Synthesis and pharmacological evaluation of N-acyl-1,2,3,4- tetrahydroisoquinoline derivatives as novel specific bradycardic agents

Article abstract of DOI:10.1016/j.bmc.2003.12.032

A series of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and evaluated for their bradycardic activities in isolated guinea pig right atria and in urethane-anesthetized rats. These efforts resulted in identification of the compound 8a

Full text of DOI:10.1016/j.bmc.2003.12.032

Bioorganic & Medicinal Chemistry 12 (2004) 871–882
Synthesis and pharmacological evaluation of
N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives as novel
specific bradycardic agents
Hideki Kubota,* Toshihiro Watanabe, Akio Kakefuda, Noriyuki Masuda,
Kouichi Wada, Noe Ishii, Shuichi Sakamoto and Shinichi Tsukamoto
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba-shi,
Ibaraki 305-8585, Japan
Received 31July 2003; accepted 26 December 2003
Abstract—A series of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized and evaluated for their bradycardic activ-
ities in isolated guinea pig right atria and in urethane-anesthetized rats. These efforts resulted in identification of the compound 8a,
which exhibits potent bradycardic activity with minimal influence on mean blood pressure in urethane-anesthetized rats. Oral
administration of compound 8a to conscious rats revealed increased potency and prolonged duration of action when compared to
Zatebradine.
# 2004 Elsevier Ltd. All rights reserved.
1. Introduction
Therefore, agents which reduce HR without negative
inotropic and hypotensive effects, namely ‘specific bra-
dycardic agents’7 are expected to be more beneficial in
the treatment of cardiovascular disorders such as
ischemic heart disease.
Chronic increase in heart rate (HR) is thought to be a
contributory factor in cardiovascular morbidity and
mortality in patients with cardiac diseases such as
ischemic heart diseases.1 Sinus tachycardia is a common
physiological response that may help to maintain
homeostasis by increasing cardiac output, but that also
causes an increase in myocardial oxygen demand and
decrease in time for myocardial relaxation and diastolic
ventricular filling.2 In the presence of flow-limiting cor-
onary artery stenosis a decrease in diastolic perfusion
time may be especially deleterious by further reducing
subendocardial myocardial perfusion.3 Under these cir-
cumstances, a reduction in HR prolongs the diastolic
perfusion time and reduces myocardial oxygen
demands, conferring an improvement in ischemic zone
perfusion and function. Reduction in HR can be
achieved by b-adrenoreceptor antagonists4 or certain
calcium channel blockers.5 However, these agents may
cause concominant negative inotropic and hypotensive
effects that are potentially deleterious during ischemia.6
In the last decade, two specific bradycadic agents,
Zatebradine8 and the related compound Ivabradine,9
have been developed and subjected to clinical testing in
ischemic heart disease (Fig. 1).
In the pursuit of novel specific bradycardic agents, 2-(3-
piperidino)-1,2,3,4-tetrahydroisoquinoline derivative 1
was found to exhibit potent and specific bradycardic
activities comparable to those of Zatebradine.10 Linkers
between tetrahydroisoquinoline and the piperidine
ring of compound 1 were investigated and it was shown
that N-acyl tetrahydroisoquinoline derivative 2 was
equipotent to Zatebradine in vitro and in vivo
(Table 1). To probe structure–activity relationships
(SAR) around compound 2, compounds described by
formula I were prepared and their biological activities
evaluated (Fig. 2). Here, the results of a SAR study on a
series of N-acyl tetrahydroisoquinoline derivatives are
reported. The bradycardic activity in conscious rats is
also described, subsequent to oral administration of
selected compounds.
Keywords: Cardiac disease; Myocardial ischemia; Bradycardic agent;
Zatebradine.
* Corresponding author. Tel.: +81-29-854-1547; fax: +81-29-852-
5387; e-mail: kubota.hideki@yamanouchi.co.jp
0968-0896/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmc.2003.12.032

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H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
2. Chemistry
of 5 with 3-aryloxypropyl bromides 7a–m12 respectively,
obtained from the corresponding phenols by treatment
with excess 1,3-dibromopropane (Scheme 1). Alkylation
of ethyl piperidin-3-ylacetate13 (9) with 3-(3,4-methyle-
nedioxyphenyl)propyl bromide (7a) followed by hydro-
lysis, yielded intermediate acid 10. Condensation of 10
with 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline
(11) afforded the desired product 12. Treatment of 3-
pyridylacetic acid with the corresponding tetra-
hydroisoquinoline derivatives 13 and 14 followed by
reduction of pyridine ring, provided amines 15 and 16,
respectively. Alkylation of 15 and 16 with 7a afforded
17 and 18, respectively (Scheme 2). 3-Arylalkyl bro-
mides 19, 20 and 21 were prepared in an analogous
manner to 7a, except that 1,3-dibromopropane was
replaced with 1,2-dibromoethane, 1,4-dibromobutane
and 1,5-dibromopentane respectively. Compounds 22,
23 and 24 were obtained by alkylation of 5 with corres-
ponding 3-aryloxyalkyl bromides 19, 20 and 21 respec-
tively (Scheme 3). Alkylation of 26 (obtained by
condensation of 2514 with 4 followed by deprotection of
BOC group) with 7a furnished the desired compound 2
(Scheme 4). Condensation of 4 with 27,15 followed by
reduction of pyridine ring and double bond, gave 29.
Alkylation of 29 with 7a afforded the desired compound
30 (Scheme 5). 1-Benzylpiperidin-3-amine16 (31) was
reacted with 4-nitrophenyl chloroformate followed by
treatment with 4 to provide urea 32. Deprotection of
benzyl group followed by alkylation with 7a provided
compound 34 (Scheme 6). Acylation of 4 with methyl
chloroformate followed by treatment with 37 (obtained
by alkylation of 3-hydroxypiperidine (36) with 7a) pro-
vided carbamate 38 (Scheme 7).
Preparation of N-acyl tetrahydroisoquinoline derivatives
is outlined in Schemes 1–7. Condensation of 311 with 6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride
(4) followed by deprotection of benzyl group, provided
amine 5. Compounds 8a–m were accessed by alkylation
Figure 1.
3. Result and discussion
Evaluation of the bradycardic activity exhibited by the
synthesized compounds was performed in isolated
Figure 2.
Table 1. Bradycardic activities of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives 2, 8a, 22–24, 30, 34, 38
Compd
x
y
EC30, mMa
Anesthetized rats % changeb at 3 mg/kg iv
HR MBP
1
2
8a
30
34
38
22
0.39
0.37Æ0.02 (3)
0.070Æ0.01(3)
0.20
À40
À10
Bond
–CH2–
–(CH2)2–
–NH–
O
–CH2–
–CH2–
–CH2–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)3–
–(CH2)2–
–(CH2)4–
–(CH2)5–
À52Æ5.4 (3)
À48Æ3.6 (3)
À31
À2.5Æ3.0 (3)
À2.7Æ4.8 (3)
À5.3
0.89
0.74
0.13
0.13
NTc
NTc
NTc
NTc
À54
À8.6
23
24
À43
À16
0.31
0.26Æ0.05 (7)
À35d
À18d
Zatebradine
À57Æ2.7 (5)
À1.9Æ2.4 (5)
a EC30 is the concentration required to produce a 30% reduction from the initial beat rates in isolated guinea pigs’ right atria. EC30 values are shown
withÆSE (number of determinations) where more than three determination were made. Otherwise results based on two determinations are given.
b Percent change from the initial value in urethane-anesthetized rats. Results are shown ÆSE (number of determinations) where more than three
determinations were made. Otherwise results based on single or two determinations are given.
c Not tested.
d Results of one experiment.

H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
873
.
Scheme 1. Synthesis of compounds 8a–m. Reagents and conditions: (i) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (4), WSC HCl,
HOBt, Et3N, DMF, THF; (ii) 4 M HCl/AcOEt; (iii) H2, 20% Pd(OH)2/C, AcOH; (iv) Br(CH2)3Br, K2CO3, CH3CN, 80 ꢀC; (v) K2CO3, CH3CN,
80 ꢀC.
Scheme 2. Synthesis of compounds 12, 17 and 18. Reagents and conditions: (i) 3-(3.4-methylenedioxyphenoxy)propyl bromide (7a), K2CO3,
ꢀ
.
CH3CN, 80 C; (ii)NaOH (aq), EtOH; (iii) 6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinoline (11), WSC HCl, HOBt, 1,2-dichloroethane; (iv) 3-
.
pyridylacetic acid hydrochloride, WSC HCl, HOBt, Et3N, 1,2-dichloroethane; (v) H2, PtO2, AcOH.
Scheme 3. Synthesis of compounds 22–24. Reagents and conditions: (i) Br(CH2)nBr, K2CO3, CH3CN, 80 ꢀC; (ii) 5, K2CO3, CH3CN, 80 ꢀC.
ꢀ
.
Scheme 4. Synthesis of compound 2. Reagents and conditions: (i) 4, WSC HCl, HOBt, DMF; (ii) 4 M HCl/AcOEt; (iii) 7a, K2CO3, CH3CN, 80 C.
.
Scheme 5. Synthesis of compound 30. Reagents and conditions: (i) 4, WSC HCl, HOBt, THF; (ii) H2, PtO2, AcOH; (iii) 4 M HCl/AcOEt; (iv) 7a,
K2CO3, CH3CN, 80 ꢀC.

