d
6.73(0.17)d
5.99(0.25)d
6.24(0.03)d
5.30(0.12)c
6.93(0.18)d
6.97(0.21)d
6.37(0.25)d
6.67 ( 0.04
6.57 ( 0.19
5.96 ( 0.09
6.87 ( 0.24
NT
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
A
B
C
A
C
A
D
E
A
B
C
B
A
C
D
E
7.20 (0.30)d 6.30 (0.15
7.09 (0.25)d 6.75 ( 0.15
7.57 (0.32)d 6.90 ( 0.13
1
2
2
1
2
1
2
2
2
1
1
2
2
1
2
1
1
2
2
1
2
-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
1
rac
R
S
7.85 (0.29)d
NT
7.59 (0.37)d 6.23 ( 0.14
7.95 (0.04)c 6.58 ( 0.05
5.55 (0.05)c 4.43 ( 0.32
6.00 (0.33)d 5.69 ( 0.07
7.03 ( 0.04
NT
NT
5.85 ( 0.14
5.16 ( 0.26
6.69 ( 0.22
NT
5.94 ( 0.13
6.29 ( 0.07
4.78 ( 0.31
NT
6.35 ( 0.15
5.35 ( 0.18
5.41 ( 0.24
5.16 ( 0.18
NT
F
F
<5c
NT
NT
G
H
A
A
A
C
C
C
C
C
G
H
D
G
H
D
E
F
G
H
5.24 (0.12)d
9.27 (0.13)c 6.07 ( 0.05
E
E
E
F
rac
rac
rac
rac
rac
rac
rac
rac
6.63 (0.09)c
NT
6.16 (0.05)c 5.63 ( 0.15
7.19 (0.26)c 5.93 ( 0.17
S
rac
rac
(-)
(+)
(-)
(+)
rac
rac
6.01 (0.07)c
7.89 (0.33)d
NT
NT
F
G
G
G
G
H
H
-
6.55 (0.28)d 5.32 ( 0.20
6.25 (0.27)d 6.01 ( 0.11
7.20 (0.21)d
NT
a
b
GPB ) guinea pig bladder cells. FSLPD ) field-stimulated
Landrace pig detrusor strips. c Number of determinations ) 2.
6.18 ( 0.22
6.59 ( 0.16
Number of determinations g 3. e Standard deviation in paren-
d
theses. f Number of determinations g 4; standard error shown.
NT ) not tested.
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
Sch em e 1a
theses. f Number of determinations g 4; standard error shown.
NT ) not tested.
Ta ble 2
pEC50
ring
fusion
compd
n
stereochem
GPBa,e
FSLPDb,f
29
30
31
32
33
34
35
36
37
38
1
2
2
1
1
2
1
2
1
2
A
A
A
C
C
C
E
E
G
G
rac
(-)
(+)
R
7.14(0.13)d
8.06(0.17)d
<5c
6.26 ( 0.06
6.61 ( 0.06
NT
7.17 ( 0.09
5.95 ( 0.12
NT
NT
NT
4.30 ( 0.11
3.88 ( 0.04
a
Conditions: (i) EtOH, 80 °C; (ii) EtOH, Et3N, 80 °C; (iii) HCl,
EtOH, 80 °C.
8.31(0.40)d
6.38(0.36)c
7.27(0.28)d
6.36(0.46)d
5.91(0.00)c
5.86(0.07)c
5.59(0.08)c
4). The individual enantiomers 30-33 were prepared
using the 8-phenylmenthylcarbamate method described
in our preceding paper (see Experimental Section for
details). Single enantiomers of other final products from
Schemes 1 and 2 were obtained by chiral HPLC of the
racemic mixtures. The reader is referred to the Experi-
mental Section for details of the separation methods.
S
rac
rac
rac
rac
rac
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.
Biologica l Assa ys
Gu in ea P ig Bla d d er (GP B) Assa y.13 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.
a variety of R1 substitutions appended to the γ-lactam
nitrogen (Scheme 3).
The preparation of single enantiomers 23-26, con-
taining a piperidine ring, was accomplished via chro-
matographic separation of diastereomeric 8-phenylmen-
thyl carbamates followed by cleavage of the chiral
auxiliary to provide the unsubstituted piperidine (Scheme

Tricyclic Dihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3183
Sch em e 2a
component, and thus are insensitive to the effects of
muscarinic blockers such as tolterodine.
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 P1075. Because of the different sensitivities of
the two assays to muscarinic antagonists, each may
model bladder overactivity of distinct etiology.
Resu lts a n d Discu ssion
a
Conditions: (i) NBS or pyridinium tribromide; (ii) 130 °C; (iii)
Analogues 7-14 containing a single oxygen incorpo-
rated into one ring (Table 1, see Figure 3 for ring
fusions) demonstrated high potency at both GPB and
FSLPD assays. For the γ-lactones 7-10, stereochemis-
try was important to KATP activity in the GPB assay as
the (S)-enantiomers 8 and 10 were more potent than
the respective antipodes 7 and 9. For the regioisomeric
pyran ring fusions (rings B and C), little difference in
potency was observed, as exemplified by examples 11-
14.
R1NH2.
Sch em e 3a
By comparison with the insertion of oxygen into one
flanking ring, insertion of nitrogen as either a lactam
NH, lactam N-Me, or piperidine NH produced the less
potent compounds 15-23 (Table 1). Nonetheless, several
of these analogues still possess substantial potency
when compared to standards such as (-)-cromakalim
(1). As was observed for the lactones in Table 1,
stereochemistry was important for activity with either
a lactam NH or piperidine NH in a flanking ring
(compounds 15-16, 23-26). Interestingly, for ring
fusion D (examples 15 and 16) the preferred stereo-
chemistry was R, opposite that for the lactones 7-10.
Compound 23 is interesting as a unique example of a
KATP opener that possesses equivalent potency to (-)-
cromakalim yet contains a basic nitrogen atom. With
regard to stereochemistry and the N-methylated lactam
nitrogen examples 17-20, the six-membered carbocyclic
analogues 19 and 20 showed similar potency, whereas
the five-membered carbocyclic analogues 17 and 18
differed by over 10-fold in potency, with the (R)-
stereochemistry being preferred. A similar phenomenon
was described in our accompanying study with respect
to stereochemistry and carbocyclic ring size. The two
thiopyran analogues 27 and 28 showed intermediate
potency between the pyran-containing (13 and 14) and
piperidine-containing (23-26) examples.
The cyclic sulfone-containing variants 29-38 (Table
2) were generally found to possess slightly diminished
potency compared to the carbocyclic variants in Table
1. One exception, however, was compound 32, which
displayed excellent potency at both GPB and FSLPD,
even when compared to compound 10. The preferred
sense of absolute stereochemistry with respect to the
oxygen-containing pyran ring of 32 is in agreement with
that of the oxygen-containing lactone of 10.16 Likewise,
the absolute stereochemistry of 32 with resepect to the
sulfonyl group is in agreement with the preferred
stereochemistry for the directly analogous carbocyclic
analogue described in our companion paper.17
a
Conditions: (i) BCl3, SOCl2; (R) mandelic acid; (ii) flash
chromatography, NaOMe; (iii) pyridinium tribromide; (iv) 130 °C;
(v) R1NH2.
Sch em e 4a
a
Conditions: (i) 8-phenylmenthol chloroformate; (ii) 48% HBr/
AcOH.
F ield -Stim u la ted La n d r a ce P ig Detr u sor (F S-
LP D) Assa y.14 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.
Sp on t a n eou s La n d r a ce P ig Det r u sor (SLP D)
Assa y.15 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
An extensive investigation was undertaken to evalu-
ate both symmetrical and unsymmetrical core struc-

3184 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
Ta ble 4
Ta ble 5
pEC50
FSLPDb,d SLPDc,d
pED50
SHRa
selectivity
SLPD:FSLPD
compd
6
9
39
44
6.37 ( 0.15 6.63 ( 0.15 7.64 ( 0.08
5.61 ( 0.03 5.96 ( 0.09 7.49 ( 0.15
6.40 ( 0.02 6.30 ( 0.15 7.63 ( 0.11
10
34
21
52
NA
6.58 ( 0.05 8.30 ( 0.18
a
SHR ) spontaneously hypertensive rat. The pED50 refers to
the negative log of the dose to produce a 50% reduction in blood
pressure relative to the maximum achieved with the KATP standard
P1075 (see Experimental Section for details). All compounds tested
achieved maximal reductions in blood pressure equal to that
pEC50
compd
R
GPBa,c
FSLPDb,d
58
59
60
cyclopropyl
ethoxyethyl
n-propyl
6.27(0.14)
6.27(0.13)
<5
NT
6.02 ( 0.12
NT
b
attained with P1075. NA ) not available. FSLPD ) field-
stimulated Landrace pig detrusor strips. c SLPD ) spontaneous
d
Landrace pig detrusor strips. Number of determinations g 4;
a
b
GPB ) guinea pig bladder cells. FSLPD ) field stimulated
standard error shown.
Landrace pig detrusor strips. c Number of determinations ) 2;
d
standard deviation in parentheses. Number of determinations
g 4; standard error shown. NT ) not tested.
tures containing heteroatoms in both the port and
starboard sides of the dihydropyridine nucleus (Table
3).18 The symmetrical oxygen- and sulfur-containing
analogues 39-41 and 49 were all highly potent KATP
openers. Among the oxygen-containing analogues, there
was little to distinguish them in either GPB or FSLPD
from a potency standpoint. In contrast, symmetrical
nitrogen-containing compounds 45-48 showed consid-
erably weaker activity than the nitrogen-containing
analogues of Table 1. The weaker activity of 46 (N-Me
on both sides of the DHP) is in accord with the
differential activities for 17 and 18, where it was
demonstrated that tolerance to the N-Me group was
stereospecific. The unsymmetrical analogues containing
two oxygens (43 and 44) or an oxygen and a sulfur (52
and 57) displayed high potency similar to the sym-
metrical versions, with the (S)-enantiomer 44 exhibiting
slightly greater potency than the (R)-enantiomer 43.
The unsymmetrical analogues in Table 3 with oxygen-
and nitrogen-containing rings on opposite sides showed
comparable potency to the nitrogen-containing ana-
logues in Table 1. In these cases, the insertion of an
oxygen into the flanking ring generally did not produce
an enhancement in potency. Compound 54 appears to
be an exception, as its potency in the GPB assay is
greater than that of 17-20.
To further explore the SAR around the analogues 15,
16, 19, and 20, a diverse array of substitutions off the
γ-lactam nitrogen was investigated. With the avail-
ability of enantiomerically pure precursors (Scheme 3),
these SAR studies were conducted in both the (R)- and
(S)-series, employing parallel synthesis techniques and
a variety of primary amines. The substitutions encom-
passed straight and branched chain alkyl, alkoxyalkyl,
arylalkyl, heteroarylalkyl, and amino alkyl groups.
Interestingly, whereas the tricyclic DHP core could be
modified extensively with retention of KATP activity,
lateral substitution was generally found to be poorly
tolerated. Indeed, in the (R)-series all substitutions
larger than methyl were found to be inactive. In the (S)-
series only cyclopropyl (58) and ethoxyethyl (59) pro-
vided appreciable KATP activity (Table 4).
F igu r e 4. Plot of pEC50 values for guinea pig bladder cells
(GPB) vs field-stimulated Landrace pig detrusor (FSLPD).
Slope ) 0.75; r2 ) 0.48.
strips. Compounds 9, 39, and 44 showed greater selec-
tivity for the spontaneous contractions relative to the
earlier generation analogue 6. Selectivity for spontane-
ous contractions may endow certain KATP openers with
selectivity for diseased bladder contractions of myogenic
origin relative to their effects on normal bladder func-
tion.
Examination of the collective data for this series of
compounds in the two primary in vitro assays shows
that the primary cell-based screen (GPB) offers some
predictive value for the tissue assay (FSLPD), as
indicated by the correlation plot (Figure 4). Generally,
however, compounds tended to display greater potency
in the GPB assay, as is also observed in the SLPD assay.
Although the dataset is relatively small, the SLPD
potencies of compounds appearing in this and our
companion paper were better predicted by the GPB
assay (Figure 5) than the FSLPD assay (Figure 6). For
this reason, the biological results from the GPB assay
were given greater weight than those from the FSLPD
assay when interpreting inconsistent SAR trends across
the two assays. Although the ability of compounds to
inhibit spontaneous bladder contractions may be the
most relevant for the condition of OAB, both the GPB
and FSLPD assays are reasonably predictive, higher
throughput assays that allow compounds to be funneled
to the more labor intensive SLPD assay.
Several analogues were also evaluated for their ability
to inhibit spontaneous bladder contractions in vitro, and
the data are summarized in Table 5. Consistent with
our previous findings, all compounds exhibited greater
potency to relax spontaneously contracting bladder

Tricyclic Dihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3185
F igu r e 6. Plot of pEC50 values for field-stimulated Landrace
pig detrusor (FSLPD) vs spontaneous Landrace pig detrusor
(SLPD). Slope ) 1.38; r2 ) 0.52.
F igu r e 5. Plot of pEC50 values for guinea pig bladder cells
(GPB) vs spontaneous Landrace pig detrusor (SLPD). Slope
) 1.16; r2 ) 0.63.
Different screening paradigms were investigated to
determine if any of the structural features among the
diverse array of potent KATP openers in Tables 1-4 led
to improved selectivity versus cardiovascular effects.
