(±)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines as a new class of specific bradycardic agents

Article abstract of DOI:10.1016/S0960-894X(03)00349-4

A series of (±)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines were prepared and their bradycardic activities were examined in isolated guinea-pigs' right atria and in anesthetized rats. Modifications on the benzyl moiety of the parent compound, 1, led to the identification of compound 11e as a potent and specific bradycardic agent.

Full text of DOI:10.1016/S0960-894X(03)00349-4

Bioorganic & Medicinal Chemistry Letters 13 (2003) 2155–2158
(Æ)-2-(3-Piperidyl)-1,2,3,4-tetrahydroisoquinolines as a
New Class of Specific Bradycardic Agents
Hideki Kubota, Akio Kakefuda,* Toshihiro Watanabe, Yasuko Taguchi, Noe Ishii,
Noriyuki Masuda, Shuichi Sakamoto and Shin-ichi Tsukamoto
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka,
Tsukuba, Ibaraki 305-8585, Japan
Received 27 January 2003; accepted 3 April 2003
Abstract—A series of (Æ)-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines were prepared and their bradycardic activities were
examined in isolated guinea-pigs’ right atria and in anesthetized rats. Modifications on the benzyl moiety of the parent compound, 1,
led to the identification of compound 11e as a potent and specific bradycardic agent.
# 2003 Elsevier Science Ltd. All rights reserved.
Introduction
examined its effects on the analogues’ bradycardic
activities in isolated guinea-pigs’ right atria and in
anesthetized rats. This provided the novel compound
11e showing a potent and specific bradycardic activity.
Myocardial ischemia always results from an imbalance
between supply and demand of oxygen. Since heart rate
(HR) is a major determinant of myocardial oxygen
consumption,1 reduction in HRis useful in treating
ischemic heart diseases.2 Reduction in HR can be
achieved by b-adrenoreceptor antagonists3 or certain
calcium channel blockers.4 However, these agents may
cause concomitant negative inotropic and hypotensive
effects which are potentially deleterious during ischemia.5
Therefore, agents which reduce HRwithout negative
inotropic and hypotensive effects, namely ‘specific
bradycardic agents’6 are expected to be more beneficial
in treating ischemic heart diseases.
Recent research efforts have yielded two specific brady-
cardic agents, Zatebradine7 and its related compound,
Ivabradine8 (Fig. 1). They have undergone clinical testing
in ischemic heart diseases patients.
In our program searching for novel specific bradycardic
agent, (Æ)-2-(1-benzyl-3-piperidyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (1, Fig. 1) was found to show
good bradycardic activities.9 To improve its potency, we
attempted modification of the benzyl moiety of 1 and
*Corresponding author. Tel.: +81-298-54-1577; fax: +81-298-52-
5387; e-mail: kakefuda@yamanouchi.co.jp
Figure 1.
0960-894X/03/$ - see front matter # 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0960-894X(03)00349-4

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H. Kubota et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2155–2158
Scheme 1. Conditions: (a) (COCl)2, DMSO, Et3N, CH2Cl2, À70 ꢀC; (b) 6,7-dimethoxy-1,2,3,4- tetrahydroisoquinoline, NaBH(OAc)3, AcOH, THF
(82% from 2); (c) 4 N HCl (g) /AcOEt, MeOH (50%); (d) 2-phenylacetaldehyde or 3-phenylpropionaldehyde, NaBH(OAc)3, AcOH, Cl(CH2)2Cl (12
.
and 61%); (e) 4-phenylbutyric acid or 5-phenylvaleric acid, EDC HCl, HOBt, Cl(CH2)2Cl; (f) LiAlH4, THF, reflux (53 and 66% from 5); (g) 1,3-
dibromopropane, K2CO3, CH3CN, 80 ꢀC (62–90%); (h) 5, K2CO3, CH3CN, 80 ꢀC (11–73%).
Chemistry
Initially, we examined the effects of modifying the tether
linking between the piperidine ring and the terminal
aromatic ring of 1 (Table 1). Among the phenylalkyl
derivatives 6–9 (n=1–4; X=CH2), the butylene ana-
logue 8 (n=3) showed the most potent in vitro activity,
and it was more potent than 1. Substitution of the
benzylic methylene of 8 by an oxygen atom (the 3-oxy-
propyl analogue 11a) maintained in vitro activity. In
anesthetized rats, compound 11a reduced HRby 40%,
which was potent than the benzyl analogue 1, whereas
compound 8 reduced HRby only 23%. Because of good
activities of 11a both in vitro and in vivo, we next stud-
ied the effects of modifying the terminal aromatic ring
of 11a (Table 2).
The target compounds were prepared by coupling of
amine, 5, which was obtained from 2 in three steps, with
arylalkyl or aryloxyalkyl components by three general
methods, Method A, B, and C shown in Scheme 1.10
Compounds 6–9 were synthesized by reductive alkyl-
ation of 5 with aldehydes (Method A), or by acylation
of 5 with carboxylic acids followed by reduction with
LiAlH4 (Method B). Compounds 11a–h were prepared
by alkylation of 5 with various 3-arylokypropyl bro-
mides, 10a–h,11 which were obtained from the corres-
ponding
1,3-dibromopropane (Method C).
phenols
by
treating
with
excess
Both of the 4-methoxy analogue 11b and the 3,4-di-
methoxy analogue 11c showed similar in vitro activity
and equivalent or improved in vivo activity compared to
11a. The 3,4,5-trimethoxy analogue 11d exhibited
weaker activity than 11a. The 3,4-methylenedioxy ana-
logue 11e showed more potent activities than 11a both
Results and Discussion
The bradycardic activities of synthesized compounds
were assessed in isolated guinea-pigs’ right atria (in
vitro),12 and in urethane-anesthetized rats (in vivo).
Table 1. The bradycardic activities of (Æ)-6,7-dimethoxy-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinolines (6–9 and 11a)
Compd
n
X
Right atria
EC30,a mM
Anesthetized rats
% change in HRb
at 3 mg/kg iv
Method
Formula
.
.
1
6
7
8
0
1
2
3
4
3
CH2
CH2
CH2
CH2
CH2
O
0.83
2.2
1.2
0.54
1.3
0.43
0.26
À33
N.T.c
N.T.c
À23
A
A
A
B
B
C
C23H30N2O2 2HCl 0.5H2O
. .
C24H32N2O2 2HCl 1.8H2O
. .
C25H34N2O2 2(CO2H)2 H2O
.
C26H36N2O2 2(CO2H)2 H2O
.
C27H38N2O2 2(CO2H)2
. .
C25H34N2O3 2(CO2H)2 H2O
.
9
11a
Zatebradine
N.T.c
À40
À47
aThe concentration required to produce a 30% reduction from the initial spontaneous beat rates in isolated guinea-pigs’ right atria as mean from at
least two experiments.
bPercentage change from the initial value in urethane-anesthetized rats as mean from at least two experiments.
cNot tested.

