Synthesis and pharmacological evaluation of 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives as specific bradycardic agents.

Article abstract of DOI:10.1248/cpb.51.390

Novel 1,2,3,4-tetrahydroisoquinoline derivatives bearing directly a cyclic amine at the 2-position were prepared and examined for their bradycardic activities in isolated right atria and in anesthetized rats. The structure-activity relationships (SAR) study revealed that the 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline skeleton is essential for the appearance of potent in vitro activity, and that the presence of at least one methoxy group at the 6- or 7-position of the 1,2,3,4-tetrahydroisoquinoline ring is important to exert potent in vitro activity. In vivo tests of selected compounds demonstrated that 2-(1-benzyl-3-piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6c) exhibited potent bradycardic activity with negligible influence on mean blood pressure in rats, although its potency is a half of that of Zatebradine.

Full text of DOI:10.1248/cpb.51.390

390
Chem. Pharm. Bull. 51(4) 390—398 (2003)
Vol. 51, No. 4
Synthesis and Pharmacological Evaluation of 2-(3-Piperidyl)-1,2,3,4-
tetrahydroisoquinoline Derivatives as Specific Bradycardic Agents
Akio KAKEFUDA, ,a Toshihiro WATANABE,a Yasuko TAGUCHI,a Noriyuki MASUDA,a Akihiro TANAKA,b
*
a
and Isao YANAGISAWA
a Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd.; 21 Miyukigaoka, Tsukuba, Ibaraki
305–8585, Japan: and b Yamanouchi U.K. Ltd.; Yamanouchi House, Pyrford Road, West Byfreet, Surrey KT14 6RA, U.K.
Received December 10, 2002; accepted January 20, 2003
Novel 1,2,3,4-tetrahydroisoquinoline derivatives bearing directly a cyclic amine at the 2-position were pre-
pared and examined for their bradycardic activities in isolated right atria and in anesthetized rats. The struc-
ture–activity relationships (SAR) study revealed that the 2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline skeleton
is essential for the appearance of potent in vitro activity, and that the presence of at least one methoxy group at
the 6- or 7-position of the 1,2,3,4-tetrahydroisoquinoline ring is important to exert potent in vitro activity. In vivo
tests of selected compounds demonstrated that 2-(1-benzyl-3-piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroiso-
quinoline (6c) exhibited potent bradycardic activity with negligible influence on mean blood pressure in rats, al-
though its potency is a half of that of Zatebradine.
Key words specific bradycardic agent; 1,2,3,4-tetrahydroisoquinoline; Zatebradine; dimethoxy
Myocardial ischemia, irrespective of its clinical expres-
sion, always results from an imbalance between the supply
and demand of oxygen. This imbalances may lead to irre-
versible myocardial damage. As heart rate is a major deter-
minant of myocardial oxygen consumption,1,2) agents that
can reduce sinus heart rate are of great interest for the treat-
ment of ischemic heart desease. Reductions in sinus heart
rate can be achieved by administering cardiodepressive
agents, such as b-adrenoreceptor antagonists3) or some cal-
cium channel blockers.4) However, these agents may cause
concomitant negative inotropic and hypotensive effects5,6)
which are potentially deleterious during ischemia.
Fig. 1
Recently, the pharmacological properties of a novel class
of substances, specific bradycardic agents, have been de-
scribed.7) Such agents induce sinus bradycardia at concentra-
tions that are devoid of additional haemodynamic effects.8—11)
Specific bradycardic agents have been shown to act by reduc-
ing the heart’s demand for oxygen and by increasing the dias-
tolic period which in turn induces increases in the subendo-
cardial blood flow.12—14) One of the most potent specific
bradycardic agent described so far, Zatebradine (7,8-
dimethoxy-3-(3-{[2-(3,4-dimethoxyphenyl)ethyl]methyl-
amino} propyl)-1,3,4,5-tetrahydro-2H-benzazepin-2-one hy-
drochloride, UL-FS 49) (2), has been reported to reduce
heart rate without concomitant negative inotropic or hypoten-
sive effects not only in animal models10,15) but also in clinical
trials.10) Zatebradine was found by modifying Verapamil
(1),16) a prominent calcium channel blocker, by replacing the
asymmetric a-isopropylphenylacetonitrile moiety with a
benzazepinone ring.17) This modification brought about a
drastic change in the pharmacological profile, especially in
terms of blood pressure and cardiac contractility.16) This re-
sult indicates that the benzene-fused hetrocyclic ring is criti-
cal for the selectivity for heart rate reduction versus the influ-
ences on blood pressure and cardiac contractility. The struc-
ture–activity relationships (SAR) of Zatebradine also demon-
strates that the basic nitrogen atom is essential for brady-
cardic activity and that the 3,4-dimethoxyphenethyl moiety is
tolerable to structural modifications.17) From these results, we
assumed that the spatial orientation between the benzene-
fused hetrocyclic ring and the basic nitrogen atom is impor-
tant to exhibit potent and specific bradycardic activities, and
that linear structure is not always necessary.
Our work to find a novel type of specific bradycardic agent
was focused on searching for a novel skeleton containing a
benzene-fused hetrocyclic ring and a basic nitrogen atom
which exert specific bradycardic activities. We designed
1,2,3,4-tetrahydroisoquinoline derivatives 3 bearing directly
a cyclic amine at the 2-position, which may possess more
rigid structure than that of Zatebradine. In this paper, we de-
scribe the synthesis, the SAR and the pharmacological prop-
erties of compounds 3.
Chemistry
The 1,2,3,4-tetrahydroisoquinolines (4a—f),18,19) which are
either commercially available or known, were condensed
with N-benzylpiperidones (5a, 5c) or a N-benzylpyrrolidone
(5b) by reductive alkylation in the presence of sodium triace-
toxyborohydride (NaBH(OAc)3)20) and acetic acid to afford
compounds 6a—h shown in Chart 1. The key intermediate
amine 10 was synthesized via the route described in Chart 1.
Compound 4a was subjected to reductive alkylation with a
N-tert-butoxycarbonyl-3-piperidone (8),21) which was ob-
tained by Swern oxidation22) of N-tert-butoxycarbonyl-3-
* To whom correspondence should be addressed. e-mail: kakefuda@yamanouchi.co.jp
© 2003 Pharmaceutical Society of Japan

April 2003
391
piperidinol (7),23) to yield the 2-(3-piperidyl)-1,2,3,4-tetrahy-
droisoquinoline derivative 9. Compound 9 was easily depro-
tected with HCl/AcOEt to give the key intermediate amine
10. Compound 10 was converted to compounds 11a—gg by
the two general methods illustrated in Chart 2. Reductive
alkylation with the corresponding aldehydes in the presence
of NaBH(OAc)3 and acetic acid (Method A) of 10 gave com-
pounds 11. By using a different method (Method B), com-
pound 10 was transformed to compounds 11 by acylation
with the corresponding carboxylic acids in the presence of 1-
ethyl-3-[3-(diethylamino)propyl]carbodiimide hydrochloride
(EDC·HCl) and 1-hydroxybenzotriazole (HOBt) followed by
reduction with lithium alminum hydride (LiAlH4). Hydro-
genation of the nitro group in 11j with PtO2 gave the 2-
aminobenzyl derivative 12 (Chart 3). Compound 12 was
treated with acetic anhydride or methanesulfonyl chloride in
pyridine to give the acetamide derivative (13a) and the
methanesulfonamide derivative (13b, Chart 3). The
piperidylmethyl derivatives (17, 18) were prepared as shown
in Chart 3. Treatment of the intermediate amine 10 with a N-
t-butoxycarbonyl-4-piperidylcarboxyaldehyde (15)24) in the
presence of NaBH(OAc)3 and acetic acid followed by depro-
tection of the t-butoxycarbonyl group afforded compound 17
(Chart 3). Compound 17 was acylated with acetic anhydride
in pyridine to give compound 18 (Chart 3).
Pharmacological Results and Discussion
In Vitro Tests25) The bradycardic activity of the synthe-
sized compounds was assessed by measuring the effect on
the spontaneous beating rates in the right atria of a guinea
pig. A EC30 value which means the concentration of the com-
pounds producing a 30% reduction from the initial sponta-
neous beating rate was determined by linear regression.
Initially, we investigated the effect of the ring size and the
substitution position of the cyclic amine as shown in Table 1.
Among them, the 3-piperidyl derivative (6c) showed potent
activity with a EC30 value of 0.83 mM, whereas neither the 4-
piperidyl derivative (6a) nor the 3-pyrrolidyl derivative (6b)
showed apparent activity. These results indicated that the 2-
(3-piperidyl)-1,2,3,4-tetrahydroisoqunoline skeleton of 6c is
essential to show potent bradycardic activity, and suggested
that it might allow the basic nitrogen and the 1,2,3,4-tetrahy-
droisoquinoline ring to interact with target molecules.
