Synthesis and Pharmacological Evaluation of 1-Oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and Related Analogues as a New Class of Specific Bradycardic Agents Possessing If Channel Inhibitory Activity

Article abstract of DOI:10.1021/jm0301742

A series of 1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and related analogues were prepared and evaluated for their bradycardic activities in isolated right atrium and in anesthetized rats. (± )-6,7-Dimethoxy-2-{1- [3-(3,4-methylenedioxyphenoxy)propyl]-3-piperidyl}-1,2,3, 4-tetrahydroisoquinoline (4) was chosen as a lead, and structural modifications were performed on the tetrahydroisoquinoline ring and the terminal aromatic ring. The modifications on the tetrahydroisoquinoline ring revealed that the 1-oxo-1,2,3,4-tetrahydroisoquinoline ring system was optimum structure for both in vitro potency and in vivo efficacy. Furthermore, methoxy, ethoxy, and methoxycarbonyl groups were identified as preferable substituents on the terminal aromatic ring. One of the 1-oxo-1,2,3,4-tetrahydroisoquinoline derivatives, (R)-10a, was further evaluated for its bradycardic activity and inhibitory activity against I_f currents. Compound (R)-10a demonstrated potent bradycardic activity in rats with minimal influence on blood pressure after oral administration. The compound also showed inhibition of I_f currents (IC₅₀ = 0.32 μM) in guinea pig pacemaker cells.

Full text of DOI:10.1021/jm0301742

4728
J . Med. Chem. 2003, 46, 4728-4740
Syn th esis a n d P h a r m a cologica l Eva lu a tion of 1-Oxo-2-(3-p ip er id yl)-1,2,3,4-
tetr a h yd r oisoqu in olin es a n d Rela ted An a logu es a s a New Cla ss of Sp ecific
Br a d yca r d ic Agen ts P ossessin g If Ch a n n el In h ibitor y Activity
Hideki Kubota, Akio Kakefuda,* Toshihiro Watanabe, Noe Ishii, Koichi Wada, Noriyuki Masuda,
Shuichi Sakamoto, and Shin-ichi Tsukamoto
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba,
Ibaraki 305-8585, J apan
Received April 15, 2003
A series of 1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines and related analogues were
prepared and evaluated for their bradycardic activities in isolated right atrium and in
anesthetized rats. (()-6,7-Dimethoxy-2-{1-[3-(3,4-methylenedioxyphenoxy)propyl]-3-piperidyl}-
1,2,3,4-tetrahydroisoquinoline (4) was chosen as a lead, and structural modifications were
performed on the tetrahydroisoquinoline ring and the terminal aromatic ring. The modifications
on the tetrahydroisoquinoline ring revealed that the 1-oxo-1,2,3,4-tetrahydroisoquinoline ring
system was optimum structure for both in vitro potency and in vivo efficacy. Furthermore,
methoxy, ethoxy, and methoxycarbonyl groups were identified as preferable substituents on
the terminal aromatic ring. One of the 1-oxo-1,2,3,4-tetrahydroisoquinoline derivatives, (R)-
10a , was further evaluated for its bradycardic activity and inhibitory activity against If currents.
Compound (R)-10a demonstrated potent bradycardic activity in rats with minimal influence
on blood pressure after oral administration. The compound also showed inhibition of If currents
(IC50 ) 0.32 µM) in guinea pig pacemaker cells.
In tr od u ction
It has been shown that chronically elevated heart rate
(HR) raises myocardial oxygen consumption and thereby
results in a decline of cardiac energetic efficiency in
patients with congestive heart failure, which originates
from ischemic heart diseases.1 Recent studies demon-
strated that an increase in HR is one of the major risk
factors contributing to cardiovascular morbidity and
mortality.2-5 Therefore, prevention of increased HR is
thought to be a desirable therapeutic approach in
patients with cardiac diseases. So-called â-blockers and
some calcium channel inhibitors are reference drugs for
bradycardia, but care must be taken in their use, due
to their undesirable effects such as negative inotropic
or hypotensive effects.6,7 These undesirable effects of
the above drugs have encouraged the development of
another class of bradycardic agents that selectively
reduce HR without affecting either strength of heart
contraction or blood pressure. This novel class, which
have been termed “specific bradycardic agents”8 includes
Zatebradine (UL-FS 49, 1),9-11 and Ivabradine (S-16257,
2),12-14 for which clinical trials are under way.15,16 It
has recently been revealed that these compounds inhibit
one of the most important pacemaker channels, If
channel, which locate in sinoatrial (SA) node pacemaker
cells.11,13 It is therefore suggested that inhibition of If
channel may be responsible for the bradycardic effects
of specific bradycardic agents.14
We found a series of (()-6,7-dimethoxy-2-(3-piperidyl)-
strated potent and specific bradycardic activities com-
1,2,3,4-tetrahydroisoquinoline derivatives which showed
parable to those of Zatebradine. In addition, electro-
potent bradycardic activities.17 In particular, a 3-(3,4-
physiological studies in SA node pacemaker cells indi-
methylenedioxyphenoxy)propyl analogue (4) demon-
cated that compound 4 might act on If channel.17 We
chose 4 as a lead for our program to investigate specific
bradycardic agents, which focused on enhancement of
* To whom correspondence should be addressed. Tel: +81-29-854-
1577. Fax: +81-29-852-5387. E-mail: kakefuda@yamanouchi.co.jp.
10.1021/jm0301742 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/27/2003

Bradycardic Agents as If Channel Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22 4729
Sch em e 1a
a
Conditions: (a) 3,4-dimethoxyphenethylamine, NaBH(OAc)3, AcOH, THF; (b) ClCO2Me, Et3N, THF; (c) Tf2O, DMAP, Cl(CH2)2Cl, 3
days; (d) 4 N HCl (g)/AcOEt; (e) H2 (3-4 kg/cm2), 10%Pd/C, AcOH; (f) 3-(aryloxy)propyl bromide (9a -w ), K2CO3, CH3CN, 80 °C; (g) H2,
10%Pd/C, EtOH.
Sch em e 2a
a
Conditions: (a) aminoactaldehyde dimethylacetal, NaBH(OAc)3, AcOH, THF; (b) 3,4-dimethoxybenzoyl chloride, Et3N, THF; (c) c.HCl,
AcOH; (d) 4 N HCl (g)/AcOEt; (e) H2 (3-4 kg/cm2), 10% Pd/C, AcOH; (f) 3-(3,4-methylenedioxyphenoxy)propyl bromide (9a ), K2CO3, CH3CN,
80 °C.
bradycardic activity. The program also aimed at eluci-
dating the effects of the analogues on If channel as well
as their structure-activity relationships (SAR).
Ch em istr y
The 1-oxo-1,2,3,4-tetrahydroisoquinoline analogues
(10) were prepared as shown in Scheme 1. The inter-
mediate amine, 7, was prepared from the carbamate (6)
by the cyclization conditions reported by Banwell et al.20
Subsequent debenzylation followed by N-alkylation with
corresponding 3-(aryloxy)propyl bromides (9a -w ) af-
forded the desired products, 10a -w . Compounds 10p
and 10f were hydrogenated to give 11 and 12, respec-
tively.
Reiffen and co-workers reported the SAR of Zatebra-
dine and its related analogues which revealed that the
benzolactam system played a crucial role in exerting
both potent bradycardic activity and selectivity versus
blood pressure and cardiac contractility.10 In addition,
a six-membered ring analogue (3) showed moderate
bradycardic activity without affecting heart contraction
or blood pressure.18 These facts prompted us to apply
the benzolactam system to 4, which gave 1-oxo-1,2,3,4-
tetrahydroisoquinoline derivatives. Subsequently, we
attempted modifications of the C-3 and C-4 position of
the isoquinoline ring. Last, we optimized the substitu-
tion pattern of the terminal aromatic ring. All com-
pounds synthesized were evaluated for their bradycardic
activities in isolated right atrium (in vitro assay).
Compounds with high in vitro activities were studied
for their effects on both HR and mean blood pressure
(MBP)19 in rats (in vivo assay). Furthermore, (R)-10a
was examined for its inhibitory activity against If
currents in SA node pacemaker cells.
Scheme 2 shows the preparation of the 1,2-dihydro-
1-oxoisoquinoline analogue (16). The dimethylacetal, 13,
was cyclized under an acidic condition to give 14.
Subsequent debenzylation and N-alkylation with bro-
mide (9a ) afforded 16.
The preparations of the 3,4-dihydro-4-oxoquinazoline
analogue (20) and benzamide analogues, 21 and 22,
were carried out as shown in Scheme 3. The piperidone
(17) was reacted with hydroxylamine followed by reduc-
tion to give the primary amine, 18. The secondary amine
(19) was prepared from 17 by reductive alkylation.
Compound 18 was condensed with anthranilic acid and

4730 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22
Kubota et al.
Sch em e 3a
a
Conditions: (a) 3-hydroxypiperidine, K2CO3, CH3CN, 80 °C; (b) (COCl)2, DMSO, Et3N, CH2CL2, -70 °C to 0 °C; (c) O-
benzylhydroxyamine, pyridine; (d) LiAlH4, THF, reflux; (e) 40% MeNH2/MeOH, NaBH(OAc)3, AcOH, THF; (f) 4,5-dimethoxyanthranilic
acid, EDC‚HCl, HOBt, Cl(CH2)2Cl; (g) HC(OEt)3, 150 °C; (h) 3,4-dimethoxybenzoyl chloride, AcOEt.
Sch em e 4a
a
Conditions: (a) pyridine, reflux; (b) NaH, DMF, 50 °C; (c) 4 N HCl (g)/AcOEt, MeOH; (d) 9a , K2CO3, CH3CN, 80 °C.
then cyclized with triethyl orthoformate to give 20.
Alternatively, benzoylation of 18 and 19 yielded benz-
amide analogues, 21 and 22, respectively.
In Vivo Assa ys. The compounds with high in vitro
activities were examined for their effects on both HR
and MBP by intravenous (iv) administration of 3 mg/
kg in urethane-anesthetized rats. The effect was ex-
pressed as a maximal percent change from the initial
value. Compound (R)-10a was further evaluated for its
effect on both HR and MBP by oral (po) administration
of 10 mg/kg in conscious rats.
For the 2,4-dioxo-1,2,3,4-tetrahydroquinazoline ana-
logue, 27 (Scheme 4), aminopiperidine (24)21 was re-
acted with 2-ethoxy-4-oxo-1,3-benzoxazin (23), which
was obtained from the corresponding anthranilic acid,22
to give 25. Compound 25 was cyclized using NaH and
deprotected to afford the 2,4-dioxo-1,2,3,4-tetrahydro-
quinazoline analogue (26). Finally, compound 26 was
converted to 27 by a similar procedure to that described
above.
In h ibitor y Effect on If Cu r r en ts. Compound (R)-
10a was tested for its inhibitory effect on If currents in
SA node pacemaker cells isolated from guinea pigs.
Resu lts a n d Discu ssion
The enantiomers of 10a were prepared respectively
from the enantiomers of 8, which were obtained using
a conventional resolution technique. The absolute con-
figuration of the enantiomers was determined by X-ray
crystallographic analysis using (R)-10a .23
The structure of the novel compounds and their
bradycardic activities in vitro and in vivo are sum-
marized in Tables 1 and 2. Initially, modifications of
the 1,2,3,4-tetrahydroisoquinoline ring were attempted
(Table 1). Introduction of an oxo moiety at the isoquino-
line C-1 of 4 (10a ) resulted in a 4-fold increase of in vitro
potency (EC30 ) 0.067 µM). In vivo tests showed that
compound 10a had potent bradycardic activity with a
slight influence on MBP. The 1,2-dihydro analogue
(16) was less potent than 10a , particularly in vivo. It
is interesting to note that compound 16 showed weak
P h a r m a cology
In Vitr o Assa ys. The compounds synthesized were
tested for their bradycardic activities in the right atrium
isolated from guinea pigs. The EC30 value means the
concentration of the compound producing a 30% reduc-
tion from the initial spontaneous beat rates.