Ideally, selectivity would be measured directly in vivo;
however, the laborious nature of such assays is prohibi-
tive when screening a large set of compounds. It was
necessary, therefore, to identify a relevant higher
throughput screen for effects on hemodynamics. In vitro
assays such as the rat aorta model were initially
investigated; however, activity in this model did not
correlate well with cardiovascular effects in vivo for a
select group of KATP openers. Consequently, we chose
to screen compounds for their ability to acutely reduce
blood pressure on intravenous dosing in spontaneously
hypertensive rats (SHR). A cumulative dosing protocol
was used (see Figure 7) to generate a dose-response
curve from which a pED50 could be determined. Effects
at a given dose were measured over a short period (2.5
min) allowing for the minimization of differences in the
pharmacokinetics of compounds. Even compounds such
as nifedipine, with a short half-life, produced rapid,
acute blood pressure responses that allowed generation
of a full dose-response curve. It should be noted that
such a screening paradigm allows for the measurement
of only relative selectivity of compounds, as efficacy was
determined in a separate in vitro bladder strip assay.
The data shown in Table 5 from the SHR assay are
typical for compounds from this dihydropyridine class.
Potency to reduce MAP tracked with potency to relax
bladder smooth muscle strips in vitro and none of these
newer analogues demonstrated a significant improve-
ment relative to 6. Thus, although subtle differences in
selectivity may exist in this compound set, the available
assays for examining large sets of compounds have only
sufficient precision to permit the measurement of
significantly larger differences in intrinsic selectivity.
F igu r e 7. Effect of compound 6 on MAP when administered
iv in a cumulative fashion to conscious spontaneously hyper-
tensive rats. Doses shown are in µmol/kg. See Experimental
Section for protocol details.
are allowed with retention of KATP activity. Certain
requirements must be met, however, with regard to the
stereochemical placement of hydrogen-bond-accepting
groups and especially hydrogen-bond-donating groups.
Lateral substitution off the tricyclic system was poorly
tolerated. Several of the analogues discovered in the
course of these investigations containing oxygen in a
flanking ring (10, 32, 41) rank among the most potent
KATP openers known. These results also provide further
evidence for the enhanced potency of KATP openers to
inhibit spontaneous bladder contractions that may be
related to diseased bladder contractions in OAB.
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, all melting points were greater than 260 °C.
Con clu sion
The results of Tables 1-4 indicate that significant
variations in the flanking rings of the dihydropyridine

3186 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
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 separations 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. All single enantiomers described
herein were enantiomerically pure to the level of detection of
either 1H NMR or chiral HPLC, depending upon the method
of separation used.
resulting solid was collected by filtration, washed with CH2-
Cl2, and dried to provide 0.074 g of the title compound as a
white solid: mp 166-168 °C; H NMR (DMSO-d6) δ 4.06 (s,
2H), 4.54 (AB q, 2H), 4.75 (s, 1H), 4.88 (d, 1H), 5.03 (d, 1H),
7.28 (d, 2H), 7.48 (d, 1H), 10.50 (s, 1H); MS (ESI+) m/z 380 (M
+ H)+.
1
Meth od E. 9-(3-Br om o-4-flu or oph en yl)-2-m eth yl-2,3,5,9-
tetr ah ydr opyr an o[3,4-b]pyr r olo[3,4-e]pyr idin e-1,8(4H,7H)-
d ion e (54). A solution of the intermediate from method D,
part 1 (0.16 g, 0.34 mmol) and 2 M MeNH2/MeOH (3.5 mL,
7.0 mmol) was stirred at room temperature for 16 h, concen-
trated, flash chromatographed on silica gel gradient eluting
with MeOH:CH2Cl2 (5:95 to 10:90), and crystallized from
EtOH, to provide 0.016 g of 54 as a white solid: 1H NMR
(DMSO-d6) δ 2.81 (s, 3H), 3.98 (d, 1H), 4.03 (s, 2H), 4.15 (d,
1H), 4.50 (AB q, 2H), 4.75 (s, 1H), 7.23 (m, 2H), 7.46 (dd, 1H),
Meth od A. 5-(3-Br om o-4-flu or oph en yl)-5,8,9,10-tetr ah y-
dr o-1H-th iopyr an o[3,4-b]qu in olin e-4,6(3H,7H)-dion e (28).
A mixture of thiopyran-3,5-dione19 (c4) (0.12 g, 1.0 mmol),
3-bromo-4-fluorobenzaldehyde (0.20 g, 1.0 mmol), 3-aminocy-
clohex-2-en-1-one (e2) (0.11 g, 1.0 mmol), and EtOH (5 mL)
was heated to 80 °C in a sealed tube for 60 h and cooled to
ambient temperature. The resulting solid was collected by
filtration, washed with EtOH, and dried to provide 0.13 g of
28: 1H NMR (DMSO-d6) δ 1.77-1.88 (m, 1H), 1.89-1.98 (m,
1H), 2.25 (dd, 2H), 2.46-2.62 (m, 2H), 3.10 (dd, 1H), 3.48 (ddd,
2H), 3.82 (d, 1H), 4.96 (s, 1H), 7.15-7.24 (m, 2H), 7.41 (dd,
10.11 (s, 1H); MS (ESI+) m/z 393 (M + H)+. Anal. (C17H14
BrFN2O3·0.5H2O) C, H, N.
-
Meth od F . Meth yl (4R)-4-(3-Br om o-4-flu or op h en yl)-2-
m eth yl-5-oxo-1,4,5,6,7,8-h exa h yd r o-3-qu in olin eca r boxy-
late an d Meth yl (4S)-4-(3-Br om o-4-flu or oph en yl)-2-m eth yl-
5-oxo-1,4,5,6,7,8-h exa h yd r o-3-qu in olin eca r boxyla te. P a r t
1. 4-(3-Br om o-4-flu or op h en yl)-2-m eth yl-5-oxo-1,4,5,6,7,8-
h exa h yd r o-3-qu in olin eca r boxylic Acid . BCl3/CH2Cl2 (1 M,
200 mL) was added to a solution of 19.7 g (50 mmol) of methyl
4-(3-bromo-4-fluorophenyl)-2-methyl-5-oxo-1,4,5,6,7,8-hexahy-
droquinoline-3-carboxylate [prepared from 3-bromo-4-fluo-
robenzaldehyde, methyl (2E)-3-aminobut-2-enoate (e5), and
cyclohexane-1,3-dione (c2) by method A] in 50 mL of CH2Cl2
at 0 °C. The reaction mixture was stirred overnight at room
temperature and diluted with ice-water (1 L) and EtOAc (0.75
L). The solid was collected, washed with EtOAc, and dried to
provide 16.9 g of the title compound as a white powder: mp
1H), 9.71 (s, 1H); MS (APCI-) m/z 406 (M - H)-. Anal. (C18H15
BrFNO2S) C, H, N.
-
Meth od B. 9-(3-Br om o-4-flu or op h en yl)-2,3,5,9-tetr a h y-
d r o-4H-p yr a n o[3,4-b]th ien o[2,3-e]p yr id in -8(7H)-on e 1,1-
Dioxid e. A mixture of 5-amino-2H-pyran-3(6H)-one20 (e3) (1.5
g, 13 mmol), 3-bromo-4-fluorobenzaldehyde (3.2 g, 16 mmol),
tetrahydrothiophene-3-oxo-1,1-dioxide (c7) (1.8 g, 13 mmol),
and triethylamine (0.93 mL, 6.6 mmol) in EtOH (20 mL) was
stirred in a sealed tube at 80 °C for 60 h, cooled, and
concentrated to dryness. The residue was dissolved in EtOH
(50 mL), treated with 1 M HCl/Et2O (5 mL), heated to reflux
for 5 min, and then cooled to room temperature. The resulting
solid was collected by filtration, washed with EtOH, and dried
under vacuum for 16 h to provide 3.2 g of the title compound:
1H NMR (DMSO-d6) δ 2.85 (m, 1H), 3.08 (m, 1H), 3.33-3.42
(m, 2H), 4.03 (s, 2H), 4.49 (AB q, 2H), 4.90 (s, 1H), 7.27 (m,
2H), 7.45 (dd, 1H), 10.14 (s, 1H); MS (ESI+) m/z 414 (M + H)+.
Met h od C. 10-(3-Br om o-4-flu or op h en yl)-3,4,5,6,7,10-
h exa h yd r o-1H ,9H -d ip yr a n o[4,3-b:3,4-e]p yr id in e-1,9-d i-
on e (40). A mixture of dihydro-2H-pyran-2,4(3H)-dione21 (c9)
(0.456 g, 4.0 mmol) and 3-bromo-4-fluorobenzaldehyde (0.406
g, 2.0 mmol) was treated with a 2 M NH3/MeOH (6.0 mmol,
3.0 mL) and stirred in a sealed tube at 75 °C for 72 h. After
cooling to room temperature, the reaction mixture was con-
centrated and the residue purified by flash chromatography
over silica gel, gradient eluting with EtOAc:CH2Cl2:MeOH (7:
1:0.1 to 7:1:1) to provide 0.08 g of the title compound as a pale
yellow solid: 1H NMR (DMSO-d6) δ 2.57 (ddd, 2H), 2.73 (ddd,
2 H), 4.16-4.22 (m, 2H), 4.27-4.33 (m, 2H), 4.76 (s, 1H), 7.23-
7.27 (m, 2H), 7.44 (dd, 1H), 9.86 (bs, 1H); MS (APCI+) m/z 394
(M + H)+. Anal. (C17H13BrFNO4) C, H, N.
1
225-228 °C; H NMR (DMSO-d6) δ 1.70-1.95 (m, 2H), 2.20
(t, 2H), 2.30 (s, 3H), 2.45 (m, 2H), 4.87 (s, 1H), 7.13 (m, 1H),
7.20 (t, 1H), 7.36 (d, 1H), 9.14 (s, 1H), 11.8 (br s, 1H); MS (ESI+)
m/z 380 (M + H)+.
P ar t 2A. (2R′,4R)-({[4-(3-Br om o-4-flu or oph en yl)-2-m eth -
yl-5-oxo-1,4,5,6,7,8-h exa h yd r o-3-q u in olin yl]ca r b on yl}-
oxy)(p h en yl)eth a n oic Acid . To a solution of the interme-
diate from part 1 (16.9 g, 44.5 mmol) in DMF (150 mL) at -10
°C was added SOCl2 (5.29 g, 44.5 mmol). After 1.5 h at -10
°C, (R)-mandelic acid (6.77 g, 44.5 mmol) and Et3N (4.5 g, 44.5
mmol) were added, and the reaction was maintained at -10
°C for 2 h and then at room temperature for 1 h, followed by
quenching with EtOAc:Et2O (1:2) and water. The organic layer
was dried, filtered, and concentrated to provide the crude
diastereomeric mixture (20 g). The title compound was isolated
as the more polar diastereomer after flash chromatography
over silica gel eluting with MeOH:CH2Cl2:AcOH (10:89.5:0.5)
to provide a yellow solid: 1H NMR (DMSO-d6) δ 1.70-1.81
(m, 1H), 1.85-1.94 (m, 1H), 2.20 (m, 2H), 2.34 (s, 3H), 2.48
(m, 2H), 4.87 (s, 1H), 7.13-7.28 (m, 3H), 7.38-7.45 (m, 5H),
9.37 (s, 1H).
P ar t 2B. (2′R,4S)-({[4-(3-Br om o-4-flu or oph en yl)-2-m eth -
yl-5-oxo-1,4,5,6,7,8-h exa h yd r o-3-q u in olin yl]ca r b on yl}-
oxy)(p h en yl)eth a n oic Acid . The less polar diastereomer was
obtained from the above chromatographic separation as a
Meth od D. P a r t 1. Meth yl 4-(3-Br om o-4-flu or op h en yl)-
2-(br om om eth yl)-5-oxo-4,5,6,8-tetr a h yd r o-1H-p yr a n o[3,4-
b]p yr id in e-3-ca r boxyla te. A solution of 0.87 g (2.2 mmol)
of methyl 4-(3-bromo-4-fluorophenyl)-2-methyl-5-oxo-4,5,6,8-
tetrahydro-1H-pyrano[3,4-b]pyridine-3-carboxylate [prepared
from 2H-pyran-3,5(4H,6H)-dione (c3),20 3-bromo-4-fluorobenz-
aldehyde, and methyl (2E)-3-aminobut-2-enoate (e5) using
method A] in CHCl3 (10 mL) was cooled to -10 °C, treated
with pyridine (0.21 mL, 2.6 mmol) and then pyridinium
tribromide (0.84 g, 2.6 mmol), stirred for 1 h, diluted with CH2-
Cl2 (150 mL), and washed with 1 N HCl (25 mL). The organic
layer was dried (MgSO4), filtered, concentrated, and flash
chromatographed over silica gel gradient eluting with MeOH:
CH2Cl2 (1:99 to 2:98) to provide 0.68 g of the title compound
that was carried directly on to part 2.
1
yellow solid: H NMR (300 MHz, DMSO-d6) δ 1.70-1.81 (m,
1H), 1.85-1.94 (m, 1H), 2.20 (m, 2H), 2.34 (s, 3H), 2.48 (m,
2H), 4.87 (s, 1H), 7.13-7.28 (m, 3H), 7.38-7.45 (m, 5H), 9.37
(s, 1H).