Conditions: (a) 1-benzylpiperidones (5a, 5c) or 1-benzylpyrrolidone (5b),
NaBH(OAc)3, AcOH, Et3N, CH2Cl2; (b) (COCl)2, DMSO, CH2Cl2, ꢀ70 °C, then Et3N;
(c) 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (4a), NaBH(OAc)3, AcOH, Et3N,
THF; (d) 4 N HCl/AcOEt, MeOH
Chart 1
Next, we investigated the effect of the methoxy group on
the 1,2,3,4-tetrahydroisoquinoline ring of 6c. The results are
presented in Table 2. Removal of both the 6-methoxy and the
7-methoxy group (6d) from 6c resulted in a complete loss of
Method A: R2CHO, NaBH(OAc)3, AcOH, Et3N, CH2Cl2
Method B: (a) R2CO2H, EDC·HCl, HOBt, Et3N, CH2Cl2; (b) LiAlH4, THF, reflux
Chart 2
Conditions: (a) H2, PtO2, EtOH–H2O; (b) aq. NaOH; (c) (MeCO)2O or MeSO2Cl, pyridine; (d) (CO2H)2; (e) N-Boc-4-piperidylcarboxyaldehyde (15), NaBH(OAc)3, AcOH,
Et3N, CH2Cl2; (f) 4 N HCl/AcOEt, MeOH; (g) (MeCO)2O, Et3N, CH2Cl2
Chart 3

392
Vol. 51, No. 4
Table 1. Physical Data and Bradycardic Activities of 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline Derivatives (6a—c)
mp (°C)
(Recryst.
solvent)
Analysis (%), Calcd. (Found)
a)
Yield
(%)
EC30
Compd.
R
Formula
(mM)
C
H
N
Cl
6a
78
10
25
124—125
(EtOH)
C23H30N2O2
75.38
(75.27)
8.25
(8.40)
7.64
(7.68)
ꢁ10
6b
219—221
(EtOH)
C22H28N2O2
·2HCl
62.12
(62.13)
7.11
(7.16)
6.59
(6.66)
16.67
(16.48)
ꢁ10
6c
2
204—206
(EtOH)
C23H30N2O2
·2HCl·0.5H2O
61.60
(61.70)
7.42
(7.40)
6.25
(6.24)
15.81
(15.88)
0.83
0.27
a) See experimental section, Pharmacology.
Table 2. Physical Data and Bradycardic Activities of 2-(1-Benzyl-3-piperidyl)-1,2,3,4-tetrahydroisoquinoline Derivatives (6c—h)
mp (°C)
(Recryst.
solvent)
Analysis (%), Calcd. (Found)
a)
Yield
(%)
EC30
Compd.
R1
Formula
(mM)
C
H
N
Cl
b)
b)
b)
b)
6c
6d
6,7-(OMe)2
H
0.83
ꢁ10
4
209—211
(EtOH)
229—235
C21H26N2
·2HCl·0.8H2O
C22H28N2O
·2HCl·0.1H2O
C22H28N2O
·2HCl·0.8H2O
C22H28N2O
·2HCl·0.3H2O
C21H25N3O2
64.05
(64.20)
64.26
(64.26)
62.35
(62.24)
63.70
(63.59)
56.10
7.58
(7.47)
7.40
(7.43)
7.52
(7.64)
7.44
(7.49)
6.68
7.11
(7.15)
6.81
(6.83)
6.61
(6.57)
6.75
(6.78)
9.35
18.01
(17.49)
17.24
(16.99)
16.73
(16.63)
17.09
(17.13)
15.77
6e
6f
6-OMe
7-OMe
8-OMe
7-NO2
7
22
15
50
0.92
0.57
2.8
(MeCN–MeOH)
182—185
(EtOH–AcOEt)
207—212
6g
6h
(MeCN)
212—215
2.5
(MeCN)
·2HCl·1.4H2O
(56.19)
(6.50)
(9.37)
(15.44)
a) See experimental section, Pharmacology. b) See Table 1.
activity. On the other hand, removal of only one methoxy position, it is steric bulkiness or hydrophobicity, rather than
group (6e, 6f) from 6c did not produce any marked effect in the electronic effect of the substituents, which affects the
potency. Both shifting the methoxy group to the 8-position level of activity, and that groups which are less bulky or
(6g) and converting the methoxy group to a nitro group at 7- which have appropriate hydrophobicity are preferable for ac-
position (6h) decreased activity by three fold. These results tivity. Among the 2,3-disubstituted derivatives (11o—q), the
demonstrated that the presence of at least one methoxy group dimethoxy (11o) and difluoro (11q) derivatives were as po-
at the 6- or 7-position of the 1,2,3,4-tetrahydroisoquinoline tent as 6c.
ring is important in inducing potent activity.
Finally, we carried out modification of the benzyl moiety
Furthermore, we investigated the influence of the sub- in 6c. The results are shown in Table 4. Replacement of the
stituent on the benzyl group of 6c, as shown in Table 3. benzyl group with a cyclohexylmethyl group (11r) lowered
Methoxy (11a—c), methyl (11d—f), and chloro groups activity by two fold, and replacement with a 4-piperidyl-
(11g—i) were introduced to study the electronic effects. The methyl group (17—18) resulted in a complete loss of activity.
comparison of 11a—i showed that the order of activity was These results indicated that the aromatic ring is preferable to
2-ꢁ3-ꢁ4-substitution and that the chloro group at the 2-po- produce potent activity. As alternative substituents for the
sition (11g) showed the best activity with a EC30 value of benzyl group, the heteroarylmethyl derivatives (11s—aa)
0.36 mM. This finding prompted us to introduce another were tested. The pyridylmethyl derivatives (11s—u) showed
groups at the 2-position. Introduction of cyano (11k) and flu- lower activity than 6c. Of the five memberd heterocycles
oro (11m) groups resulted in increases in activity compared (11v—aa), the 3-methyl-2-thienylmethyl derivative (11z) in-
to 6c, whereas nitro (11j), trifluoromethyl (11l), acetamide duced the most potent activity with a EC30 value of 0.43 mM.
(13a), methanesulfonamide (13b), hydroxy (11n) and amino The bicyclic and tricyclic derivatives (11bb—gg) were also
(12) derivatives were found to be less effective than 6c. evaluated. The 1-naphtylmethyl derivative (11bb) was
These results indicated that for groups introduced at the 2- slightly more potent than 6c. All the nitrogen-containing bi-

April 2003
393
Table 3. Physical Data and Bradycardic Activities of 2-(1-Benzyl-3-piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Derivatives (6c, 11a—q, 12,
13a, b)
mp (°C)
(Recryst.
solvent)
Analysis (%), Calcd. (Found)
b)
Yield
(%)
EC30
Compd.
R3
Methoda)
Formula
(mM)
C
H
N
Others
a)
c)
c)
c)
c)
6c
11a
H
2-OMe
0.83
1.8
A
70
175—177
(EtOH–Et2O)
171—173
(EtOH–Et2O)
195—197
(MeCN)
135—137
(MeCN)
150—152
(MeCN)
152—154
(MeCN)
112—115
(MeCN)
109—113
(MeCN)
138—142
(MeCN)
116—118
(MeOH)
103—110
(MeCN)
120—124
(MeCN)
118—122
(MeCN)
C24H32N2O3
·2HCl·0.5H2O
C24H32N2O3
·2HCl·1.2H2O
C24H32N2O3
·2HCl·0.5H2O
C24H32N2O2
·2(CO2H)2·0.3H2O
C24H32N2O2
60.25
(60.23)
58.70
(58.71)
60.25
(60.28)
59.42
(59.33)
61.82
(61.92)
61.82
(61.51)
53.02
(53.08)
52.64
(52.33)
55.82
(56.14)
53.20
(53.32)
56.69
(56.68)
51.98
(52.02)
58.09
(57.87)
57.36
(57.18)
56.26
(56.23)
57.65
(57.47)
58.42
7.37
(7.50)
7.47
(7.68)
7.37
(7.19)
6.52
(6.54)
6.92
(6.74)
6.92
(6.88)
6.00
(5.97)
5.89
(5.50)
5.72
(5.89)
5.79
(5.75)
6.01
(5.93)
5.70
(5.52)
6.37
(6.20)
6.21
(6.39)
6.46
(6.23)
6.09
(6.02)
6.79
5.85
(5.80)
5.70
(5.59)
5.85
(5.83)
4.95
(4.93)
5.34
(5.34)
5.34
(5.35)
4.58
(4.53)
4.55
(4.40)
4.82
(5.02)
6.89
(6.80)
7.08
(7.05)
4.33
(4.29)
5.21
(5.24)
6.92
(7.27)
7.57
(7.52)
4.98
(5.00)
7.86
Cl, 14.82
(15.05)
Cl, 14.44
(14.31)
11b
11c
11d
11e
11f
3-OMe
4-OMe
2-Me
3-Me
4-Me
2-Cl
A
A
A
A
A
A
A
A
A
A
A
47
27
78
31
60
69
54
64
79
48
48
67
67
49
60
73
49
65
95
3.1
Cl, 14.82 ꢁ10
(15.04)
0.68
1.1
·1.5(CO2H)2·0.5H2O
C24H32N2O2
1.4
·1.5(CO2H)2·0.5H2O
C23H29N2O2Cl
·2(CO2H)2·1.7H2O
C23H29N2O2Cl
·2(CO2H)2·2H2O
C23H29N2O2Cl
·2(CO2H)2
C23H29N3O4
·2(CO2H)2·H2O
C24H29N3O2
·2(CO2H)2·1.2H2O
C24H29N2O2F3
·2(CO2H)2·1.8H2O
C23H29N2O2
·1.5(CO2H)2·H2O
C25H33N3O3
·2(CO2H)2·0.2H2O
C24H33N3O4S
·(CO2H)2·0.3H2O
C23H30N2O3
·2(CO2H)2
C23H31N3O2
·1.5(CO2H)2·H2O
C25H34N2O4
·2HCl·H2
C24H30N2O4
·1.5(CO2H)2·0.5H2O
C23H28N2O2F2
·2(CO2H)2·H2O
11g
11h
11i
Cl, 5.80
(5.92)
Cl, 5.76
(6.01)
Cl, 6.10
(6.95)
0.36
0.58
1.2
3-Cl
4-Cl
11j
2-NO2
2-CN
2-CF3
2-F
1.3
11k
11l
0.59
1.0
F, 8.81
(8.89)
F, 3.35
(3.59)
11m
13a
13b
11n
12
A
0.73
2.3
a)
2-NH
COMe
2-NH
SO2Me
2-OH
amorphous
a)
215—216
(MeOH)
203—204
(MeOH)
126—134
(MeOH)
156—158
(MeCN)
164—166
(MeCN)
126—128
(MeCN)
S, 5.78
(5.94)
3.8
A
1.6
a)
2-NH2
2,3-(OMe)2
2,3-(OCH2O)
2,3-F2
1.5
(58.55)
58.03
(57.99)
58.48
(58.32)
53.68
(53.64)
(6.59)
7.40
(7.75)
6.18
(5.88)
5.74
(5.65)
(7.81)
5.41
(5.45)
5.05
(5.08)
4.64
(4.56)
11o
11p
11q
A
A
A
Cl, 13.70
(13.58)
0.83
1.4
F, 6.29
(6.43)
0.75
a) See experimental section, Chemistry. b) See experimental section, Pharmacology. c) See Table 1.