Bradycardic Agents as If Channel Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22 4731
Ta ble 1. Effect of Modifications of the 1,2,3,4-Tetrahydroisoquinoline Ring
a
The concentration required to produce a 30% reduction from the initial spontaneous beat rates in right atrium of guinea pigs. Each
b
value indicates a mean ( SEM from three to six experiments. Percent change from the initial value in rats as mean ( SEM from three
to four experiments. c The doses are in terms of the salt form. Recrystallization solvents: A, AcOEt; N, CH3CN; E, EtOH; M, MeOH; T,
d
Et2O. e Mean from two experiments. f Not tested.
hypertensive activity (11% increase). The 3,4-dihydro-
4-oxoquinazoline analogue (20) had less potency than
10a . In addition, compound 20 seemed to have a certain
hypotensive effect despite its weaker bradycardic activ-
ity. The 2,4-dioxo-1,2,3,4-tetrahydroquinazoline ana-
logue (27) was an even weaker agent. The ring-opening
analogues (benzamide analogues), 21 and 22, showed
considerably weak activities in comparison to 10a (EC30
) 0.42 µM and 3.5 µM, respectively). These results
allowed us to conclude that the 1-oxo-1,2,3,4-tetrahy-
droisoquinoline ring system was optimum for this part
of the structure. The results also demonstrated that
modifications on the isoquinoline C-3 and C-4 positions
markedly and diversely affected not only the compounds’
bradycardic potencies but also their effects on MBP.
Despite the similarity in the electronic and steric
characteristics of 10a and 22, a 50-fold difference
between their level of bradycardic activity in vitro was
observed. The rigid bicyclic structure of 10a may
contribute to the enhancement of in vitro activity by
keeping the molecule in a desirable conformation. Thus
we chose 10a as a new lead and proceeded to make
further modifications on the terminal aromatic ring
(Table 2).
vitro activity. Among the monosubstituted analogues
(10c-e), the 4-methoxy analogue (10e) showed the
highest level of in vitro activity (EC30 ) 0.099 µM).
Moreover, compound 10e had an equal in vivo potency
to that of 10a . These results suggested that the sub-
stituent at the 4-position was important in both in vitro
and in vivo activity. We then examined the effects of
substituents at the 4-position in terms of electronic,
steric, and hydrophobic properties. Compounds with an
electron-withdrawing group (10f-k ) showed between
1/4 and 1/10 activity of 10a . Among them, the nitro
analogue (10f) alone exhibited striking hypertensive
activity (41% increase) without bradycardic activity. The
ethoxy analogue (10m ) showed potent in vitro and in
vivo activity, being comparable to those of the methoxy
analogue (10e). However, the bulkier the ethereal alkyl
groups from 10m , the weaker in vitro potencies by the
analogues (10n -p ). Compounds with hydrophilic sub-
stituents, namely the acetamide (10q), hydroxy (11),
and amino (12) analogues had 1/10 or less of the level
of in vitro activity of 10a . It was noteworthy that
the methoxycarbonyl analogue (10r ) showed potent
activity (EC30 ) 0.11 µM), whereas the carboxamide
analogue (10s) had considerably weaker potency (EC30
) 5.7 µM), despite no significant differences between
these compounds with respect to electronic and steric
Substitution for the 3,4-methylenedioxy moiety of
10a by hydrogens (10b) caused a 6-fold decrease of in

4732 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22
Ta ble 2. Effect of Modifications of the Terminal Aromatic Ring
Kubota et al.
d
a-c See the corresponding footnotes of Table 1. Recrystallization solvents: A, AcOEt; N, CH3CN; E, EtOH; M, MeOH; I, i-PrOH; P,
g
n-PrOH. e Not tested. f Mean from two experiments. Calcd 7.27; found 6.82.

Bradycardic Agents as If Channel Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22 4733
Ta ble 3. Enantiomers of Compound 10a
anesthetized rats
% changeb at 3 mg/kg ivc
right atrium
mp, C
a
compd
EC30
,
µM
HR
MBP
(solventd)
formula
anal.
10a
(S)-10a
(R)-10a
0.067 ( 0.003
0.068 ( 0.005
0.079 ( 0.007
-48 ( 5
-53 ( 3
-55 ( 2
-14 ( 4
-23 ( 2
-13 ( 2
212-217 (A-N)
200-202 (E)
190-194 (E)
C
C
C
26H32N2O6‚HCl
C,H,N,Cl
C,H,N,Cl
C,H,N,Cl
26H32N2O6‚HCl
26H32N2O6‚HCl‚0.2H2O
d
a-c See the corresponding footnotes of Table 1. Recrystallization solvents: A, AcOEt; N, CH3CN; E, EtOH.
properties. Based on these results, we performed cor-
relation analyses using substituent parameters. We
plotted pEC30 (-log EC30) against three substituent
parameters; π (hydrophobicity), σp (electronic property),
and MR (steric bulk)24 (Figure 1). As shown in the Panel
A, a characteristic reversed U-shape correlation was
observed in the pEC30 - π plot, with a summit around
π ) 0. In contrast, there seemed to be no correlation
between pEC30 versus σp or MR (Panels B, C). It was
assumed that appropriate hydrophobicity (around π )
0) at the 4-position was important to exert potent in
vitro activity (e.g., methoxy, ethoxy, methoxycarbonyl).
We made further modifications on the terminal aromatic
ring. The 3,4-dimethoxy (10t) and 3,4-ethylenedioxy
(10v) analogues showed potent in vitro and in vivo
activities. However, the 3,4,5-trimethoxy analogue (10t)
was a considerably weaker agent. There may be a
limited bulk-tolerance in this region. Substitution for
two oxygens of 10a by methylenes gave the indane
analogue (10w ), which showed 13-fold less potent in
vitro activity of 10a . The oxygen atoms on the aromatic
ring of 10a may contribute to the potent in vitro activity
by producing the appropriate hydrophobicity of the
molecule, or by interacting directly with the active sites.
The contribution of the oxygen atoms was also sup-
ported by the lower activity observed for the indole
analogue (10x).
Last, the enantiomers of 10a were evaluated (Table
3). There was no significant difference in both in vitro
activity and the effect on HR between the enantiomers.
However, it was clear that (R)-10a had a lesser effect
on MBP (13% decrease) than (S)-10a did (23% decrease).
Consequently, we recognized (R)-10a as an excellent
“specific bradycardic agent”.
On the basis of in vitro and in vivo assay results, (R)-
10a was submitted to a further pharmacological evalu-
ation. Compound (R)-10a (10 mg/kg, the salt form) was
orally administered to conscious rats and HR and MBP
were monitored (Figure 2). Compound (R)-10a reduced
spontaneous HR up to a 29% decrease with minimal
influence on MBP. Moreover, its bradycardic effect was
long-lasting (over 8 h).
The HR is regulated by an electrical impulse that
originates in SA node pacemaker cells. In these cells,
If channel is hypothesized to be responsible for the
rate of Phase 4 slow depolarization, which affects the
impulse frequency:25,26 That is, activation of If channel
leads to an increase in the impulse frequency () HR)
through an increase of the rate of Phase 4 slow depo-
larization. Thus we examined the effect of (R)-10a on
If currents in SA node pacemaker cells using whole-
cell patch configuration. Compound (R)-10a inhibited
If currents concentration-dependently with an IC50
value of 0.32 µM (Figure 3), suggesting that the
potent bradycardic effect of (R)-10a was associated
F igu r e 1. Plot of pEC30 against π, σp, and MR of 4-substituent,
for 10b, 10e-o, 10q-s, 11, and 12.
with direct inhibition of If channel in SA node pace-
maker cells.

4734 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22
Kubota et al.
F igu r e 2. Effects of (R)-10a on heart rate and mean blood pressure in conscious rats. Compound (R)-10a (10 mg/kg, the salt
form) was orally administered at time 0. The values are mean ( SEM from four experiments.
tions of the terminal aromatic ring revealed that
appropriate hydrophobicity (around π ) 0) at the
4-position was important to exert potent in vitro activity
(e.g., methoxy, ethoxy, methoxycarbonyl). At the same
time, it was found that the oxygen atoms on the
aromatic ring contribute to the potent in vitro activity.
The optical resolution of 10a led to the finding that (R)-
10a was an excellent “specific bradycardic agent.” On
the basis of pharmacodynamic observation, it appears
that (R)-10a was orally absorbed and its bradycardic
effect was long-lasting. In electrophysiological studies,
(R)-10a was found to inhibit If currents with an IC50
value of 0.32 µM. The inhibition of If currents by (R)-
10a strongly suggested implication of If channel in the
potent bradycardic activity of the compound. This study
could provide a novel approach to If channel inhibitors
with potent bradycardic activities.
F igu r e 3. Effects of (R)-10a on If currents. Each point
represents mean ( SEM from four experiments. The line
represents the linear regression.
Exp er im en ta l Section
Ch em istr y. Melting points were determined with a Yanaco
MP-500D melting point apparatus and are uncorrected. 1H
NMR spectra were recorded on a J EOL J NM-LA300 or a J EOL
J NM-EX400 spectrometer and the chemical shifts are ex-
pressed in δ (ppm) values with tetramethylsilane as an
internal standard (in NMR description, s ) singlet, d )
doublet, t ) triplet, m ) multiplet, and br ) broad peak). Mass
spectra were recorded on a J EOL J MS-LX2000 spectrometer.
For salts, assignments of ion peaks are based on the basic
component. The elemental analyses were performed with a
Yanaco MT-5 microanalyzer (C, H, N) and a Yokogawa IC-
7000S ion chromatographic analyzer (halogens) and were
Con clu sion
A series of 1-oxo-2-(3-piperidyl)-1,2,3,4-tetrahydroiso-
quinolines and related analogues, which were derived
from 4, have been described as bradycardic agents.
Introduction of an oxo moiety at the isoquinoline C-1
position gave the compound 10a , which had a 4-fold
higher in vitro potency. Modifications of the C-3 and C-4
positions of the tetrahydroisoquinoline ring markedly
and diversely affected not only the compounds’ brady-
cardic potencies but also their effects on MBP. Modifica-