P a r t 3A. Meth yl (4R)-4-(3-Br om o-4-flu or op h en yl)-2-
m eth yl-5-oxo-1,4,5,6,7,8-h exa h yd r o-3-qu in olin eca r boxy-
la te. To the intermediate from part 2A (257 mg, 0.5 mmol) in
MeOH (50 mL), was added sodium (0.58 g, 25 mmol), and the
reaction refluxed for 16 h. After concentration, the residue was
treated with 2 M HCl to pH 7, diluted with water (50 mL),
and extracted with CH2Cl2. The organics were dried (MgSO4),
filtered, and concentrated to provide 153 mg of the title
compound as a white foam.
Met h od D. P a r t 2. 9-(3-Br om o-4-flu or op h en yl)-5,9-
d ih yd r o-3H-fu r o[3,4-b]p yr a n o[4,3-e]p yr id in e-1,8(4H,7H)-
d ion e. The intermediate from part 1 (0.30 g, 0.63 mmol) was
heated neat under N2 to 130 °C for 15 min and cooled to room
temperature. The residue was treated with CH2Cl2, and the
P a r t 3B. Meth yl (4S)-4-(3-Br om o-4-flu or op h en yl)-2-
m eth yl-5-oxo-1,4,5,6,7,8-h exa h yd r o-3-qu in olin eca r boxy-
la te. The product from part 2B (257 mg, 0.5 mmol) was treated

Tricyclic Dihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3187
according to the method of part 3A to provide 153 mg of the
title compound as a white foamy solid. The absolute stereo-
chemistry was determined by X-ray crystallographic analysis
(see Supporting Information).
with NH4OH, and extracted with CH2Cl2. The organic phase
was dried (Na2SO4), filtered, and concentrated. The residue
was purified by flash chromatography over silica gel eluting
with CH2Cl2 (saturated with NH4OH):EtOH (90:10) to provide
0.070 g of 24 as a free base which was converted to the
hydrochloride salt: [R]20D +117.64° (DMSO); 1H NMR (DMSO-
d6) (free base) δ 2.28 (t, 2H), 2.52-2.65 (m, 2H), 3.18 (s, 2H),
3.52 (d, 2H), 4.68 (s, 1H), 7.2 (m, 2H), 7.43 (d, 1H) 10.1 (s,
1H); MS (ESI-) m/z 375 (M - H)-. Anal. (C17H13BrFN2O2‚HCl‚
0.5H2O) C, H, N.
Meth od G. (-)-5-(3-Br om o-4-flu or op h en yl)-2,3,5,7,8,9-
h exa h yd r o-1H -cyclop en t a [b][1,7]n a p h t h yr id in e-4,6-d i-
on e Hyd r och lor id e (23) a n d (+)-5-(3-Br om o-4-flu or op h e-
n yl)-2,3,5,7,8,9-h exa h yd r o-1H -cyclop en t a [b][1,7]n a p h -
th yr id in e-4,6-d ion e Hyd r och lor id e (24). P a r t 1. 2-Ben zyl-
5-(3-b r om o-4-flu or op h e n yl)-2,3,5,7,8,9-h e xa h yd r o-1H -
cyclop en ta [b][1,7]n a p h th yr id in e-4,6-d ion e. A mixture of
3-aminocyclopent-2-en-1-one (e1) (0.97 g, 10 mmol), 3-bromo-
4-fluorobenzaldehyde (2.0 g, 10 mmol), and 1-benzylpiperidine-
3,5-dione22 (c5) (2.2 g, 10 mmol) in EtOH (10 mL) was heated
to reflux for 72 h and cooled to room temperature. The solvent
was evaporated and the residue purified by flash chromatog-
raphy over silica gel eluting with EtOH:CH2Cl2 (5:95) to
provide 3.0 g of the title compound: 1H NMR (DMSO-d6) δ
2.28 (m, 2H), 2.5-2.7 (m, 2H), 3.07 (AB qu, 2H), 3.4 (m, 2H),
3.65 (s, 2H), 4.65 (s, 1H), 7.15-7.45 (m, 8H), 10.25, (s, 1H).
MS (ESI-) m/z 465 (M - H)-.
P a r t 2A. (1R,2S,5R)-5-Met h yl-2-(1-m et h yl-1-p h en yl-
eth yl)cycloh exyl 5-(3-Br om o-4-flu or op h en yl)-4,6-d ioxo-
1,3,4,5,6,7,8,9-octa h yd r o-2H-cyclop en ta [b][1,7]n a p h th y-
r id in e-2-ca r boxyla te (less p ola r d ia ster eom er ). A solution
of the product from part 1 (1.9 g, 4.0 mmol) in THF (30 mL)
was treated with a solution of 1.45 g (4.92 mmol) of 8-phenyl-
menthyl chloroformate (prepared from (-)-8-phenylmenthol)
in THF (10 mL), stirred for 3 days at room temperature, and
partitioned between aqueous NaHCO3 and CH2Cl2. The or-
ganic layer was separated, dried (Na2SO4), filtered, and
concentrated to provide a mixture of diastereomeric carbam-
ates. The diastereomeric mixture was subjected to flash
chromatography over silica gel eluting with hexane:EtOAc (20:
80) to provide 0.32 g of the title compound as the less polar
diastereomer and 0.9 g of mixed fractions containing both
diastereomers: 1H NMR (DMSO-d6) δ 0.8 (m, 4H), 1.1 (s, 3H),
1.18 (m, 2H), 1.22 (s, 3H), 1.6 (m, 2H), 1.8 (m, 1H), 2.02 (m,
2H), 2.3 (m, 2H), 2.6 (m, 1H), 2.75 (m, 1H), 3.02 (d, 1H), 3.62
(d, 1H), 3.9 (d, 1H), 4.58 (d, 2H), 4.68 (s, 1H), 7.02-7.38 (m,
8H); MS (ESI-) m/z 635 (M - H)-.
P a r t 2B. (1R,2S,5R)-5-Met h yl-2-(1-m et h yl-1-p h en yl-
eth yl)cycloh exyl 5-(3-Br om o-4-flu or op h en yl)-4,6-d ioxo-
1,3,4,5,6,7,8,9-octa h yd r o-2H-cyclop en ta [b][1,7]n a p h th y-
r id in e-2-ca r boxyla te (m or e p ola r d ia ster eom er ). The
mixed fractions from above were crystallized from EtOH to
provide 0.45 g of the title compound as the more polar
diastereomer: 1H NMR (DMSO-d6) δ 0.82 (d, 3H), 1.02 (s, 3H),
1.18 (s, 3H), 1.18 (m, 2H), 1.58 (m, 2H), 1.68 (s, 1H), 1.98 (m,
2H), 2.3 (m, 2H), 2.61 (m, 1H), 2.75 (m, 1H), 3.2 (m, 1H), 3.6
(m, 2H), 4.0 (m, 1H), 4.52 (m, 2H), 4.55 (s, 1H), 6.45(m, 1H),
6.82 (m, 2H), 7.1 (m, 2H), 7.25 (m, 2H), 7.41 (m, 1H); MS (ESI-)
m/z 635 (M - H)-.
P a r t 3A. (-)-5-(3-Br om o-4-flu or op h en yl)-2,3,5,7,8,9-
h exa h yd r o-1H -cyclop en t a [b][1,7]n a p h t h yr id in e-4,6-d i-
on e Hyd r och lor id e (23). A solution of the product from part
2A (0.32 g, 0.52 mmol) in 48% HBr/AcOH (4 mL) was heated
to 50 °C for 48 h, cooled to room temperature, neutralized with
NH4OH, and extracted with CH2Cl2. The organic layer was
dried (Na2SO4), filtered, and concentrated. The residue was
purified by flash chromatography over silica gel eluting with
CH2Cl2 (saturated with NH4OH):EtOH (90:10) to provide 0.10
(-)-(8S)-(3-Br om o-4-flu or op h en yl)-4,5,6,8-tetr a h yd r o-
1H-cyclopen ta[b]fu r o[3,4-e]pyr idin e-1,7(3H)-dion e (8) an d
(+)-(8R)-(3-Br om o-4-flu or op h en yl)-4,5,6,8-tetr a h yd r o-1H-
cyclop en ta [b]fu r o[3,4-e]p yr id in e-1,7(3H)-d ion e (7). 3-Bro-
mo-4-fluorobenzaldehyde, methyl acetoacetate (c6), and 3-ami-
nocyclopent-2-en-1-one (e1) were treated according to method
A with the variations of MeOH for solvent, 65 °C for reaction
temperature, and reaction time of 5 days to provide methyl
4-(3-bromo-4-fluorophenyl)-4,5,6,7-tetrahydro-2-methyl-5-oxo-
1H-cyclopenta[b]pyridine-3-carboxylate: 1H NMR (CDCl3) δ
2.45 (s, 3H), 3.60 (s, 3H), 4.90 (s, 1H), 6.33 (s, 1H), 6.98 (t,
1H), 7.23 (m, 1H), 7.37 (d, 1H). This intermediate (1.9 g, 5.0
mmol) in IPA (30 mL) was treated with NBS (890 mg, 5.0
mmol) and stirred at room temperature for 45 min. The solvent
was evaporated and the crude product flash chromatographed
over silica gel eluting with 2.5% MeOH/CH2Cl2 to provide 1.19
g methyl 4-(3-bromo-4-fluorophenyl)-2-(bromomethyl)-4,5,6,7-
tetrahydro-5-oxo-1H-cyclopenta[b]pyridine-3-carboxylate: 1H
NMR (CDCl3) δ 2.47 (m, 2H), 2.65 (m, 2H), 3.63 (s, 3H), 4.83
(AB q, 2H), 4.90 (s, 1H), 6.80 (br s, 1H), 7.00 (t, 1H), 7.23 (m,
1H), 7.40 (dd, 1H). This intermediate was reacted according
to method D, part 2 at 180 °C for 1 h to provide the racemate
that was separated into the individual enantiomers by chiral
HPLC using an (R,R)-Whelk-O1 column eluting with hexane:
MeOH:CH2Cl2 (50:34:16). The (-)-(S)-enantiomer 8 eluted
first: [R]20D -80.8° (DMSO); 1H NMR (DMSO-d6) δ 2.35 (t, 2H),
2.70 (m, 2H), 4.60 (s, 1H), 4.98 (q, 2H), 7.26 (m, 2H), 7.50 (d,
1H), 10.71 (s, 1H); MS (ESI+) m/z 364 (M + H)+. Anal. (C16H11
-
BrFNO3) C, H, N. The (+)-(R)-enantiomer 7 eluted second:
[R]20D +88.2° (DMSO); 1H NMR (DMSO-d6) δ 2.35 (t, 2H), 2.70
(m, 2H), 4.60 (s, 1H), 4.98 (q, 2H), 7.26 (m, 2H), 7.50 (d, 1H),
10.71 (s, 1H); MS (ESI+) m/z 364 (M + H)+. Anal. (C16H11
-
BrFNO3) C, H, N. The absolute stereochemistry for 7 and 8
was determined indirectly through independent synthesis of
8 from (4S)-methyl 4-(3-bromo-4-fluorophenyl)-4,5,6,7-tetrahy-
dro-2-methyl-5-oxo-1H-cyclopenta[b]pyridine-3-carboxylate (see
the Supporting Information for X-ray analysis) using the same
method as described above. The enantiomerically pure (S)-
ester intermediate, in turn, was obtained by chiral HPLC of
the racemate over a Whelk-O1 column eluting with 80:13:7
hexane:MeOH:CH2Cl2.
(+)-(9R)-9-(3-Br om o-4-flu or op h en yl)-5,6,7,9-t et r a h y-
d r ofu r o[3,4-b]qu in olin e-1,8(3H,4H)-d ion e (9). The product
from method F, part 3A was treated according to method D at
180 °C for 1 h to provide 9 as a brown solid: [R]20 +171.4°
D
(DMSO); 1H NMR (DMSO-d6) δ 1.92 (m, 2H), 2.25 (m, 2H),
2.57 (m, 2H), 4.68 (s, 1H), 4.88 (q, 2H), 7.23 (m, 2H), 7.44 (d,
1H), 10.18 (s, 1H); MS (APCI-) m/z 376 (M - H)-. Anal.
(C17H13BrFNO3) C, H, N.
(-)-(9S)-9-(3-Br om o-4-flu or op h en yl)-5,6,7,9-t et r a h y-
d r ofu r o[3,4-b]qu in olin e-1,8(3H,4H)-d ion e (10). The prod-
uct from method F, part 3B was treated as described in
example 9 to provide 10 as a light pink powder. [R]20D -179.0°
(DMSO); 1H NMR (DMSO-d6) δ 1.91 (m, 2H), 2.26 (m, 2H),
2.58 (m, 2H), 4.68 (s, 1H), 4.89 (q, 2H), 7.23 (m, 2H), 7.44 (d,
g of 23 as the free base which was converted to the hydro-
1
chloride salt: [R]20 -125.88° (DMSO); H NMR (DMSO-d6)
D
(free base) δ 2.28 (t, 2H), 2.53-2.76 (m, 2H), 3.18 (s, 2H), 3.62
(d, 2H), 4.67 (s, 1H), 7.22 (d, 2H), 7.45 (d, 1H) 10.1 (s, 1H);
MS (ESI-) m/z 375 (M - H)-. Anal. Calcd for C17H13BrFN2O2‚
HCl‚0.5H2O: C, 48.43; H, 4.08; N, 6.28. Found: C, 48.42; H,
3.59; N, 6.64.
1H), 10.17 (s, 1H); MS (ESI-) m/z 376 (M - H)-. Anal. (C17H13
BrFNO3‚0.2H2O) C, H, N.