cyclic derivatives (11cc—ff) showed higher activity than 6c, that of Zatebradine. Compounds 11d, 11k, 11o, 11y, 11z,
except for the 3-indolylmethyl derivative (11cc). Particularly, 11bb, 11ee, and 11ff showed moderate in vivo activities,
the 4-quinolylmethyl derivative (11ee) was shown to be a po- whereas compounds 6f, 11g, 11q and 11dd were not effec-
tent one with a EC30 value of 0.37 mM. These results sug- tive in rats, in spite of its potent in vitro activities. These re-
gested that the nitrogen atom of the bicyclic derivatives may sults indicated that the 6,7-dimethoxy groups of 1,2,3,4-
contribute to the improved activity.
tetrahydroisoquinoline ring are necessary to exhibit potent in
In Vivo Tests Compounds with high in vitro activities vivo activity. These results also suggested that the in vivo ac-
were selected and were examined for their effect on heart rate tivity level might be affected by different factors from those
in urethane-anesthetized rats. The doses of compounds re- in in vitro tests, for example, protein binding or distribution.
quired to produce a 30% decrease of basal values of heart
rate are expressed as ED30 values. These results are listed in Conclusions
Table 5. Compound 6c dose-dependently reduced heart rate
Novel 1,2,3,4-tetrahydroisoquinoline derivatives bearing
after intravenous administration with a ED30 of 1.4 mg/kg iv, directly a cyclic amine at the 2-position were designed and
with negligible influence on mean blood pressure (8.4% de- examined for their bradycardic activities in in vitro and in
crease at 3 mg/kg iv: Fig. 2), although its potency is a half of vivo tests. From their in vitro SAR, we obtained the follow-

394
Vol. 51, No. 4
Table 4. Physical Data and Bradycardic Activities of 2-(3-Piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline Derivatives (6c, 11r—gg, 17, 18)
mp (°C)
(Recryst.
solvent)
Analysis (%), Calcd. (Found)
b)
Yield
(%)
EC30
Compd.
R2
Methoda)
Formula
(mM)
C
H
N
Others
a)
c)
c)
c)
c)
6c
11r
Ph
0.83
1.5
cyclohexyl
A
59
128—134
(MeCN)
C23H36N2O2
·1.5(CO2H)2·2H2O
C22H35N3O2
·3HCl·1.4H2O
C24H37N3O3
·2(CO2H)2·1.7H2O
C22H29N3O2
·2(CO2H)2·0.8H2O
C22H29N3O2
·3(CO2H)2·2H2O
C22H29N3O2
·3(CO2H)2·2H2O
C21H28N2O2S
·2(CO2H)2·0.5H2O
C21H28N2O2S
·1.5(CO2H)2·1.2H2O
C21H28N2O3
·1.5(CO2H)2·1.2H2O
C21H28N2O3
·2(CO2H)2·1.6H2O
C22H30N2O2S
·1.5(CO2H)2·1.1H2O
C20H27N3O2S
·2(CO2H)2·1.2H2O
C27H32N2O2
·1.5(CO2H)2·0.5H2O
C25H31N3O2
·2(CO2H)2·0.1H2O
C25H31N3O2
·1.5(CO2H)2·0.5H2O
C26H31N3O2
57.44
(57.47)
52.00
(52.17)
53.70
(53.78)
55.57
(55.84)
49.93
(49.86)
49.93
(49.67)
53.47
(53.54)
54.47
(54.28)
54.64
(54.37)
53.11
(53.17)
55.46
(55.36)
50.12
(49.97)
64.27
(64.30)
59.30
(59.15)
61.19
(61.09)
60.29
(60.15)
61.04
7.97
(7.82)
8.09
(8.64)
7.15
(7.36)
6.21
(6.65)
5.84
(5.83)
5.84
(5.09)
5.92
(6.32)
6.36
(6.42)
6.69
(6.60)
6.28
(6.33)
6.55
(6.56)
5.85
(6.03)
6.47
(6.47)
6.04
(6.27)
6.42
(6.36)
5.90
(6.18)
6.36
5.15
(5.12)
8.27
(8.11)
6.71
(6.77)
7.48
(7.73)
6.24
(6.29)
6.24
(6.24)
4.99
(5.23)
5.29
(5.38)
5.31
(5.20)
4.95
(5.17)
5.17
(5.18)
7.31
(7.40)
5.00
(5.04)
7.15
(7.30)
7.65
(7.73)
7.03
(7.32)
7.36
a)
17
4-piperidyl
4-Ac-piperidyl
2-pyridyl
3-pyridyl
4-pyridyl
2-thienyl
3-thienyl
2-furyl
80
36
26
34
15
63
56
74
56
35
67
76
72
51
56
12
51
209—213
(MeOH–AcOEt)
115—119
(MeCN–AcOEt)
100—103
(MeCN)
Cl, 20.93 ꢁ10
(20.44)
a)
18
ꢁ10
11s
A
A
A
A
A
A
A
B
A
A
A
B
A
B
A
0.95
11t
164—167
(MeCN)
173—177
(MeCN)
132—134
(MeOH)
126—129
(MeOH)
2.0
11u
11v
11w
11x
11y
11z
1.4
S, 5.71
(5.84)
S, 6.06
(5.99)
0.79
0.87
1.4
112—115
(MeCN)
3-furyl
121—123
(MeCN–MeOH)
127—129
(MeOH)
0.73
0.43
1.4
3-Me-2-
thienyl
2-thiazolyl
S, 5.92
(5.94)
S, 5.57
(5.67)
11aa
11bb
11cc
11dd
11ee
11ff
11gg
117—120
(MeCN)
146—148
(MeCN)
149—153
(MeCN)
173—175
(MeOH)
182—186
(MeCN)
133—136
(MeCN)
145—146
(MeCN)
1-naphtyl
3-indolyl
0.73
1.0
4-indolyl
0.58
0.37
0.55
1.6
4-quinolyl
8-quinolyl
2-fluorenyl
·2(CO2H)2
C26H31N3O2
·1.5(CO2H)2·H2O
C30H34N2O2
(61.05)
79.26
(79.59)
(6.64)
7.54
(7.42)
(7.28)
6.16
(6.26)
a) See experimental section, Chemistry. b) See experimental section, Pharmacology. c) See Table 1.
Table 5. Bradycardic Activities of Selected Compounds in Urethane-
Anesthetized Rats
Compd.
ED30a) (mg/kg iv)
6c
6f
1.4
ꢁ10
3.5
ꢁ10
3.8
6.2
1.9
ꢁ10
3.8
11d
11g
11k
11m
11o
11q
11y
11z
11bb
11dd
11ee
11ff
2
Fig. 2. Effect of 6c on Heart Rate (HR) and Mean Blood Pressure (MBP)
in Urethane-Anesthetized Rats
3.7
3.2
9.8
4.4
2.3
0.76
The values are meanꢂS.E.M. from three experiments.
ing findings. 1) The 2-(3-piperidyl)-1,2,3,4-tetrahydroiso-
quinoline skeleton is essential for the appearance of potent
activity. 2) The presence of at least one methoxy group at the
6- or 7-position of the 1,2,3,4-tetrahydroisoquinoline ring is
a) See experimental section, Pharmacology.

April 2003
395
Table 6. Spectral Data for Compounds 11a—gg
Compd.