Bradycardic Agents as If Channel Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22 4735
within (0.4% of theoretical values, unless otherwise stated.
The optical purity of optically active compounds were exam-
ined by analytical chiral column (Daicel CHIRALPAK AD, i.d.
) 0.46 cm, l ) 25 cm). The HPLC condition was as follows:
mobile phase, i-PrOH/hexane/Et2NH ) 500/500/1; flow rate,
0.5 mL/min; detection wavelength, 254 nm. Optical rotation
measurements were obtained with a Horiba SEPA-200 pola-
rimeter. Drying of organic solutions during workup was done
over anhydrous Na2SO4.
(9a ) is typical. To a solution of sesamol (6.91 g, 50.0 mmol) in
CH3CN (100 mL) were added K2CO3 (10.4 g, 75.0 mmol) and
1,3-dibromopropane (25.4 mL, 250 mmol), and the mixture was
stirred at 80 °C for 7 h. After being cooled at room tempera-
ture, the mixture was concentrated in vacuo. The residue was
taken up with CHCl3 (100 mL), and the CHCl3 layer was
washed with 0.2 N NaOH aq (100 mL × 2), then dried and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (hexane/AcOEt ) 9/1) to give 9a
(9.61 g, 74%) as a colorless solid: 1H NMR (90 MHz, CDCl3) δ
2.14-2.41 (2H, m), 3.59 (2H, t, J ) 6.4 Hz), 4.03 (2H, t, J )
5.9 Hz), 5.91 (2H, s), 6.32 (1H, dd, J ) 8.4, 2.4 Hz), 6.50 (1H,
d, J ) 2.4 Hz), 6.70 (1H, d, J ) 8.4 Hz); MS (FAB) m/z 259
(MH+), 261 (MH+ + 2).
Meth yl (()-N-(1-Ben zyl-3-p ip er id yl)-N′-(3,4-d im eth oxy-
p h en eth yl)ca r ba m a te (6). To a suspension of 1-benzyl-3-
piperidone monohydrochloride monohydrate 5 (10.0 g, 44.3
mmol) and 3,4-dimethoxyphenethylamine (8.03 g, 44.3 mmol)
in THF (100 mL) were added AcOH (2.54 mL, 44.3 mmol) and
NaBH(OAc)3 (10.3 g, 48.7 mmol), and the mixture was stirred
at room temperature for 1 h. The reaction mixture was made
alkaline with 5 N NaOH aq at 0 °C, then extracted with CHCl3
(50 mL × 2). The combined extract was dried and concentrated
in vacuo to give 1-benzyl-3-[(3,4-dimethoxyphenethyl)amino]-
piperidine (14.2 g) as a yellow oil. To a solution of compound
obtained above (14.2 g, 40.1 mmol) and Et3N (6.70 mL, 48.1
mmol) in THF (100 mL) was added dropwise a solution of
methyl chloroformate (3.40 mL, 44.1 mmol) in THF (10 mL)
at 0 °C, and the mixture was stirred at 0 °C for 1 h. The
resulting mixture was concentrated in vacuo, and the residue
was dissolved in H2O (150 mL), then extracted with AcOEt
(50 mL × 2). The combined extract was washed with 1 N
NaOH aq (100 mL) and was dried and concentrated in vacuo
to give 6 (16.2 g, 88% from 5) as a yellow oil. This material
may be used next cyclization step or converted to its oxalate
salt. The oxalate salt was obtained from MeOH-AcOEt as a
colorless powder: 1H NMR (400 MHz, DMSO-d6) δ 1.68-1.78
(4H, m), 2.41 (2H, br s), 2.66 (2H, br s), 2.95-2.97 (2H, m),
3.27-3.29 (2H, m), 3.60 (3H, s), 3.72 (3H, s), 3.74 (3H, s), 3.95
(3H, br s), 6.70 (1H, d, J ) 7.2 Hz), 6.78 (1H, s), 6.86 (1H, d,
J ) 7.2 Hz), 7.40 (5H, br s); MS (FAB) m/z 413 (MH+).
(()-2-(1-Ben zyl-3-piper idyl)-6,7-dim eth oxy-1-oxo-1,2,3,4-
tetr a h yd r oisoqu in olin e (7). To a solution of 6 (6.31 g, 15.3
mmol) and 4-(dimethylamino)pyridine (4.67 g, 38.2 mmol) in
CH2Cl2 (120 mL) was added dropwise a solution of trifluoro-
methanesulfonic anhydride (10.3 mL, 61.2 mmol) in CH2Cl2
(10 mL) at 0 °C, and the mixture was stirred at room
temperature for 3 days. The reaction mixture was partitioned
between CHCl3 (50 mL × 2) and H2O (150 mL), and the CHCl3
layer was dried and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (CHCl3/MeOH
) 49/1) to give 7 (3.11 g, 53%) as a yellow oil. This material
may be converted to its hydrochloride salt. The hydrochride
salt was obtained from EtOH-AcOEt as a colorless powder:
1H NMR (400 MHz, DMSO-d6) δ 1.74-1.83 (4H, m), 2.87 (2H,
br s), 2.88 (1H, br s), 3.19-3.24 (2H, m), 3.31 (1H, br s), 3.44
(2H, br s), 3.75 (3H, s), 3.81 (3H, s), 4.32 (2H, t, J ) 4.8 Hz),
4.85-4.87 (1H, m), 6.89 (1H, s), 7.34 (1H, s), 7.46-7.48 (3H,
m), 7.59-7.61 (2H, m), 10.64 (1H, br s); MS (FAB) m/z 381
(MH+).
Gen er a l P r oced u r e for th e P r ep a r a tion of (()-2-{1-[3-
(Ar yloxy)pr opyl]-3-piper idyl}-6,7- dim eth oxy-1-oxo-1,2,3,4-
tetr a h yd r oisoqu in olin e 10a -x. The compounds were pre-
pared by treatment of 8 with 9.
(()-6,7-Dim eth oxy-2-{1-[3-(3,4-m eth ylen edioxyph en oxy)-
pr opyl]-3-piper idyl}-1-oxo-1,2,3,4-tetr ah ydr oisoqu in olin e
Hyd r och lor id e (10a ). To a solution of 8 (581 mg, 2.00 mmol)
in CH3CN (10 mL) were added K2CO3 (304 mg, 2.20 mmol)
and 9a (544 mg, 2.10 mmol), and the mixture was stirred at
80 °C for 12 h. After being cooled at room temperature, the
mixture was concentrated in vacuo. The residue was parti-
tioned between CHCl3 (30 mL × 2) and H2O (40 mL), then
the CHCl3 layer was dried and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(CHCl3/MeOH ) 49/1) to give the free base of 10a (962 mg,
100%) as a slightly yellow oil. This material was converted to
its hydrochloride salt by treating with 4 N HCl (g)/AcOEt
(0.600 mL, 2.40 mmol). The crude salt was recrystallized from
AcOEt-CH3CN to give 10a (780 mg, 77%) as a colorless
powder: mp 212-217 °C; 1H NMR (400 MHz, DMSO-d6) δ
1.74-1.95 (4H, m), 2.15-2.20 (2H, m), 2.86-2.92 (3H, m),
3.16-3.22 (3H, m), 3.39-3.49 (4H, m), 3.77 (3H, s), 3.82 (3H,
s), 3.98 (2H, t, J ) 6.0 Hz), 4.86-4.92 (1H, m), 5.96 (2H, s),
6.38 (1H, dd, J ) 8.4, 2.2 Hz), 6.64 (1H, d, J ) 2.0 Hz), 6.82
(1H, d, J ) 8.8 Hz), 6.90 (1H, s), 7.38 (1H, s), 10.47 (1H, br s);
MS (FAB) m/z 469 (MH+). Anal. (C26H32N2O6‚HCl) C, H, N,
Cl.
(()-6,7-Dim eth oxy-2-[1-(3-ph en oxypr opyl)-3-piper idyl]-
1-oxo-1,2,3,4-tetr ah ydr oisoqu in olin e Hydr och lor ide (10b):
(84%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-1.95 (4H, m),
2.19-2.26 (2H, m), 2.86-2.89 (3H, m), 3.18-3.25 (3H, m),
3.40-3.50 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 4.06 (2H, t, J )
6.0 Hz), 4.88-4.93 (1H, m), 6.90 (1H, s), 6.93-6.98 (3H, m),
7.30 (2H, t, J ) 8.0 Hz), 7.38 (1H, s), 10.65 (1H, br s); MS
(FAB) m/z 425 (MH+). Anal. (C25H32N2O4‚HCl‚0.2H2O) C, H,
N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(2-m eth oxyph en oxy)p r op yl]-
3-p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10c): (69%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-
1.96 (4H, m), 2.20-2.24 (2H, m), 2.86-2.89 (3H, m), 3.19-
3.30 (3H, m), 3.39-3.52 (4H, m), 3.76 (3H, s), 3.77 (3H, s), 3.82
(3H, s), 4.04 (2H, t, J ) 6.0 Hz), 4.88-4.94 (1H, m), 6.86-6.94
(3H, m), 6.97-6.99 (2H, m), 7.38 (1H, s), 10.53 (1H, br s); MS
(FAB) m/z 455 (MH+). Anal. (C26H34N2O5‚HCl‚0.5H2O) C, H,
N, Cl.
(()-6,7-Dim eth oxy-1-oxo-2-(3-piper idyl)-1,2,3,4-tetr ah y-
d r oisoqu in olin e (8). To a solution of 7 (3.09 g, 8.12 mmol)
in AcOEt (40 mL) was added 4 N HCl (g)/AcOEt (2.44 mL,
9.75 mmol), and the mixture was concentrated in vacuo. To a
solution of the residual solid in AcOH (20 mL) was added Pd/C
(10 w/w %, 339 mg), and the mixture was stirred under
hydrogen pressure (3-4 kg/cm2) at room temperature for 24
h. The catalyst was removed by filtration and the filtrate was
concentrated in vacuo. The residue was dissolved in H2O (20
mL) and made alkaline with 5 N NaOH aq at 0 °C, then
extracted with CHCl3 (30 mL × 2). The combined extract was
dried and concentrated in vacuo to give 8 (1.86 g, 79%) as a
yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.58-1.73 (2H, m),
1.80-1.90 (2H, m), 2.46-2.53 (1H, m), 2.66-2.72 (1H, m),
2.84-2.87 (2H, m), 3.02-3.09 (2H, m), 3.41-3.53 (2H, m), 3.73
(3H, s), 3.84 (3H, s), 4.59-4.66 (1H, m), 6.63 (1H, s), 7.60 (1H,
s); MS (FAB) m/z 291 (MH+).
(()-6,7-Dim eth oxy-2-{1-[3-(3-m eth oxyph en oxy)p r op yl]-
3-p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10d ): (16%); 1H NMR (400 MHz, DMSO-d6) δ 1.74-
2.00 (4H, m), 2.18-2.20 (2H, m), 2.85-2.92 (3H, m), 3.20-
3.47 (7H, m), 3.73 (3H, s), 3.77 (3H, s), 3.82 (3H, s), 4.05 (2H,
t, J ) 6.0 Hz), 4.80-4.90 (1H, m), 6.48-6.56 (3H, m), 6.90 (1H,
s), 7.16-7.22 (1H, m), 7.38 (1H, s), 10.30 (1H, br s); MS (FAB)
m/z 455 (MH+). Anal. (C26H34N2O5‚HCl) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(4-m eth oxyph en oxy)p r op yl]-
3-p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10e): (80%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-
1.95 (4H, m), 2.14-2.21 (2H, m), 2.86-2.89 (3H, m), 3.16-
3.24 (3H, m), 3.39-3.50 (4H, m), 3.69 (3H, s), 3.77 (3H, s), 3.82
(3H, s), 3.99 (2H, t, J ) 6.0 Hz), 4.86-4.92 (1H, m), 6.85-6.90
3-(Ar yloxy)p r op yl Br om id e 9a -x: Gen er a l P r oced u r e.
The synthesis of 3-(3,4-methylenedioxyphenoxy)propyl bromide

