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

Article abstract of DOI:10.1016/j.bmcl.2004.04.031

A series of piperidinoalkanoyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized, and their bradycardic activities were investigated in the isolated right atria of guinea pigs and in conscious rats. These efforts identified the achiral compound 2f, which exhibited potent and long-lasting bradycardic activity with minimal effects on mean blood pressure in conscious rats.

Full text of DOI:10.1016/j.bmcl.2004.04.031

Bioorganic & Medicinal Chemistry Letters 14 (2004) 3049–3052
Synthesis and pharmacological evaluation of piperidinoalkanoyl-
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 Shin-ichi Tsukamoto
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd, 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan
Received 21 March 2004; revised 12 April 2004; accepted 13 April 2004
Abstract—A series of piperidinoalkanoyl-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized, and their bradycardic activit-
ies were investigated in the isolated right atria of guinea pigs and in conscious rats. These efforts identified the achiral compound 2f,
which exhibited potent and long-lasting bradycardic activity with minimal effects on mean blood pressure in conscious rats.
Ó 2004 Elsevier Ltd. All rights reserved.
OMe
OMe
The reduction of sinus heart rate (HR) is of major
interest in the treatment of cardiac ischemia. Myocardial
ischemia results from an imbalance between oxygen
supply and demand. HR reduction can correct this
imbalance by improving myocardial perfusion and
reducing myocardial oxygen demand.1;2 A reduction in
HR can be achieved by b-adrenoreceptor antagonists3
and certain calcium-channel blockers.4 However, these
agents can cause concomitant negative inotropic and
hypotensive effects, which are potentially deleterious
during ischemia.5 Therefore, agents that reduce HR
without negative inotropic and hypotensive effects,
namely ‘specific bradycardic agents’6 are predicted to be
more beneficial in the treatment of cardiac ischemia.
O
MeO
MeO
N
Me
N
Zatebradine
O
MeO
MeO
OMe
OMe
N
N
Me
Ivabradine
Figure 1.
exhibit potent specific bradycardic activities that are
comparable with those of Zatebradine.9 Therefore, to
further investigate the structure–activity relationship
(SAR) of compound 1, we designed compound 2a by
opening the existing piperidine ring of 1 and joining the
nitrogen to the b-carbon with a three-carbon linker (Fig.
2). Compound 2a was found to be equipotent to
Zatebradine both in vitro and in vivo (Table 1 and Fig.
3). To examine the SAR of compound 2a, the com-
pounds described by Formula I were synthesized and
their biological activities were evaluated. The results of
the SAR study on this series of piperidinoalkanoyl-
1,2,3,4-tetrahydroisoquinoline derivatives are reported
here.
During the past few decades, two specific bradycardic
agents, Zatebradine7 and the related compound Ivabra-
dine,8 have been developed and subjected to clinical
testing for the treatment of ischemic heart disease (Fig.
1).
In our present program, which aims to search for novel
specific bradycardic agents, the 2-(3-piperidino)-1,2,3,4-
tetrahydroisoquinoline derivative 1 has been shown to
The preparation of the piperidinoalkanoyl-1,2,3,4-tet-
rahydroisoquinoline derivatives is outlined in Scheme 1.
Condensation of 3-pyridylethanol (3) with sesamol,
followed by reduction of the pyridine ring, produced 7c.
Keywords: Cardiac disease; Myocardial ischemia; Bradycardic agent;
Zatebradine.
* Corresponding author. Tel.: +81-29-863-6689; fax: +81-29-852-5387;
e-mail: kubota.hideki@yamanouchi.co.jp
0960-894X/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.04.031