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H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
Scheme 6. Synthesis of compound 34. Reagents and conditions: (i) 4-nitrophenyl chloroformate, Et3N, THF; (ii) 4, Et3N, DMF, 60 ꢀC; (iii) H2, 1 0%
Pd/C, AcOH; (iv) 4 M HCl/AcOEt; (v) 7a, K2CO3, CH3CN, 80 ꢀC.
Scheme 7. Synthesis of compound 38. Reagents and conditions: (i) ClCO2CH3, Et3N, THF; (ii) 7a, K2CO3, CH3CN, 80 ꢀC; (iii) NaH, toluene,
reflux.
guinea pigs right atria in vitro. An EC30 value, defined
as the concentration of the compound that produces a
30% reduction in the initial spontaneous beating rate,
was determined by linear regression. Compounds with
high in vitro activities were examined for their effect on
HR in urethane-anesthetized rats subsequent to inter-
venous administration, or conscious rats following oral
administration.
The influence of the aryl substituents R1and R2 on
biological activity of 8a was also evaluated in this study
(Table 2). Although bridging the 6,7-positions with
methylenedioxy moiety (12) did not influence in vitro
activity, in vivo bradycardic activity of 12 was less
potent than that of 8a. Removal of the methoxy group
from the 6- (18) or 7-position (17) on 1,2,3,4-tetra-
hydroisoquinoline was well tolerated in vitro and in
vivo. These derivatives, however, showed a relative
increase in hypotensive effect, compared to 8a. These
results indicated that 6,7-dimethoxy groups on 1,2,3,4-
tetrahydroisoquinoline ring are necessary to confer spe-
cific bradycardic activity.
Parent compound 2 exhibited potent bradycardic activ-
ity comparable to Zatebradine, with minimal influence
on mean blood pressure (MBP). Encouraged by these
results, further SAR studies around 2 were conducted in
order to establish the effect of the linkers, between the
piperidine C-3 position and carbonyl moiety (x linker)
and between the piperidine nitrogen atom and the oxy-
gen atom (y linker).
The effect of the aryl substituent R3 on biological
activity was subsequently studied (Table 2). Although
exchange of 3,4-methylenedioxy group into 3,4-dime-
thoxy group (8b) was well tolerated with regard to in
vitro activity, this modification resulted in an increase
in hypotensive activity. Furthermore, the effects of mono-
substituent on bradycardic and hypotensive activity was
examined by introduction of methoxy (8c–e) and
chloro (8f–h) groups. Compounds 8c–g exhibited a
marked hypotensive activity in spite of their potent
bradycardic effects. On the other hand, 4-chlorophenyl
derivative 8h was demonstrated to show moderate bra-
dycardic activity with negligible influence on MBP. This
finding prompted investigation into the effect of alter-
native substituents in the para-position. Introduction of
the fluoro (8i) and methyl (8e) substituents were well
tolerated in the level of in vitro activity. However, these
compounds also exhibited comparable hypotensive
activity to methoxy derivative 8c. A series of 4-substituted
derivatives bearing electron-withdrawing groups, such
as the cyano (8l) and trifluoromethyl (8m) groups, dis-
played negligible hypotensive activity and in addition to
Insertion of methylene moiety into x linker (8a) con-
ferred a 5-fold improvement in bradycardic activity in
vitro, with an EC30 value of 0.07Æ0.01 mM. Addition-
ally, compound 8a showed potent bradycardic activity
with minimal influence on MBP in vivo. The analogue
that possessed a two carbon x linker (30) was somewhat
less active compared to 2, in in vivo studies. Replace-
ment of the methylene linker of 8a with nitrogen (34) or
oxygen (38), resulted in a 10-fold loss of in vitro activity.
Among the analogues that contain three-carbon y linkers,
those containing zero- or one-carbon x linkers were
identified as optimal for specific bradycardic activity (2
and 8a). Although shortening (22) or extension (23 and
24) of the y linker alkyl chain was tolerated in terms
of in vitro and in vivo bradycardic activities, these
compounds affected blood pressure more significantly
than 8a. These results indicated that the optimal compo-
sition of the y linker is a propyl chain.

H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
875
Table 2. Bradycardic activities of N-acyl-1,2,3,4-tetrahydroisoquinoline derivatives 8a–m 15–17
Compd
R1R2
OMe
–OCH2O–
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
R3
EC
30, mMa
Anesthetized rats % changeb at 3 mg/kg iv
HR
MBP
8a
12
17
18
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
OMe
3,4-OCH2O–
3,4-OCH2O–
3,4-OCH2O–
3,4-OCH2O–
3,4-diOMe
2-OMe
3-OMe
4-OMe
2-Cl
0.070Æ0.01(3)
0.17
0.18
À48Æ3.6 (3)
À17
À2.7Æ4.8 (3)
À17
H
À40
À17
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
0.13
0.20
0.16
0.20
0.16
0.16
0.18
0.24
À46
À20
À43
À12
À60
À28
À48Æ4.2 (3)
À49
À22Æ5.2 (3)
À19
À52
À29
3-Cl
4-Cl
4-F
4-Me
4-NO2
4-CN
4-CF3
À52
À17
À39d
2.0d
0.13
0.29
À50
À30
À41d
À20d
0.19
0.18Æ0.02 (3)
À30
À9.4
À45Æ4.2 (3)
À30Æ2.4 (3)
À57Æ2.7 (5)
À4.5Æ3.3 (3)
À7.4Æ6.1(3)
1.9Æ2.4 (5)
0.50
0.26Æ0.05 (7)
Zatebradine
a ,b,c,d
See footnote in Table 1.
this, 8l exhibited potent bradycardic activity compar-
able to that of 8a in vivo. As a result of these experi-
ments, the 3,4-methylenedioxy and 4-cyano substituents
were identified as optimal for specific bradycardic
activity. These observations indicate that the substituent
of benzene and their position on the ring are critical in
the achievement of specific bradycardic activity.
On the basis of the potent and specific bradycardic
activity displayed in isolated guinea pig right atria and
in urethane-anesthetized rats, 8a and 8l were submitted
for further pharmacological evaluation. Compounds 8a
and 8l (10 mg/kg) were administrated orally to con-
scious rats and the effect on HR and MBP were exam-
ined (Fig. 3). Compound 8a reduced spontaneous HR
up to À106Æ14.3 beats/min, with negligible influence
on MBP (À12.3Æ5.86 mmHg), and this bradycardic
effect was sustained for more than 6 h. In this experi-
ment, 8a showed increased potency and duration of
action compared to those of Zatebradine. Although 8l
was equipotent to 8a after intravenous administration,
8l was found to show weaker bradycardic activity and
shorter duration of action subsequent to oral adminis-
tration. Compound 8l reduced spontaneous HR up to
À56.3Æ15.9 beats/min and its bradycardic effect was
sustained for less than 2 h. These results probably indi-
cate that 8a is better absorbed and has an increase
metabolic stability when compared to 8l.
4. Conclusions
Figure 3. Effects of 8a, 8l and Zatebradine on heart rate and mean
blood pressure in consious rats. Compounds were orally administrated
at time zero. Each point represents meanÆSEM from three to four
experiments.
A series of N-acyl-1,2,3,4-tetrahydroisoquinoline deri-
vatives were synthesized and evaluated. SAR studies