4736 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22
Kubota et al.
(5H, m), 7.38 (1H, s), 10.45 (1H, br s); MS (FAB) m/z 455
(MH+). Anal. (C26H34N2O5‚HCl) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(4-p r op oxyp h en oxy)p r op yl]-
3-p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10n ): (80%); 1H NMR (400 MHz, DMSO-d6) δ 0.96
(3H, t, J ) 7.6 Hz), 1.64-1.73 (2H, m), 1.75-1.95 (4H, m),
2.18 (2H, br s), 2.86-2.89 (3H, m), 3.20-3.22 (3H, m), 3.39-
3.48 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 3.84 (2H, t, J ) 6.8
Hz), 3.99 (2H, t, J ) 6.0 Hz), 4.89 (1H, br s), 6.86 (4H, s), 6.90
(1H, s), 7.38 (1H, s), 10.55 (1H, br s); MS (FAB) m/z 483 (MH+).
Anal. (C28H38N2O5‚HCl‚0.1H2O) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(4-n itr op h en oxy)p r op yl]-3-
p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10f): (81%); 1H NMR (400 MHz, DMSO-d6) δ 1.76-
1.96 (4H, m), 2.25-2.28 (2H, m), 2.88 (3H, br s), 3.17-3.30
(3H, m), 3.41-3.51 (4H, m), 3.77 (3H, s), 3.81 (3H, s), 4.24 (2H,
t, J ) 6.0 Hz), 4.86-4.92 (1H, m), 6.90 (1H, s), 7.17 (2H, d, J
) 9.6 Hz), 7.38 (1H, s), 8.23 (2H, d, J ) 8.8 Hz), 10.33 (1H, br
s); MS (FAB) m/z 470 (MH+). Anal. (C25H31N3O6‚HCl‚) C, H,
N, Cl.
(()-2-{1-[3-(4-Cya n op h en oxy)p r op yl]-3-p ip er id yl}-6,7-
d im eth oxy-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10g): (72%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-
1.96 (4H, m), 2.21-2.25 (2H, m), 2.86-2.89 (3H, m), 3.16-
3.24 (3H, m), 3.40-3.51 (4H, m), 3.77 (3H, s), 3.81 (3H, s), 4.17
(2H, t, J ) 6.0 Hz), 4.88 (1H, br s), 6.90 (1H, s), 7.12 (2H, d, J
) 8.8 Hz), 7.38 (1H, s), 7.80 (2H, d, J ) 9.6 Hz), 10.38 (1H, br
s); MS (FAB) m/z 450 (MH+). Anal. (C26H31N3O4‚HCl) C, H,
N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(4-tr iflu or om eth ylp h en oxy)-
p r op yl]-3-p ip er id yl}-1-oxo-1,2,3,4-t et r a h yd r oisoq u in o-
lin e Hyd r och lor id e (10h ): (61%); 1H NMR (400 MHz,
DMSO-d6) δ 1.76-1.99 (4H, m), 2.21-2.28 (2H, m), 2.86-2.93
(3H, m), 3.17-3.25 (3H, m), 3.41-3.51 (4H, m), 3.77 (3H, s),
3.82 (3H, s), 4.16 (2H, t, J ) 6.0 Hz), 4.87-4.93 (1H, m), 6.90
(1H, s), 7.14 (2H, d, J ) 8.8 Hz), 7.38 (1H, s), 7.67 (2H, d, J )
8.8 Hz), 10.54 (1H, br s); MS (FAB) m/z 493 (MH+). Anal.
(C26H31N2O4F3‚HCl) C, H, N, Cl, F.
(()-6,7-Dim eth oxy-2-{1-[3-(4-flu or op h en oxy)p r op yl]-3-
p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10i): (71%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-
1.96 (4H, m), 2.17-2.21 (2H, m), 2.86-2.89 (3H, m), 3.16-
3.24 (3H, m), 3.40-3.51 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 4.04
(2H, t, J ) 6.0 Hz), 4.88 (1H, br s), 6.90 (1H, s), 6.94-6.98
(2H, m), 7.10-7.16 (2H, m), 7.38 (1H, s), 10.33 (1H, br s); MS
(FAB) m/z 443 (MH+). Anal. (C25H31N2O4F3‚HCl‚0.2H2O) C, H,
N, Cl, F.
(()-6,7-Dim eth oxy-2-{1-[3-(4-isop r op oxyp h en oxy)p r o-
pyl]-3-piper idyl}-1-oxo-1,2,3,4-tetr ah ydr oisoqu in olin e Hy-
1
d r och lor id e (10o): (84%); H NMR (400 MHz, DMSO-d6) δ
1.21 (3H, s), 1.22 (3H, s), 1.75-1.95 (4H, m), 2.14-2.21 (2H,
m), 2.86-2.89 (3H, m), 3.16-3.24 (3H, m), 3.39-3.50 (4H, m),
3.77 (3H, s), 3.82 (3H, s), 3.99 (2H, t, J ) 6.4 Hz), 4.42-4.51
(1H, m), 4.86-4.92 (1H, m), 6.85 (4H, s), 6.90 (1H, s), 7.38 (1H,
s), 10.44 (1H, br s); MS (FAB) m/z 483 (MH+). Anal.
(C28H38N2O5‚HCl) C, H, N, Cl.
(()-2-{1-[3-(4-Ben zyloxyp h en oxy)p r op yl]-3-p ip er id yl}-
6,7-d im eth oxy-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hy-
1
d r och lor id e (10p ): (91%); H NMR (400 MHz, DMSO-d6) δ
1.74-1.95 (4H, m), 2.18 (2H, br s), 2.86-2.89 (3H, m), 3.17-
3.22 (3H, m), 3.39-3.49 (4H, m), 3.77 (3H, s), 3.81 (3H, s), 4.01
(2H, t, J ) 6.4 Hz), 4.87-4.92 (1H, m), 5.03 (2H, s), 6.87-6.90
(3H, m), 6.92-6.96 (2H, m), 7.30-7.44 (6H, m), 10.54 (1H, br
s); MS (FAB) m/z 531 (MH+). Anal. (C32H38N2O5‚HCl) C, H,
N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(4-Aceta m id op h en oxy)p r o-
pyl]-3-piper idyl}-1-oxo-1,2,3,4-tetr ah ydr oisoqu in olin e Hy-
1
d r och lor id e (10q): (67%); H NMR (400 MHz, DMSO-d6) δ
1.74-1.95 (4H, m), 2.00 (3H, s), 2.19 (2H, br s), 2.86-2.89 (3H,
m), 3.16-3.24 (3H, m), 3.40-3.50 (4H, m), 3.77 (3H, s), 3.81
(3H, s), 4.01 (2H, t, J ) 6.0 Hz), 4.86-4.92 (1H, m), 6.87 (2H,
d, J ) 8.8 Hz), 6.90 (1H, s), 7.38 (1H, s), 7.49 (2H, d, J ) 9.2
Hz), 9.86 (1H, s), 10.40 (1H, br s); MS (FAB) m/z 482 (MH+).
Anal. (C27H35N3O5‚HCl) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(4-m eth oxycar bon ylph en oxy)-
pr opyl]-3-piper idyl}-1-oxo-1,2,3,4-tetr ah ydr oisoqu in olin e
Hyd r och lor id e (10r ): (65%); 1H NMR (400 MHz, DMSO-d6)
δ 1.75-1.95 (4H, m), 2.24-2.27 (2H, m), 2.86-2.89 (3H, m),
3.18-3.26 (3H, m), 3.40-3.50 (4H, m), 3.77 (3H, s), 3.81 (3H,
s), 3.82 (3H, s), 4.16 (2H, t, J ) 6.4 Hz), 4.88-4.94 (1H, m),
6.90 (1H, s), 7.06 (2H, d, J ) 8.8 Hz), 7.38 (1H, s), 7.92 (2H, d,
J ) 8.4 Hz), 10.72 (1H, br s); MS (FAB) m/z 483 (MH+). Anal.
(C27H34N2O6‚HCl) C, H, N, Cl.
(()-2-{1-[3-(4-Am in oca r bon ylp h en oxy)p r op yl]-3-p ip er -
id yl}-6,7-d im eth oxy-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e
Hyd r och lor id e (10s): (33%); 1H NMR (400 MHz, DMSO-d6)
δ 1.75-1.96 (4H, m), 2.23 (2H, br s), 2.86-2.93 (3H, m), 3.17-
3.25 (3H, m), 3.41-3.51 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 4.13
(2H, t, J ) 6.0 Hz), 4.89 (1H, br s), 6.90 (1H, s), 6.99 (2H, d, J
) 8.8 Hz), 7.20 (1H, br s), 7.38 (1H, s), 7.85-7.87 (3H, m),
10.44 (1H, br s); MS (FAB) m/z 468 (MH+). Anal. (C26H33N3O5‚
HCl‚0.6H2O) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(3,4-d im eth oxyp h en oxy)p r o-
pyl]-3-piper idyl}-1-oxo-1,2,3,4-tetr ah ydr oisoqu in olin e Hy-
d r och lor id e (10t): (88%); 1H NMR (400 MHz, DMSO-d6) δ
1.75-1.99 (4H, m), 2.15-2.22 (2H, m), 2.86-2.90 (3H, m),
3.17-3.25 (3H, m), 3.40-3.50 (4H, m), 3.68 (3H, s), 3.74 (3H,
s), 3.77 (3H, s), 3.82 (3H, s), 4.00 (2H, t, J ) 6.4 Hz), 4.87-
4.93 (1H, m), 6.44 (1H, dd, J ) 8.8, 2.8 Hz), 6.57 (1H, d, J )
2.8 Hz), 6.85 (1H, d, J ) 10.0 Hz), 6.90 (1H, s), 7.38 (1H, s),
10.48 (1H, br s); MS (FAB) m/z 485 (MH+). Anal. (C27H36N2O6‚
HCl) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(3,4-eth ylen ed ioxyp h en oxy)-
p r op yl]-3-p ip er id yl}-1-oxo-1,2,3,4-t et r a h yd r oisoq u in o-
lin e Hyd r och lor id e (10u ): (81%); 1H NMR (400 MHz,
DMSO-d6) δ 1.75-1.94 (4H, m), 2.17 (2H, br s), 2.88 (3H, br
s), 3.19-3.22 (3H, m), 3.38-3.48 (4H, m), 3.77 (3H, s), 3.82
(3H, s), 3.96 (2H, t, J ) 6.4 Hz), 4.16-4.17 (2H, m), 4.20-4.21
(2H, m), 4.89 (1H, br s), 6.42 (1H, dd, J ) 8.8, 2.8 Hz), 6.47
(1H, d, J ) 2.8 Hz), 6.76 (1H, d, J ) 8.8 Hz), 6.90 (1H, s), 7.38
(1H, s), 10.61 (1H, br s); MS (FAB) m/z 483 (MH+). Anal.
(C27H34N2O6‚HCl) C, H, N, Cl.
(()-2-{1-[3-(4-Ch lor op h en oxy)p r op yl]-3-p ip er id yl}-6,7-
d im eth oxy-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10j): (75%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-
1.95 (4H, m), 2.19-2.23 (2H, m), 2.86-2.89 (3H, m), 3.17-
3.22 (3H, m), 3.39-3.49 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 4.06
(2H, t, J ) 6.0 Hz), 4.87-4.93 (1H, m), 6.90 (1H, s), 6.97 (2H,
dt, J ) 10.4, 2.4 Hz), 7.34 (2H, dt, J ) 10.4, 2.4 Hz), 7.38 (1H,
s), 10.59 (1H, br s); MS (FAB) m/z 459 (MH+). Anal.
(C25H31N2O4Cl‚HCl) C, H, N, Cl.
(()-2-{1-[3-(4-Br om op h en oxy)p r op yl]-3-p ip er id yl}-6,7-
d im eth oxy- -1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10k ): (40%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-
1.95 (4H, m), 2.17-2.24 (2H, m), 2.86-2.89 (3H, m), 3.17-
3.24 (3H, m), 3.39-3.50 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 4.06
(2H, t, J ) 6.0 Hz), 4.86-4.92 (1H, m), 6.90 (1H, s), 6.93 (2H,
dt, J ) 10.4, 2.8 Hz), 7.38 (1H, s), 7.46 (2H, dt, J ) 10.4, 3.2
Hz), 10.54 (1H, br s); MS (FAB) m/z 503 (MH+), 505 (MH+
2). Anal. (C25H31N2O4Br‚HCl) C, H, N, Br, Cl.
+
(()-6,7-Dim eth oxy-2-{1-[3-(4-m eth ylp h en oxy)p r op yl]-
3-p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10l): (70%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-
1.95 (4H, m), 2.17-2.20 (2H, m), 2.23 (3H, s), 2.86-2.89 (3H,
m), 3.17-3.22 (3H, m), 3.39-3.50 (4H, m), 3.77 (3H, s), 3.81
(3H, s), 4.01 (2H, t, J ) 6.0 Hz), 4.86-4.89 (1H, m), 6.83 (2H,
d, J ) 8.8 Hz), 6.90 (1H, s), 7.09 (2H, d, J ) 8.4 Hz), 7.38 (1H,
s), 10.52 (1H, br s); MS (FAB) m/z 439 (MH+). Anal.
(C26H34N2O4‚HCl‚0.2H2O) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(4-eth oxyp h en oxy)p r op yl]-
3-p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (10m ): (67%); 1H NMR (400 MHz, DMSO-d6) δ 1.29
(3H, t, J ) 6.8 Hz), 1.74-1.95 (4H, m), 2.16-2.19 (2H, m),
2.86-2.89 (3H, m), 3.16-3.30 (3H, m), 3.39-3.50 (4H, m), 3.77
(3H, s), 3.81 (3H, s), 3.94 (2H, q, J ) 6.8 Hz), 3.99 (2H, t, J )
6.0 Hz), 4.86-4.92 (1H, m), 6.83-6.88 (4H,m), 6.90 (1H, s),
7.38 (1H, s), 10.40 (1H, br s); MS (FAB) m/z 469 (MH+). Anal.
(C27H36N2O5‚HCl) C, H, N, Cl.