1H-NMR (DMSO-d6) d
MS m/z
11a
11b
(500 MHz) 1.79—1.97 (3H, m), 2.27—2.33 (1H, m), 2.82—3.00 (2H, m), 3.27—3.51 (5H, m), 3.73 (3H, s), 3.75 (3H, s),
3.87 (3H, s), 3.96—4.02 (2H, m), 4.29—4.45 (4H, m), 6.78 (1H, s), 6.82 (1H, s), 7.02 (1H, t, Jꢄ7.5 Hz)
(500 MHz) 1.79—1.98 (3H, m), 2.31—2.37 (1H, m), 2.85—3.02 (2H, m), 3.22 (2H, br s), 3.36—3.55 (3H, m), 3.73 (3H, s),
3.74 (3H, s), 3.80 (3H, s), 4.00 (2H, br s), 4.29—4.37 (4H, m), 6.79 (1H, s), 6.82 (1H, s), 7.01 (1H, d, Jꢄ7.5 Hz), 7.19
(1H, s), 7.34—7.37 (2H, m), 11.89—11.99 (2H, m)
(500 MHz) 1.75—2.00 (3H, m), 2.27—2.35 (1H, m), 2.81—3.03 (2H, m), 3.17—3.48 (5H, m), 3.73 (3H, s), 3.74 (3H, s),
3.78 (3H, s), 3.94—4.01 (2H, m), 4.23—4.35 (4H, m), 6.75 (1H, s), 6.82 (1H, s), 7.00 (2H, d, Jꢄ8.5 Hz), 7.56 (2H, br s),
11.60—11.77 (2H, m)
(400 MHz) 1.51—1.63 (2H, m), 1.82—1.86 (1H, m), 2.01 (1H, br s), 2.28—2.37 (1H, m), 2.34 (3H, s), 2.50 (1H, br s),
2.75—2.78 (1H, m), 2.91—2.92 (2H, m), 3.12—3.15 (1H, m), 3.30 (3H, br s), 3.67 (2H, br s), 3.71 (3H, s), 3.72 (3H, s),
4.13 (2H, br s), 6.68 (1H, s), 6.77 (1H, s), 7.15—7.24 (3H, m), 7.30 (1H, d, Jꢄ6.8 Hz)
(400 MHz) 1.57—1.59 (2H, m), 1.84 (1H, br s), 1.97 (1H, br s), 2.32 (3H, s), 2.35 (1H, br s), 2.50—2.56 (1H, m), 2.85 (3H,
br s), 3.15 (4H, br s), 3.70 (3H, s), 3.72 (3H, s), 3.75—3.82 (2H, m), 4.01 (2H, br s), 6.67 (1H, s), 6.74 (1H, s), 7.15—
7.21 (3H, m), 7.27 (1H, t, Jꢄ7.6 Hz)
(400 MHz) 1.56—1.60 (2H, m), 1.83—1.86 (1H, m), 1.98 (1H, br s), 2.31 (3H, s), 2.40 (1H, br s), 2.60 (1H, br s), 2.83
(2H, br s), 2.91 (1H, d, Jꢄ11.2 Hz), 3.10—3.21 (4H, m), 3.70 (3H, s), 3.71 (3H, s), 3.85—3.86 (2H, m), 3.96 (2H, s), 6.67
(1H, s), 6.73 (1H, s), 7.20 (2H, d, Jꢄ7.6 Hz), 7.29 (2H, d, Jꢄ8.0 Hz)
(400 MHz) 1.52—1.66 (2H, m), 1.81—1.85 (1H, m), 2.05 (1H, br s), 2.22 (1H, br s), 2.47—2.51 (1H, m), 2.72—2.75
(1H, m), 2.94—2.97 (2H, m), 3.15—3.18 (1H, m), 3.37—3.42 (3H, m), 3.71 (2H, br s), 3.71 (3H, s), 3.74 (3H, s), 4.26
(2H, s), 6.74 (1H, s), 6.79 (1H, s), 7.30—7.37 (2H, m), 7.45 (1H, dd, Jꢄ7.2, 2.0 Hz), 7.52 (1H, dd, Jꢄ6.8, 2.0 Hz)
(400 MHz) 1.57—1.62 (2H, m), 1.82—1.85 (1H, m), 2.01 (1H, br s), 2.22—2.27 (1H, m), 2.47—2.51 (1H, m), 2.73—2.76
(1H, m), 2.93 (2H, br s), 3.10—3.13 (1H, m), 3.34 (3H, br s), 3.72 (3H, s), 3.73 (3H, s), 3.75 (2H, br s), 4.19 (2H, br s),
6.72 (1H, s), 6.78 (1H, s), 7.33—7.34 (1H, m), 7.36—7.42 (2H, m), 7.45 (1H, s)
397 (Mꢃꢃ1)
(FAB)
397 (Mꢃꢃ1)
(FAB)
11c
11d
11e
11f
397 (Mꢃꢃ1)
(FAB)
380 (Mꢃ)
(EI)
380 (Mꢃ)
(EI)
381 (Mꢃꢃ1)
(FAB)
11g
11h
11i
401 (Mꢃꢃ1)
(FAB)
401 (Mꢃꢃ1)
(FAB)
(400 MHz) 1.56—1.58 (2H, m), 1.83 (1H, br s), 2.01 (1H, br s), 2.20—2.25 (1H, m), 2.46—2.50 (1H, m), 2.77—2.80
(1H, m), 2.89—2.92 (2H, m), 3.14—3.16 (1H, m), 3.28 (3H, br s), 3.71 (3H, s), 3.72 (3H, s), 3.74 (2H, br s), 4.13 (2H,
br s), 6.71 (1H, s), 6.77 (1H, s), 7.39—7.45 (4H, m)
401 (Mꢃꢃ1)
(FAB)
11j
(400 MHz) 1.42—1.57 (2H, m), 1.75—1.79 (1H, m), 2.06—2.11 (2H, m), 2.39 (1H, br s), 2.56—2.58 (1H, m), 2.95 (2H,
br s), 3.05 (1H, d, Jꢄ10.0 Hz), 3.25 (1H, br s), 3.41 (2H, br s), 3.71 (3H, s), 3.73 (3H, s), 3.83 (2H, s), 4.25 (2H, s), 6.75
(1H, s), 6.79 (1H, s), 7.54 (1H, dt, Jꢄ8.4, 2.0 Hz), 7.65—7.71 (2H, m), 7.91 (1H, d, Jꢄ7.2 Hz)
(400 MHz) 1.50—1.63 (2H, m), 1.80—1.83 (1H, m), 2.06—2.07 (1H, m), 2.17 (1H, br s), 2.45—2.50 (1H, m), 2.66—2.68
(1H, m), 2.96 (2H, br s), 3.12 (1H, br s), 3.36—3.44 (3H, m), 3.70—3.80 (2H, m), 3.72 (3H, s), 3.73 (3H, s), 4.28 (2H, s),
6.75 (1H, s), 6.80 (1H, s), 7.49 (1H, br s), 7.61 (1H, d, Jꢄ7.2 Hz), 7.70 (1H, br s), 7.84 (1H, d, Jꢄ7.2 Hz)
(400 MHz) 1.58—1.61 (2H, m), 1.81—1.84 (1H, m), 2.07—2.13 (2H, m), 2.40—2.50 (1H, m), 2.64—2.67 (1H, m), 2.97
(2H, br s), 3.11—3.14 (1H, m), 3.39 (3H, br s), 3.71 (3H, s), 3.72 (2H, br s), 3.73 (3H, s), 4.29 (2H, br s), 6.75 (1H, s), 6.80
(1H, s), 7.49 (1H, br s), 7.68 (1H, br s), 7.72 (1H, d, Jꢄ8.0 Hz), 7.80 (1H, d, Jꢄ8.0 Hz)
(400 MHz) 1.54—1.56 (2H, m), 1.83 (1H, br s), 2.01 (1H, br s), 2.22 (1H, br s), 2.45—2.50 (1H, m), 2.75—2.77 (1H, m),
2.92 (2H, br s), 3.15—3.17 (1H, m), 3.34 (3H, br s), 3.71 (3H, s), 3.72 (3H, s), 3.73 (2H, br s), 4.18 (2H, br s), 6.72 (1H, s),
6.78 (1H, s), 7.19—7.23 (2H, m), 7.35—7.40 (1H, m), 7.44—7.48 (1H, m)
(400 MHz) 1.60—1.65 (2H, m), 1.87—1.90 (1H, m), 1.95—1.97 (1H, m), 2.58—2.60 (1H, m), 2.76—2.81 (3H, m),
3.03—3.05 (3H, m), 3.15 (1H, br s), 3.32 (1H, d, Jꢄ10.8 Hz), 3.70 (3H, s), 3.71 (3H, s), 3.91 (2H, br s), 3.99 (2H, s),
6.65 (1H, s), 6.72 (1H, s), 6.83 (1H, br s), 6.89 (1H, d, Jꢄ7.6 Hz), 7.21 (1H, br s), 7.29 (1H, dd, Jꢄ7.6, 1.2 Hz)
(500 MHz) 1.79—1.97 (3H, m), 2.27 (1H, br s), 2.84—2.95 (2H, m), 3.23—3.40 (5H, m), 3.73 (3H, s), 3.74 (3H, s), 3.82
(3H, s), 3.84 (3H, s), 3.98 (2H, br s), 4.31—4.44 (4H, m), 6.77 (1H, s), 6.82 (1H, s), 7.12—7.16 (3H, m), 7.33 (1H, br s),
11.50—11.81 (2H, m)
412 (Mꢃꢃ1)
(FAB)
11k
11l
392 (Mꢃꢃ1)
(FAB)
435 (Mꢃꢃ1)
(FAB)
11m
11n
11o
11p
11q
11r
11s
11t
368 (Mꢃꢃ1)
(FAB)
383 (Mꢃꢃ1)
(FAB)
427 (Mꢃꢃ1)
(FAB)
(500 MHz) 1.55—1.56 (2H, m), 1.83 (1H, br s), 1.97 (1H, br s), 2.27 (1H, br s), 2.49 (1H, br s), 2.79 (1H, br s), 2.90 (2H,
br s), 3.14—3.16 (1H, m), 3.27 (3H, br s), 3.68—3.70 (2H, m), 3.71 (3H, s), 3.72 (3H, s), 4.12 (2H, s), 6.01 (2H, s), 6.70
(1H, s), 6.77 (1H, s), 6.83—6.89 (3H, m)
411 (Mꢃꢃ1)
(FAB)
(400 MHz) 1.53—1.59 (2H, m), 1.83 (1H, br s), 2.01 (1H, br s), 2.12—2.17 (1H, m), 2.40—2.47 (1H, m), 2.70—2.72 (1H, m), 403 (Mꢃꢃ1)
2.95 (2H, br s), 3.10—3.12 (1H, m), 3.33—3.40 (3H, m), 3.72 (3H, s), 3.73 (3H, s), 3.71—3.73 (2H, m), 4.24 (2H, s), 6.74
(1H, s), 6.80 (1H, s), 7.19—7.29 (2H, m), 7.35—7.41 (1H, m)
(400 MHz) 0.86—0.95 (2H, m), 1.08—1.36 (3H, m), 1.53—1.73 (8H, m), 1.85—1.88 (1H, m), 1.97 (1H, br s), 2.50—2.64
(1H, m), 2.66—2.75 (3H, m), 2.81 (2H, br s), 3.04 (2H, br s), 3.13—3.16 (2H, m), 3.34 (1H, br s), 3.70 (3H, s), 3.71 (3H,
s), 3.91 (2H, s), 6.67 (1H, s), 6.72 (1H, s)
(FAB)
373 (Mꢃꢃ1)
(FAB)
(400 MHz) 1.57—1.62 (2H, m), 1.85 (1H, br s), 2.00 (1H, br s), 2.39 (1H, br s), 2.64 (1H, br s), 2.89 (3H, br s), 3.18—3.24