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H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
1
within this novel class of compounds revealed that aro-
matic ring substituents and their position in the ring are
critical to the specific induction of bradycardic activity.
In this series, compounds 8a and 8l show potent and
highly specific bradycardic activity subsequent to intra-
venous administration. Compound 8a also shows potent
and specific bradycardic activity in conscious rats fol-
lowing oral administration. Therefore, compound 8a
may be regarded as a novel lead in pursuit of specific
bradycardic agents, on the basis of its pharmacological
properties.
give 5 (2.29 g, 78%) as a colorless powder. H NMR
(300 MHz, DMSO-d6) d: 1.20–1.25 (m, 1H), 1.63–1.80
(m, 3H), 2.20 (brs, 1H), 2.38–2.44 (m, 2H), 2.48–2.80
(m, 4H), 3.15–3.29 (m, 2H), 3.60–3.68 (m, 2H), 3.72 (s,
6H), 4.54 (d, J=7.5 Hz, 2H), 6.73–6.81(m, 3H); MS
(FAB) m/z=319 (M+H)+. Anal. calcd for
.
C18H26N2O3 HCl: C, 60.92; H, 7.67; N, 7.89; Cl, 9.99.
Found: C, 60.69; H, 7.64; N, 7.83; Cl, 10.02.
5.1.2. 3-(Aryloxy)propyl bromide (7a–m): General proce-
dure. The synthesis of 3-(3,4-methylenedioxyphenoxy)-
propyl bromide (7a) is typical. To a solution of sesamol
(6.91g, 50.0 mmol) in CH CN (100 mL) were added
3
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 cooling at room temperature, the
mixture was concentrated in vacuo. The residue was
taken with CHCl3 and the CHCl3 layer was washed with
0.2 M NaOH (aq), dried over Na2SO4, filtered and con-
centrated in vacuo. The residue was purified by silica gel
column chromatography (hexane/AcOEt=9/1) to give
7a (9.61g, 74%) as colorless solid. 1H NMR (90 MHz,
CDCl3) d: 2.14–2.41 (m, 2H), 3.59 (t, J=6.4 Hz, 2H),
4.03 (t, J=5.9 Hz, 2H), 5.91(s, 2H), 6.32 (dd, J=8.4,
5. Experimental
5.1. Chemistry
In general, reagents and solvents were used as pur-
chased without further purification. Melting points were
determined with a Yanaco MP-500D melting point
1
apparatus and left uncorrected. H NMR spectra were
recorded on a JEOL JNM-LA300 or a JEOL JNM-
EX400 spectrometer. Chemical shifts were expressed in
d (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 JEOL JMS-LX2000 spec-
trometer. The elemental analyses were performed with a
Yanaco MT-5 microanalyzer (C, H, N) and Yokogawa
IC-7000S ion chromatographic analyzer (halogens) and
were within Æ0.4% of theoretical values.
2.4 Hz, 1H), 6.50 (d, J=2.4 Hz, 1H), 6.70 (d, J=8.4 Hz,
+
1H); MS (FAB) m/z=259, 261(M+H)
.
5.1.3. (Æ)-6,7-Dimethoxy-2-({1-[3-(3,4-methylenedioxy-
phenoxy)propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydro-
isoquinoline monooxalate (8a). To a solution of 5 (248
mg, 0.700 mmol) in CH3CN (6.00 mL) were added
K2CO3 (203 mg, 1.47 mmol) and 7a (190 mg, 0.735
mmol), and the mixture was stirred at 80 ꢀC for 6 h.
After cooling at room temperature, the mixture was
concentrated in vacuo. The residue was partitioned
between CHCl3 and H2O, then the organic layer was
dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by silica gel column chroma-
tography (CHCl3/MeOH=98/2–96/4) to give the free
base of 8a (348 mg, 100%) as a light yellow form. The
free base of 8a was dissolved in MeOH (6.00 mL) and
was added oxalic acid (57 mg, 0.63 mmol), and the
mixture was concentrated in vacuo. The crude salt was
recrystallized from AcOEt–CH3CN to give 8a (296 mg,
5.1.1. (Æ)-6,7-Dimethoxy-2-[(piperidin-3-yl)acetyl]-1,2,3,4-
tetrahydroisoquinoline hydrochloride (5). To a solution
of 4 (1.91 g, 8.33 mmol) in THF (30.0 mL) was added
Et3N (1.16 mL, 8.33 mmol), and the mixture was stirred
at room temperature for 10 min. After cooling at 0 ꢀC,
to the reaction mixture were added solution of 3 (8.33
mmol) in THF (10.0 mL) and DMF (5.00 mL), HOBt
.
(0.563 g, 4.17 mmol) and WSC HCl (1.76 g, 9.16 mmol),
and the mixture was stirred at room temperature for 9
h. The mixture was partitioned between AcOEt and
H2O, and the organic layer was washed with brine,
dried over Na2SO4, filtered and concentrated in vacuo.
The residue was purified by silica gel column chroma-
tography (CHCl3/MeOH=98/2–96/4) to give 2-[(1-
benzylpiperidin-3-yl) acetyl]-6,7-dimethoxy-1,2,3,4-tet-
rahydroisoquinoline (4.51g) as colorless syrup. To a
solution of compound obtained above in MeOH (50.0
mL) was added 4 M HCl (g)/AcOEt (2.49 mL, 9.96
mmol), and the mixture was concentrated in vacuo. To
a solution of the residual solid in AcOH (30.0 mL) was
added Pd(OH)2/C (20 w/w%, 0.185 g), and the mixture
was stirred under hydrogen pressure (3.2 kg/cm2) at
room temperature for 15.5 h. The catalyst was filtrated
on Celite and the filtrate was concentrated in vacuo.
The residue was alkalined with 1M NaOH (aq), then
partitioned between CHCl3 and brine. The organic layer
was dried over Na2SO4, filtered and concentrated in
vacuo to give the free base of 5 as colorless syrup. This
material was converted to its hydrochloride salt by
treating with 4 M HCl (g)/AcOEt (2.49 mL, 9.96 mmol).
The crude salt was recrystallized from AcOEt–MeOH to
72%) as colorless powder. mp: 172–173 ꢀC; H NMR
1
(400 MHz, DMSO-d6) d: 1.18 (brs, 1H), 1.71–1.80 (m,
3H), 2.05 (brs, 2H), 2.25 (brs, 2H), 2.35–2.41(m, 2H),
2.61–2.68 (m, 2H), 2.76 (brs, 2H), 3.10 (brs, 2H), 3.39
(brs, 2H), 3.61–3.65 (m, 2H), 3.72 (s, 6H), 3.95 (brs,
2H), 4.54 (d, J=8.0 Hz, 2H), 5.95 (s, 2H), 6.37 (dd,
J=8.8, 2.4 Hz, 1H), 6.63 (d, J=2.4 Hz, 1H), 6.74–6.82
(m, 3H); MS (FAB) m/z=497 (M+H)+. Anal. calcd
.
.
for C28H36N2O6 C2H2O4 0.1H2O: C, 61.23; H, 6.54; N,
4.76. Found: C, 61.09; H, 6.26; N, 4.77.
5.1.4. (Æ)-2-({1-[3-(3,4-Dimethoxyphenoxy)propyl]-3-pi-
peridyl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line monooxalate (8b). Compound 8b was prepared
from 5 and 7b in a manner similar to that described for
compound 8a with a yield of 73%. mp: 124–125 ꢀC
1
(AcOEt–CH3CN); H NMR (400 MHz, DMSO-d6) d:
1.16–1.18 (m, 1H), 1.73–1.80 (m, 3H), 2.07 (brs, 2H),
2.26 (brs, 1H), 2.36–2.45 (m, 2H), 2.62–2.68 (m, 2H),

H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
877
1
2.74–2.77 (m, 2H), 3.10–3.12 (m, 2H), 3.40 (brs, 2H),
3.61–3.64 (m, 2H), 3.68 (s, 3H), 3.71–3.73 (m, 9H),
3.96–3.97 (m, 2H), 4.54 (d, J=9.6 Hz, 2H), 6.42 (dd,
J=8.8, 2.8 Hz, 1H), 6.56 (d, J=2.8 Hz, 1H), 6.74–6.78
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.16–1.19
(m, 1H), 1.68–1.80 (m, 3H), 2.11–2.16 (m, 2H), 2.25
(brs, 1H), 2.40–2.42 (m, 2H), 2.60–2.68 (m, 2H), 2.76 (t,
J=5.8 Hz, 2H), 3.12–3.14 (m, 2H), 3.40 (brs, 2H), 3.61–
3.67 (m, 2H), 3.71 (s, 6H), 4.11–4.14 (m, 2H), 4.54 (d,
J=8.3 Hz, 2H), 6.74 (s, 1H), 6.78 (d, J=3.6 Hz, 1H),
6.97 (dt, J=7.6, 1.1 Hz, 1H), 7.15 (dd, J=1.0 Hz, 1H),
7.33 (dt, J=7.8, 1.5 Hz, 1H), 7.40–7.45 (dd, J=7.8, 1.5
Hz, 1H); MS (FAB) m/z=487 (M+H)+. Anal. calcd for
(m, 2H), 6.84 (d, J=8.8 Hz, 1H); MS (FAB) m/z=513
+
.
(M+H) . Anal. calcd for C29H40N2O6 C2H2O4: C,
61.78; H, 7.02; N, 4.65. Found: C, 61.60; H, 7.03; N, 4.65.
5.1.5. (Æ)-6,7-Dimethoxy-2-({1-[3-(2-methoxyphenoxy)-
propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoquinoline
monooxalate (8c). Compound 8c was prepared from 5
and 7c in a manner similar to that described for com-
pound 8a with a yield of 75%. mp: 102–105 ꢀC (AcOEt–
.
.
C27H35N2O4Cl C2H2O4 0.1H2O: C, 60.17; H, 6.48; N,
4.84, Cl, 6.12. Found: C, 60.17; H, 6.19; N, 4.84; Cl, 6.03.
5.1.9. (Æ)-2-({1-[3-(3-Chlorophenoxy)propyl]-3-piperid-
yl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
monooxalate hemi hydrate (8g). Compound 8g was pre-
pared from 5 and 7g in a manner similar to that descri-
bed for compound 8a with a yield of 55%. mp: 90–94 ꢀC
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.16–1.19
(m, 1H), 1.68–1.80 (m, 3H), 2.08–2.12 (m, 2H), 2.25
(brs, 1H), 2.41–2.47 (m, 2H), 2.61–2.68 (m, 2H), 2.76 (t,
J=5.6 Hz, 2H), 3.13 (brs, 2H), 3.39 (brs, 2H), 3.41 (brs,
2H), 3.61–3.67 (m, 2H), 3.71 (s, 6H), 3.75 (s, 3H), 4.00–
4.02 (m, 2H), 4.54 (d, J=8.4 Hz, 2H), 6.74 (s, 1H), 6.78
(d, J=4.4 Hz, 1H), 6.87 (dd, J=7.6, 2.0 Hz, 1H), 6.90
(m, 3H), 6.90 (t, J=2.0 Hz, 1H), 6.93 (dd, J=7.2, 2.0 Hz,
1
(AcOEt–CH3CN); H NMR (400 MHz, DMSO-d6) d:
1.16–1.19 (m, 1H), 1.66–1.80 (m, 3H), 2.08 (brs, 2H),
2.24 (brs, 1H), 2.39–2.43 (m, 2H), 2.59–2.68 (m, 2H),
2.76 (t, J=5.6 Hz, 2H), 3.11 (brs, 2H), 3.39 (brs, 2H),
3.61–3.64 (m, 2H), 3.71 (s, 6H), 4.05–4.08 (m, 2H), 4.54
(d, J=8.3 Hz, 2H), 6.74 (s, 1H), 6.78 (d, J=3.9 Hz, 1H),
6.90–6.94 (m, 1H), 6.98–7.04 (m, 2H), 7.32 (t, J=8.1
Hz, 1H); MS (FAB) m/z=487 (M+H)+. Anal. calcd
1H), 6.97 (dt, J=7.6, 2.0 Hz, 1H); MS (FAB) m/z=483
+
.
.
(M+H) . Anal. calcd for C28H38N2O5 C2H2O4 0.6H2O:
C, 61.76; H, 7.12; N, 4.80. Found: C, 61.67; H, 6.99; N,
4.80.
.
.
for C27H35N2O4Cl C2H2O4 0.5H2O: C, 59.43; H, 6.54; N,
4.78, Cl, 6.05. Found: C, 59.43; H, 6.18; N, 4.71; Cl, 5.80.
5.1.6. (Æ)-6,7-Dimethoxy-2-({1-[3-(3-methoxyphenoxy)-
propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoquinoline
monooxalate (8d). Compound 8d was prepared from 5
and 7d in a manner similar to that described for com-
pound 8a with a yield of 64%. mp: 88–93 ꢀC (AcOEt–
5.1.10. (Æ)-2-({1-[3-(4-Chlorophenoxy)propyl]-3-piperid-
yl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
monooxalate (8h). Compound 8h was prepared from 5
and 7h in a manner similar to that described for com-
pound 8a with a yield of 81%. mp: 117–120 ꢀC (AcOEt–
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.16–1.19
(m, 1H), 1.68–1.80 (m, 3H), 2.08 (brs, 2H), 2.25 (brs,
1H), 2.39–2.47 (m, 2H), 2.61–2.68 (m, 2H), 2.76 (t,
J=6.0 Hz, 2H), 3.10–3.12 (m, 2H), 3.40 (brs, 2H), 3.61–
3.67 (m, 2H), 3.71(s, 6H), 3.73 (s, 3H), 4.00–4.03 (m,
2H), 4.54 (d, J=8.0 Hz, 2H), 6.48 (t, J=2.4 Hz, 1H),
6.51–6.54 (m, 2H), 6.74 (s, 1H), 6.78 (d, J=3.2 Hz, 1H),
7.18 (t, J=8.4 Hz, 1H); MS (FAB) m/z=483 (M+H)+.
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.18 (brs,
1H), 1.68–1.79 (m, 3H), 2.08–2.11 (m, 2H), 2.25 (brs,
1H), 2.39–2.43 (m, 2H), 2.60–2.68 (m, 2H), 2.76 (t,
J=5.6 Hz, 2H), 3.09–3.11 (m, 2H), 3.39 (brs, 2H), 3.61–
3.64 (m, 2H), 3.71(s, 6H), 4.01–4.04 (m, 2H), 4.54 (d,
J=8.4 Hz, 2H), 6.74 (s, 1H), 6.78 (d, J=3.6 Hz, 1H),
6.96 (dt, J=8.8, 3.6 Hz, 1H), 7.33 (dt, J=8.4, 3.6 Hz,
1H); MS (FAB) m/z=487 (M+H)+. Anal. calcd for
C27H35N2O4Cl C2H2O4 0.5H2O: C, 59.43; H, 6.54; N,
4.78, Cl, 6.05. Found: C, 59.33; H, 6.25; N, 4.77; Cl,
6.05.
.
.
Anal. calcd for C28H38N2O5 C2H2O4 0.8H2O: C, 61.38;
H, 7.14; N, 4.77. Found: C, 61.38; H, 7.15; N, 4.69.
.
.
5.1.7. (Æ)-6,7-Dimethoxy-2-({1-[3-(4-methoxyphenoxy)-
propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoquinoline
monooxalate (8e). Compound 8e was prepared from 5
and 7e in a manner similar to that described for com-
pound 8a with a yield of 76%. mp: 132–136 ꢀC (AcOEt–
5.1.11. (Æ)-2-({1-[3-(4-Fluorophenoxy)propyl]-3-piperi-
dyl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
monooxalate (8i). Compound 8i was prepared from 5
and 7i in a manner similar to that described for com-
pound 8a with a yield of 81%. mp: 102–106 ꢀC (AcOEt–
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.16–1.18
(m, 1H), 1.67–1.80 (m, 3H), 2.06–2.08 (m, 2H), 2.24
(brs, 1H), 2.39–2.43 (m, 2H), 2.60–2.68 (m, 2H), 2.76 (t,
J=5.6 Hz, 2H), 3.09–3.11 (m, 2H), 3.40 (brs, 2H), 3.61–
3.65 (m, 2H), 3.69 (s, 3H), 3.71(s, 6H), 3.95–3.98 (m,
2H), 4.54 (d, J=8.0 Hz, 2H), 6.74 (s, 1H), 6.78 (d,
1
CH3CN); H NMR (400 MHz, DMSO-d6) d: 1.18 (brs,
1H), 1.67–1.83 (m, 3H), 2.10–2.15 (m, 2H), 3.71 (s, 6H),
3.99–4.00 (m, 2H), 4.54 (d, J=8.0 Hz, 2H), 6.74 (s, 1H),
6.78 (d, J=3.6 Hz, 1H), 6.92–6.97 (m, 2H), 7.09–7.14
(m, 2H); MS (FAB) m/z=471(M+H) +. Anal. calcd
for C27H35N2O4F C2H2O4 0.6H2O: C, 60.96; H, 6.74;
N, 4.90, F, 3.32. Found: C, 60.90; H, 6.61; N, 4.73; F,
3.42.
J=3.6 Hz, 1H), 6.86 (s, 4H); MS (FAB) m/z=483
+
.
.
(M+H) . Anal. calcd for C28H38N2O5 C2H2O4 0.8H2O:
C, 61.38; H, 7.14; N, 4.77. Found: C, 61.35; H, 7.05; N,
4.67.
.
.
5.1.8. (Æ)-2-({1-[3-(2-Chlorophenoxy)propyl]-3-piperid-
yl}acetyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
monooxalate (8f). Compound 8f was prepared from 5
and 7f in a manner similar to that described for com-
pound 8a with a yield of 48%. mp: 156–158 ꢀC (AcOEt–
5.1.12. (Æ)-6,7-Dimethoxy-2-({1-[3-(4-methylphenoxy)-
propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoquinoline
monooxalate (8j). Compound 8j was prepared from 5
and 7j in a manner similar to that described for