3050
H. Kubota et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3049–3052
HR
MeO
MeO
40
N
O
N
N
O
20
O
O
0
-20
1
MeO
MeO
-40
O
N
O
O
-60
O
N
-80
2a
-100
-120
MeO
MeO
O
O
x
N
0
1
2
3
4
6
7
8
5
3
y
O
(
)
(
)
Time (hr)
O
4
MBP
I
40
20
Figure 2.
0
-20
-40
-60
-80
-100
-120
Alkylation of sesamol with the corresponding pyr-
idylalkylhalides 4a,b, and 4c, followed by reduction of
the pyridine ring, yielded 7a,d, and 7h, respectively.
Condensation of 5a,b, and 5c with sesamol, followed by
deprotection, afforded 7b,f, and 7e, respectively. Alkyl-
ation of sesamol with 6,10 followed by deprotection,
produced 7g. Acylation of 6,7-dimethoxy-1,2,3,4-tetra-
hydroisoquinoline (8) with 2-chloroacetylchloride pro-
vided 9a. Compounds 9b and 9c were prepared in an
analogous manner to 9a, except that 2-chloroacetyl-
chloride was replaced with acryloyl chloride and
4-chlorobutyryl chloride, respectively. Compounds 10
and 11 were obtained by alkylation of 7a with the cor-
responding alkyl halides 9a and 9c, respectively. Com-
pounds 2a–h were accessed by alkylation of 7a–h,
respectively, with 9b.
2a (n=4)
2e (n=3)
2f (n=5)
Zatebradine (n=4)
0
1
2
3
4
5
6
7
8
Time (hr)
Figure 3. Effects of piperidinoalkanoyl-1,2,3,4-tetrahydroisoquinoline
derivatives 2a,e, and 2f on heart rate (HR) and mean blood pressure
(MBP) in consious rats. Compounds were orally administrated at time
zero. Each point represents mean SEM from three to five experi-
ments.
Our previous SAR studies indicated that the 1,2,3,4-
tetrahydroisoquinoline ring, the basic nitrogen of the
piperidine ring and the terminal phenyl ring are all
essential for the production of potent bradycardic
activity.9;11 The SAR study of compound 1 confirmed
that the spatial orientation of these three essential
components plays a crucial role in bradycardic activity.9
We therefore designed compound 2a by opening the
existing piperidine ring of 1 and joining the nitrogen to
the b-carbon with a three-carbon linker, which main-
tained the spatial orientation between these three parts.
Evaluation of the bradycardic activity exhibited by the
synthesized compounds was performed in vitro in the
isolated right atria of guinea pigs. The EC30 value, which
is defined as the concentration of the compound that
produces a 30% reduction in the initial spontaneous
beating rate, was determined for each compound using
linear regression.9 The effects on HR of the compounds
with high in vitro activities were examined in conscious
rats following oral administration.9
Table 1. Bradycardic activities of piperidinoalkanoyl-1,2,3,4-tetrahydroisoquinolin derivatives 2a–h, 10, and 11
MeO
O
x
N
N
3
y
O
(
)
MeO
(
)
O
O
4
Compounds
x
y
Position
EC30, lMa
1
2a
0.37 0.02(3)
0.17
1.17
–(CH2)2–
–CH2–
–CH2–
–CH2–
–CH2–
Bond
3
3
3
3
3
3
4
4
4
4
10
11
–(CH2)3–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
–(CH2)2–
0.85
3.03
2b
2c
–(CH2)2–
–(CH2)3–
–CH2–
0.34
0.39
2d
2e
0.47
0.44
2f
2g
Bond
–(CH2)2–
–(CH2)3–
0.45
0.62
2h
Zatebradine
0.26 0.05 (7)
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
with SE (number of determinations) where more than three determinations were made. Otherwise results based on two determinations are given.