(4H, m), 3.71 (3H, s), 3.72 (3H, s), 3.90 (2H, s), 4.09 (2H, s), 6.70 (1H, s), 6.76 (1H, s), 7.34 (1H, dd, Jꢄ10.8, 6.0 Hz),
7.48 (1H, d, Jꢄ7.2 Hz), 7.82 (1H, br s), 8.55 (1H, d, Jꢄ5.2 Hz)
368 (Mꢃꢃ1)
(FAB)
(400 MHz) 1.56—1.62 (2H, m), 1.85 (1H, br s), 2.02 (1H, br s), 2.21—2.25 (1H, m), 2.48—2.51 (1H, m), 2.73—2.76 (1H, m), 368 (Mꢃꢃ1)
2.94 (2H, br s), 3.11—3.14 (1H, m), 3.37 (3H, br s), 3.69—3.78 (2H, m), 3.72 (3H, s), 3.73 (3H, s), 4.21 (2H, br s), 6.73
(1H, s), 6.79 (1H, s), 7.41 (1H, br s), 7.78 (1H, d, Jꢄ8.0 Hz), 8.53 (1H, br s), 8.58 (1H, br s)
(400 MHz) 1.54—1.62 (2H, m), 1.81—1.84 (1H, m), 2.05—2.07 (1H, m), 2.14—2.19 (1H, m), 2.42—2.47 (1H, m),
2.68—2.71 (1H, m), 2.96 (2H, br s), 3.09—3.12 (1H, m), 3.40—3.41 (3H, m), 3.62—3.72 (2H, m), 3.72 (3H, s), 3.73 (3H,
s), 4.28 (2H, br s), 6.75 (1H, s), 6.80 (1H, s), 7.38 (2H, d, Jꢄ4.8 Hz), 8.55 (2H, d, Jꢄ2.4 Hz)
(400 MHz) 1.55 (2H, br s), 1.83 (1H, br s), 2.02 (1H, br s), 2.20 (1H, br s), 2.44 (1H, br s), 2.82 (1H, br s), 2.91—2.93 (2H,
m), 3.18—3.30 (4H, m), 3.70 (3H, s), 3.71 (3H, s), 3.91 (2H, br s), 4.15 (2H, s), 6.72 (1H, s), 6.77 (1H, s), 7.02 (1H, dd,
Jꢄ5.2, 3.6 Hz), 7.06 (1H, d, Jꢄ2.8 Hz), 7.50 (1H, dd, Jꢄ5.2, 1.6 Hz)
(400 MHz) 1.54—1.62 (2H, m), 1.84—1.87 (1H, m), 1.95—1.98 (1H, m), 2.41 (1H, br s), 2.61 (1H, br s), 2.83 (2H, br s),
2.94 (1H, br s), 3.11—3.24 (4H, m), 3.71 (3H, s), 3.71 (3H, s), 3.93 (2H, s), 3.97 (2H, s), 6.67 (1H, s), 6.73 (1H, s), 7.16
(1H, d, Jꢄ4.8 Hz), 7.54 (1H, d, Jꢄ3.2 Hz), 7.58 (1H, dd, Jꢄ5.2, 3.2 Hz)
(FAB)
11u
11v
11w
368 (Mꢃꢃ1)
(FAB)
373 (Mꢃꢃ1)
(FAB)
373 (Mꢃꢃ1)
FAB)

396
Vol. 51, No. 4
Table 6. Continued
Compd.
1H-NMR (DMSO-d6) d
MS m/z
11x
11y
(400 MHz) 1.54 (2H, br s), 1.81 (1H, br s), 1.99 (1H, br s), 2.24 (1H, br s), 2.45—2.50 (1H, m), 2.78 (1H, br s), 2.91 (2H,
br s), 3.13 (1H, br s), 3.23—3.29 (3H, m), 3.72 (3H, s), 3.73 (3H, s), 3.75 (2H, d, Jꢄ5.2 Hz), 4.13 (2H, s), 6.41 (1H, d,
Jꢄ3.2 Hz), 6.46 (1H, t, Jꢄ2.4 Hz), 6.72 (1H, s), 6.77 (1H, s), 7.65 (1H, s)
(400 MHz) 1.51—1.59 (2H, m), 1.81—1.84 (1H, m), 2.01 (1H, br s), 2.18 (3H, s), 2.23 (1H, br s), 2.44 (1H, br s), 2.82
(1H, br s), 2.91 (1H, br s), 3.19—3.29 (4H, m), 3.71 (3H, s), 3.72 (3H, s), 3.81 (2H, s), 4.14 (2H, s), 6.71 (1H, s), 6.76
(1H, s), 6.87 (1H, d, Jꢄ5.2 Hz), 7.39 (1H, d, Jꢄ5.2 Hz)
(400 MHz) 1.57—1.59 (2H, m), 1.84 (1H, br s), 1.97 (1H, br s), 2.32 (3H, s), 2.35 (1H, br s), 2.50—2.56 (1H, m), 2.85
(3H, br s), 3.15 (4H, br s), 3.70 (3H, s), 3.72 (3H, s), 3.93 (2H, s), 3.75—3.78 (2H, m), 4.01 (2H, br s), 6.67 (1H, s), 6.74
(1H, s), 7.15—7.21 (3H, m), 7.27 (1H, t, Jꢄ7.6 Hz)
(400 MHz) 1.55 (2H, br s), 1.84 (1H, br s), 2.09 (1H, br s), 2.21 (1H, br s), 2.47 (1H, br s), 2.81 (1H, br s), 2.96 (2H, br s),
3.24 (1H, br s), 3.33 (1H, br s), 3.42 (2H, br s), 3.71 (3H, s), 3.73 (3H, s), 3.96 (2H, s), 4.26 (2H, s), 6.75 (1H, s), 6.79
(1H, s), 7.69 (1H, d, Jꢄ2.8 Hz), 7.75 (1H, d, Jꢄ3.6 Hz)
(400 MHz) 1.48—1.62 (2H, m), 1.80—1.84 (1H, m), 2.03—2.07 (1H, br s), 2.29 (1H, br s), 2.54 (1H, br s), 2.81 (1H, br s),
2.89 (2H, br s), 3.25—3.30 (4H, m), 3.71 (3H, s), 3.72 (3H, s), 4.04—4.14 (4H, m), 6.65 (1H, s), 6.76 (1H, s), 7.47—7.58
(4H, m), 7.89 (1H, d, Jꢄ8.0 Hz), 7.95 (1H, dd, Jꢄ6.8, 2.4 Hz), 8.27 (1H, dd, Jꢄ8.0, 2.0 Hz)
(400 MHz) 1.53—1.68 (2H, m), 1.89 (2H, br s), 2.73—3.04 (7H, m), 3.25 (1H, br s), 3.48 (1H, br s), 3.69 (3H, s), 3.70
(3H, s), 3.75 (2H, s), 4.37 (2H, br s), 6.60 (1H, s), 6.67 (1H, s), 7.09 (1H, dt, Jꢄ6.8, 1.2 Hz), 7.15 (1H, br s), 7.44 (1H,
d, Jꢄ8.4 Hz), 7.57 (1H, d, Jꢄ2.4 Hz), 7.76 (1H, d, Jꢄ7.6 Hz), 11.48 (1H, s)
(400 MHz) 1.58—1.62 (2H, m), 1.85—1.95 (2H, m), 2.59 (1H, br s), 2.78 (3H, br s), 3.01 (3H, br s), 3.12 (1H, br s), 3.33
(1H, br s), 3.70 (3H, s), 3.71 (3H, s), 3.88 (2H, s), 4.22 (2H, br s), 6.61 (1H, s), 6.69—6.70 (2H, m), 7.10—7.13 (2H, m),
7.40—7.44 (2H, m), 11.28 (1H, br s)
(400 MHz) 1.52—1.63 (2H, m), 1.82—1.85 (1H, m), 2.08 (1H, br s), 2.24 (1H, br s), 2.46 (1H, br s), 2.79 (1H, br s), 2.93
(2H, br s), 3.22 (1H, br s), 3.36—3.41 (3H, m), 3.71 (3H, s), 3.73 (3H, s), 4.06 (2H, s), 4.24 (2H, s), 6.70 (1H, s), 6.78
(1H, s), 7.53 (1H, d, Jꢄ4.4 Hz), 7.64 (1H, br s), 7.77 (1H, br s), 8.05 (1H, br s), 8.27 (1H, br s), 8.87 (1H, d, Jꢄ4.4 Hz)
(400 MHz) 1.57—1.65 (2H, m), 1.78 (1H, br s), 1.85 (1H, br s), 1.97 (1H, br s), 2.69—2.89 (4H, m), 3.11—3.26 (2H, m),
3.56—3.66 (2H, m), 3.70 (3H, s), 3.72 (3H, s), 3.93—4.18 (3H, m), 4.61 (1H, br s), 5.62—6.24 (1H, m), 6.42 (1H, br s),
6.63—6.87 (3H, m), 7.59—7.67 (1H, m), 7.93—8.03 (1H, m), 8.44—8.92 (1H, m)
357 (Mꢃꢃ1)
(FAB)
357 (Mꢃꢃ1)
(FAB)
11z
387 (Mꢃꢃ1)
(FAB)
11aa
11bb
11cc
11dd
11ee
11ff
374 (Mꢃꢃ1)
(FAB)
417 (Mꢃꢃ1)
(FAB)
406 (Mꢃꢃ1)
(FAB)
406 (Mꢃꢃ1)
(FAB)
418 (Mꢃꢃ1)
(FAB)
418 (Mꢃꢃ1)
(FAB)
11gg
(400 MHz) 1.23—1.31 (1H, m), 1.43—1.52 (1H, m), 1.68—1.72 (1H, m), 1.86—1.91 (2H, m), 1.94—1.99 (1H, m),
2.55—2.78 (6H, m), 2.96—2.99 (1H, m), 3.54 (2H, s), 3.59 (2H, s), 3.66 (3H, s), 3.68 (3H, s), 3.90 (2H, s), 6.57 (1H, s),
6.60 (1H, s), 7.27—7.39 (3H, m), 7.51 (1H, s), 7.57 (1H, d, Jꢄ7.2 Hz), 7.82—7.87 (2H, m)
455 (Mꢃꢃ1)
(FAB)
1
important to exert potent activity. 3) Replacement of the ben- powder. mp 124—125 °C. H-NMR (500 MHz, CDCl3) d: 1.68—1.73 (2H,
m), 1.85—1.87 (2H, m), 2.01 (2H, t, Jꢄ11.0 Hz), 2.44—2.48 (1H, m),
2.80—2.81 (4H, m), 2.97 (2H, d, Jꢄ12.0 Hz), 3.51 (2H, s), 3.70 (2H, s),
3.82 (3H, s), 3.83 (3H, s), 6.51 (1H, s), 6.58 (1H, s), 7.23—7.25 (2H, m),
zene ring in the benzyl group with a nitrogen-containing bi-
cyclic ring improved activity. In vivo tests of selected com-
pounds demonstrated that compound 6c exhibited potent
bradycardic activity with negligible influence on mean blood
pressure in rats, although its potency is a half of that of Zate-
bradine. From these results, we have identified the 2-(3-
piperidyl)-1,2,3,4-tetrahydroisoquinoline derivatives includ-
ing 6c as a specific bradycardic agents possessing a novel
skeleton.