878
H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
compound 8a with a yield of 67%. mp: 141–142 ꢀC
(AcOEt–CH3CN); H NMR (400 MHz, DMSO-d6) d:
19.3 mmol) and 7a (5.00 g, 19.3 mmol), and the mixture
was stirred at 80 ꢀC for overnight. After cooling at room
temperature, the mixture was concentrated in vacuo.
The residue was partitioned between CHCl3 and
NaHCO3 (aq). The organic layer was dried over
MgSO4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography
(CHCl3/MeOH=100/1–50/1) to give (Æ)-ethyl {1-[3-
(1,3-benzodioxol-5-yloxy)propyl]piperidin-3-yl}acetate
(4.23 g, 70%) as yellow oil. To a solution of compound
obtained above in EtOH (20.0 mL) was added 1M
NaOH (aq), and the mixture was stirred at room temp-
erature for 1h. To the reaction mixture was added 1M
HCl (aq) (12.0 mL), and the mixture was concentrated
in vacuo. The residue was suspended in EtOH, filtered
and concentrated in vacuo to give 10 (4.76 g, quant.) as
1
1.16–1.19 (m, 1H), 1.68–1.79 (m, 3H), 2.07–2.10 (m,
2H), 2.22 (s, 3H), 2.26 (brs, 1H), 2.35–2.47 (m, 2H),
2.61–2.68 (m, 2H), 2.74–2.77 (m, 2H), 3.10–3.14 (m,
2H), 3.40 (brs, 2H), 3.61–3.67 (m, 2H), 3.71 (s, 6H),
3.97–4.00 (m, 2H), 4.54 (d, J=8.4 Hz, 2H), 6.74 (s, 1H),
6.78 (d, J=3.2 Hz, 1H), 6.82 (d, J=8.8 Hz, 2H), 7.08
(d, J=8.8 Hz, 2H); MS (FAB) m/z=467 (M+H)+.
.
Anal. calcd for C28H38N2O4 C2H2O4: C, 64.73; H, 7.24;
N, 5.03. Found: C, 64.51; H, 7.13; N, 4.99.
5.1.13. (Æ)-6,7-Dimethoxy-2-({1-[3-(4-nitrophenoxy)pro-
pyl] - 3 - piperidyl}acetyl) - 1,2,3,4 - tetrahydroisoquinoline
monooxalate hemi hydrate (8k). Compound 8k was pre-
pared from 5 and 7k in a manner similar to that descri-
bed for compound 8a with a yield of 86%. mp: 119–
1
colorless amorphous. H NMR (300 MHz, CDCl3) d:
122 ꢀC (AcOEt–CH3CN); H NMR (400 MHz, DMSO-
1.04 (brs, 1H), 1.60–2.40 (m, 9H), 2.75 (brs, 2H), 3.05
(brs, 1H), 3.89 (brs, 2H), 5.88 (s, 2H), 6.27 (d, J=7.8 Hz,
1H), 6.45 (s, 1H), 6.66 (d, J=8.4 Hz, 1H); MS (FAB)
m/z=322 (M+H)+.
1
d6) d: 1.18 (brs, 1H), 1.68–1.80 (m, 3H), 2.12–2.14 (m,
2H), 2.25 (brs, 3H), 2.39–2.43 (m, 2H), 2.59–2.68 (m,
2H), 2.76 (d, J=5.6 Hz, 2H), 3.10–3.12 (m, 2H), 3.39
(brs, 2H), 3.61–3.64 (m, 2H), 3.71 (s, 6H), 4.19–4.20 (m,
2H), 4.54 (d, J=9.6 Hz, 2H), 6.74 (s, 1H), 6.78 (d,
J=2.4 Hz, 1H), 7.15 (d, J=9.2 Hz, 2H), 8.22 (d, J=9.2
Hz, 2H); MS (FAB) m/z=498 (M+H)+. Anal. calcd
5.1.17. (Æ)-6,7-Methylenedioxy-2-({1-[3-(3,4-methylene-
dioxyphenoxy)propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahy-
droisoquinoline monooxalate (12). To a solution of 10
(720 mg, 2.24 mmol) and 11 (360 mg, 2.03 mmol) in 1,2-
dichloroethane (20.0 mL) were added HOBt (140 mg,
.
.
for C27H35N3O6 C2H2O4 0.5H2O: C, 58.38; H, 6.42; N,
7.04. Found: C, 58.40; H, 6.43; N, 6.80.
.
1.02 mmol) and WSC HCl (430 mg, 2.24 mmol), and
5.1.14. (Æ)-4-(3-{3-[2-(6,7-Dimethoxy-1,2,3,4-tetrahydro-
2-isoquinolyl)-2-oxoethyl]-1-piperidyl}propoxy)benzoni-
trile monooxalate (8l). Compound 8l was prepared
from 5 and 7l in a manner similar to that described for
compound 8a with a yield of 75%. mp: 120–123 ꢀC
the mixture was stirred at room temperature for 6 h.
The reaction mixture was alkalized with 1M NaOH
(aq), then extracted with CHCl3. The organic layer was
dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by silica gel column chroma-
tography (CHCl3/MeOH=100/1–50/1) to give the free
base of 12. To a solution of free base of 12 in MeOH
(10.0 mL) was added oxalic acid (160 mg), and the
mixture was concentrated in vacuo. The crude salt was
recrystallized from AcOEt–EtOH to give 12 (400 mg,
35%) as colorless powder. mp: 130–133 ꢀC (AcOEt–
1
(AcOEt–CH3CN); H NMR (400 MHz, DMSO-d6) d:
1.18 (brs, 1H), 1.70–1.79 (m, 3H), 2.11 (brs, 2H), 2.24
(brs, 1H), 2.39–2.43 (m, 2H), 2.59–2.68 (m, 2H), 2.74–
2.77 (m, 2H), 3.11 (brs, 2H), 3.39 (brs, 2H), 3.61–3.64
(m, 2H), 3.71(s, 6H), 4.14 (brs, 2H), 4.53 (d, J=8.8 Hz,
2H), 6.74 (s, 1H), 6.78 (d, J=3.2 Hz, 1H), 7.11 (d,
J=8.8 Hz, 2H), 7.78 (d, J=8.4 Hz, 2H); MS (FAB) m/z
=478 (M+H)+. Anal. calcd for C28H35N3O4
.
.
C2H2O4 0.3H2O: C, 62.88; H, 6.61; N, 7.33. Found: C,
62.83; H, 6.65; N, 7.23.
1
EtOH); H NMR (400 MHz, DMSO-d6) d: 1.16–1.19
(m, 1H), 1.65–1.80 (m, 3H), 2.05–2.06 (m, 2H), 2.25
(brs, 1H), 2.34–2.41 (m, 2H), 2.60–2.69 (m, 2H), 2.74 (t,
J=5.4 Hz, 2H), 3.11 (brs, 2H), 3.32–3.48 (m, 2H), 3.56–
3.66 (m, 2H), 3.95 (t, J=5.9 Hz, 2H), 4.50 (d, J=9.7
Hz, 2H), 5.95 (s, 4H), 6.37 (dd, J=8.3, 2.4 Hz, 1H), 6.63
5.1.15. (Æ)-6,7-Dimethoxy-2-({1-[3-(4-trifluoromethyl-
phenoxy)propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroi-
soquinoline monooxalate (8m). Compound 8m was
prepared from 5 and 7m in a manner similar to that
described for compound 8a with a yield of 83%. mp:
86–88 ꢀC (AcOEt); 1H NMR (400 MHz, DMSO-d6)
d: 1.18 (brs, 1H), 1.68–1.80 (m, 3H), 2.11–2.14 (m,
2H), 2.25 (brs, 1H), 2.40–2.43 (m, 2H), 2.61–2.68
(m, 2H), 2.76 (t, J=5.6 Hz, 2H), 3.10–3.12 (m, 2H), 3.40
(brs, 2H), 3.63–3.67 (m, 2H), 3.71 (s, 6H), 4.11–4.14 (m,
2H), 4.54 (d, J=8.8 Hz, 2H), 6.74 (s, 1H), 6.78 (d, J=
2.8 Hz, 1H), 7.12 (d, J=8.8 Hz, 2H), 7.66 (d, J=8.8 Hz,
2H); MS (FAB) m/z=521(M+H) +. Anal. calcd for
(d, J=2.4 Hz, 2H), 6.73–6.82 (m, 3H); MS (FAB) m/
+
.-
z=481(M+H)
.
. Anal. calcd for C27H34N2O5
C2H2O4 0.1H2O: C, 61.04; H, 6.01; N, 4.91. Found: C,
60.92; H, 5.96; N, 4.70.
5.1.18. (Æ)-6-Methoxy-2-[(piperidin-3-yl)acetyl]-1,2,3,4-
tetrahydroisoquinoline (15). To a suspension of 13 (3.18
g, 15.9 mmol) in 1,2-dichloroethane (90.0 mL) were
added Et3N (5.08 mL, 36.6 mmol), 3-pyridylaceticacid
hydrochloride (3.32 g, 19.1 mmol), HOBt (1.07 g, 7.95
.
mmol) and WSC HCl (3.66 g, 19.1 mmol), and the
mixture was stirred at room temperature for overnight.
The reaction mixture was alkalized with 1M NaOH
(aq), then extracted with CHCl3. The organic layer was
dried over MgSO4, filtered and concentrated in vacuo.
The residue was purified by silica gel column chroma-
tography (CHCl3/MeOH=100/0–100/1) to give 6-meth-
oxy-2-[(pyridin-3-yl)acetyl]-1,2,3,4-tetrahydroisoquinoline
.
.
C28H35N3O4F3 C2H2O4 0.7H2O: C, 57.82; H, 6.21; N,
4.49; F, 9.15. Found: C, 57.95; H, 6.10; N, 4.19; F, 9.15.
5.1.16. (Æ)-{1-[4-(1,3-Benzodioxol-5-yl)butyl]piperidin-3-
yl}acetic acid (10). To a solution of 9 (3.00 g, 17.5
mmol) in CH3CN (30.0 mL) were added K2CO3 (2.66 g,