-
9-(3-Br om o-4-flu or op h en yl)-3,4,5,6,7,9-h exa h yd r ocy-
clop en ta [b]p yr a n o[3,4-e]p yr id in e-1,8-d ion e (11). A mix-
ture of dihydro-2H-pyran-2,4(3H)-dione (c9) (1.5 mmol, 171
mg), 3-bromo-4-fluorobenzaldehyde (1.5 mmol, 305 mg), and
3-amino-2-cyclopenten-1-one (e1) (1.5 mmol, 146 mg) was
treated according to method A to provide 246 mg of 11: 1H
NMR (DMSO-d6) δ 2.28 (t, 2H), 2.52-2.86 (m, 4H), 4.20-4.38
P a r t 3B. (+)-5-(3-Br om o-4-flu or op h en yl)-2,3,5,7,8,9-
h exa h yd r o-1H -cyclop en t a [b][1,7]n a p h t h yr id in e-4,6-d i-
on e Hyd r och lor id e (24). A solution of the product from part
2B (0.25 g, 0.41 mmol) in 48% HBr/AcOH (3 mL) was heated
for 3 days at 50 °C, cooled to room temperature, neutralized

3188 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
(m, 2H), 4.63 (s, 1H), 7.20-7.27 (m, 2H), 7.45 (d, 1H), 10.27
Carroll et al.
(+)-(9R)-9-(3-Br om o-4-flu or oph en yl)-2-m eth yl-2,3,5,6,7,9-
h exah ydr o-1H-pyr r olo[3,4-b]qu in olin e-1,8(4H)-dion e (19).
The product from method F, part 3A was treated according to
method D, part 1 and method E to provide 19 as a white
(bs, 1H); MS (APCI+) m/z 378 (M + H)+. Anal. Calcd for C17H13
-
BrFNO3: C, 53.99; H, 3.46; N, 3.70. Found: C, 53.38; H, 3.76;
N, 3.49.
powder: [R]20 +152.15° (DMSO); 1H NMR (DMSO-d6) δ 1.91
10-(3-Br om o-4-flu or op h en yl)-3,4,6,7,8,10-h exa h yd r o-
1H-p yr a n o[4,3-b]qu in olin e-1,9(5H)-d ion e (12). A mixture
of dihydro-2H-pyran-2,4(3H)-dione (c9) (1.5 mmol, 171 mg),
3-bromo-4-fluorobenzaldehyde (1.5 mmol, 305 mg), and 3-amino-
2-cyclohexen-1-one (e2) (1.5 mmol, 167 mg) was treated
according to method A to provide 265 mg of 12: 1H NMR
(DMSO-d6) δ 1.73-2.00 (m, 2H), 2.19-2.29 (m, 2H), 2.54-2.80
(m, 4H), 4.10-4.35 (m, 2H), 4.80 (s, 1H), 7.18-7.23 (m, 2H),
7.39 (dd, 1H), 9.72 (bs, 1H); MS (APCI-) m/z 390 (M - H)-.
Anal. (C18H15BrFNO3) C, H, N.
5-(3-Br om o-4-flu or op h en yl)-5,7,8,9-t et r a h yd r ocyclo-
p en ta [b]p yr a n o[4,3-e]p yr id in e-4,6(1H,3H)-d ion e (13). A
mixture of 5-amino-2H-pyran-3(6H)-one (e3) (0.23 g, 2.0
mmol), 3-bromo-4-fluorobenzaldehyde (0.49 g, 2.4 mmol), and
1,3-cyclopentanedione (c1) (0.20 g, 2.0 mmol) was treated
according to method B. The product was recrystallized from
MeOH/CH2Cl2 to provide 0.14 g of 13: 1H NMR (DMSO-d6) δ
2.31 (t, 2H), 2.59 (dt, 1H), 2.73 (dt, 1H), 4.04 (s, 2H), 4.53 (AB
q, 2H), 4.71 (s, 1H), 7.22 (m, 2H), 7.43 (dd, 1H), 10.36 (bs, 1H);
MS (ESI+) m/z 378 (M + H)+. Anal. (C17H13BrFNO3) C, H, N.
5-(3-Br om o-4-flu or oph en yl)-5,8,9,10-tetr ah ydr o-1H-pyr -
a n o[3,4-b]qu in olin e-4,6(3H,7H)-d ion e (14). A mixture of
5-amino-2H-pyran-3(6H)-one (e3) (0.23 g, 2.0 mmol), 3-bromo-
4-fluorobenzaldehyde (0.49 g, 2.4 mmol), and 1,3-cyclohex-
anedione (c2) (0.23 g, 2.0 mmol) was treated according to
method B. The product was recrystallized from MeOH/CH2-
Cl2 to provide 0.37 g of 14: 1H NMR (DMSO-d6) δ 1.76-2.01
(m, 2H), 2.25 (t, 2H), 2.43-2.64 (m, 2H), 4.01 (s, 2H), 4.48 (AB
q, 2H), 4.90 (s, 1H), 7.20 (m, 2H), 7.39 (dd, 1H), 9.82 (bs, 1H);
MS (ESI+) m/z 392 (M + H)+. Anal. (C18H15BrFHO3) C, H, N.
D
(m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 2.79 (s, 3H), 4.02 (q, 2H),
4.70 (s, 1H), 7.19 (m, 2H), 7.42 (d, 1H), 9.82 (s, 1H); MS (ESI+)
m/z 391 (M + H)+. Anal. (C18H16BrFN2O2‚0.4CH2Cl2) C, H, N.
(9S)-9-(3-Br om o-4-flu or op h en yl)-2-m et h yl-2,3,5,6,7,9-
h exah ydr o-1H-pyr r olo[3,4-b]qu in olin e-1,8(4H)-dion e (20).
The product from method F, part 3B was treated according to
method D, part 1 and method E to provide 20 as a pale yellow
solid: 1H NMR (DMSO-d6) δ 1.90 (m, 2H), 2.24 (m, 2H), 2.55
(m, 2H), 2.78 (s, 3H), 4.02 (q, 2H), 4.69 (s, 1H), 7.18 (m, 2H),
7.43 (d, 1H), 9.80 (s, 1H); MS (ESI+) m/z 391 (M + H)+. Anal.
(C18H16BrFN2O2) C, H, N.
9-(3-Br om o-4-flu or op h en yl)-3,4,5,6,7,9-h exa h yd r o-1H-
cyclop en ta [b][1,6]n a p h th yr id in e-1,8(2H)-d ion e (21). A
mixture of 3-bromo-4-fluorobenzaldehyde (1 mmol, 203 mg),
piperidine-2,4-dione23 (c10) (1 mmol, 113 mg), and 3-aminocy-
clopent-2-en-1-one (e1) (1 mmol, 97 mg) was treated according
to method A to provide 122 mg of 21: 1H NMR (DMSO-d6) δ
2.25 (t, 2H), 2.40-2.70 (m, 4H), 3.15-3.35 (m, 2H), 4.70 (s,
1H), 7.07 (bs, 1H), 7.17-7.22 (m, 2H), 7.42 (dd, 1H), 9.83 (s,
1H); MS (APCI+) m/z 377 (M + H)+. Anal. (C17H14BrFN2O2)
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-
ben zo[b][1,6]n a p h th yr id in e-1,9(2H,5H)-d ion e (22). A mix-
ture of 3-bromo-4-fluorobenzaldehyde (1 mmol, 203 mg),
piperidine-2,4-dione (c10) (1 mmol, 113 mg), and 3-aminocy-
clohex-2-en-1-one (e2) (1 mmol, 111 mg) was treated according
to method A to provide 218 mg of 22: 1H NMR (DMSO-d6) δ
1.70-1.97 (m, 2H), 2.15-2.25 (m, 2H), 2.36-2.59 (m, 4H),
3.13-3.23 (m, 2H), 4.90 (s, 1H), 7.00 (bs, 1H), 7.15-7.20 (m,
2H), 7.39 (dd, 1H), 9.28 (s, 1H); MS (ESI+) m/z 391 (M + H)+.
Anal. (C18H16BrFN2O2) C, H, N.
(+)-(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 o-1H-p yr r olo[3,4-b]qu in olin e-1,8(4H)-d ion e (15). The
product from method F, part 3A was treated according to
method D, part 1 and method E using NH3 at room temper-
(-)-5-(3-Br om o-4-flu or op h en yl)-2,3,5,8,9,10-h exa h yd r o-
ben zo[b][1,7]n aph th yr idin e-4,6(1H,7H)-dion e Hydr och lo-
r id e (25) a n d (+)-5-(3-Br om o-4-flu or op h en yl)-2,3,5,8,9,-
10-h exa h yd r oben zo[b][1,7]n a p h th yr id in e-4,6(1H,7H)-d i-
on e Hyd r och lor id e (26). A mixture of 3-aminocyclohex-2-
en-1-one (e2) (0.55 g, 5.0 mmol), 3-bromo-4-fluorobenzaldehyde
(1.01 g, 5.0 mmol) and 1-benzylpiperidine-3,5-dione (c5) (1.01
g, 5.0 mmol) was treated according to method G, part 1 to
provide 0.84 g of 2-benzyl-5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,-
10-hexahydrobenzo[b][1,7]naphthyridine-4,6(1H,7H)-dione: 1H
NMR (CDCl3) (free base) δ 2.0 (m, 2H), 2.67 (m, 2H), 2.48 (m,
2H), 3.05-3.48 (m, 4H), 3.7 (m, 2H), 5.1 (s, 1H), 6.05 (bs, 1H),
6.99 (t, 1H), 7.32 (m, 6H), 7.41 (dd, 1H). This intermediate
(1.23 g, 2.5 mmol) was treated according to method G, part 2
to provide two diastereomers of (1R,2S,5R)-5-methyl-2-(1-
methyl-1-phenylethyl)cyclohexyl 5-(3-bromo-4-fluorophenyl)-
4,6-dioxo-3,4,5,6,7,8,9,10-octahydrobenzo[b][1,7]naphthyridine-
2(1H)-carboxylate. The less polar diastereomer (0.32 g): 1H
NMR (CDCl3) δ 0.88 (d, 3H), 0.9 (m, 1H), 1.13 (m, 1H), 1.19
(s, 3H), 1.28 (m, 2H), 1.32 (s, 3H), 1.72 (m, 2H), 1.88 (m, 1H),
2.05 (m, 3H), 2.38 (m, 2H), 2.51 (m, 2H), 2.72 (d, 1H), 3.56 (d,
1H), 3.82 (d, 1H), 4.71 (m, 2H), 5.07 (s, 1H), 6.92 (t, 1H), 7.12
(m, 1H), 7.28 (m, 6H). The more polar diastereomer (0.24 g):
1H NMR (CDCl3) δ 0.88 (d, 3H), 0.92 (m, 1H), 1.13 (s, 3H),
1.18-1.32 (m, 6H), 1.73 (m, 2H), 1.92 (m, 1H), 2.05 (m, 3H),
2.38 (m, 2H), 2.53 (m, 2H), 2.81 (d, 1H), 3.2 (d, 1H), 3.9 (d,
1H), 4.56 (d, 1H), 4.75 (m, 1H), 5.1 (s, 1H), 6.41 (t, 1H), 6.8
(m, 2H), 7.05 (m, 1H), 7.12 (d, 1H), 7.31 (m, 1H), 7.4 (m, 1H),
7.5 (d, 1H). The less polar diastereomer (0.32 g) was reacted
ature for 20 h in a pressure bomb to provide 15 as a yellow
1
powder: [R]20 +180.2° (DMSO); H NMR (DMSO-d6) δ 1.90
D
(m, 2H), 2.23 (m, 2H), 2.55 (m, 2H), 3.93 (q, 2H), 4.70 (s, 1H),
7.20 (m, 2H), 7.42 (d, 1H), 7.47 (s, 1H), 9.80 (s, 1H); MS
(APCI-) m/z 375 (M - H)-. Anal. (C17H14BrFN2O2‚0.5H2O) C,
H, N.
(-)-(9S)-9-(3-Br om o-4-flu or op h en yl)-2,3,5,6,7,9-h exa h y-
d r o-1H-p yr r olo[3,4-b]qu in olin e-1,8(4H)-d ion e (16). The
product from method F, part 3B was treated according to
method D, part 1 and method E using NH3 at room temper-
ature for 20 h in a pressure bomb to provide 16 as a beige
solid: [R]20 -169.4° (DMSO); 1H NMR (DMSO-d6) δ 1.90 (m,
D
2H), 2.23 (m, 2H), 2.55 (m, 2H), 3.93 (q, 2H), 4.69 (s, 1H), 7.19
(m, 2H), 7.42 (d, 1H), 7.48 (s, 1H), 9.80 (s, 1H); MS (ESI+) m/z
377 (M + H)+. Anal. (C17H14BrFN2O2‚0.4CH2Cl2) C, H, N.