Further research to obtain specific bradycardic agent with
superior properties is in progress and will be described in a
forthcoming paper.
7.30—7.32 (3H, m). FAB-MS m/z: 367 (Mꢃꢃ1). Anal. Calcd for
C23H30N2O2: C, 75.38; H, 8.25; N, 7.64. Found: C, 7 5.27; H, 8.40; N, 7.68.
2-(1-Benzyl-3-pyrrolidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquino-
line Dihydrochroride (6b) The title compound was prepared in the same
manner as described for 6a using 1-benzyl-3-pyrrolidone (5b) instead of 5a,
1
in 10% yield. mp 219—221 °C. H-NMR (500 MHz, DMSO-d6) d: 2.37—
2.62 (4H, m), 2.91 (1H, br s), 3.15—3.32 (2H, m), 3.48 (3H, br s), 3.62—
3.88 (1H, m), 3.72 (3H, s), 3.74 (3H, s), 4.17—4.51 (4H, m), 6.75—6.82
(2H, m), 7.46 (3H, s), 7.62—7.68 (2H, m). FAB-MS m/z: 353 (Mꢃꢃ1).
Anal. Calcd for C22H28N2O2·2HCl: C, 62.12; H, 7.11; N, 6.59; Cl, 16.67.
Found: C, 62.13; H, 7.16; N, 6.66; Cl, 16.48.
2-(1-Benzyl-3-piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline
Dihydrochloride (6c) The title compound was prepared in the same man-
ner as described for 6a using 1-benzyl-3-piperidone (5c) instead of 5a, in
25% yield. mp 219—221 °C. 1H-NMR (500 MHz, DMSO-d6) d: 1.76—1.98
(3H, m), 2.27—2.35 (1H, m), 2.84—3.01 (2H, m), 3.15—3.36 (5H, m), 3.73
(3H, s), 3.75 (3H, s), 3.93 (2H, br s), 4.35 (4H, br s), 6.77 (1H, s), 6.82 (1H,
s), 7.47 (3H, br s), 7.65 (2H, br s), 11.56—11.70 (2H, m). FAB-MS m/z: 367
(Mꢃꢃ1). Anal. Calcd for C23H30N2O2·2HCl·0.5H2O: C, 61.60; H, 7.42; N,
6.25; Cl, 15.81. Found: C, 61.70; H, 7.40; N, 6.24; Cl, 15.88.
Experimental
All melting points were measured with a Yanaco MP-500D melting point
apparatus without correction. 1H-NMR spectra were obtained on a JEOL
JNM-LA300 or a JNM-EX400 or a JNM-GX500 spectrometer and the
chemical shifts are expressed in d (ppm) values with tetramethylsilane as an
1
internal standard. Abbreviations of H-NMR signal patterns are as follows:
s, singlet; d, doublet; dd, double doublet; t, triplet; q, quartet; m, multiplet;
br, broad. Mass spectra were obtained on a JEOL JMS-DX300 or Hitachi M-
80 spectrometer. Column chromatography on silica gel was performed with
Kieselgel 60 (E. Merck).
2-(1-Benzyl-3-piperidyl)-1,2,3,4-tetrahydroisoquinoline Dihydrochlo-
ride (6d) The title compound was prepared in the same manner as de-
scribed for 6a using 1,2,3,4-tetrahydroisoquinoline (4b) and 5c instead of 4a
Chemistry.
droisoquinoline (6a)
2-(1-Benzyl-4-piperidyl)-6,7-dimethoxy-1,2,3,4-tetrahy-
suspension of 6,7-dimethoxy-1,2,3,4-tetrahy-
1
and 5a, in 4% yield. mp 209—211 °C. H-NMR (500 MHz, DMSO-d6) d:
A
1.78—1.99 (3H, m), 2.29 (1H, br s), 2.86 (1H, br s), 3.06 (1H, br s), 3.27—
3.42 (5H, m), 3.94 (2H, br s), 4.35—4.49 (4H, m), 7.20—7.28 (4H, m), 7.46
(3H, br s), 7.65 (2H, br s), 11.60—11.75 (2H, m). FAB-MS m/z: 307
(Mꢃꢃ1). Anal. Calcd for C21H26N3·2HCl·0.8H2O: C, 64.05; H, 7.58; N,
7.11; Cl, 18.01. Found: C, 64.20; H, 7.47; N, 7.15; Cl, 17.49.
2-(1-Benzyl-3-piperidyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline Di-
hydrochloride (6e) The title compound was prepared in the same manner
as described for 6a using 6-methoxy-1,2,3,4-tetrahydroisoquinoline (4c)18)
and 5c instead of 4a and 5a, in 7% yield. mp 229—235 °C. 1H-NMR
droisoquinoline hydrochloride (4a, 3.00 g, 12.7 mmol) in CH2Cl2 (30 ml)
was treated with Et3N (1.77 ml, 12.7 mmol), and the mixture was stirred for
10 min at room temperature. To the mixture were added 1-benzyl-4-piperi-
done (5a, 2.51 g, 13.3 mmol), acetic acid (1.81 ml, 31.7 mmol) and sodium
acetoxyborohydride (NaBH(OAc)3) (3.12 g, 15.2 mmol), and the mixture
was stirred for 2 h at room temperature. The mixture was made alkaline with
1 N aqueous NaOH and was extracted with CHCl3 (30 mlꢅ2). The combined
extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was crystallized from EtOH to give 9 (3.61 g, 78%) as a colorless

April 2003
397
3.00 mmol) and NaBH(OAc)3 (0.699 g, 3.30 mmol), and the mixture was
stirred for 13 h at room temperature. The mixture was made alkaline with 1 N
aqueous NaOH and was extracted with CHCl3 (30 mlꢅ2). The combined ex-
tract was dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (CHCl3/MeOHꢄ24/1, /v)
to give 6,7-dimethoxy-2-[1-(2-nitrobenzyl)-3-piperidyl]-1,2,3,4-tetrahydroiso-
quinoline (1.47 g, quantitative) as a yellow syrup. This compound was con-
verted to corresponding oxalate and recrystallized from MeOH to give 11j
(400 MHz, DMSO-d6) d: 1.68—1.97 (3H, m), 2.28 (1H, br s), 2.86—3.64
(7H, m), 3.75 (3H, s), 3.94 (2H, br s), 4.36 (4H, br s), 6.82 (1H, s), 6.86 (1H,
d, Jꢄ8.0 Hz), 7.12 (1H, d, Jꢄ8.8 Hz), 7.46 (3H, s), 7.66 (2H, s), 11.68—
11.80 (2H, m). EI-MS m/z: 336 (Mꢃ). Anal. Calcd for C22H28N2O2·2HCl·
0.1H2O: C, 64.26; H, 7.40; N, 6.81; Cl, 17.24. Found: C, 64.26; H, 7.43; N,
6.83; Cl, 16.99.