Bradycardic Agents as If Channel Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22 4737
(()-6,7-Dim eth oxy-2-{1-[3-(3,4,5-tr im eth oxyp h en oxy)-
p r op yl]-3-p ip er id yl}-1-oxo-1,2,3,4-t et r a h yd r oisoq u in o-
lin e Hyd r och lor id e (10v): (63%); 1H NMR (400 MHz, DMSO-
d6) δ 1.75-1.96 (4H, m), 2.17-2.19 (2H, m), 2.86-2.90 (3H,
m), 3.17-3.25 (3H, m), 3.41-3.50 (4H, m), 3.57 (3H, s), 3.76
(6H, s), 3.77 (3H, s), 3.82 (3H, s), 4.05 (2H, t, J ) 6.4 Hz),
4.87-4.93 (1H, m), 6.25 (2H, s), 6.90 (1H, s), 7.38 (1H, s), 10.52
(1H, br s); MS (FAB) m/z 515 (MH+). Anal. (C28H38N2O7‚HCl‚
0.3H2O) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(5-in d a n yloxy)p r op yl]-3-p i-
p er id yl}-1-oxo-1,2,3,4-t et r a h yd r oisoq u in olin e H yd r o-
ch lor id e (10w ): (70%); 1H NMR (400 MHz, DMSO-d6) δ 1.74-
2.03 (6H, m), 2.15-2.22 (2H, m), 2.77(2H, t, J ) 8.0 Hz), 2.81
(2H, t, J ) 7.6 Hz), 2.86-2.89 (3H, m), 3.16-3.24 (3H, m),
3.39-3.50 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 4.01 (2H, t, J )
6.4 Hz), 4.86-4.92 (1H, m), 6.69 (1H, dd, J ) 8.4, 2.4 Hz), 6.82
(1H, d, J ) 2.4 Hz), 6.90 (1H, s), 7.11 (1H, d, J ) 8.0 Hz), 7.38
(1H, s), 10.39 (1H, br s); MS (FAB) m/z 465 (MH+). Anal.
(C28H36N2O4‚HCl) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(5-in d oloxy)p r op yl]-3-p ip er -
id yl}-1-oxo-1,2,3,4-t et r a h yd r oisoq u in olin e H yd r och lo-
r id e (10x): (70%); 1H NMR (400 MHz, DMSO-d6) δ 1.75-1.96
(4H, m), 2.21 (2H, br s), 2.86-2.89 (3H, m), 3.18-3.26 (3H,
m), 3.42-3.52 (4H, m), 3.77 (3H, s), 3.82 (3H, s), 4.04 (2H, t,
J ) 6.4 Hz), 4.87-4.93 (1H, m), 6.32 (1H, t, J ) 2.0 Hz), 6.74
(1H, dd, J ) 8.8, 2.4 Hz), 6.90 (1H, s), 7.06 (1H, d, J ) 2.0
Hz), 7.27-7.29 (2H, m), 7.38 (1H, s), 10.42 (1H, br s), 10.96
(1H, s); MS (FAB) m/z 464 (MH+). Anal. (C27H33N3O5‚HCl‚
0.8H2O) C, H, N, Cl.
(()-6,7-Dim eth oxy-2-{1-[3-(4-h yd r oxyp h en oxy)p r op yl]-
3-p ip er id yl}-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (11). To a solution of 10p (486 mg, 0.856 mmol) in
MeOH-H2O (10 mL) was added Pd/C (10 w/w %, 49 mg), and
the mixture was stirred under hydrogen atmosphere at room
temperature for 5 h. The catalyst was removed by filtration
and the filtrate was concentrated in vacuo. The residual solid
was recrystallized from i-PrOH-MeOH to give 11 (315 mg,
77%) as a colorless powder: mp 215-220 °C; 1H NMR (400
MHz, DMSO-d6) δ 1.74-1.95 (4H, m), 2.17 (2H, br s), 2.86-
2.89 (3H, m), 3.17-3.22 (3H, m), 3.39-3.48 (4H, m), 3.77 (3H,
s), 3.82 (3H, s), 3.94 (2H, t, J ) 5.6 Hz), 4.87-4.93 (1H, m),
6.69 (2H, dt, J ) 9.6, 3.2 Hz), 6.76 (2H, dt, J ) 10.0, 3.2 Hz),
6.90 (1H, s), 7.36 (1H, s), 9.00 (1H, s), 10.56 (1H, br s); MS
(FAB) m/z 441 (MH+). Anal. (C25H32N2O5‚HCl‚0.6H2O) C, H,
N, Cl. Cl calcd 7.27 found 6.82.
residue was purified by column chromatography on silica gel
(CHCl3/MeOH ) 99/1) to give 13 (2.11 g, 70% from 5) as a
brown oil: 1H NMR (300 MHz, CDCl3) δ 1.51-1.89 (4H, m),
2.10 (2H, br s), 2.74-2.84 (2H, m), 3.34-3.68 (10H, m), 3.80
(3H, s), 3.91 (1H, br s), 3.92 (3H, s), 4.65 (1H, br s), 6.81-6.88
(3H, m), 7.24-7.33 (5H, m); MS (FAB) m/z 443 (MH+).
(()-2-(1-Ben zyl-3-p ip er id yl)-6,7-d im et h oxy-1-oxo-1,2-
d ih yd r oisoqu in olin e (14). To a solution of 13 (2.10 g, 4.75
mmol) in AcOH (5 mL) was added c.HCl (5 mL), and the
mixture was stirred at room temperature for 24 h. The mixture
was poured into H2O (30 mL) and made alkaline with 5 N
NaOH aq at 0 °C, then extracted with CHCl3 (30 mL × 2).
The combined extract was dried and concentrated in vacuo.
The residue was purified by column chromatography on silica
gel (CHCl3/MeOH ) 49/1) to give 14 (1.13 g, 52%) as a
yellow oil: 1H NMR (400 MHz, CDCl3) δ 1.64-1.80 (3H, m),
1.93-1.96 (1H, m), 2.18 (1H, br s), 2.31-2.36 (1H, m),
2.77-2.80 (1H, m), 2.97-2.99 (1H, m), 3.57 (2H, s), 3.98 (3H,
s), 3.99 (3H, s), 5.15-5.19 (1H, m), 6.40 (1H, d, J ) 7.2 Hz),
6.72 (1H, s), 7.24-7.37 (6H, m), 7.80 (1H, s); MS (FAB) m/z
379 (MH+).
(()-6,7-Dim eth oxy-1-oxo-2-(3-piper idyl)-1,2-dih ydr oiso-
qu in olin e Hyd r och lor id e (15). To a solution of 14 (1.10 g,
2.91 mmol) in AcOEt (10 mL) was added 4 N HCl (g)/AcOEt
(0.873 mL, 3.49 mmol), and the mixture was concentrated in
vacuo. To a solution of the residual solid in AcOH (10 mL)
was added Pd/C (10 w/w %, 110 mg), and the mixture was
stirred under hydrogen pressure (3-4 kg/cm2) at room tem-
perature for 2 days. The catalyst was removed by filtration
and the filtrate was concentrated in vacuo. The residue was
dissolved in H2O (20 mL) and made alkaline with 5 N NaOH
aq at 0 °C, then extracted with CHCl3 (20 mL × 2). The
combined extract was dried and concentrated in vacuo to give
the free base of 15 (811 mg, 97%) as a slightly yellow oil. This
material was converted to its hydrochloride salt by treating
with 4 N HCl (g)/AcOEt (1.05 mL, 4.22 mmol). The crude salt
was recrystallized from CH3CN to give 15 (600 mg, 64%) as a
slightly yellow powder: 1H NMR (400 MHz, DMSO-d6) δ 1.84-
2.09 (4H, m), 2.87 (1H, br s), 3.27-3.29 (3H, m), 3.86 (3H, s),
3.89 (3H, s), 5.21-5.22 (1H, m), 6.63 (1H, d, J ) 7.6 Hz), 7.17
(1H, s), 7.46 (1H, d, J ) 7.6 Hz), 7.59 (1H, s), 9.13 (1H, br s),
9.59 (1H, br s); MS (FAB) m/z 289 (MH+).
(()-6,7-Dim eth oxy-2-{1-[3-(3,4-m eth ylen edioxyph en oxy)-
p r op yl]-3-p ip er id yl}-1-oxo-1,2-d ih yd r oisoqu in olin e Hy-
d r och lor id e (16): prepared from 15 by a procedure similar
to that described for 10a (67%): mp 205-208 °C (from AcOEt-
CH3CN); 1H NMR (400 MHz, DMSO-d6) δ 1.89-2.21 (6H, m),
2.97-3.00 (1H, m), 3.23-3.57 (5H, m), 3.86 (3H, s), 3.89 (3H,
s), 3.98 (2H, t, J ) 6.0 Hz), 5.32 (1H, br s), 5.95 (2H, s), 6.38
(1H, dd, J ) 8.0, 2.4 Hz), 6.63-6.66 (2H, m), 6.81 (1H, d, J )
8.4 Hz), 7.17 (1H, s), 7.40 (1H, d, J ) 7.2 Hz), 7.59 (1H, s),
10.76 (1H, br s); MS (FAB) m/z 467 (MH+). Anal. (C26H30N2O6‚
HCl) C, H, N, Cl.
(()-2-{1-[3-(4-Am in op h en oxy)p r op yl]-3-p ip er id yl}-6,7-
d im eth oxy-1-oxo-1,2,3,4-tetr a h yd r oisoqu in olin e Hyd r o-
ch lor id e (12): prepared from 10f by a procedure similar to
that described for 11 (64%): mp 223-231 °C (from AcOEt-
1
EtOH); H NMR (400 MHz, DMSO-d6) δ 1.73-1.92 (4H, m),
2.10-2.13 (2H, m), 2.81-2.83 (3H, m), 2.86-2.89 (3H, m), 3.16
(3H, br s), 3.33-3.48 (4H, m), 3.77 (3H, s), 3.81 (3H, s), 3.91
(2H, t, J ) 6.4 Hz), 4.85 (1H, br s), 6.57 (2H, d, J ) 8.4 Hz),
6.69 (2H, d, J ) 8.8 Hz), 6.89 (1H, s), 7.38 (1H, s), 10.38 (1H,
br s); MS (FAB) m/z 440 (MH+). Anal. (C25H33N3O4‚HCl) C, H,
N, Cl.
1-[3-(3,4-Meth ylen edioxyph en oxy)pr opyl]-3-piper idon e
(17). To a solution of (()-3-hydroxypiperidine (1.21 g, 12.0
mmol) in CH3CN (15 mL) were added K2CO3 (1.82 g, 13.2
mmol) and 9a (3.26 g, 12.6 mmol), and the mixture was stirred
at 80 °C for 4 h. After being cooled at room temperature, the
mixture was concentrated in vacuo. The residue was parti-
tioned between CHCl3 (40 mL × 2) and H2O (40 mL), then
the CHCl3 layer was dried and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(CHCl3/MeOH ) 24/1) to give (()-3-hydroxy-1-[3-(3,4-methyl-
enedioxyphenoxy)propyl]piperidine (3.35 g, 12.0 mmol). To a
cooled (-70 °C) solution of (COCl)2 (2.06 mL, 24.0 mmol) in
CH2Cl2 (20 mL) was added dropwise a solution of DMSO (2.13
mL, 30.0 mmol) in CH2Cl2 (5 mL), and the mixture was stirred
at -70 °C for 10 min. To the mixture was added dropwise a
solution of compound obtained above (3.35 g, 12.0 mmol) in
CH2Cl2 (10 mL) at -70 °C, and the mixture was stirred at
ambient temperature for 1 h. To the mixture was added Et3N
(6.69 mL, 48.0 mmol), and the mixture was allowed to warm
and stir at 0 °C for 1 h. To the mixture was added sat. NaHCO3
aq (20 mL), and the mixture was partitioned between CHCl3
(()-N-(1-Ben zyl-3-p ip er id yl)-N′-(2,2-d im eth oxyeth yl)-
3,4-d im eth oxyben za m id e (13). To a suspension of 5 (4.51
g, 20.0 mmol) and aminoacetaldehyde dimethylacetal (2.10 g,
20.0 mmol) in THF (50 mL) were added AcOH (2.29 mL, 40.0
mmol) and NaBH(OAc)3 (5.09 g, 24.0 mmol), and the mixture
was stirred room temperature for 3 h. The mixture was made
alkaline with 5 N NaOH aq at 0 °C, then extracted with CHCl3
(40 mL × 2). The combined extract was dried and concentrated
in vacuo to give 1-benzyl-3-[(2,2-dimethoxyethyl)amino]piperi-
dine (4.12 g) as a brown oil. To a solution of compound obtained
above (1.39 g, 5.00 mmol) and Et3N (0.767 mL, 5.50 mmol) in
THF (20 mL) was added dropwise a solution of 3,4-dimethoxy-
benzoyl chloride (1.05 g, 5.25 mmol) in THF (5 mL) at 0 °C,
and the mixture was stirred at room temperature for 3 h. The
resulting mixture was concentrated in vacuo and the residue
was dissolved in H2O (50 mL), then extracted with AcOEt (30
mL × 2). The combined extract was washed with 1 N NaOH
aq (30 mL) and was dried and concentrated in vacuo. The