(+)-(8R)-(3-Br om o-4-flu or op h en yl)-2-m eth yl-2,3,4,5,6,8-
h exa h yd r ocyclop en t a [b]p yr r olo[3,4-e]p yr id in e-1,7-d i-
on e (17) a n d (-)-(8S)-(3-Br om o-4-flu or op h en yl)-2-m eth yl-
2,3,4,5,6,8-h exah ydr ocyclopen ta[b]pyr r olo[3,4-e]pyr idin e-
1,7-d ion e (18). Methyl 4-(3-bromo-4-fluorophenyl)-2-(bromo-
methyl)-4,5,6,7-tetrahydro-5-oxo-1H-cyclopenta[b]pyridine-3-
carboxylate (0.11 g) from examples 7 and 8 was treated
according to method D, part 1 and method E to provide 0.052
g of the title compound that was separated into the two
enantiomers after chiral HPLC resolution (Chiralcel OD, 4.6
× 250 mm, hexane:EtOH, 90:10). The less polar enantiomer
1
was 17, a light yellow solid: [R]20 +68.5° (DMSO); H NMR
D
(DMSO-d6) δ 2.30 (t, 2H), 2.55-2.67 (m, 2H), 2.80 (s, 3H), 4.08
(q, 2H), 4.56 (s, 1H), 7.21 (m, 2H), 7.44 (d, 1H); MS (ESI+) m/z
377 (M + H)+. Anal. (C17H14BrFN2O2) C, H, N. The more polar
according to method G, part 3 to provide 0.125 g 25: [R]20
D
-10° (CH3CN); 1H NMR (DMSO-d6) δ 1.72-1.99 (m, 2H), 2.22
(t, 2H), 2.98 (m, 1H), 3.15 (s, 2H), 3.4 (m, 2H), 3.57 (s, 2H),
4.88 (s, 1H), 7.18 (m, 2H), 7.4 (d, 1H); MS (ESI-) m/z 389 (M
- H)-. Anal. Calcd for C18H15BrFN2O2‚HCl: C, 50.67; H, 3.78;
N, 6.57. Found: C, 50.18; H, 4.22; N, 6.16. The more polar
diastereomer from above (0.24 g) was reacted according to
enantiomer was 18: [R]20 -66.9° (DMSO); 1H NMR (DMSO-
D
d6) δ 2.30 (t, 2H), 2.55-2.67 (m, 2H), 2.80 (s, 3H), 4.08 (q, 2H),
4.56 (s, 1H), 7.21 (m, 2H), 7.44 (d, 1H); MS (ESI+) m/z 377 (M
+ H)+. Anal. (C17H14BrFN2O2‚0.5H2O) C, H, N. A single-crystal
X-ray confirmed the stereochemistry (see the Supporting
Information).
method G, part 3 to provide 0.070 g of 26: [R]20 +9.52°
D

Tricyclic Dihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3189
1
(CH3CN); H NMR (DMSO-d6) δ 1.75-1.98 (m, 2H), 2.25 (t,
2.18-2.22 (m, 2H), 2.56-2.61 (m, 2H), 3.18-3.23 (m, 2H), 4.86
(s, 1H), 4.87 (q, 2H), 7.28 (m, 2H), 7.47 (d, 1H), 10.03 (br s,
1H); MS (ESI-) m/z 412 (M - H)-. Anal. (C16H13BrFNO4S) C,
H, N. The more polar diastereomer from above (655 mg) was
reacted as described for the less polar diastereomer to provide
290 mg of 30 as a white solid: [R]20D -133.6° (DMSO); 1H NMR
(DMSO-d6) δ 2.18-2.22 (m, 2H), 2.56-2.61 (m, 2H), 3.18-3.23
(m, 2H), 4.86 (s, 1H), 4.87 (q, 2H), 7.28 (m, 2H), 7.47 (d, 1H),
2H), 2.95 (s, 1H), 3.15 (s, 2H), 3.45 (m, 2H), 3.57 (s, 2H), 4.89
(s, 1H), 7.17 (m, 2H), 7.39 (d, 1H), 9.6 (s, 1H); MS (ESI-) m/z
389 (M - H)-. Anal. (C18H16BrFN2O2‚HCl) C, H, N.
5-(3-Br om o-4-flu or op h en yl)-5,7,8,9-t et r a h yd r ocyclo-
p en ta [b]th iop yr a n o[4,3-e]p yr id in e-4,6(1H,3H)-d ion e (27).
A mixture of 2H-thiopyran-3,5(4H,6H)-dione (c4), 3-bromo-4-
fluorobenzaldehyde, and 3-aminocyclopent-2-en-1-one (e1) was
treated according to method A and purified by flash chroma-
tography on silica gel eluting with acetone:CH2Cl2 (1:1) to
provide 0.13 g of 27: 1H NMR (DMSO-d6) δ 2.28 (t, 2H), 2.48-
2.73 (m, 2H), 3.14 (dd, 1H), 3.47 (dd, 1H), 3.54 (dd, 1H), 3.82
(dd, 1H), 4.72 (s, 1H), 7.18-7.25 (m, 2H), 7.42 (dd, 1H), 10.27
(s, 1H); MS (APCI+) m/z 394 (M + H)+. Anal. (C17H13BrFNO2S)
C, H, N.
10.03 (br s, 1H); MS (ESI-) m/z 412 (M - H)-. Anal. (C16H13
-
BrFNO4S) C, H, N.
(+)-(9R)-(3-Br om o-4-flu or op h en yl)-2,3,5,9-tetr a h yd r o-
4H-p yr a n o[3,4-b]th ien o[2,3-e]p yr id in -8(7H)-on e 1,1-Di-
oxid e (32) a n d (-)-9-(3-Br om o-4-flu or op h en yl)-2,3,5,9-
tetr a h yd r o-4H-p yr a n o[3,4-b]th ien o[2,3-e]p yr id in -8(7H)-
on e 1,1-Dioxid e (33). The racemic product from method B
was separated into the individual enantiomers using the same
protocol as used for examples 30 and 31 except eluting with
3:2:1 CHCl3:hexanes:Et2O during the separation of the dia-
stereomeric intermediates. From the less polar diastereomeric
intermediate (0.98 g, 1.4 mmol) was obtained 0.36 g of 32 (see
8-(3-Br om o-4-flu or op h en yl)-2,3,5,8-tetr a h yd r ofu r o[3,4-
b]th ien o[2,3-e]p yr id in -7(4H)-on e 1,1-Dioxid e (29). A mix-
ture of the dihydrothiophen-3(2H)-one 1,1-dioxide (c7) (1.29
g, 9.60 mmol), 3-bromo-4-fluorobenzaldehyde (2.03 g, 10.0
mmol), and methyl (2E)-3-aminobut-2-enoate (e5) (1.15 g, 10.0
mmol) was treated according to method B to provide 2.88 g of
methyl 7-(3-bromo-4-fluorophenyl)-5-methyl-2,3,4,7-tetrahy-
drothieno[3,2-b]pyridine-6-carboxylate 1,1-dioxide: 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). This intermediate (0.83 g, 2.0 mmol) in
CHCl3 (40 mL) was treated with NBS (0.42 g, 2.4 mmol),
stirred at room temperature for 30 min, concentrated to
dryness, heated under N2 to 130 °C for 15 min, and cooled to
room temperature. The residue was purified by chromatogra-
phy on silica gel eluting with MeOH:CH2Cl2 (3:97) to provide
0.085 g of 29: 1H NMR (DMSO-d6) δ 2.80-2.92 (m, 1H), 2.99-
3.12 (dt, 1H), 3.37-3.47 (m, 2H), 4.82 (s, 1H), 4.91 (AB q, 2H),
7.31 (m, 2H), 7.55 (dd, 1H), 10.40 (bs, 1H); MS (ESI+) m/z 399
(M + H)+. Anal. (C15H11BrFO4NS) C, H, N.
(+)-9-(3-Br om o-4-flu or op h en yl)-3,4,6,9-tetr a h yd r o-2H-
fu r o[3,4-b]th iop yr a n o[2,3-e]p yr id in -8(5H)-on e 1,1-Diox-
id e (31) a n d (-)-9-(3-Br om o-4-flu or op h en yl)-3,4,6,9-tet-
r a h yd r o-2H -fu r o[3,4-b]t h iop yr a n o[2,3-e]p yr id in -8(5H )-
on e 1,1-Dioxid e (30). A mixture of 3-bromo-4-fluorobenz-
aldehyde (2.03 g, 10 mmol), methyl (2E)-3-aminobut-2-enoate
(e5) (1.15 g, 10 mmol), and dihydro-2H-thiopyran-3(4H)-one
1,1-dioxide (c8) (1.48 g, 10 mmol) in MeOH was treated
according to method A at 65 °C for 24 h to provide 3.11 g of
methyl 8-(3-bromo-4-fluorophenyl)-6-methyl-3,4,5,8-tetrahy-
dro-2H-thiopyrano[3,2-b]pyridine-7-carboxylate 1,1-dioxide: 1H
NMR (DMSO-d6) δ 2.18 (m, 2H), 2.27 (s, 3H), 2.43-2.55 (m,
2H), 3.14-3.22 (m, 2H), 3.58 (s, 3H), 4.97 (s, 1H), 7.19 (m, 1H),
7.25 (t, 1H), 7.36 (d, 1H), 9.12 (s, 1H). This intermediate (860
mg, 2.0 mmol) was treated according to method D, parts 1 and
2 to provide 345 mg of 9-(3-bromo-4-fluorophenyl)-3,4,6,9-
tetrahydro-2H-furo[3,4-b]thiopyrano[2,3-e]pyridin-8(5H)-one 1,1-
dioxide as a white solid: 1H NMR (DMSO-d6) δ 2.18-2.22 (m,
2H), 2.56-2.61 (m, 2H), 3.18-3.23 (m, 2H), 4.86 (s, 1H), 4.87
(q, 2H), 7.28 (m, 2H), 7.47 (d, 1H), 10.03 (br s, 1H). To a
suspension of this racemate (1.02 g, 2.46 mmol) in THF (10
mL) at 0 °C under N2 was added slowly 1 M KOtBu/THF (2.46
mL), and the reaction warmed to room temperature for 10 min
and cooled to 0 °C. A solution of 8-phenylmenthol chlorofor-
mate (0.727 g, 2.46 mmol, prepared from (-)-8-phenylmenthol)
in THF (25 mL), was added. The reaction was warmed to room
temperature 2 h, quenched in sat. NaHCO3, and extracted with
Et2O:EtOAc (4:1). The organic portion was dried (MgSO4),
filtered, and concentrated. Flash column chromatography on
silica gel eluting with Et2O:hexane (85:15) provided 750 mg
of the less polar diastereomer and 655 mg of the more polar
diastereomer. A solution of the less polar diastereomer (639
mg) in MeOH (10 mL) was treated with catalytic 25% NaOMe/
MeOH under N2. The solution slowly turned into a suspension.
After completion of the reaction (evidenced by TLC), a few
drops of AcOH were added, resulting in the formation of a
the Supporting Information for X-ray crystal analysis): [R]23
D
+117° (c ) 0.925, DMSO); 1H NMR (DMSO-d6) δ 2.85 (m, 1H),
3.08 (m, 1H), 3.33-3.42 (m, 2H), 4.03 (s, 2H), 4.49 (AB q, 2H),
4.90 (s, 1H), 7.27 (m, 2H), 7.45 (dd, 1H), 10.14 (s, 1H); MS
(ESI+) m/z 414 (M + H)+. Anal. (C16H13BrFNO4S): C, H, N.
From the more polar diastereomeric intermediate (1.0 g, 15
mmol) was obtained 0.40 g of 33: [R]23 -117° (c ) 1.01,
D
DMSO); 1H NMR (DMSO-d6) δ 2.85 (m, 1H), 3.08 (m, 1H),
3.33-3.42 (m, 2H), 4.03 (s, 2H), 4.49 (AB q, 2H), 4.90 (s, 1H),
7.27 (m, 2H), 7.45 (dd, 1H), 10.14 (s, 1H); MS (ESI+) m/z 414
(M + H)+. Anal. (C16H13BrFNO4S): C, H, N.
10-(3-Br om o-4-flu or oph en yl)-3,4,6,10-tetr ah ydr o-2H,5H-
p yr a n o[3,4-b]th iop yr a n o[2,3-e]p yr id in -9(8H)-on e 1,1-Di-
oxid e (34). A mixture of 5-amino-2H-pyran-3(6H)-one (e3)
(0.23 g, 2.0 mmol), 3-bromo-4-fluorobenzaldehyde (0.49 g, 2.4
mmol), and dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide (c8)
(0.30 g, 2.0 mmol) was treated according to method A to
provide 0.25 g of 34: 1H NMR (DMSO-d6) δ 2.22 (m, 2H), 2.41-
2.56 (m, 1H), 2.64 (dt, 1H), 3.09-3.35 (m, 2H), 4.02 (s, 2H),
4.43 (AB q, 2H), 5.06 (s, 1H), 7.25 (m, 2H), 7.41 (dd, 1H), 9.67
(bs, 1H); MS (ESI+) m/z 428 (M + H)+. Anal. (C17H15BrFNO4S)
C, H, N.
8-(3-Br om o-4-flu or op h en yl)-6-m et h yl-2,3,5,8-t et r a h y-
d r op yr r olo[3,4-b]th ien o[2,3-e]p yr id in -7(4H)-on e 1,1-Di-
oxid e (35). Methyl 7-(3-bromo-4-fluorophenyl)-5-methyl-
2,3,4,7-tetrahydrothieno[3,2-b]pyridine-6-carboxylate, 1,1-
dioxide (52 mg, 0.13 mmol) from example 29 was treated
according to method D, part 1 to provide an intermediate
bromo derivative that was reacted directly with 2.0 M MeNH2/
MeOH (0.7 mL), stirred overnight at room temperature, and
evaporated to dryness. The residue was flash chromatographed
with 7.5% MeOH/CH2Cl2 to yield 26 mg of 35 as a light yellow
solid: 1H NMR (DMSO-d6) δ 2.78 (s, 3H), 2.8-2.9 (m, 1H), 3.0-
3.1 (m, 1H), 3.3-3.4 (m, 2H), 4.3 (AB q, 2H), 4.77 (s, 1H), 7.27
(m, 2H), 7.48 (d, 1H), 9.97 (s, 1H); MS (ESI-) m/z 413 (M -
H)-. Anal. (C16H14BrFN2O3S‚0.1H2O) C, H, N.