H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
879
(3.49 g, 78%). To a solution of compound obtained
above in AcOH (35.0 mL) was added PtO2 (350 mg),
and the mixture was stirred under hydrogen pressure
(3.0 kg/cm2) at room temperature for 5 h. The catalyst
was removed by filtration on Celite and the filtrate was
concentrated in vacuo. The residue was alkalized with
1M NaOH (aq), then extracted with CHCl 3. The
organic layer was dried over MgSO4, filtered and con-
centrated in vacuo. The residue was purified by silica gel
column chromatography (CHCl3/MeOH/NH4OH=100/
1/0–30/1/0.1–20/1/0.1) to give 15 (1.50 g, 42%). as
yellow oil. 1H NMR (300 MHz, CDCl3) d: 1.11–1.26 (m,
1H), 1.35–2.40 (m, 6H), 2.50–2.62 (m, 1H), 2.70–2.15
(m, 6H), 3.35 (d, J=10.2 Hz, 1H), 3.66 (t, J=6.00 Hz,
1H), 3.62–3.67 (m, 2H), 3.79 (s, 3H), 4.56–4.66 (m, 2H),
6.66–6.72 (m, 1H), 6.76 (dd, J=8.4, 2.4 Hz, 1H), 7.03
(dd, J=16.8, 8.4 Hz, 1H); MS (FAB) m/z=289
(M+H)+.
J=8.3 Hz, 1H); MS (FAB) m/z=467 (M+H)+. Anal.
calcd for C27H34N2O5 C2H2O4 0.1H2O: C, 62.38; H,
6.53; N, 5.02. Found: C, 62.27; H, 6.62; N, 5.02.
.
.
5.1.22. 2-(3,4-Methylenedioxyphenoxy)ethyl bromide (19).
Compound 19 was prepared from 6a and 1,2-dibromo-
ethane in a manner similar to that described for com-
1
pound 7a with a yield of 18%. H NMR (400 MHz,
CDCl3) d: 3.60 (t, J=6.0 Hz, 2H), 4.21(t, J=6.0 Hz,
2H), 5.92 (s, 2H), 6.34 (dd, J=8.4, 2.8 Hz, 1H), 6.52
(d, J=2.4 Hz, 1H), 6.70 (d, J=8.8 Hz, 1H); MS (EI)
m/z=244, 246 (M)+.
5.1.23. 4-(3,4-Methylenedioxyphenoxy)butyl bromide (20).
Compound 20 was prepared from 6a and 1,4-dibromo-
butane in a manner similar to that described for com-
1
pound 7a with a yield of 73%. H NMR (400 MHz,
CDCl3) d: 1.86–1.96 (m, 2H), 2.00–2.12 (m, 2H), 3.48 (t,
J=6.8 Hz, 2H), 4.92 (t, J=6.0 Hz, 2H), 5.91(s, 2H),
6.30 (dd, J=8.4, 2.4 Hz, 1H), 6.48 (d, J=2.8 Hz, 1H),
6.70 (d, J=8.8 Hz, 1H); MS (EI) m/z=272, 274 (M)+.
5.1.19. (Æ)-7-Methoxy-2-[(piperidin-3-yl)acetyl]-1,2,3,4-
tetrahydroisoquinoline hydrochloride (16). Compound
16 was prepared from 14 in a manner similar to that
1
described for compound 15 with a yield of 75%. H
5.1.24. 5-(3,4-Methylenedioxyphenoxy)pentyl bromide (21).
Compound 21 was prepared from 6a and 1,5-dibromo-
pentane in a manner similar to that described for com-
NMR (300 MHz, DMSO-d6) d: 1.15–1.26 (m, 1H),
1.62–1.74 (m, 3H), 2.20 (brs, 1H), 2.41–2.43 (m, 2H),
2.56–2.70 (m, 2H), 2.78 (t, J=5.9 Hz, 2H), 3.14–3.25
(m, 2H), 3.62–3.67 (m, 2H), 3.72 (d, J=3.0 Hz, 2H),
4.60 (d, J=8.7 Hz, 2H), 6.74–6.78 (m, 2H), 7.08 (d,
J=8.4 Hz, 1H), 8.83 (brs, 1H), 9.13 (brs, 1H); MS
(FAB) m/z=289 (M+H)+. Anal. calcd for
1
pound 7a with a yield of 92%. H NMR (400 MHz,
CDCl3) d: 1.55–1.65 (2H, m), 1.70–1.85 (m, 2H), 1.89–
1.96 (m, 2H), 3.43 (t, J=7.2 Hz, 2H), 3.89 (t, J=6.4 Hz,
2H), 5.90 (s, 2H), 6.31(dd, J=8.6, 2.4 Hz, 1H), 6.48 (d,
J=2.4 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H); MS (EI)
m/z=286, 288 (M)+.
.
C17H24N2O2 HCl: C, 61.83; H, 7.81; N, 8.48; Cl, 10.73.
Found: C, 61.56; H, 7.75; N, 8.47; Cl, 10.91.
5.1.25. (Æ)-6,7-Dimethoxy-2-({1-[3-(3,4-methylenedioxy-
phenoxy)ethyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroiso-
quinoline monooxalate (22). Compound 22 was prepared
from 7a and 19 in a manner similar to that described for
compound 8a with a yield of 59%. mp: 108–116 ꢀC
5.1.20. (Æ)-6-Methoxy-2-({1-[3-(3,4-methylenedioxyphe-
noxy)propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoqui-
noline monooxalate (17). Compound 17 was prepared
from 7a and 15 in a manner similar to that described for
compound 8a with a yield of 38%. mp: 78–81 ꢀC
(AcOEt–EtOH); 1H NMR (400 MHz, DMSO-d6) d:
1.16–1.20 (m, 1H), 1.60–1.85 (m, 3H), 2.03–2.10 (m,
2H), 2.20–2.30 (m, 1H), 2.38–2.45 (m, 2H), 2.50–2.65
(m, 2H), 2.70–2.85 (m, 4H), 3.11 (brs, 2H), 3.40 (brs,
2H), 3.60–3.67 (m, 2H), 3.72 (s, 3H), 3.95 (t, J=5.9 Hz,
2H), 4.54 (d, J=12.2 Hz, 2H), 5.95 (s, 2H), 6.37 (dd,
J=8.3, 2.4 Hz, 1H), 6.63 (d, J=2.4 Hz, 2H), 6.73–6.78
(m, 2H), 6.80 (d, J=8.3 Hz, 1H), 7.10 (d, J=8.8 Hz,
1H); MS (FAB) m/z=467 (M+H)+. Anal. calcd for
1
(AcOEt–CH3CN); H NMR (400 MHz, DMSO-d6) d:
1.13–1.16 (m, 1H), 1.77 (brs, 3H), 2.27 (brs, 1H), 2.34–
2.46 (m, 2H), 2.66 (t, J=6.0 Hz, 2H), 2.75 (t, J=6.4 Hz,
2H), 3.30–3.44 (m, 4H), 3.64 (dd, J=12.4, 6.0 Hz, 3H),
3.71(s, 6H), 4.20–4.21(m, 2H), 4.53 (d, J=12.0 Hz,
2H), 5.97 (s, 2H), 6.41(dt, J=8.8, 2.8 Hz, 1H), 6.681 (d,
J=2.4 Hz, 1H), 6.74 (s, 1H), 6.77 (d, J=2.4 Hz, 1H),
6.82 (dd, J=8.8, 5.2 Hz, 1H); MS (FAB) m/z=483
+
.
.
(M+H) . Anal. calcd for C27H34N2O6 C2H2O4 0.4H2O:
C, 60.07; H, 6.40; N, 4.83. Found: C, 60.01; H, 6.68; N,
4.80.
.
.
C27H34N2O5 C2H2O4 0.3H2O: C, 61.98; H, 6.56; N,
4.98. Found: C, 61.87; H, 6.71; N, 4.88.
5.1.26. (Æ)-6,7-Dimethoxy-2-({1-[3-(3,4-methylenedioxy-
phenoxy)butyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroiso-
quinoline monooxalate 0.1 hydrate (23). Compound 23
was prepared from 7a and 20 in a manner similar to that
described for compound 8a with a yield of 86%. mp:
159–161 ꢀC (AcOEt–CH3CN); 1H NMR (400 MHz,
DMSO-d6) d: 1.16–1.18 (m, 1H), 1.69–1.79 (m, 7H),
2.25 (brs, 1H), 2.35–2.47 (m, 2H), 2.66 (t, J=6.0 Hz,
2H), 2.76 (t, J=6.0 Hz, 2H), 3.02 (brs, 2H), 3.38 (brs,
2H), 3.61–3.66 (m, 2H), 3.71 (s, 6H), 3.90 (t, J=6.0 Hz,
2H), 4.53 (d, J=7.2 Hz, 2H), 5.95 (s, 2H), 6.36 (dd,
J=8.4, 2.0 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.74 (s,
1H), 6.77 (d, J=3.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H);
MS (FAB) m/z=511 (M+H)+. Anal. calcd for
5.1.21. (Æ)-7-Methoxy-2-({1-[3-(3,4-methylenedioxyphe-
noxy)propyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroisoqui-
noline monooxalate (18). Compound 18 was prepared
from 7a and 16 in a manner similar to that described for
compound 8a with a yield of 63%. mp: 121–123 ꢀC
1
(AcOEt–CH3CN); H NMR (400 MHz, DMSO-d6) d:
1.16–1.18 (m, 1H), 1.67–1.79 (m, 3H), 2.03–2.07 (m,
2H), 2.25 (brs, 1H), 2.40–2.41 (m, 2H), 2.60–2.69 (m,
2H), 2.77 (t, J=5.9 Hz, 2H), 3.10 (brs, 2H), 3.39 (brs,
2H), 3.62–3.67 (m, 2H), 3.72 (d, J=2.9 Hz, 3H), 3.95 (t,
J=5.9 Hz, 2H), 4.60 (d, J=9.7 Hz, 2H), 5.95 (s, 2H),
6.37 (dd, J=8.8, 2.4 Hz, 1H), 6.63 (d, J=2.4 Hz, 2H),
6.74–6.78 (m, 2H), 6.81(d, J=8.3 Hz, 1H), 7.08 (d,