2-(1-Benzyl-3-piperidyl)-7-methoxy-1,2,3,4-tetrahydroisoquinoline Di-
hydrochloride (6f) The title compound was prepared in the same manner
as described for 6a using 7-methoxy-1,2,3,4-tetrahydroisoquinoline (4d)18)
and 5c instead of 4a and 5a, in 22% yield. mp 182—185 °C. 1H-NMR
(400 MHz, DMSO-d6) d: 1.79—1.99 (3H, m), 2.31 (1H, br s), 2.85—3.45
(7H, m), 3.74 (3H, s), 3.97 (2H, br s), 4.36—4.43 (4H, m), 6.78 (1H, br s),
6.88 (1H, d, Jꢄ5.6 Hz), 7.16 (1H, d, Jꢄ8.1 Hz), 7.46—7.47 (3H, m), 7.66
(2H, br s), 11.88 (2H, br s). FAB-MS m/z: 337 (Mꢃꢃ1). Anal. Calcd for
C22H28N2O2·2HCl·0.8H2O: C, 62.35; H, 7.54; N, 6.61; Cl, 16.73. Found: C,
62.24; H, 7.64; N, 6.57; Cl, 16.63.
1
(1.40 g, 79%) as a colorless powder. mp 116—118 °C. H-NMR (400 MHz,
CDCl3) d: 1.42—1.57 (2H, m), 1.75—1.79 (1H, m), 2.06—2.11 (2H, m),
2.39 (1H, br s), 2.56—2.58 (1H, m), 2.95 (2H, br s), 3.05 (1H, br s), 3.25
(1H, br s), 3.41 (2H, br s), 3.71 (3H, s), 3.73 (3H, s), 3.83 (2H, s), 4.25 (2H,
s), 6.75 (1H, s), 6.79 (1H, s), 7.54 (1H, dt, Jꢄ8.4, 2.0 Hz), 7.65—7.71 (2H,
m), 7.91 (1H, d, Jꢄ7.2 Hz) FAB-MS m/z: 412 (Mꢃꢃ1). Anal. Calcd for
C23H29N3O4·2(CO2H)2·H2O: C, 53.20; H, 5.79; N, 6.89. Found: C, 53.32;
H, 5.75; N, 6.80.
6,7-Dimethoxy-2-{1-[(4-indolyl)methyl]-3-piperidyl}-1,2,3,4-tetrahy-
droisoquinoline Sesquioxalate (11dd, Method B) 1) A suspension of 10
(0.349 g,1.00 mmol) in CH2Cl2 (10 ml) was treated with Et3N (0.279 ml,
2.00 mmol), and the mixture was stirred for 10 min at room temperature. To
the mixture were added HOBt (0.068 g, 0.50 mmol), EDC·HCl (0.230 g,
1.20 mmol) and indol-4-carboxylic acid (0.161 g, 1.00 mmol), and the mix-
ture was stirred for 13 h at room temperature. The mixture was partitioned
between CHCl3 (15 mlꢅ2) and 0.2 N aqueous NaOH (30 ml). The combined
extract was dried over anhydrous Na2SO4 and concentrated in vacuo. The
residue was purified by column chromatography (CHCl3/MeOHꢄ24/1, v/v)
to give 6,7-dimethoxy-2-{1-[(4-indolyl)carbonyl]-3-piperidyl}-1,2,3,4-tetrahy-
droisoquinoline (0.390 g, 93%) as a yellow foam. 2) To a suspension of
LiAlH4 (0.069 g, 1.8 mmol) in tetrahydrofuran (5 ml) was added a solution of
6,7-dimethoxy-2-{1-[(4-indolyl)carbonyl]-3-piperidyl}-1,2,3,4-tetrahydroiso-
quinoline (0.380 g, 0.906 mmol) in tetrahydrofuran (5 ml), and the mixture
was stirred for 1 h under reflux, then cooled to room temperature. To the
mixture was added H2O (3 ml) at ꢀ40 °C, and the mixture was stirred for 1 h
at room temperature. The resulting suspension was filtered through Celite
pad and the filtrate was partitioned between AcOEt (15 mlꢅ2) and saturated
NaCl (30 ml). The combined AcOEt layer was dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by column chromatog-
raphy (CHCl3/MeOHꢄ24/1, v/v) to give 6,7-dimethoxy-2-{1-[(4-indolyl)-
methyl]-3-piperidyl}-1,2,3,4-tetrahydroisoquinoline (0.321 g, 87%) as a col-
orless foam. This compound was converted to corresponding oxalate and re-
crystallized from MeOH to give 11dd (0.290 g, 55%) as a colorless powder.
2-(1-Benzyl-3-piperidyl)-8-methoxy-1,2,3,4-tetrahydroisoquinoline Di-
hydrochloride (6g) The title compound was prepared in the same manner
as described for 6a using 8-methoxy-1,2,3,4-tetrahydroisoquinoline (4e)18)
and 5c instead of 4a and 5a, in 15% yield. mp 207—212 °C. 1H-NMR
(400 MHz, DMSO-d6) d: 1.88—1.97 (3H, m), 2.30 (1H, br s), 2.88—2.99
(2H, m), 3.26—3.33 (3H, m), 3.60 (1H, br s), 3.83 (3H, s), 4.01 (1H, br s),
4.20—4.36 (6H, m), 6.83 (1H, d, Jꢄ7.6 Hz), 6.93 (1H, d, Jꢄ8.0 Hz), 7.27
(1H, t, Jꢄ7.6 Hz), 7.46—7.47 (3H, m), 7.66 (2H, s), 11.68—11.80 (2H, m).
FAB-MS m/z: 337 (Mꢃꢃ1). Anal. Calcd for C22H28N2O2·2HCl·0.3H2O: C,
63.70; H, 7.44; N, 6.75; Cl, 17.09. Found: C, 63.59; H, 7.49; N, 6.78; Cl,
17.13.
2-(1-Benzyl-3-piperidyl)-7-nitro-1,2,3,4-tetrahydroisoquinoline Dihy-
drochloride (6h) The title compound was prepared in the same manner as
described for 6a using 7-nitro-1,2,3,4-tetrahydroisoquinoline (4f)19) and 5c
1
instead of 4a and 5a, in 50% yield. mp 212—215 °C. H-NMR (400 MHz,
DMSO-d6) d: 1.78—2.02 (4H, m), 2.33 (1H, br s), 2.67 (1H, br s), 3.25—
3.33 (4H, m), 3.70 (2H, br s), 3.95 (1H, br s), 4.34—4.37 (2H, m), 4.59 (2H,
br s), 7.46—7.47 (3H, m), 7.50—7.56 (1H, m), 7.66 (2H, s), 8.13—8.17
(2H, m), 11.70—12.00 (2H, m). FAB-MS m/z: 352 (Mꢃꢃ1). Anal. Calcd for
C21H25N3O2·2HCl·1.4H2O: C, 56.10; H, 6.68; N, 9.35; Cl, 15.77. Found: C,
56.19; H, 6.50; N, 9.37; Cl, 15.44.
6,7-Dimethoxy-2-(3-piperidyl)-1,2,3,4-tetrahydroisoquinoline
Dihy-
drochloride (10) 1) To a solution of oxalyl chloride (4.72 ml, 55.0 mmol)
in CH2Cl2 (50 ml) was added dropwise a solution of dimethylsulfoxide (4.88
ml, 68.8 mmol) in CH2Cl2 (10 ml) at ꢀ70 °C, and the mixture was stirred for
10 min at ꢀ70 °C. To the mixture was added dropwise a solution of 7 (5.88
g, 27.5 mmol) in CH2Cl2 (15 ml) at ꢀ70 °C, and the mixture was stirred for
1 h at ꢀ70 °C. To the mixture was added Et3N (15.3 ml, 110 mmol) at
ꢀ70 °C, and the mixture was stirred for 1 h at 0 °C. To the mixture was
added 2 N aqueous NH4Cl (55 ml), and the whole was partitioned between
CHCl3 (30 mlꢅ2) and H2O (50 ml). The combined CHCl3 layer was dried
over anhydrous Na2SO4 and concentrated in vacuo to give crude 8. Then a
suspension of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride
(4a, 5.74 g, 25.0 mmol) in tetrahydrofuran (60 ml) was treated with Et3N
(3.48 ml, 25.0 mmol), and the mixture was stirred for 10 min at room tem-
perature. To the mixture were added crude 8, acetic acid (1.43 ml, 25.0
mmol) and NaBH(OAc)3 (5.83 g, 27.5 mmol), and the mixture was stirred
for 5 h at room temperature. The mixture was made alkaline with 1 N aque-
ous NaOH and was extracted with AcOEt (30 mlꢅ2). The combined extract
was washed with saturated NaCl (50 ml) and dried over anhydrous Na2SO4
and concentrated in vacuo. The residue was purified by column chromatog-
raphy (CHCl3·MeOHꢄ49/1, v/v) to give 9 (7.76 g, 82%) as a yellow syrup.
2) To a solution of 9 (7.76 g, 20.6 mmol) in MeOH (30 ml) was added 4 N
HCl/AcOEt (25.7 ml) at 0 °C, and the mixture was stirred for 7 h at room
temperature. The mixture was concentrated in vacuo and residual solid was
recrystallized from EtOH–MeOH to give 10 (3.60 g, 50%) as a beige pow-
1
mp 173—175 °C. H-NMR (400 MHz, DMSO-d6) d: 1.58—1.62 (2H, m),
1.85—1.95 (2H, m), 2.59 (1H, br s), 2.78 (3H, br s), 3.01 (3H, br s), 3.12
(1H, br s), 3.33 (1H, br s), 3.70 (3H, s), 3.71 (3H, s), 3.88 (2H, s), 4.22 (2H,
br s), 6.61 (1H, s), 6.69—6.70 (2H, m), 7.10—7.13 (2H, m), 7.40—7.44
(2H, m), 11.28 (1H, br s). FAB-MS m/z: 406 (Mꢃꢃ1). Anal. Calcd for
C25H31N3O2·1.5(CO2H)2·0.5H2O: C, 61.19; H, 6.42; N, 7.65. Found: C,
61.09; H, 6.36; N, 7.73.