9-(3-Br om o-4-flu or oph en yl)-7-m eth yl-3,4,5,6,7,9-h exah y-
d r op yr r olo[3,4-b]th iop yr a n o[2,3-e]p yr id in -8(2H)-on e 1,1-
Dioxid e (36). A mixture of 3-bromo-4-fluorobenzaldehyde
(2.03 g, 10 mmol), methyl (2E)-3-aminobut-2-enoate (e5) (1.15
g, 10 mmol), and dihydro-2H-thiopyran-3(4H)-one 1,1-dioxide
(c8) (1.48 g, 10 mmol) was treated according to method A to
provide 3.11 g of methyl 8-(3-bromo-4-fluorophenyl)-6-methyl-
3,4,5,8-tetrahydro-2H-thiopyrano[3,2-b]pyridine-7-carboxy-
late 1,1-dioxide: 1H NMR (DMSO-d6) δ 2.18 (m, 2H), 2.27 (s,
3H), 2.43-2.55 (m, 2H), 3.14-3.22 (m, 2H), 3.58 (s, 3H), 4.97
(s, 1H), 7.19 (m, 1H), 7.25 (t, 1H), 7.36 (d, 1H), 9.12 (s, 1H).
This intermediate (107.5 mg, 0.25 mmol) was treated according
to method D, part 1 and method E to provide 49 mg of 36 as
a light yellow powder: 1H NMR (DMSO-d6) δ 2.18-2.24 (m,
2H), 2.58 (m, 2H), 2.78 (s, 3H), 3.16-3.22 (m, 2H), 3.98 (q,
2H), 4.86 (s, 1H), 7.26 (m, 2H), 7.43 (d, 1H), 9.60 (s, 1H); MS
(ESI+) m/z 427 (M + H)+. Anal. Calcd for C17H16BrFN2O3S:
C, 47.79; H, 3.77; N, 6.56. Found: C, 47.31; H, 4.03; N, 6.31.
precipitate that was isolated by filtration and dried to provide
210 mg of 31: [R]20 +150.0° (DMSO); H NMR (DMSO-d6) δ
1
D

3190 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
9-(3-Br om o-4-flu or oph en yl)-2,3,5,6,7,9-h exah ydr oth ien o-
[3,2-b][1,7]n a p h th yr id in -8(4H)-on e 1,1-Dioxid e Hyd r o-
ch lor id e (37). A solution of 1-benzylpiperidine-3,5-dione (c5)
(0.55 g, 2.5 mmol) in EtOH (5 mL) was reacted with 2.0 M
NH3/EtOH (1.25 mL) for 4 h in a sealed tube, treated with
dihydrothiophen-3(2H)-one 1,1-dioxide (c7) (0.33 g, 2.5 mmol)
and 3-bromo-4-fluorobenzaldehyde (0.51 g, 2.5 mmol), stirred
at 75 °C for 48 h, cooled, concentrated, and flash chromato-
graphed over silica gel eluting with CH2Cl2/EtOH (90:10) to
provide 0.28 g of 6-benzyl-9-(3-bromo-4-fluorophenyl)-2,3,5,6,7,9-
hexahydrothieno[3,2-b][1,7]naphthyridin-8(4H)-one 1,1-diox-
ide: 1H NMR (DMSO-d6) δ 2.8 (m, 1H), 3.0 (m, 2H), 3.08-3.3
(m, 2H), 3.42 (m, 3H), 3.62 (m, 2H), 4.85 (s, 1H), 7.2-7.48 (m,
8H), 9.98 (s, 1H). This intermediate (0.22 g, 0.43 mmol) in CH2-
Cl2 (5 mL) was reacted with vinyl chloroformate (0.10 mL, 0.94
mmol) at room temperature for 24 h and partitioned between
CH2Cl2/aq NaHCO3. The organics were dried (Na2SO4), fil-
tered, and concentrated to provide 0.28 g of vinyl 9-(3-bromo-
4-fluorophenyl)-8-oxo-2,3,5,7,8,9-hexahydrothieno[3,2-b][1,7]-
naphthyridine-6(4H)-carboxylate 1,1-dioxide: 1H NMR (DMSO-
d6) δ 2.88 (m, 2H), 3.1 (m, 3H), 3.5 (m, 1H), 3.75 (q, 2H), 4.12
(s, 2H), 4.9 (s, 1H), 7.29 (m, 2H), 7.48 (d, 1H), 10.1 (s, 1H).
This intermediate (0.28 g) in EtOH (5 mL) was reacted with 6
N HCl (1 mL) at reflux for 3 h, cooled to room temperature,
concentrated, and flash chromatographed over silica gel eluting
with CH2Cl2 (saturated with NH4OH):EtOH (90:10) to provide
0.070 g of 37: 1H NMR (DMSO-d6) δ 2.75 (m, 2H), 3.02 (m,
1H), 3.15 (s, 2H), 3.58 (m, 3H), 4.87 (s, 1H), 7.25 (d, 2H), 7.43
(d, 1H), 9.9 (s, 1H); MS (ESI-) m/z 411 (M - H)-. Anal. Calcd
for C16H14BrFN2SO3·HCl·0.5C2H5OH: C, 43.19; H, 3.84; N,
5.93; Cl, 7.50. Found: C, 43.69; H, 3.85; N, 5.83; Cl, 7.66.
1H), 7.42 (dd, 1H). This intermediate (1.27 g, 3.00 mmol) in
MeOH (60 mL) was reacted with NBS (1.068 g, 6.00 mmol)
for 1.5 h at room temperature and poured into water. The
precipitate was collected and crystallized from acetone/hexane
to provide 685 mg of diethyl 2,6-bis-(bromomethyl)-4-(3-bromo-
4-fluorophenyl)-1,4-dihydro-3,5-pyridine dicarboxylate as a
yellow solid: 1H NMR (CDCl3) δ 1.25 (t, 6H), 4.15 (m, 4H),
4.76 (AB q, 4H), 4.96 (s, 1H), 6.48 (s, 1H), 6.99 (t, 1H), 7.18
(m, 1H), 7.43 (dd, 1H). This intermediate (90 mg) was heated
in an oil bath at 180 °C for 1 h, cooled to room temperature,
and triturated with acetone. The solid was collected, washed
with acetone, and dried to provide 32 mg of 39 as a light-yellow
solid: 1H NMR (DMSO-d6) δ 4.69 (s, 1H), 4.98 (q, 4H), 7.32
(m, 2H), 7.57 (d, 1H), 10.73 (s, 1H); MS (ESI-) m/z 364 (M -
H)-. Anal. (C15H9BrFNO4) C, H, N.
5-(3-Br om o-4-flu or op h en yl)-5,10-d ih yd r o-1H,3H-d ip y-
r a n o[3,4-b:4,3-e]p yr id in e-4,6(7H,9H)-d ion e (41). A mixture
of dihydro-2H-pyran-2,4(3H)-dione (c9) (0.10 g, 0.88 mmol),
3-bromo-4-fluorobenzaldehyde (0.24 g, 1.2 mmol), and 5-amino-
2H-pyran-3(6H)-one (e3) (0.10 g, 0.88 mmol) was treated
according to method A to provide 0.20 g of 41: 1H NMR
(DMSO-d6) δ 4.06 (s, 4H), 4.41-4.60 (AB q, 4H), 4.94 (s, 1H),
7.19-7.32 (m, 2H), 7.42 (dd, 1H), 10.12 (br s, 1H); MS (APCI-)
m/z 392 (M - H)-. Anal. (C17H13BrFNO4‚0.5H2O) C, H, N.
9-(3-Br om o-4-flu or oph en yl)-4,5,6,9-tetr ah ydr o-1H-fu r o-
[3,4-b]p yr a n o[3,4-e]p yr id in e-1,8(3H)-d ion e (42). A mixture
of dihydro-2H-pyran-2,4(3H)-dione (c9) (0.171 g, 1.5 mmol),
3-bromo-4-fluorobenzaldehyde (0.304 g, 1.5 mmol), and methyl
(2E)-3-aminobut-2-enoate (e5) (0.173 g, 1.5 mmol) was treated
according to method A to provide 0.12 g of methyl 4-(3-bromo-
4-fluorophenyl)-2-methyl-5-oxo-1,5,7,8-tetrahydro-4H-pyrano-
[4,3-b]pyridine-3-carboxylate. This intermediate (0.235 g, 0.59
mmol) was reacted according to method D, parts 1 and 2 but
modified by conducting the cyclization in CHCl3 (5 mL) at 50
°C for 12 h to provide 0.050 g of 42: 1H NMR (DMSO-d6) δ
2.61 (ddd, 1H), 2.79 (ddd, 1H), 4.22-4.36 (m, 2H), 4.94 (s, 1H),
4.91 (ABq, 2H), 7.23-7.32 (m, 2H), 7.48 (dd, 1H), 10.34 (bs,
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 -t h iop yr a n o[3,2-b][1,7]n a p h t h yr id in -9(5H )-on e 1,1-
Dioxide Hydr och lor ide (38). A solution of 1-benzylpiperidine-
3,5-dione (c5) (0.55 g, 2.5 mmol) in EtOH (5 mL) was reacted
with 2.0 M NH3/EtOH (1.25 mL, 2.5 mmol) for 30 min in a
sealed tube, treated with dihydro-2H-thiopyran-3(4H)-one 1,1-
dioxide (c8) (0.36 g, 2.5 mmol) and 3-bromo-4-fluorobenzalde-
hyde (0.51 g, 2.5 mmol), stirred at 75 °C for 48 h, cooled, and
concentrated. The residue was purified by flash chromatog-
raphy over silica gel eluting with EtOH:CH2Cl2 (5:95) to
provide 0.50 g of 7-benzyl-10-(3-bromo-4-fluorophenyl)-3,4,6,7,8,-
10-hexahydro-2H-thiopyrano[3,2-b][1,7]naphthyridin-9(5H)-
one 1,1-dioxide: 1H NMR (DMSO-d6) δ 2.18 (m, 2H), 2.42 (m,
2H), 2.95 (m, 2H), 3.15 (m, 4H), 3.42 (m, 2H), 3.6 (q, 2H), 5.0
(s, 1H), 7.18-7.5 (m, 8H), 9.5 (s, 1H). This intermediate (0.48
g, 0.92 mmol) in THF (5 mL) was reacted with vinyl chloro-
formate (0.10 mL, 0.94 mmol) at room temperature for 24 h,
the solvent was evaporated, and the residue was purified by
flash chromatography over silica gel eluting with EtOH/CH2-
Cl2 (10:90) to provide 0.25 g of vinyl 10-(3-bromo-4-fluorophe-
nyl)-9-oxo-3,4,6,8,9,10-hexahydro-2H-thiopyrano[3,2-b][1,7]-
naphthyridine-7(5H)-carboxylate 1,1-dioxide: 1H NMR (DMSO-
d6) δ 2.21 (m, 2H), 2.68 (m, 2H), 3.18 (m, 2H), 3.28 (m, 2H),
3.5 (m, 1H), 3.75 (q, 2H), 4.11 (s, 2H), 5.08 (s, 1H), 7.28 (m,
2H), 7.41 (d, 1H), 9.5 (br s, 1H). A solution of this intermediate
(0.25 g) in EtOH was reacted with 6 N HCl (1 mL) at reflux
for 2 h, cooled to room temperature, and concentrated. The
residue was purified by flash chromatography over silica gel
eluting with CH2Cl2 (saturated with NH4OH):EtOH (85:15) to
provide 0.09 g of 38: 1H NMR (DMSO-d6) (free base) δ 2.2 (m,
2H), 2.6 (m, 2H), 3.15 (s, 2H), 3.22 (m, 2H), 3.52 (d, 2H), 5.02
(s, 1H), 7.22 (m, 2H), 7.4 (m, 1H), 9.5 (br s, 1H); MS (ESI-)
m/z 425 (M - H)-. Anal. (C17H16BrFN2SO3‚HCl‚0.5C2H5OH)
C, H, N.
1H); MS (APCI+) m/z 380 (M + H)+. Anal. Calcd for C16H11
-
BrFNO4: C, 50.99; H, 3.47; N, 3.29. Found: C, 50.55; H, 2.92;
N, 3.55.
(+)-(9R)-(3-Br om o-4-flu or oph en yl)-5,9-dih ydr o-3H-fu r o-
[3,4-b]p yr a n o[4,3-e]p yr id in e-1,8(4H,7H)-d ion e (43) a n d
(-)-(9S)-(3-Br om o-4-flu or op h en yl)-5,9-d ih yd r o-3H-fu r o-
[3,4-b]p yr a n o[4,3-e]p yr id in e-1,8(4H,7H)-d ion e (44). 9-(3-
Bromo-4-fluorophenyl)-5,9-dihydro-3H-furo[3,4-b]pyrano[4,3-
e]pyridine-1,8(4H,7H)-dione from method D was separated into
the individual enantiomers by chiral chromatography on a
Chiralpak AS column (5.0 cm inner diameter, 50 cm length,
20 micron packing) using hexane:EtOH (80:20) at a flow rate
of 117 mL/min. From 227 mg of racemate in 100 mL of hot
ethanol (three injections of 20, 40, and 40 mL) was obtained
the less polar enantiomer which was repurified by flash
chromatography on silica gel using a gradient of 1%-2% and
5% MeOH in CH2Cl2 to provide 0.080 g of 43: [R] ) +212 (c )
0.27, acetone); 1H NMR (DMSO-d6) δ 4.06 (s, 2H), 4.54 (AB q,
2H), 4.75 (s, 1H), 4.88 (d, 1H), 5.03 (d, 1H), 7.28 (d, 2H), 7.48
(d, 1H), 10.50 (s, 1H); MS (ESI+) m/z 380 (M + H)+. Anal.