880
H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
.
.
C29H38N2O6 C2H2O4 0.1H2O: C, 61.80; H, 6.73; N,
4.65. Found: C, 61.97; H, 7.03; N, 4.69.
at room temperature for 10 min. After cooling at 0 ꢀC,
to the reaction mixture were added solution of 27 (1.46
g, 9.80 mmol) in THF (10.0 mL), HOBt (0.602 g, 4.46
.
5.1.27. (Æ)-6,7-Dimethoxy-2-({1-[3-(3,4-methylenedioxy-
phenoxy)pentyl]-3-piperidyl}acetyl)-1,2,3,4-tetrahydroiso-
quinoline monooxalate (24). Compound 24 was prepared
from 7a and 21 in a manner similar to that described for
compound 8a with a yield of 73%. mp: 132–140 ꢀC
mmol) and WSC HCl (1.88 g, 9.80 mmol), and the
mixture was stirred at room temperature for 4.5 h. The
mixture was partitioned between AcOEt and H2O, and
the organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography
(CHCl3/MeOH=98/2–96/4) to give 28 (2.19 g, 76%) as
light yellow syrup. 1H NMR (300 MHz, CDCl3) d: 2.80–
2.95 (m, 2H), 3.79–3.93 (m, 8H), 4.78 (brs, 2H), 6.59–
6.70 (m, 2H), 7.07 (d, J=15.3 Hz, 1H), 7.32 (dd, J=8.1,
4.8 Hz, 1H), 7.69 (d, J=15.3 Hz, 3H), 7.80–7.88 (m,
1H), 8.58 (dd, J=4.7, 1.5 Hz, 1H), 8.79 (d, J=1.8 Hz,
1H), 6.681 (d, J=2.4 Hz, 1H), 6.74 (s, 1H), 6.77 (d,
J=2.4 Hz, 1H), 6.82 (dd, J=8.8, 5.2 Hz, 1H); MS
(FAB) m/z=325 (M+H)+.
1
(AcOEt–CH3CN); H NMR (400 MHz, DMSO-d6) d:
1.16 (brs, 1H), 1.39–1.42 (m, 2H), 1.66–1.71 (m, 5H),
1.78 (brs, 2H), 2.25 (brs, 1H), 2.35–2.47 (m, 2H), 2.66 (t,
J=6.0 Hz, 2H), 2.76 (t, J=6.0 Hz, 2H), 2.96–2.98 (m,
2H), 3.38 (brs, 2H), 3.61–3.65 (m, 2H), 3.72 (s, 6H), 3.88
(t, J=6.4 Hz, 2H), 4.53 (d, J=8.0 Hz, 2H), 5.94 (s, 2H),
6.35 (dd, J=8.4, 2.4 Hz, 1H), 6.60 (d, J=2.4 Hz, 1H),
6.74 (s, 1H), 6.77 (s, 1H), 6.79 (d, J=8.4 Hz, 1H);
MS (FAB) m/z=525 (M+H)+. Anal. calcd for
.
C30H40N2O6 C2H2O4: C, 62.53; H, 6.89; N, 4.56.
Found: C, 62.63; H, 7.42; N, 4.52.
5.1.31. (Æ)-6,7-Dimethoxy-2-(3-piperidin-3-ylpropanoyl)-
1,2,3,4-tetrahydroisoquinoline hydrochloride (29). To a
solution of 28 (2.17 g, 6.68 mmol) in AcOH (20.0 mL)
was added PtO2 (217 mg), and the mixture was stirred
under hydrogen pressure (3.2 kg/cm2) at room temper-
ature for 6 h. The catalyst was filtrated on Celite and the
filtrate was concentrated in vacuo. The residue was
alkalined with 1M NaOH (aq), then partitioned
between CHCl3 and brine. The organic layer was dried
over Na2SO4, filtered and concentrated in vacuo to give
the free base of 29 as colorless syrup. This material was
converted to its hydrochloride salt by treating with 4 M
HCl (g)/AcOEt (2.00 mL, 8.02 mmol). The crude salt
was recrystallized from AcOEt–EtOH to give 29 (2.21g,
90%) as light yellow powder. 1H NMR (300 MHz,
DMSO-d6) d: 1.02–1.22 (m, 1H), 1.38–1.86 (m, 6H),
2.43 (t, J=5.9 Hz, 2H), 2.62–2.80 (m, 3H), 3.19 (t,
J=12.9 Hz, 2H), 3.35 (brs, 1H), 3.64 (t, J=5.9 Hz, 2H),
3.71(s, 6H), 4.54 (d, J=16.8 Hz, 2H), 6.74 (s, 1H), 6.78
5.1.28. (Æ)-6,7-Dimethoxy-2-[(piperidin-3-yl)carbonyl]-
1,2,3,4-tetrahydroisoquinoline (26). To a suspension of 4
(1.19 g, 5.00 mmol) in 1,2-dichloroethane (30.0 mL)
were added Et3N (0.694 mL, 5.00 mmol), 25 (1.08 g,
.
5.00 mmol), HOBt (0.340 g, 2.50 mmol) and WSC HCl
(1.15 g, 6.00 mmol), and the mixture was stirred at room
temperature for 4 h. The reaction mixture was washed
with 5% citric acid (aq), NaHCO3 (aq) and brine. The
organic layer was dried over MgSO4, filtered and con-
centrated in vacuo. The residue was purified by silica gel
column chromatography (CHCl3/MeOH=100/0–100/1)
to give tert-butyl 3-[(6,7-dimethoxy-3,4-dihydroisoqui-
nolin-2-(1H)-yl)carbonyl]piperidine-1-carboxylate (1.84
g, 91%). To this compound was added 4 M HCl (g)/
AcOEt (5.00 mL), and the mixture was stirred at room
temperature for 2.5 h. The mixture was concentrated in
vacuo. The residue was alkalized with 1M NaOH (aq),
then extracted with CHCl3. The organic layer was dried
over MgSO4, filtered and concentrated in vacuo to give
(s, 1H), 8.76–8.84 (m, 1H), 9.00–9.10 (m, 1H); MS (FAB)
+
1
. .
m/z=333 (M+H) . Anal. calcd for C19H28N2O3 HCl
26 (1.32 g, 95%) as colorless oil. H NMR (400 MHz,
CDCl3) d: 1.45–1.60 (m, 1H), 1.68–1.80 (m, 2H), 1.90
(brs, 1H), 2.62–2.95 (m, 5H), 2.96–3.12 (m, 2H), 3.68–
3.84 (m, 4H), 3.86 (s, 6H), 4.58–4.67 (m, 2H), 6.57–6.65
(m, 2H); MS (FAB) m/z=305 (M+H)+.
0.5H2O: C, 60.39; H, 8.00; N, 7.41; Cl, 9.38. Found: C,
60.33; H, 8.05; N, 7.23; Cl, 9.26.
5.1.32. (Æ)-6,7-Dimethoxy-2-(3-{1-[3-(3,4-methylenedioxy-
phenoxy)propyl]-3-piperidyl}propanoyl)-1,2,3,4-tetrahydro-
isoquinoline monooxalate (30). Compound 29 was
prepared from 7a and 28 in a manner similar to that
described for compound 8a with a yield of 88%. mp:
147–149 ꢀC (AcOEt–CH3CN); 1H NMR (400 MHz,
DMSO-d6) d: 1.06–1.09 (m, 1H), 1.47–1.53 (m, 2H),
1.64–1.67 (m, 1H), 1.79–1.82 (m, 3H), 2.07–2.08 (m,
2H), 2.45 (t, J=7.2 Hz, 2H), 2.52 (brs, 1H), 2.65 (t,
J=5.6 Hz, 1H), 2.75–2.78 (m, 2H), 3.08–3.09 (m, 2H),
3.39 (brs, 2H), 3.64 (t, J=6.0 Hz, 2H), 3.71(s, 3H), 3.72
(s, 3H), 3.95 (t, J=6.0 Hz, 2H), 4.54 (d, J=20.8 Hz,
2H), 5.95 (s, 2H), 6.37 (dd, J=8.8, 2.4 Hz, 1H), 6.62 (d,
J=2.4 Hz, 1H), 6.74 (s, 1H), 6.77 (d, J=4.0 Hz, 1H),
6.81(d, J=8.4 Hz, 1H); MS (FAB) m/z=511 (M+H)+.
5.1.29. (Æ)-6,7-Dimethoxy-2-({1-[3-(3,4-methylenedioxy-
phenoxy)propyl]-3-piperidyl}carbonyl)-1,2,3,4-tetrahydro-
isoquinoline monohydrochloride (2). Compound 2 was
prepared from 7a and 25 in a manner similar to that
1
described for compound 8a with a yield of 29%. H
NMR (400 MHz, DMSO-d6) d: 1.18–1.92 (m, 1H),
1.80–1.95 (m, 3H), 2.10–2.20 (m, 2H), 2.65–3.10 (m,
4H), 2.61–2.68 (m, 2H), 3.21 (brs, 2H), 3.35–3.65 (m,
3H), 3.72 (s, 6H), 3.96–3.98 (m, 2H), 4.45–4.70 (m, 2H),
5.96(s, 2H), 6.35–6.42 (m, 1H), 6.62–6.66 (m, 1H), 6.74–
6.83 (m, 3H); MS (FAB) m/z=483 (M+H)+. Anal. calcd
.
.
for C27H34N2O6 HCl 1.2H2O: C, 59.98; H, 6.97; N, 5.18;
Cl, 6.59. Found: C, 61.09; H, 6.26; N, 4.77; Cl, 6.54.
.
Anal. calcd for C29H38N2O6 C2H2O4: C, 61.99; H, 6.71;
N, 4.66. Found: C, 61.76; H, 6.69; N, 4.66.
5.1.30. (Æ)-6,7-Dimethoxy-2-[(2E)-3-pyridin-3-ylprop-2-
enoyl]-1,2,3,4-tetrahydroisoquinoline (28). To a solution
of 4 (2.05 g, 8.91mmol) in THF (30.0 mL) was added
Et3N (1.24 mL, 8.91 mmol), and the mixture was stirred
5.1.33. (Æ)-N-(1-Benzylpiperidin-3-yl)-6,7-dimethoxy-3,4-
dihydroisoquinoline-2(1H)-carboxamide (32). To
a