Compounds 11a—i, 11k—cc and 11ee—gg were prepared in the same
manner as described above (Method A or B). Their isolated yield, melting
1
points, elemental analyses and yields are listed in Table 3—4, and their H-
NMR and MS data in Table 6.
2-[1-(2-Aminobenzyl)-3-piperidyl]-6,7-dimethoxy-1,2,3,4-tetrahy-
droisoquinoline Sesquioxalate (12) A suspension of 11j (1.28 g, 2.16
mmol) and PtO2 (0.022 g) in EtOH–H2O (3 : 2, 25 ml) was stirred under hy-
drogen atmosphere for 2 h at room temperature. The mixture was filtered
through Celite pad and the filtrate was concentrated in vacuo. The residue
was made alkaline with 1 N aqueous NaOH and was extracted with CHCl3
(30 mlꢅ2). The combined extract was dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified by column chromatography
(CHCl3/MeOHꢄ24/1, v/v) to give 2-[1-(3-Aminobenzyl)-3-piperidyl]-6,7-
dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.836 g, quantitative) as a yellow
syrup. This compound was converted to corresponding oxalate and recrys-
tallized from MeOH to give 12 (0.886 g, 73%) as a colorless powder. mp
126—134 °C. 1H-NMR (400 MHz, DMSO-d6) d: 1.57—1.59 (2H, m),
1.82—1.84 (1H, m), 1.99 (1H, br s), 2.35 (1H, br s), 2.56 (1H, br s), 2.86
(3H, br s), 3.17 (4H, br s), 3.63—3.74 (2H, m), 3.71 (3H, s), 3.72 (3H, s),
4.03 (2H, s), 6.54 (1H, dt, Jꢄ7.2, 0.8 Hz), 6.66—6.69 (2H, m), 6.74 (1H, s),
7.03—7.06 (2H, m). FAB-MS m/z: 382 (Mꢃꢃ1). Anal. Calcd for
C23H31N3O2·1.5(CO2H)2·H2O: C, 58.42; H, 6.79; N, 7.86. Found: C, 58.55;
H, 6.59; N, 7.81.
1
der. mp 205—216 °C. H-NMR (300 MHz, DMSO-d6) d: 1.75—1.86 (2H,
m), 1.96—2.00 (1H, m), 2.27 (1H, br s), 2.81—2.94 (2H, m), 3.22—3.40
(5H, m), 3.72 (2H, br s), 3.73 (3H, s), 3.74 (3H, s), 4.34 (2H, br s), 6.78 (1H,
s), 6.82 (1H, s), 9.56 (1H, br s), 9.89 (1H, br s), 11.75 (1H, br s). FAB-MS
m/z: 277 (Mꢃꢃ1). Anal. Calcd for C16H24N2O2·2HCl: C, 55.02; H, 7.50; N,
8.02; Cl, 20.30. Found: C, 54.79; H, 7.55; N, 7.99; Cl, 20.16.
6,7-Dimethoxy-2-[1-(2-nitrobenzyl)-3-piperidyl]-1,2,3,4-tetrahydroiso-
quinoline Dioxalate (11j, Method A) A suspension of 10 (1.05 g,
3.00 mmol) in CH2Cl2 (20 ml) was treated with Et3N (0.836 ml, 6.00 mmol),
and the mixture was stirred for 10 min at room temperature. To the mixture
were added 2-nitrobenzaldehyde (0.453 g, 3.00 mmol), acetic acid (0.172 ml,
2-{[3-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)piperidino]-
methyl}acetanilide Dioxalate (13a) A solution of 12 (1.06 g, 1.89 mmol)

398
Vol. 51, No. 4
in H2O (10 ml) was made alkaline with 1 N aqueous NaOH and was extracted
was recorded, a drug dissolved in distilled water and diluted with the experi-
with CHCl3 (20 mlꢅ2). The combined extract was dried over anhydrous mental Krebs–Henseleit solution to the desired concentration was added to
Na2SO4 and concentrated in vacuo to give 2-[1-(3-aminobenzyl)-3- the bath solution cumulatively at 30 min intervals and a concentration–re-
piperidyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (0.722 g, quantita- sponse curve was constructed. A EC30 value that mean the concentration of
tive). To a solution of 2-[1-(3-aminobenzyl)-3-piperidyl]-6,7-dimethoxy- the compounds producing a 30% reduction from initial spontaneous rate of
1,2,3,4-tetrahydroisoquinoline (0.339 g, 0.890 mmol) in pyridine (5 ml) was beating, was determined by linear regression.
added acetic anhydride (0.101 ml, 1.07 mmol) at 0 °C, and the mixture was
stirred for 1 h at room temperature. The mixture was concentrated in vacuo
and the residue was partitioned between CHCl3 (15 mlꢅ2) and 0.2 N aqueous
In Vivo Tests Male Wister rats (270—350 g) were anesthetized with
urethane (1.0 g/kg i.p.). The body temperature was kept constant at 37 °C.
The femoral vein was cannulated for intravenous administration of drugs.
NaOH (40 ml). The combined CHCl3 layer was dried over anhydrous The common carotid artery were cannulated for the recording of systemic
Na2SO4 and concentrated in vacuo. The residue was purified by column blood pressure. Blood pressure was recorded through the cannula connected
chromatography (CHCl3/MeOHꢄ24/1, v/v) to give 2-{[3-(6,7-dimethoxy- to a pressure transducer (AP-200T, Nihon Kohden, Tokyo, Japan) and a
1,2,3,4-tetrahydro-2-isoquinolyl)-1-piperidyl]methyl}acetanilide (0.526 g, pressure amplifier (AP-621G, Nihon Kohden, Tokyo, Japan). Heart rate was
quantitative) as a yellow syrup. This compound was converted to corre- measured with tachometer (AT-600G, Nihon Kohden, Tokyo, Japan) trig-
sponding oxalate to give 13a (0.357 g, 67%) as a yellow amorphous powder. gered by the pulsewave of blood pressure. The doses of each compound re-
1H-NMR (400 MHz, DMSO-d6) d: 1.55—1.61 (2H, m), 1.83—1.86 (1H, quired to produce a 30% decrease of basal values of heart rate were ex-
m), 2.07 (3H, s), 2.07—2.16 (2H, m), 2.41 (1H, t, Jꢄ10.4 Hz), 2.77—2.79 pressed as ED30 values. To obtain a ED30 value, tested compounds (0.3—
(1H, m), 2.91 (2H, br s), 3.16 (1H, d, Jꢄ10.4 Hz), 3.32 (3H, br s), 3.71 (2H, 10.0 mg/kg) were administered intravenously in an increasing fashion at
br s), 3.71 (3H, s), 3.72 (3H, s), 4.16 (2H, s), 6.71 (1H, s), 6.77 (1H, s), 7.10
30 min intervals after the stabilization of heart rate and a dose–response
(1H, t, Jꢄ7.6 Hz), 7.27—7.32 (2H, m), 7.79 (1H, d, Jꢄ7.6 Hz). FAB-MS curve was constructed. When the time course of effects of compounds on
m/z: 424 (Mꢃꢃ1). Anal. Calcd for C25H33N3O3·2(CO2H)2·0.2H2O: C, heart rate and mean blood pressure was evaluated, a compound was adminis-
57.36; H, 6.21; N, 6.92. Found: C, 57.18; H, 6.39; N, 7.27.
tered intravenously with single doses after 30 min stabilizing period, and
2-{[3-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-isoquinolyl)piperidino]- changes in heart rate and blood pressure were observed for 60 min after the
methyl}methanesulfonanilide Monooxalate (13a) The title compound
was prepared in the same manner as described for 13a using methanesul-
fonyl chloride instead of acetic anhydride, in 49% yield. mp 215—216 °C.
administration.
Acknowledgments We thank Mrs. N. Ishii for performing pharmaco-
1H-NMR (400 MHz, DMSO-d6) d: 1.52 (2H, br s), 1.84 (1H, br s), 2.04— logical experiments, and members of the Division of Analytical Research for
2.10 (2H, m), 2.32 (1H, t, Jꢄ10.8 Hz), 2.86 (2H, br s), 3.07 (3H, s), 3.07— carrying out instrumental analyses.
3.11 (2H, m), 3.20 (2H, br s), 3.70 (3H, s), 3.71 (3H, s), 3.71—3.81 (2H, m),
4.06 (2H, s), 6.69 (1H, s), 6.74 (1H, s), 7.14 (1H, dt, Jꢄ8.0, 1.6 Hz), 7.31—
7.34 (2H, m), 7.37—7.39 (1H, m). FAB-MS m/z: 460 (Mꢃꢃ1). Anal. Calcd
for C24H33N3O4S·(CO2H)2·0.3H2O: C, 56.26; H, 6.46; N, 7.57; S, 5.78.
Found: C, 56.23; H, 6.23; N, 7.52; S, .94.
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1
bonyl-4-piperidylcarboxyaldehyde (15) instead of 5a. H-NMR (400 MHz,
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m/z: 415 (Mꢃꢃ1). Anal. Calcd for C24H37N3O3·2(CO2H)2·1.7H2O: C,
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