(C16H11BrFNO4‚0.19CH2Cl2) C, H, N. The absolute stereo-
chemistry for 43 was determined via X-ray analysis (see the
Supporting Information). From the preceding chiral chroma-
tography was also obtained 0.080 g of the more polar enanti-
omer 44: [R] ) -212 (c ) 0.25, acetone) 1H NMR (DMSO-d6)
δ 4.06 (s, 2H), 4.54 (AB q, 2H), 4.75 (s, 1H), 4.88 (d, 1H), 5.03
(d, 1H), 7.28 (d, 2H), 7.48 (d, 1H), 10.50 (s, 1H); MS (ESI+)
m/z 380 (M + H)+. Anal. (C16H11BrFNO4‚0.13CH2Cl2) C, H,
N.
8-(3-Br om o-4-flu or op h en yl)-5,8-d ih yd r o-1H,3H-d ifu r o-
[3,4-b:3,4-e]p yr id in e-1,7(4H)-d ion e (39). 3-Bromo-4-fluo-
robenzaldehyde (6.00 g, 29.6 mmol), ethyl acetoacetate (7.81
g, 60 mmol), and concentrated NH4OH (6.2 mL, added in two
portions over a period of 2 days) were reacted according to
method C to provide 11.3 g of diethyl 4-(3-bromo-4-fluorophe-
nyl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate as a
light yellow solid: 1H NMR (CDCl3) δ 1.22 (t, 6H), 2.35 (s, 6H),
4.10 (m, 4H), 4.94 (s, 1H), 5.56 (s, 1H), 6.95 (t, 1H), 7.18 (m,
8-(3-Br om o-4-flu or oph en yl)-2,3,4,5,6,8-h exah ydr odipyr -
r olo[3,4-b:3,4-e]p yr id in e-1,7-d ion e (45). Diethyl 2,6-bis-
(bromomethyl)-4-(3-bromo-4-fluorophenyl)-1,4-dihydro-3,5-py-
ridine dicarboxylate from example 39 (0.29 g, 0.50 mmol) was
treated with NH3 (25 mL) in EtOH (25 mL) at room temper-
ature for 2 days in
a pressure bomb. The solvent was
evaporated and the resultant solid triturated with hot EtOH/
EtOAc. This solid was washed with water and then Et2O and

Tricyclic Dihydropyridine-Containing KATP Openers
J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12 3191
dried to provide 26 mg of 45 as a yellow solid: 1H NMR
(DMSO-d6) δ 3.95 (q, 4H), 4.58 (s, 1H), 7.25 (d, 2H), 7.42 (s,
2H), 7.46 (s, 1H), 9.83 (s, 1H); MS (APCI+) m/z 364 (M + H)+.
Anal. (C15H11BrFN3O2·0.3H2O·0.5C2H6O) C, H, N.
8-(3-Br om o-4-flu or op h en yl)-2,6-d im et h yl-2,3,4,5,6,8-
h exa h yd r od ip yr r olo[3,4-b:3,4-e]p yr id in e-1,7-d ion e (46).
Diethyl 2,6-bis-(bromomethyl)-4-(3-bromo-4-fluorophenyl)-1,4-
dihydro-3,5-pyridine dicarboxylate (0.812 g, 1.4 mmol) was
treated according to method E to provide 183 mg of 46: 1H
NMR (DMSO-d6) δ 2.80 (s, 6H), 4.05 (q, 4H), 4.59 (s, 1H), 7.22
(d, 2H), 7.45 (d, 1H), 9.88 (s, 1H); MS (APCI+) m/z 392 (M +
H)+. Anal. (C17H15BrFN3O2‚0.25 H2O) 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 op y-
r id o[4,3-b][1,6]n a p h th yr id in e-1,9(2H,5H)-d ion e (47). A
mixture of 3-bromo-4-fluorobenzaldehyde (1 mmol, 203 mg)
and piperidine-2,4-dione (c10) (2 mmol, 226 mg) was treated
according to method C to provide 150 mg of 47: 1H NMR
(DMSO-d6) δ 2.32-2.56 (m, 4H), 3.12-3.22 (m, 4H), 4.93 (s,
1H), 6.94 (bs, 2H), 7.18-7.22 (m, 2H), 7.42 (dd, 1H), 8.98 (s,
1H); MS (APCI+) m/z 392 (M + H)+. Anal. (C17H15BrFN3O2)
C, H, N.
nyl)-2-methyl-5-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,4-b]pyri-
dine-3-carboxylate. This intermediate was reacted according
to the procedure for 42 to provide 42 mg of 50: 1H NMR
(DMSO-d6) δ 4.00 (ABq, 2H), 4.61 (s, 1H), 4.91 (AB q, 2H),
7.24-7.30 (m, 2H), 7.50 (d, 1H), 7.58 (s, 1H); MS (APCI+) m/z
365 (M + H)+. Anal. (C15H10N2O3FBr 1.0 H2O) C, H, N.
9-(3-Br om o-4-flu or op h en yl)-5,6,7,9-tetr a h yd r ofu r o[3,4-
b][1,7]n a p h t h yr id in e-1,8(3H ,4H )-d ion e H yd r och lor id e
(51). A mixture of methyl (2E)-3-aminobut-2-enoate (e5) (0.58
g, 5 mmol), 3-bromo-4-fluorobenzaldehyde (1.0 g, 5 mmol), and
1-benzylpiperidine-3,5-dione (c5) (1.1 g, 5 mmol) was treated
according to method A and purified by flash chromatography
over silica gel eluting with EtOH:CH2Cl2 (5:95) to provide 1.3
g of methyl 7-benzyl-4-(3-bromo-4-fluorophenyl)-2-methyl-5-
oxo-1,4,5,6,7,8-hexahydro[1,7]naphthyridine-3-carboxylate. This
intermediate (3.1 g) was reacted according to method D, parts
1 and 2 but modified by conducting the cyclization for 16 h in
CHCl3 at reflux to provide 2.1 g of 6-benzyl-9-(3-bromo-4-
fluorophenyl)-5,6,7,9-tetrahydrofuro[3,4-b][1,7]naphthyridine-
1,8(3H,4H)-dione: 1H NMR (DMSO-d6) δ 3.08 (AB q, 2H), 3.5
(d, 2H), 3.65 (d,2H), 4.7 (s, 1H), 4.9 (AB q, 2H), 7.3 (m, 7H),
7.47 (m, 1H). 10.1 (1H). This intermediate (0.35 g, 0.75 mmol)
was deprotected using the same procedure as in example 37
to provide 0.08 g of 51: mp 255-257 °C; 1H NMR (DMSO-d6)
(free base) δ 3.2 (s, 2H), 3.62 (s, 2H), 4.7 (s, 1H), 4.83 (d, 1H),
4.99 (d, 1H), 7.27 (m, 2H), 7.49 (dd, 1H), 10.25 (s, 1H); MS
(ESI-) m/z 377 (M - H)-. Anal. (C16H11BrFN2O3‚HCl‚0.5C2H5-
OH) C, H, N.
9-(3-Br om o-4-flu or op h en yl)-5,9-d ih yd r o-3H-fu r o[3,4-b]-
th iop yr a n o[4,3-e]p yr id in e-1,8(4H,7H)-d ion e (52). A mix-
ture of the 2H-thiopyran-3,5(4H,6H)-dione (c4) (1.0 g, 7.7
mmol), 3-bromo-4-fluorobenzaldehyde (2.0 g, 10 mmol), and
methyl (2E)-3-aminobut-2-enoate (e5) (1.1 g, 9.2 mmol) was
treated according to method A to provide 1.8 g of methyl 4-(3-
bromo-4-fluorophenyl)-2-methyl-5-oxo-4,5,6,8-tetrahydro-1H-
thiopyrano[3,4-b]pyridine-3-carboxylate. This intermediate (0.50
g, 1.2 mmol) was treated according to method D, parts 1 and
2 to provide 0.076 g of 52: 1H NMR (DMSO-d6) δ 3.18 (dd,
1H), 3.49 (dd, 1H), 3.56 (dd, 1H), 3.82 (d, 1H), 4.74 (s, 1H),
4.73 (d 1H), 4.98 (d 1H), 7.26 (m 2H), 7.45 (dd, 1H), 10.38 (bs,
1H); MS (ESI+) m/z 396 (M + H)+. Anal. (C16H11BrFO3NS·
0.5C4H8O2) C, H, N.
5-(3-Br om o-4-flu or op h en yl)-2,3,5,8,9,10-h exa h yd r op y-
r id o[3,4-b][1,7]n a p h th yr id in e-4,6(1H,7H)-d ion e Dih yd r o-
ch lor id e (48). A mixture of 1-benzylpiperidine-3,5-dione (c5)
(2.2 g, 10 mmol) and 3-bromo-4-fluorobenzaldehyde (1.02 g,
5.0 mmol) was treated according to method C to provide 0.62
g of 2,8-dibenzyl-5-(3-bromo-4-fluorophenyl)-2,3,5,8,9,10-hexahy-
dropyrido[3,4-b][1,7]naphthyridine-4,6(1H,7H)-dione: 1H NMR
(DMSO-d6) δ 2.97 (d, 2H), 3.16 (m, 2H), 3.42 (m, 3H), 3.61 (q,
4H), 4.82 (s, 1H), 7.13-7.42 (m, 13H), 9.32 (s, 1H). This
intermediate (0.5 g, 0.87 mmol) was debenzylated as in ex-
ample 37 to provide 0.3 g of divinyl 5-(3-bromo-4-fluorophenyl)-
4,6-dioxo-4,5,6,7,9,10-hexahydropyrido[3,4-b][1,7]naphthyridine-
2,8(1H,3H)-dicarboxylate: 1H NMR (DMSO-d6) δ 3.95 (d, 2H),
4.2 (d, 2H), 4.46 (d, 2H), 4.65 (d, 2H), 4.77-4.94 (m, 4H), 5.15
(s, 1H), 7.0 (t, 1H), 7.1 (d, 1H), 7.14 (d, 1H), 7.32 (m, 1H), 7.4
(m, 1H). This intermediate was deprotected using the same
procedure as 37 to provide 0.12 g of 48: 1H NMR (DMSO-d6)
(free base) δ 3.78 (q, 4H), 4.22 (q, 4H), 4.95 (s, 1H), 7.22 (t,
1H), 7.32 (m, 1H), 7.48 (dd, 1H), 11.48 (s, 1H); MS (ESI-) m/z
391 (M - H)-. Anal. Calcd for C17H15BrFN3O2‚2HCl: C, 43.90;
H, 3.68; N, 9.03. Found: C, 44.45; H, 3.86; N, 8.75.
9-(3-Br om o-4-flu or op h en yl)-2,3,5,9-tetr a h yd r op yr a n o-
[3,4-b]p yr r olo[3,4-e]p yr id in e-1,8(4H,7H)-d ion e (53). The
product from method D, part 1 (0.22 g, 0.46 mmol) was treated
according to method E with NH3 (30 mL) in MeOH (30 mL) in
a metal Parr reactor with stirring for 2.5 days at room
temperature to provide 0.026 g of 53: 1H NMR (DMSO-d6) δ
3.90 (d, 1H), 4.03 (s, 2H), 4.07 (d, 1H), 4.50 (AB q, 2H), 4.75
(s, 1H), 7.19-7.29 (m, 2H), 7.44 (dd, 1H), 7.59 (s, 1H), 10.09
(s, 1H); MS (ESI+) m/z 379 (M + H)+. Anal. (C16H12BrFN2O3·
0.5H2O) C, H, N.
5-(3-Br om o-4-flu or op h en yl)-5,10-dih yd r o-1H,3H-bisth i-
op yr a n o[3,4-b:4′,3′-e]p yr id in e-4,6(7H,9H)-d ion e (49). A
solution of 2H-thiopyran-3,5(4H,6H)-dione (c4) (0.51 g, 3.9
mmol) in EtOH (25 mL) was treated with concentrated H2-
SO4 (0.5 mL), heated to 80 °C under N2 for 4 h, cooled to room
temperature, and poured into a mixture of Et2O (250 mL) and
aqueous NaHCO3. The layers were separated, and the aqueous
layer was extracted with Et2O (100 mL). The combined organic
layers were washed (brine), dried (MgSO4), filtered, and
concentrated to provide 0.55 g of crude 5-ethoxy-2H-thiopyran-
3(6H)-one as an oil: 1H NMR (CDCl3) δ 1.38 (t, 3H), 3.24 (s,
2H), 3.34 (s, 2H), 3.93 (q, 2H), 5.37 (2, 1H); MS (DCI/NH3):
m/z 159 (M + H)+. This intermediate was treated with 2 M
NH3/MeOH (40 mL), stirred for 40 h, concentrated, and flash
chromatographed on silica eluting with 5%-10% MeOH/CH2-
Cl2 to provide 0.30 g of 5-amino-2H-thiopyran-3(6H)-one: 1H
NMR (DMSO-d6) δ 3.03 (s, 2H), 3.32 (s, 2H), 4.94 (s, 1H), 6.95
(bs, 2H); MS (DCI/NH3) m/z 130 (M + H)+. A mixture of the
intermediate enamine (0.065 g, 0.51 mmol), 3-bromo-4-fluo-
robenzaldehyde (0.13 g, 0.66 mmol), and thiopyran-3,5-dione
(0.065 g, 0.51 mmol) was treated according to method A to
provide 0.021 g of 49: 1H NMR (DMSO-d6) δ 3.11 (dd, 2H),
3.45 (dd, 2H), 3.51 (dd, 2H), 3.81 (d, 2H), 5.01 (s, 1H), 7.19 (dt
1H), 7.25 (t 1H), 7.39 (dd, 1H), 9.90 (bs, 1H); MS (ESI+) m/z
425 (M + H)+. Anal. (C17H13BrFO2NS2) C, H, N.