H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
881
solution of 31 (0.951g, 5.00 mmol) and Et N (0.836
3
5.1.36. Methyl 6,7 - dimethoxy - 3,4 - dihydroisoquinoline-
2(1H)-carboxylate (35). To a solution of free base of 4
(0.966 g, 5.00 mmol) and Et3N (0.836 mL, 6.00 mmol)
in THF (15.0 mL) were added dropwise methyl chloro-
formate (0.425 mL, 5.50 mmol) in THF (3.00 mL) at
0 ꢀC, and the mixture was stirred at room temperature
for 40 min. The mixture was concentrated in vacuo. The
residue was partitioned between AcOEt and 5% (w/v)
citric acid (aq), and washed with brine. The organic
layer was dried over Na2SO4, filtered and concentrated
in vacuo to give 35 (1.36 g, 100%) as colorless syrup. 1H
NMR (90 MHz, CDCl3) d: 2.77 (t, J=5.8 Hz, 2H), 3.68
(t, J=6.2 Hz, 2H), 3.79 (s, 3H), 3.85 (s, 6H), 4.55 (s,
2H), 6.59 (s, 1H), 6.62 (s, 1H); MS (FAB) m/z=252
(M+H)+.
mL, 6.00 mmol) in THF (15.0 mL) was added 4-nitro-
phenyl chloroformate (1.11 g, 5.50 mmol) at 0 ꢀC, and
the mixture was stirred at room temperature for 40 min.
The mixture was partitioned between AcOEt and H2O.
The organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo to give 4-
nitrophenyl(1-benzylpiperidin-3-yl)carbamate as yellow
syrup. To the solution of compound obtained above in
DMF (20.0 mL) were added Et3N (1.39 mL, 10.0 mmol)
and free base of 4 (1.16 g, 6.00 mmol), and the mixture
was stirred at 60 ꢀC for 18 h. After cooling at 0 ꢀC, the
mixture was partitioned between AcOEt and H2O. The
organic layer was washed with brine, dried over
Na2SO4, filtered and concentrated in vacuo. The residue
was purified by silica gel column chromatography
(CHCl3/MeOH=99/12–98/2) to give 32 (2.12 g, 100%)
5.1.37. 1-[3-(1,2-Benzodioxol-5-yloxy)propyl]piperidin-3-ol
(37). Compound 37 was prepared from 7a and 36 in a
manner similar to that described for compound 8a with
1
as yellow syrup. H NMR (300 MHz, CDCl3) d: 1.54–
1.67 (m, 4H), 2.20–2.64 (m, 3H), 2.80 (t, J=6.0 Hz, 2H),
2.85–2.97 (m, 1H), 3.46–3.65 (m, 4H), 3.87 (s, 6H), 4.02
(brs, 1H), 4.46 (s, 2H), 6.65 (d, J=3.0 Hz, 2H), 7.24–
7.33 (m, 5H); MS (FAB) m/z=410 (M+H)+.
1
a yield of 100%. H NMR (90 MHz, CDCl3) d: 1.56–
2.59 (m, 12H), 3.82–4.00 (m, 3H), 5.90 (s, 2H), 6.31 (dd,
J=8.5, 2.6 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 6.69 (d,
J=8.4 Hz, 1H); MS (EI) m/z=279 (M)+.
5.1.34. (Æ)-6,7-Dimethoxy-N-piperidin-3-yl-3,4-dihydro-
isoquinoline-2(1H)-carboxamide hydrochloride (33). To
a solution of 32 (2.10 g, 4.90 mmol) in MeOH (20.0 mL)
was added 4 M HCl (g) / AcOEt (1.47 mL, 5.88 mmol),
and the mixture was concentrated in vacuo. To a solu-
tion of the residual solid in AcOH (20.0 mL) was added
Pd/C (10 w/w%, 109 mg), and the mixture was stirred
under hydrogen pressure (3.2 kg/cm2) at 70 ꢀC for 24 h.
The catalyst was filtrated on Celite and the filtrate was
concentrated in vacuo. The residue was alkalined with
1M NaOH (aq), then partitioned between CHCl 3 and
brine. The organic layer was dried over Na2SO4, filtered
and concentrated in vacuo to give the free base of 33 as
a light yellow syrup. This material was converted to its
hydrochloride salt by treating with 4 M HCl (g)/AcOEt
(1.47 mL, 5.88 mmol). The crude salt was recrystallized
from Et2O–EtOH to give 32 (1.35 g, 77%) as pale yellow
5.1.38. (Æ)-1-[3-(3,4-Methylenedioxyphenoxy)propyl]-3-
piperidyl-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline-2-
carboxylate monooxalate (38). To a solution of 35 (251
mg, 1.00 mmol) and 37 (419 mg, 1.50 mmol) in toluene
(6.00 mL) were added NaH (60% in oil, 20 mg, 0.50
mmol), and the mixture was stirred at 140 ꢀC for 6.5 h.
After cooling at room temperature, to the mixture was
added H2O (2.00 mL), and the mixture was partitioned
between CHCl3 and brine. The organic layer was dried
over Na2SO4, filtered and concentrated in vacuo. The
residue was purified by silica gel column chromato-
graphy (CHCl3/MeOH=99/1–98/2) to give the free
base of 38 (246 mg, 0.493 mmol) as a light yellow form.
To the solution of free base of 38 in MeOH (5.00 mL)
was added oxalic acid (44 mg, 0.49 mmol), and the
mixture was concentrated in vacuo. The crude salt was
recrystallized from AcOEt–MeOH to give 38 (171 mg,
29%) as colorless powder. mp: 125–128 ꢀC (AcOEt–
1
powder. H NMR (300 MHz, DMSO-d6) d: 1.54–1.60
(m, 1H), 1.67–1.82 (m, 3H), 2.66 (t, J=5.4 Hz, 2H), 2.85–
2.97 (m, 2H), 3.03–3.20 (m, 2H), 3.33 (brs, 1H), 3.54 (t,
J=6.0 Hz, 2H), 3.70 (s, 6H), 3.88 (brs, 1H), 4.41 (s, 2H),
6.62 (d, J=7.5 Hz, 1H), 6.69 (d, J=9.6 Hz, 1H), 8.88
(brs, 1H), 9.22 (brs, 1H); MS (FAB) m/z=320 (M+H)+.
1
MeOH); H NMR (400 MHz, DMSO-d6) d: 1.66 (brs,
2H), 1.83–1.86 (m, 2H), 2.03 (brs, 2H), 2.69 (t, J=5.2
Hz, 2H), 3.01–3.03 (m, 4H), 3.22–3.35 (m, 2H), 3.56–
3.63 (m, 3H), 3.71(s, 6H), (t, J=6.0 Hz, 2H), 4.44–4.54
(m, 2H), 4.89 (brs, 1H), 5.95 (s, 2H), 6.36 (dd, J=8.4,
2.4 Hz, 1H), 6.62 (d, J=2.4 Hz, 1H), 6.72–6.80 (m, 3H);
MS (FAB) m/z=499 (M+H)+. Anal. calcd for
5.1.35. (Æ)-6,7-Dimethoxy-2-(3-{1-[3-(3,4-methylenedioxy-
phenoxy)propyl]-3-piperidyl}propanoyl)-1,2,3,4-tetrahydro-
isoquinoline monooxalate (34). Compound 34 was
prepared from 7a and 33 in a manner similar to that
described for compound 8a with a yield of 58%. mp:
101–105 ꢀC (AcOEt–CH3CN); 1H NMR (400 MHz,
DMSO-d6) d: 1.47–1.50 (m, 1H), 1.67–1.89 (m, 3H),
2.03–2.07 (m, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.78 (brs,
2H), 3.10 (t, J=7.6 Hz, 2H), 3.25–3.34 (m, 2H), 3.53 (t,
J=5.6 Hz, 2H), 3.71(s, 6H), 3.92 (brs, 1H), 3.94 (t,
J=6.0 Hz, 2H), 4.41(s, 2H), 5.95 (s, 2H), 6.37 (dd,
J=8.0, 2.4 Hz, 1H), 6.58 (d, J=7.2 Hz, 1H), 6.63 (d,
J=2.4 Hz, 1H), 6.71 (s, 1H), 6.72 (s, 1H), 6.81 (d,
J=8.8 Hz, 1H); MS (FAB) m/z=498 (M+H)+. Anal.
.
.
C27H34N2O7 C2H2O4 0.3H2O: C, 58.64; H, 6.21; N,
4.72. Found: C, 58.59; H, 6.12; N, 4.74.
5.2. Pharmacology
5.2.1. In vitro assay. Male Hartley guinea pigs (250–400
g) were sacrificed by cervical dislocation, and their
hearts were removed rapidly. Right atria were cut from
the heart and mounted vertically in a 30 mL organ bath
containing Tyrode’s solution at 37 ꢀC and equibrated
with 95% O2 and 5% CO2. Tension was placed on the
atria by suspending a 1g mass from it. The atria was
allowed to equilibrate for 90 min, the bath solution was
exchanged every 15 min before a compound treatment.
.
.
calcd for C27H35N3O6 C2H2O4 H2O: C, 57.51; H, 6.49;
N, 6.94. Found: C, 57.28; H, 6.42; N, 6.90.