4738 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22
Kubota et al.
(30 mL × 2) and H2O (40 mL). The CHCl3 layer was dried
and concentrated in vacuo to give 17 (3.40 g, 99%) as a light
yellow oil. This compound was used in the next step without
further purification.
5.95 (2H, s), 6.38 (1H, dd, J ) 8.4, 2.4 Hz), 6.63 (1H, d, J )
2.4 Hz), 6.81 (1H, d, J ) 8.8 Hz), 7.16 (1H, s), 7.46 (1H, s),
8.33 (1H, s), 10.85 (1H, br s); MS (FAB) m/z 468 (MH+). Anal.
(C25H29N3O6‚HCl‚1.5H2O) C, H, N, Cl.
(()-3-Am in o-1-[3-(3,4-m eth ylen ed ioxyp h en oxy)p r op yl]-
p ip er id in e (18). To a solution of 17 (3.40 g, 12.0 mmol) in
pyridine (30 mL) was added O-benzylhydroxylamine hydro-
chloride (2.11 g, 13.2 mmol), and the mixture was stirred at
room temperature for 18 h, then concentrated in vacuo. After
coevaporated with toluene, the residue was partitioned be-
tween CHCl3 (30 mL × 2) and 0.2 N NaOH aq (40 mL). The
CHCl3 layer was dried and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (CHCl3/
MeOH ) 49/1) to give O-benzyl 1-[3-(3,4-methylenedioxyphen-
oxy)propyl]-3-piperidone oxime (4.44 g, 11.6 mmol) as a yellow
oil. To a suspension of LiAlH4 (1.10 g, 29.0 mmol) in THF (20
mL) was added a solution of compound obtained above (4.44
g, 11.6 mmol) in THF (10 mL), and the mixture was stirred
under reflux for 1 h. After being cooled at room temperature,
to the cooled (-40 °C) mixture were added dropwise H2O (3
mL), 1 N NaOH aq (3 mL), and H2O (3 mL), then the mixture
was stirred at room temperature for 2 h. The precipitate was
filtered off, and the filtrate was concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(CHCl3/MeOH ) 22/3) to give 18 (1.93 g, 60%) as a light yellow
oil: 1H NMR (300 MHz, CDCl3) δ 1.05-1.17 (1H, m), 1.49-
1.98 (6H, m), 2.02-2.08 (1H, m), 2.46-2.51 (2H, m), 2.64-
2.67 (1H, m), 2.78-2.93 (2H, m), 3.93 (2H, t, J ) 6.3 Hz), 5.90
(2H, s), 6.32 (1H, dd, J ) 8.4, 2.4 Hz), 6.49 (1H, d, J ) 2.4
Hz), 6.69 (1H, d, J ) 8.4 Hz); MS (FAB) m/z 279 (MH+).
(()-3-Meth yla m in o-1-[3-(3,4-m eth ylen ed ioxyp h en oxy)-
p r op yl]p ip er id in e (19). To a solution of 17 (416 mg, 1.50
mmol) and 40% MeNH2/MeOH (349 mg, 4.50 mmol) in THF
(10 mL) were added AcOH (0.258 mL, 4.50 mmol) and NaBH-
(OAc)3 (413 mg, 1.95 mmol) at 0 °C, and the mixture was
stirred at room temperature for 17 h. The reaction mixture
was made alkaline with 1 N NaOH aq at 0 °C, then extracted
with CHCl3 (15 mL × 2). The combined extract was dried and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (CHCl3/MeOH ) 22/3) to give
19 (286 mg, 65%) as a slightly yellow oil: 1H NMR (300 MHz,
CDCl3) δ 1.27-1.30 (1H, m), 1.51-2.23 (7H, m), 2.32 (2H, br
s), 2.47 (3H, s), 2.51-2.53 (2H, m), 2.65-2.79 (2H, m), 2.85-
2.89 (1H, m), 3.93 (2H, t, J ) 6.3 Hz), 5.90 (2H, s), 6.32 (1H,
dd, J ) 8.4, 2.4 Hz), 6.49 (1H, d, J ) 2.4 Hz), 6.69 (1H, d, J )
8.4 Hz); MS (FAB) m/z 293 (MH+).
(()-6,7-Dim eth oxy-3-{1-[3-(3,4-m eth ylen edioxyph en oxy)-
p r op yl]-3-p ip er id yl}-4-oxo-3,4-d ih yd r oqu in a zolin e Hy-
d r och lor id e (20). To a solution of 18 (418 mg, 1.50 mmol) in
Cl(CH2)2Cl (8 mL) were added HOBt (101 mg, 0.750 mmol),
EDC‚HCl (316 mg, 1.65 mmol), and 4,5-dimethoxyanthranilic
acid (311 mg, 1.58 mmol) at 0 °C, and the mixture was stirred
at room temperature for 6 h. The mixture was partitioned
between CHCl3 (20 mL × 2) and H2O (30 mL), and the CHCl3
layer was dried and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (CHCl3/MeOH
) 49/1) to give (()-2-amino-4,5-dimethoxy-N-{1-[3- (3,4-meth-
ylenedioxyphenoxy)propyl]-3-piperidyl}benzamide (623 mg,
1.36 mmol) as a yellow oil. A solution of compound obtained
above (613 mg, 1.34 mmol) in HC(OEt)3 (8 mL) was stirred
under reflux for 21 h. After being cooled at room temperature,
the mixture was concentrated in vacuo and the residue was
partitioned between CHCl3 (20 mL × 2) and H2O (30 mL), and
the CHCl3 layer was dried and concentrated in vacuo. The
residue was purified by column chromatography on silica gel
(CHCl3/MeOH ) 49/1) to give the free base of 20 (545 mg, 87%)
as a slightly yellow oil. This material was converted to its
hydrochloride salt by treating with 4 N HCl (g)/AcOEt (0.350
mL, 1.40 mmol). The crude salt was recrystallized from
AcOEt-CH3CN to give 20 (300 mg, 44%) as a slightly yellow
powder: mp 142-146 °C; 1H NMR (400 MHz, DMSO-d6) δ
1.98-2.04 (3H, m), 2.16-2.19 (3H, m), 2.96-2.99 (1H, m),
3.23-3.26 (2H, m), 3.48-3.58 (2H, m), 3.69 (1H, br s), 3.88
(3H, s), 3.92 (3H, s), 3.99 (2H, t, J ) 6.0 Hz), 5.16 (1H, br s),
(()-3,4-Dimethoxy-N-{1-[3-(3,4-methylenedioxyphenoxy)-
p r op yl]-3-p ip er id yl}ben za m id e Hyd r och lor id e (21). To a
solution of 18 (167 mg, 0.600 mmol) in AcOEt (3 mL) was
added a solution of 3,4-dimethoxybenzoyl chloride (126 mg,
0.630 mmol) in AcOEt (2 mL) at 0 °C, and the mixture was
stirred at room temperature for 14 h. The mixture was
partitioned between AcOEt (15 mL × 2) and 1 N NaOH aq
(30 mL), and the AcOEt layer was washed with sat.NaCl (20
mL), then dried and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (CHCl3/MeOH
) 49/1) to give the free base of 21 (266 mg, 100%) as a slightly
yellow oil. This material was converted to its hydrochloride
salt by treating with 4 N HCl (g)/AcOEt (0.180 mL, 0.720
mmol). The crude salt was recrystallized from EtOH-Et2O to
give 21 (188 mg, 65%) as a slightly pink powder: mp 165-
1
167 °C; H NMR (400 MHz, DMSO-d6) δ 1.60-1.93 (4H, m),
2.13-2.22 (2H, m), 2.75-2.99 (2H, m), 3.26 (2H, br s), 3.50-
3.59 (2H, m), 3.81-3.85 (6H, m), 3.96-3.99 (2H, m), 4.28 (2/
3H, br s), 4.49 (1/3H, br s), 5.96 (2H, s), 6.37-6.40 (1H, m),
6.65 (1H, t, J ) 2.4 Hz), 6.81 (1H, dd, J ) 8.4, 3.6 Hz), 7.02
(1H, t, J ) 8.8 Hz), 7.45-7.71 (2H, m), 8.44 (2/3H, d, J ) 8.0
Hz), 8.95 (1/3H, d, J ) 7.6 Hz), 10.20 (2/3H, br s), 11.11 (1/
3H, br s); MS (FAB) m/z 443 (MH+). Anal. (C24H30N2O6‚HCl)
C, H, N, Cl.
(()-3,4-Dim et h oxy-N-m et h yl-N′-{1-[3-(3,4-m et h ylen e-
d ioxyp h en oxy)p r op yl]-3-p ip er id yl}b en za m id e H yd r o-
ch lor id e (22): prepared from 19 by a procedure similar to that
described for 21 (58%): mp 178-181 °C (from EtOH); 1H NMR
(400 MHz, DMSO-d6) δ 1.82-1.94 (4H, m), 2.14 (2H, br s), 2.85
(3H, s), 2.87 (2H, br s), 3.19-3.22 (4H, m), 3.48-3.51 (1H, m),
3.78 (3H, s), 3.79 (3H, s), 3.98 (2H, t, J ) 6.0 Hz), 5.96 (2H, s),
6.38 (1H, dd, J ) 8.8, 2.8 Hz), 6.64 (1H, d J ) 2.8 Hz), 6.82
(1H, d, J ) 8.0 Hz), 6.99-7.02 (3H, m), 10.20 (1H, br s); MS
(FAB) m/z 457 (MH+). Anal. (C25H32N2O6‚HCl) C, H, N, Cl.
(()-N-(1-ter t-Bu toxyca r bon yl-3-p ip er id yl)-3,4-d im eth -
oxy-6-(eth oxyca r bon yla m in o)ben za m id e (25). To a solu-
tion of tert-butyl 3-aminopiperidin-1-carboxylate (24)21 in
pyridine (15 mL) was added 6,7-dimethoxy-2-ethoxy-4-oxo-1,3-
benzoxazin 2322 (1.26 g, 5.00 mmol), and the mixture was
stirred at 120 °C for 2 h. After being cooled at room temper-
ature, the mixture was concentrated in vacuo. The residue was
partitioned between CHCl3 (30 mL × 2) and 5% (w/v) citric
acid aq (30 mL), and the CHCl3 layer was dried and concen-
trated in vacuo. The residue was purified by column chroma-
tography on silica gel (hexane/AcOEt ) 1/2) to give 25 (1.95
g, 86%) as a colorless foam:1H NMR (400 MHz, CDCl3) δ 1.33
(3H, t, J ) 7.2 Hz), 1.45 (9H, s), 1.66-2.04 (4H, m), 3.25-3.76
(4H, m), 3.88 (3H, s), 3.95 (3H, s), 4.05 (1H, br s), 4.13-4.23
(2H, m), 6.89 (1H, br s), 8.11 (1H, s), 10.74 (1H, br s); MS (FAB)
m/z 452 (MH+).
(()-6,7-Dim eth oxy-2,4-d ioxo-3-(3-p ip er id yl)-1,2,3,4-tet-
r a h yd r oqu in a zolin e Hyd r och lor id e (26). To a suspension
of NaH (60%, 344 mg, 8.59 mmol) in DMF (30 mL) was added
dropwise a solution of 25 (1.94 g, 4.30 mmol) in DMF (10 mL),
and the mixture was stirred at 50 °C for 12 h. After being
cooled at room temperature, to the mixture was added H2O
(50 mL), then extracted with CHCl3 (40 mL × 2). The combined
extract was dried and concentrated in vacuo. The residual solid
was recrystallized from AcOEt-hexane to give (()-3-(1-tert-
butoxycarbonyl-3-piperidyl)-6,7-dimethoxy-2,4-dioxo-1,2,3,4-
tetrahydroquinazoline (1.19 g, 2.93 mmol) as a beige powder.
To a solution of the compound obtained above in MeOH (5 mL)
was added 4 N HCl (g)/AcOEt (3.63 mL, 14.5 mmol), and the
mixture was stirred at room temperature for 10 h. The mixture
was concentrated in vacuo, and the residual solid was recrys-
tallized from MeOH to give 26 (850 mg, 58% from 25) as a
colorless powder:1H NMR (400 MHz, DMSO-d6) δ 1.73-1.79
(2H, m), 1.91-1.94 (1H, m), 2.41-2.47 (1H, m), 2.76-2.79 (1H,
m), 3.24-3.29 (2H, m), 3.73-3.76 (1H, m), 3.79 (3H, s), 3.83