10-(3-Br om o-4-flu or op h en yl)-3,4,6,10-t et r a h yd r o-2H -
p yr a n o[3,4-b][1,6]n a p h th yr id in e-1,9(5H,8H)-d ion e (55). A
mixture of 5-amino-2H-pyran-3(6H)-one (e3),20 3-bromo-4-
fluorobenzaldehyde, and piperidine-2,4-dione (c10) was treated
according to method A to provide 55: 1H NMR (DMSO-d6) δ
2.38-2.60 (m, 2H), 3.18-3.26 (m, 2H), 4.00 (s, 2H), 4.45 (AB
q, 2H), 4.95 (s, 1H), 7.14 (s, 1H), 7.16-7.28 (m, 2H), 7.41 (dd,
1H), 9.59 (s, 1H); MS (APCI+) m/z 393 (M + H)+. Anal. (C17H14
BrFN2O3) C, H, N.
-
5-(3-Br om o-4-flu or op h en yl)-5,8,9,10-tetr a h yd r o-1H-p y-
r a n o[3,4-b][1,7]n a p h th yr id in e-4,6(3H,7H)-d ion e Hyd r o-
ch lor id e (56). A mixture of 5-amino-2H-pyran-3(6H)-one (e3),
3-bromo-4-fluorobenzaldehyde, 1-benzylpiperidine-3,5-dione
(c5) was treated according to method A to provide 8-benzyl-
5-(3-bromo-4-fluorophenyl)-5,8,9,10-tetrahydro-1H-pyrano[3,4-
b][1,7]naphthyridine-4,6(3H,7H)-dione. This intermediate (0.29
g, 0.69 mmol) was debenzylated using the two-step protocol
8-(3-Br om o-4-flu or oph en yl)-4,5,6,8-tetr ah ydr o-1H-fu r o-
[3,4-b]p yr r olo[3,4-e]p yr id in e-1,7(3H)-d ion e (50). A mixture
of pyrrolidine-2,4-dione24 (c11) (2 mmol, 198 mg), 3-bromo-4-
fluorobenzaldehyde (2 mmol, 406 mg), and methyl (2E)-3-
aminobut-2-enoate (e5) (2 mmol) was treated according to
method A to provide 165 mg of methyl 4-(3-bromo-4-fluorophe-
1
for example 37 to provide 0.080 g of 56: mp 232-235 °C; H
NMR (DMSO-d6) δ 3.78 (AB q, 2H), 4.07 (s, 2H), 4.19 (s, 2H),
4.54 (AB q, 2H), 4.95 (s, 1H), 7.27 (m, 2H), 7.46 (dd, 1H), 9.86
(bs, 2H), 10.71 (s, 1H); MS (ESI+) m/z 393 (M + H)+. Anal.
(C17H14BrFN2O3‚H2O‚0.25EtOH) C, H, N.

3192 J ournal of Medicinal Chemistry, 2004, Vol. 47, No. 12
Carroll et al.
(4) Miki, T.; Inagaki, N.; Nagashima, K.; Gonoi, T.; Seino, S.
Structure and function of ATP-sensitive potassium channels.
Curr. Top. Membr. 1999, 46, 373-385.
(5) Chutkow, W. A.; Makielski, J . C.; Nelson, D. J .; Burant, C. F.;
Fan, Z. Alternative Splicing of sur2 Exon 17 Regulates Nucle-
otide Sensitivity of the ATP-sensitive Potassium Channel. J .
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the Normal and the Diseased State: Pathophysiology, Diagnosis
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(7) Andersson, K.-E. The Overactive Bladder: Pharmacologic Basis
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Cromakalim on the Normal and Hyperreflexic Human Detrusor
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research. Curr. Opin. CPNS Invest. Drugs 2000, 2, 268-282.
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Freeden, C.; Graceffa, R. F.; Hirth, B. H.; J enkins, D.; Lennox,
J . R.; Matelan, E.; Norton, N. W.; Quagliato, D.; Sheldon, J . H.;
Spinelli, W.; Warga, D.; Wojdan, A.; Woods, M. Design and SAR
of Novel Potassium Channel Openers Targeted for Urge Urinary
Incontinence I. N-Cyanoguanidine Bioisosteres Possessing in
Vivo Bladder Selectivity. J . Med. Chem. 2000, 43, 1187-1202.
(11) Gilbert, A. M.; Antane, M. M.; Argentieri, T. M.; Butera, J . A.;
Francisco, G. D.; Freeden, C.; Gundersen, E. G.; Graceffa, R. F.;
Herbst, D.; Hirth, B. H.; Lennox, J . R.; McFarlane, G.; Norton,
N. W.; Quagliato, D.; Sheldon, J . H.; Warga, D.; Wojdan, A.;
Woods, M. Design and SAR of Novel Potassium Channel Openers
Targeted for Urge Urinary Incontinence. 2. Selective and Potent
Benzylamino Cyclobutenediones. J . Med. Chem. 2000, 43, 1203-
1214.
(12) Li, J . H. Pharmacology of ZM244085: A Novel Bladder-Selective
Dihydropyridine KATP Channel Activator. Cardiovasc. Drug Rev.
1997, 15, 220-231.
(13) Gopalakrishnan, M.; Whiteaker, K. L.; Molinari, E. J .; Davis-
Taber, R.; Scott, V. E. S.; Shieh, C.-C.; Buckner, S. A.; Milicic,
I.; Cain, J . C.; Postl, S.; Sullivan, J . P.; Brioni, J . D. Character-
ization of the ATP-Sensitive Potassium Channels (KATP) Ex-
pressed in Guinea Pig Bladder Smooth Muscle Cells. J . Phar-
macol. Exp. Ther. 1999, 289, 551-558.
(14) Buckner, S. A.; Milicic, I.; Daza, A.; Davis-Taber, R.; Scott, V.
E. S.; Sullivan, J . P.; Brioni, J . D. Pharmacological and molecular
analysis of ATP-sensitive K+ channels in the pig and human
detrusor. Eur. J . Pharmacol. 2000, 400, 287-295.
(15) Buckner, S. A.; Milicic, I.; Daza, A. V.; Coghlan, M. J .; Go-
palakrishnan, M. Spontaneous phasic activity of the pig urinary
bladder smooth muscle: Characteristics and sensitivity to
potassium channel modulators. Br. J . Pharmacol. 2002, 135,
639-648.
(16) Although the preferred sense of the absolute stereochemistry is
the same for 10 and 32, the stereochemical designation of R or
S is opposite due to the priority of sulfur for example 32.
(17) See examples 13 and 14 from the companion paper (Carroll, W.
A.; et al. J . Med. Chem. 2004, 47, 3163-3179.
(18) Mannhold, R. Medicinal Chemistry of DHP-Like Calcium
Antagonists. Drugs Today 1994, 30, 103-122.
(19) Fehnel, E. A.; Paul, A. P. Thiapyran Derivatives. V. The
Monosulfinyl and Monosulfonyl Analogues of Phloroglucinol. J .
Am. Chem. Soc. 1955, 77 (16), 4241-4244.
(20) Altenbach, R. J .; Agrios, K.; Drizin, I.; Carroll, W. A. 5-Amino-
2H-pyran-3(6H)-one, 1, a Convenient Intermediate in the Syn-
thesis of Pyran Containing 1,4-Dihydropyridines. Synth. Com-
mun. 2004, 34, 541-549.
5-(3-Br om o-4-flu or oph en yl)-5,10-dih ydr o-1H,3H-pyr an o-
[3,4-b]th iop yr a n o[4,3-e]p yr id in e-4,6(7H,9H)-d ion e (57). A
mixture of 5-amino-2H-pyran-3(6H)-one (e3) (0.23 g, 2.0
mmol), 3-bromo-4-fluorobenzaldehyde (0.49 g, 2.4 mmol), 2H-
thiopyran-3,5(4H,6H)-dione (c4) (0.26 g, 2.0 mmol) was treated
according to method A to provide 0.37 g of 57. 1H NMR
(DMSO-d6) δ 3.12 (d, 1H), 3.50 (d, 2H), 3.81 (dd, 1H), 4.03 (s,
2H), 4.48 (AB q, 2H), 4.97 (s, 1H), 7.20 (ddd, 1H), 7.26 (t, 1H),
7.40 (dd, 1H), 9.98 (bs, 1H); MS (ESI+) m/z 410 (M + H)+. Anal.
(C17H13BrFNO3S) C, H, N.
(9S )-9-(3-Br om o-4-flu or op h e n yl)-2-(2-e t h oxye t h yl)-
2,3,5,6,7,9-h exa h ydr o-1H-p yr r olo[3,4-b]qu in olin e-1,8(4H)-
d ion e (59). The product from method F, part 3B was treated
according to method D, part 1 and method E (substituting
2-ethoxyethylamine for methylamine) to provide 59 as a yellow
solid: [R] ) -103.52 (DMSO); 1H NMR (DMSO-d6) δ 1.6 (t,
3H), 1.85-1.94 (m, 2H), 2.22-2.28 (m, 2H), 2.53-2.58 (m, 2H),
3.34-3.45 (m, 6H), 4.18 (q, 2H), 4.70 (s, 1H), 7.17-7.22 (m,
2H), 7.42 (d, 1H), 9.82 (s, 1H); MS (ESI+) m/z 449 (M + H)+.
Anal. (C21H22BrFN2O3) C, H, N.
Biology. Con sciou s Sp on ta n eou sly Hyp er ten sive Ra t
(SHR) Assa y. Male spontaneously hypertensive rats (300-
350 g, Charles River Laboratories, Wilmington, MA) were
anesthetized with methoxyflurane (Penthrane, Abbott Labs,
North Chicago, IL). The left femoral artery and vein were
catheterized using polyethylene (PE50) tubing for the mea-
surement of arterial pressure and drug administration, re-
spectively. The catheters were filled with a 0.9% saline solution
containing 10 U of heparin/mL and were passed subcutane-
ously to a point behind the neck and exteriorized through a
skin puncture. The rats were placed in Centrap restraining
cages (12.5 × 4 × 3.5 In., Biodec, Inc., Cincinnati, OH) and
allowed to recover from surgery for 2-3 h before dosing. The
arterial catheter was connected to a Gould Statham p23ID
transducer and the pressure waveform was recorded on a
Grass 7D polygraph. Mean arterial pressure (MAP) (mmHg)
and heart rate (HR) (beats/min) were determined on-line using
a BUXCO cardiovascular analyzer (BUXCO Electronics, Sharon,
CT) and stored on a MicroVAX II computer (Digital Equipment
Corporation, Nashua, NH). After a 30 min predose control
period, each rat was given a slow iv bolus of a test compound
over a period of 1 min, and the MAP and HR were monitored
for changes. Subsequent cumulative doses were given after
MAP and HR changes had reached their respective maxima
and responses had begun to return to baseline. At the end of
each experiment, P1075 was administered at 1 µmol/kg iv
bolus to establish a maximum response level for changes in
MAP and confirm the site of iv drug injections. MAP and HR
data were collected over a 2.5 min period at the point of
maximum response for each dosing period, and the percent
change from an average pre-dose control value was calculated.
Dose-response curves were generated and the results were
expressed as pED50 (-log ED50). For iv dosing, compounds were
dissolved in an aqueous solution containing equal parts of a
hydroxypropyl-â-cyclodextrin solution (100 g/200 mL water)
and sterile water.
(21) Carroll, W. A.; Agrios, K. A.; Basha, F. Z.; Chen, Y.; Kort, M.
E.; Kym, P. R.; Tang, R.; Turner, S. C.; Yi, L. Synthesis of
tricyclic fused dihydropyridine derivatives as potassium channel
openers. PCT Int. Appl. 2001 WO 0183480.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystallo-
graphic analysis of various compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) Ziegler, F. E.; Bennett, G. B. Claisen rearrangement in indole
alkaloid synthesis. Total synthesis of (+)-tabersonine. J . Am.
Chem. Soc. 1973, 95, 7458-7464.
(23) Prepared from â-alanine ethyl ester hydrochloride and ethyl
malonyl chloride using a similar procedure as described in ref
24.
(24) Lowe, G.; Yeung, H. W. Synthesis of a â-lactam related to the
cephalosporins J . Chem. Soc., Perkin 1 1973, 2907-2910.
(25) The data appearing on this graph come from Table 5 of this
publication and Table 6 of the companion paper (ref 17).
Refer en ces
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inwardly rectifying potassium channels in smooth muscle.
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K.; Babenko, A.; Bryan, J . Toward understanding the assembly
and structure of KATP channels. Physiol. Rev. 1998, 78, 227-
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(3) Ashcroft, F. M.; Gribble, F. M. Correlating structure and function
in ATP-sensitive K+ channels. Trends Neurosci. 1998, 21, 288-
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J M030357O