882
H. Kubota et al. / Bioorg. Med. Chem. 12 (2004) 871–882
Amplitude of contraction was measured isometrically
by a force-displacement transducer (Nikon Kohden SB-
1T) and measured with cardiotachometer (Nikon Kohden
AT-600G) triggered by the concentration. 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 con-
structed. The effects of compounds were presented the
percent change from the initial beat rates.
Laboratories for the elemental analysis and spectral
measurement.
References and notes
1. (a) Kannel, W. B.; Kannel, C.; Paffenbarger, R. S., Jr.;
Cupples, A. Am. Heart. J. 1987, 113, 1489. (b) Hjalmarson,
A.; Gilpin, E. A.; Kjekshus, J.; Sculman, G.; Nichido, P.;
Whining, H.; Ross, J., Jr. Am. J. Cardiol. 1990, 65, 547.
(c) Sharper, A. G.; Wannamethee, G.; Mancfarlane,
P. W.; Walker, M. Br. Heart. J. 1993, 70, 49. (d) Palatini,
P.; Julius, S. J. Hypertension 1997, 15, 3. (e) Palatini, P.
Drugs 1999, 57, 713.
2. Sonnenblick, F. H.; Ross, J.; Braunwald, E. Am. J. Cardiol.
1968, 32, 328.
3. (a) Boudoulas, H.; Rittgers, S. E.; Lewis, R. P.; Leier,
C. V.; Weissler, A. M. Circulation 1979, 60, 164. (b)
Hoffman, J. I. E. Circulation 1984, 70, 153.
5.3. In vivo assay
iv Study: Male Wistar rats (270–350 g) were anesthe-
tized with urethane (1g/kg ip). A polyethylene cannula
(PE-50) was implanted in the left common carotid
artery to measure blood pressure. Blood pressure was
measured with a pressure transducer (Nikon Kohden
DX-100) coupled to the cannula and a pressure ampli-
fier (Nikon Kohden AP-621G), and continuously
recorded via a polygraph system. Heart rate was mea-
sured with a cardiotachometer (Nikon Kohden AT-
600G) triggered by the pulse wave of blood pressure.
After a more than 30 min stabilization period, a test
compound (or a saline) was administered intravenously
through the catheter implanted into the femoral vein a
dose of 3 mg/kg.
4. Buckberg, G. D.; Fixler, D. E.; Archie, J. P.; Hoffman,
J. I. E. Circ. Res. 1972, 30, 67.
5. Buckberg, G. D.; Fixler, D. E.; Archie, J. P.; Henney,
R. P.; Hoffman, J. I. E. Cardiovasc. Res. 1975, 9, 1 .
6. (a) Opie, L. H. Cardiovasc. Drugs Ther. 1989, 3, 257. (b)
Kern, M. J.; Deligonul, U.; Labovitz, A. Am. Heart J.
1989, 1989, 118 361.
7. Kobinger, W.; Lillie, C. Eur. Heart J. 1987, 8 (Suppl. L),
7.
8. (a) Reiffen, M.; Eberlein, W.; Muller, P.; Psiorz, M.; Noll,
K.; Heider, J.; Lillie, C.; Kobinger, W.; Luger, P. J. Med.
Chem. 1990, 33, 1496. (b) Goethals, M.; Raes, A.; von
Bogaert, P. P. Circulation 1993, 88, 2389.
9. (a) Thollon, C.; Cambarrat, C.; Vian, J.; Prost, J.;
Peglion, J. L.; Vilain, J. P. Br. J. Pharmacol. 1994, 112, 37.
(b) Thollon, C.; Bidouard, J.; Cambarrat, C.; Lesage, L.;
Reure, H.; Delescluse, I.; Vian, J.; Peglion, J. L.; Vilain,
J. P. Eur. J. Pharmacol. 1997, 339, 43.
10. Kubota, H.; Kakefuda, A.; Watanabe, T.; Ishii, N.;
Masuda, N.; Sakamoto, S.; Tsukamoto, S. Bioorg. Med.
Chem. Lett. 2003, 13, 2155.
11. Nagai, Y. Chem. Pharm. Bull. 1977, 25, 1911.
12. (a) For examples, see: Katakami, J.; Yokoyama, T.;
Miyamoto, M.; Mori, H.; Kawauchi, N.; Nobori, T.; San-
nohe, K.; Kaiho, T. J. Med. Chem. 1992, 35, 3325. (b)
Lunney, E. A.; Hagen, S. E.; Domagala, J. M.; Humblet,
C.; Kosinski, J.; Tait, B. D.; Warmus, J. S.; Wilson, M.;
Ferguson, D.; Hupe, D.; Tummino, P. J.; Baldwin, E. T.;
Bhat, T. N.; Liu, B.; Erickson, J. W. J. Med. Chem. 1994,
37, 2664. (c) Dodic, N.; Dumaitre, B.; Daugan, A.; Pia-
netti, P. J. Med. Chem. 1995, 38, 2418.
po Study: Male Wistar rats (200–300 g) were anesthe-
tized with pentobarbital (60 mg/kg ip). A polyethylene
cannula was implanted in the left common carotid
artery and to measure blood pressure and heart rate, the
free end of catheter was routed to an exit site at the back
of the neck. The incisions were closed surgically and
each rat was housed separately. The animals were
allowed to recover for about 2 days after surgery, dur-
ing which time they were housed in individually with
free access to rat chow and water. On the day of the
experiment, blood pressure was measured with a pres-
sure transducer coupled to the cannula and a pressure
amplifier, and continuously recorded via a polygraph
system. Heart rate was measured with a cardiotach-
ometer triggered by the pulse wave. After a 30 min
measurement period to establish baseline values, a test
compound (or a saline) was administrated orally by
gavage at a dose of 10 mg/kg.
13. Najer, H.; Giudicelli, R.; Loiseau, J.; Menin, J. Bull. Soc.
Chim. Fr. 1963, 434, 2831.
14. Villalgordo, J. M.; Heimgartner, H. Tetrahedron 1993, 49,
7215.
Acknowledgements
The authors deeply acknowledge Dr. Minoru Okada for
helpful support for preparing this manuscript, and also
grateful to the staff of the Division of Analytical Science
15. Kempf, D. J.; Codacovi, L.; Wang, X. C.; Kohlbrenner,
W. E.; Wideburg, N. E. J. Med. Chem. 1993, 36, 320.
16. Buerki, H. R.; Eur, J. Med. Chem. Chim. Ther. 1978, 13, 479.