Bradycardic Agents as If Channel Inhibitors
J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22 4739
(3H, s), 5.14-5.20 (1H, m), 6.71 (1H, s), 7.27 (1H, s), 8.98 (1H,
br s), 9.40 (1H, br s), 11.33 (1H, s); MS (FAB) m/z 306 (MH+).
of compounds were presented the percent change from the
initial beat rates.
(()-6,7-Dim eth oxy-3-{1-[3-(3,4-m eth ylen edioxyph en oxy)-
propyl]-3-piperidyl}-2,4-dioxo-1,2,3,4-tetrahydroquinazoline
Hyd r och lor id e (27): prepared from 26 by a procedure similar
to that described for 10a (45%): mp 227-233 °C (from CH3-
In Vivo Assa y. General Procedure: Male Wister rats (270-
350 g) were anesthetized with pentobarbital (1.0 g/kg ip for iv
study, 60 mg/kg ip for po study). One polyethylene cannulae
(PE-50) was implanted in the common carotid artery and
one was implanted in the right jugular vein. The other ends
of catheters were routed to an exit site at the back of the
neck. Blood pressure was measured with a pressure trans-
ducer (Nihon Kohden DX-100) coupled to the cannula intro-
duced into carotid artery and a pressure amplifier (Nihon
Kohden AP-621G), and continuously recorded via a poly-
graph system. Mean blood pressure (MBP)19 was calculated
from the following formula: MBP ) DBP + (SBP-DBP)/3,
where DBP represents diastolic blood pressure and SBP
represents systolic blood pressure. Heart rate was measured
with a cardiotachometer (Nihon Kohden AT-600G) triggered
by the pulsewave of blood pressure.
1
CN-MeOH); H NMR (400 MHz, DMSO-d6) δ 1.76-1.78 (1H,
m), 1.96 (2H, br s), 2.08 (2H, br s), 2.41-2.50 (1H, m), 2.92-
2.95 (1H, m), 3.25-3.30 (3H, m), 3.51-3.65 (2H, m), 3.79 (3H,
s), 3.83 (3H, s), 3.97 (2H, t, J ) 6.0 Hz), 5.31 (1H, br s), 5.95
(2H, s), 6.38 (1H, dd, J ) 8.4, 2.8 Hz), 6.63 (1H, d, J ) 2.4
Hz), 6.71 (1H, s), 6.81 (1H, d, J ) 8.4 Hz), 7.26 (1H, s), 10.64
(1H, br s), 11.37 (1H, s); MS (FAB) m/z 484 (MH+). Anal.
(C25H29N3O7‚HCl‚0.4H2O) C, H, N, Cl.
(S)-(-)-6,7-Dim eth oxy-1-oxo-2-(3-p ip er id yl)-1,2,3,4-tet-
r a h yd r oisoqu in olin e D-Ta r tr a te ((S)-8) a n d (R)-(+)-6,7-
Dim et h oxy-1-oxo-2-(3-p ip er id yl)-1,2,3,4-t et r a h yd r oiso-
qu in olin e l-Ta r tr a te ((R)-8). To a solution of 8 (1.60 g, 5.51
mmol) in EtOH (20 mL) was added a solution of D-tartaric acid
(826 mg, 5.51 mmol) in EtOH (8 mL), and the mixture was
concentrated in vacuo. The residual solid was recrystallized
four times from 95% (v/v) EtOH aq (25-50 mL) to give (S)-8
(650 mg, 27%, tR ) 12.3 min., 99.8% ee) as a colorless powder:
1H NMR (400 MHz, DMSO-d6) δ 1.69-1.89 (4H, m), 2.70-
2.76 (1H, m), 2.85 (2H, t, J ) 6.4 Hz), 2.97-3.03 (1H, m), 3.12-
3.19 (2H, m), 3.45 (2H, t, J ) 6.4 Hz), 3.76 (3H, s), 3.81 (3H,
s), 3.87 (2H, s), 4.72 (1H, br s), 6.89 (1H, s), 7.37 (1H, s); MS
iv Study: After the general procedure, a test compound as
an aqueous solution (or a saline) was administered intra-
venously through the catheter implanted into the jugular vein
at a dose of 3 mg/kg (the salt form).
po Study: The animals were allowed to recover for 1 to 2
days after operation, during which time they were housed in
individually with free access to rat chow and water. After a
30 min measurement period to establish baseline values, a test
compound as an aqueous solution (or a saline) was adminis-
tered orally by gavage at a dose of 10 mg/kg (the salt form).
(FAB) m/z 291 (MH+); [R]25 ) -26.8° (c ) 1.0, MeOH). The
D
mother liquor of (S)-8 was concentrated in vacuo. The residue
was dissolved in H2O and made alkaline with 1 N NaOH aq,
then extracted with CHCl3 (20 mL × 2). The combined extract
was dried and concentrated in vacuo. To a solution of the
residual oil in EtOH (10 mL) was added a solution of L-tartaric
acid (320 mg, 2.13 mmol) in EtOH (6 mL), and the mixture
was concentrated in vacuo. The residual solid was recrystal-
lized two times from 95% (v/v) EtOH aq (30-50 mL) to
give (R)-8 (460 mg, 19%, tR ) 16.2 min., 99.7% ee) as a color-
In h ibitor y Effect on If Cu r r en ts. SA node cell dissocia-
tion: Male Hartley guinea pigs (250-400 g) were sacrificed
by cervical dislocation, and their hearts were removed quickly
and placed in Tyrode’s solution. The SA node region was
isolated and incubated in Ca2+-free Tyrode’s solution contain-
ing 3 mg/mL collagenase (Worthington Type II) at 37 °C for
30 min. After incubation, the tissue was placed in a KB
recovery solution and agitated by suction using a blunt glass
pipet to release single cells. Pacemaker cells isolated from SA
node were transferred to a recording chamber on the stage of
microscope (Nikon) and were perfused continuously with the
external solution. Electrical recording of If current: Membrane
currents were measured using a conventional whole-cell patch
configuration. Recording electrodes were pulled from a glass
tube with an inner filament (Narishige GD-1.5) using a
micropipet puller (Sutter Instrument P-97/IVF), and were
fired-polished on a microforge (Narishige MF-9). The electrodes
had a resistance of about 3-5 MΩ when filled with the internal
solution. Whole-cell membrane currents were recorded in
voltage-clamp mode using a high-impedance patch clamp
amplifir (Axon Instruments Axopatch 200A). Voltage clamp
steps were controlled and applied by the pCLAMP version 6.0.3
software (Axon Instruments) via an analogue to digital conver-
sion board (Axon Instruments Digidata 1200A) running on
Windows 95. The currents were low-pass filtered at 1 kHz and
were sampled at 1.25 kHz. All data were stored on the floppy
disks. If currents were elicited by a hyperpolarization voltage
step pulses from a holding potential of -40 mV to -120 mV
for 1 s, which were applied to cells every 5 s. After recording
stable If currents as control, the solution perfused to cells was
changed to the external solution containing a test compound
at a certain concentration, and then If currents were succes-
sively recorded for further 7-8 min. The inhibitory effect of a
test compound on If currents was evaluated as a percent
inhibition of the initial amplitude of If currents. Concentra-
tion-response relationship was constructed from the average
of percent inhibition of If currents obtained from a single cell
at each concentration.
less powder: [R]25 ) +28.8° (c ) 1.0, MeOH). The 1H NMR
D
and mass spectra of (R)-8 were identical to those observed for
(S)-8.
(S)-(-)-6,7-Dim eth oxy-2-{1-[3-(3,4-m eth ylen edioxyph en -
oxy)pr opyl]-3-piper idyl}-1-oxo-1,2,3,4-tetr ah ydr oisoqu in o-
lin e Hyd r och lor id e ((S)-10a ): prepared from (S)-8 by a
procedure similar to that described for 10a (81%, tR ) 23.8
min., >99.8% ee): mp 200-202 °C (from EtOH); [R]25
)
D
-16.8° (c ) 1.0, MeOH). Anal. (C26H32N2O6‚HCl) C, H, N, Cl.
(R)-(+)-6,7-Dim eth oxy-2-{1-[3-(3,4-m eth ylen edioxyph en -
oxy)pr opyl]-3-piper idyl}-1-oxo-1,2,3,4-tetr ah ydr oisoqu in o-
lin e Hyd r och lor id e ((R)-10a ): prepared from (R)-8 by a
procedure similar to that described for 10a (83%, tR ) 28.3
min., >99.8% ee): mp 190-194 °C (from EtOH); [R]25
)
D
+16.6° (c ) 1.0, MeOH). Anal. (C26H32N2O6‚HCl‚0.2H2O) C,
H, N, Cl.
Cor r ela tion An a lyses. Three descriptors for aromatic
substituents, namely, π, σp, and MR, were attempted in the
correlation analyses for 10b, 10e-o, 10q-s, 11, and 12. Data
analyses were carried out using Microsoft Excel Version 2000
(Microsoft Corporation) running on Windows 2000.
P h a r m a cology. In Vitr o Assa y. Male Hartley guinea pigs
(250-400 g) were sacrificed by cervical dislocation, and their
hearts were removed rapidly. Right atrium were cut from the
heart and mounted vertically in a 30 mL organ bath containing
Tyrode’s solution at 37 °C and equilibrated with 95% O2 and
5% CO2. Tension was placed on the atria by suspending a
1 g mass from it. The atria was allowed to equilibrate for
90 min, the bath solution was exchanged every 15 min before
a compound treatment. Amplitude of contraction was mea-
sured isometrically by a force-displacement transducer (Nihon
Kohden SB-1T) and measured with a cardiotachometer (Nihon
Kohden AT-600G) triggered by the contraction. After initial
spontaneous beat rates were recorded, a compound was added
cumulatively to the bath solution at 45 min intervals, and a
concentration-response curve was constructed. The effects
External solution (Tyrode’s solution) (mM): NaCl, 140; KCl,
5.4; CaCl2, 1.8; MgCl2, 0.5; HEPES, 5; glucose, 10. Ca2+-free
Tyrode’s solution (mM): NaCl, 140; KCl, 5.4; MgCl2, 3.5;
HEPES, 5; glucose, 10; taurine, 20; EGTA, 0.05. KB recovery
solution (mM): KCl, 70; HEPES, 5; glucose, 10; taurine, 20;
K2ATP, 5; MgSO4, 5; KH2PO4, 20; glutamic acid, 5; creatine,
5; succinic acid, 5. Internal solution (mM): KCl, 140; MgCl2,