H. Kubota et al. / Bioorg. Med. Chem. Lett. 13 (2003) 2155–2158
2157
Table 2. The bradycardic activities of (Æ)-6,7-dimethoxy-2-[1-(3-aryloxypropyl)-3-piperidyl]-1,2,3,4- tetrahydroisoquinolines (11b–h)
Compd
Ar
Ph
Right atria
EC30,a mM
Anesthetized rats
% change in HRb
at 3 mg/kg iv
Method
Formula
11a
11b
0.43
0.39
À40
À40
.
.
C26H36N2O4 2(CO2H)2 H2O
C
C
. .
C27H38N2O5 2HCl 0.6H2O
11c
11d
0.38
1.5
À47
N.T.c
C
.
C28H40N2O6 2(CO2H)2 H2O
.
. .
C26H34N2O5 2HCl 0.5H2O
11e
11f
11g
0.25
0.66
0.84
À47
À38
À23
C
C
C
.
C28H38N2O3 2HCl 0.6H2O
.
.
C29H36N2O3 2HCl 0.6H2O
.
N.T.c
C
. .
C32H38N2O3 1.5HCl 0.5H2O
11h
4.1
aSee the corresponding footnotes of Table 1.
bSee the corresponding footnotes of Table 1.
cSee the corresponding footnotes of Table 1.
in vitro and in vivo, with an EC30 value of 0.25 mM and
a HRreduction by 47%, being comparable to Zatebra-
dine. In contrast, the indane analogue 11f and the
naphthalene analogue 11g had 3-4-fold less in vitro
potency than 11e. The fluorene analogue 11h showed
considerably poor activity.
Among them, compound 11e showed potent brady-
cardic activities with minimal influence on mean blood
pressure in anesthetized rats. Compound 11e is a novel
specific bradycardic agent which would be beneficial in
treating ischemic heart diseases.
In anesthetized rats, compound 11e, which was one of
the most potent bradycardic agents in this series, had
minimal influence on mean blood pressure even at a
dose of 10 mg/kg iv (5.5% decrease from the initial
value). This result proved that 11e was a specific brady-
cardic agent. Further characterization on electro-
physiological studies in guinea-pigs’ sino-atrial node
revealed that 11e significantly decreased the rate of
Phase 4 slow depolarization (dV/dt4; 56.6% decrease
from control at 1 mM) without change in the maximal
diastolic potential (MDP) at the same concentration.
Since the If channels are thought to be the channels
responsible for Phase 4 depolarization,13 the brady-
cardic effects of 11e may be reffered to its effect on the If
channels.
Acknowledgements
We thank Dr. A. Tanaka for his advice and Dr. T.
Yasunaga for his critical reading of the manuscript, and
the staff of Analysis & Metabolism Laboratories for
performing spectral measurements.
References and Notes
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Conclusion
We have discovered that (Æ)-2-(3-piperidyl)-1,2,3,4-tetra-
hydroisoquinolines have good bradycardic activities.

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4.33–4.43 (2H, m), 5.96 (2H, s), 6.44 (1H, dd, J=8.8, 2.4 Hz),
6.65 (1H, d, J=2.4 Hz), 6.76–6.83 (3H, m), 11.69–12.00 (2H,
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get compounds. Example, 11e: colorless powder; mp 167–
169 ꢀC; H NMR(400 MHz, DMSO- d6) d 1.84–2.01 (2H, m),
1
2.23–2.33 (2H, m), 2.94 (2H, brs), 3.25–3.53 (8H, m), 3.70–
3.73 (1H, m), 3.73 (3H, s), 3.74 (3H, s), 3.91–4.02 (4H, m),