H. Kubota et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3049–3052
3051
y
Cl
(
)
N
N
OH
i, ii
iii, ii
v, vi
3
O
O
4a: 3-pyridyl, y = 1
4b: 3-pyridyl, y = 3
4c: 4-pyridyl, y = 3
y
(
)
O
HN
i, iv
7a: 3-piperidyl, y = 1
7b: 3-piperidyl, y = 0
7c: 3-piperidyl, y = 2
7d: 3-piperidyl, y = 3
7e: 4-piperidyl, y = 1
7f: 4-piperidyl, y = 0
7g: 4-piperidyl, y = 2
7h: 4-piperidyl, y = 3
I
y
(
)
OH
N
N
Z
Boc
6
5a: 3-piperidyl, y = 0
5b: 4-piperidyl, y = 0
5c: 4-piperidyl, y = 1
MeO
MeO
MeO
MeO
MeO
MeO
vii
viii or ix
O
O
x
N
N
R
NH
N
(
)
y
O
(
)
O
O
8
9a: R = -CH 2Cl
9b: R = -CH=CH 2
9c: R = -(CH 2)3Cl
Scheme 1. Synthesis of compounds 2a–h, 10, and 11. Reagents and conditions: (i) sesamol, PPh3, DEAD, THF; (ii) H2, PtO2, AcOH; (iii) sesamol,
K2CO3, DMF, D; (iv) 4 M HCl/AcOEt; (v) sesamol, K2CO3, CH3CN, D; (vi) H2, 10% Pd/C, AcOH; (vii) RCOCl, Et3N, THF; (viii) 7, K2CO3,
CH3CN, D; (ix) 7, toluene, D.
As a result, the parent compound 2a exhibited potent
bradycardic activity that was comparable to that of
Zatebradine both in vitro and in vivo (Table 1 and Fig.
3). Encouraged by these results, further SAR studies of
2a were conducted in order to establish the effect of the
linkers between the piperidine nitrogen atom and the
carbonyl moiety (x-linker), and between the piperidine
C-3 or C-4 position and the oxygen atom (y-linker).
of analogues with a two-carbon x-linker, chain exten-
sions of up to three carbon atoms were well tolerated
(compounds 2g and 2h).
On the basis of the potent bradycardic activity displayed
in the isolated right atria of guinea pigs, and as a result
of their achiral nature, 2e and 2f were subjected to fur-
ther pharmacological evaluation as the representatives
in the 4-piperidyl series (2e–h). These compounds were
administrated orally (10 mg/kg) to conscious rats, and
the effects on HR and mean blood pressure (MBP) were
examined (Fig. 3). Although the 4-piperidyl derivative
2e was equipotent to the corresponding 3-piperidyl
derivative 2a in vitro, it was significantly less active in
vivo. Compound 2e reduced spontaneous HR by less
than )20.0 14.7 beats/min ()5.28 2.59% from initial
value). By contrast, compound 2f reduced spontaneous
In the 3-piperidyl series of analogues with a one-carbon
y-linker, shortening (10) or extending (11) the x-linker
resulted in a fivefold to sevenfold loss of in vitro activity.
These results indicated that the optimal composition of
the x-linker was an ethyl chain. Among the analogues
that contained two-carbon x-linkers, shortening the y-
linker alkyl chain drastically reduced the bradycardic
activity (2b). By contrast, extensions of the y-linker alkyl
chain of up to three carbon atoms were well tolerated
(2c and 2d). These results indicated that there might be
sufficient variability for further structural manipulations
in the y-linker portion.
HR
by
as
much
as
)87.8 11.0 beats/min
()23.5 2.64% from initial value) with minimal influ-
ence on MBP (2.00 2.73 mmHg, 2.12 2.68% from
initial value). Furthermore, its bradycardic effect was
sustained for more than 8 h. These results suggest that 2f
is better absorbed and has increased metabolic stability
compared with 2e. In fact, 2f showed comparable
potency and increased duration of action compared with
Zatebradine.
We investigated achiral analogues in which the y-linker
was attached to the C-4 position of the piperidine ring
because the 3-piperidyl series would confer considerable
disadvantages associated with the preparation of a sin-
gle enantiomer, either by stereoselective synthesis or
resolution.
In conclusion, a series of piperidinoalkanoyl-1,2,3,4-
tetrahydroisoquinoline derivatives were synthesized and
evaluated. These efforts identified the achiral compound
2f, which showed potent bradycardic activity that was
comparable to lead compound 1. Compound 2f also
showed potent and long-lasting bradycardic activity
with a minimal influence on MBP in conscious rats
following oral administration. On the basis of its phar-
macological properties and structural simplicity (no
chiral center), compound 2f represents a novel lead for
Fortunately, the 4-piperidyl derivative 2e was equipo-
tent to the corresponding 3-piperidyl derivative 2a,
which was probably the result of the variability of the y-
linker portion. Encouraged by the potency of compound
2e, we conducted further SAR studies on the 4-piperidyl
derivatives. In contrast to the 3-piperidyl derivatives,
shortening of the alkyl chain of the y-linker to y ¼ 0 (2f)
was well tolerated. Furthermore, in the 4-piperidyl series

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H. Kubota et al. / Bioorg. Med. Chem. Lett. 14 (2004) 3049–3052
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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
Laboratories for the elemental analysis and spectral
measurement.
9. Kubota, H.; Watanabe, T.; Kakefuda, A.; Masuda, N.;
Wada, K.; Ishii, N.; Sakamoto, S.; Tsukamoto, S. Bioorg.
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