4740 J ournal of Medicinal Chemistry, 2003, Vol. 46, No. 22
Kubota et al.
(14) Thollon, C.; Bidouard, J . P.; Cambarrat, C.; Lesage, J .;
Reure, H.; Delescluse, I.; Vian, J .; Peglion, J . L.; Vilaine, J . P.
Stereospecific in vitro and in vivo effects of the new sinos node
inhibitor (+)-S-16257. Eur. J . Pharmacol. 1997, 339, 43-51.
(15) Baiker, W.; Czako, E. V.; Keck, M.; Nehmiz, G. Efficacy and
duration of action three doses of Zatebradine (UL-FS 49CL) in
patients with chronic angina pectoris compared to placebo.
Hjalmarson, A., Remme, W. J ., Eds. In Sinus node inhibitors;
Springer-Verlag: New York, 1991; pp 55-63.
3; HEPES, 11; K2ATP, 3; GTP (Na salt), 0.4; triphospho-
creatine, 5. All solution were adjusted to pH 7.2.
Ack n ow led gm en t. We thank Dr. T. Satoh for
performing the If currents experiments, Dr. H. Naka-
hara for carrying out the X-ray analysis. We also thank
Drs. A. Tanaka and T. Yasunaga for his useful advises,
and members of the Division of Analytical Research for
performing instrumental analyses.
(16) Ragueneau, I.; Laveille, C.; J ochemsen, R.; Resplandy, G.; Funck-
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a direct sinos node
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