2a-[4-(tetrahydropyridoindol-2-yl)butyl]tetrahydrobenzindole derivatives: New selective antagonists of the 5-hydroxytryptamine7 receptor

Article abstract of DOI:10.1021/jm0104264

A series of tetrahydrobenzindoles was prepared, and the affinity of these compounds for the 5-hydroxytryptamine₇ (5-HT₇) receptor and other receptors was evaluated. Most of the compounds showed high affinity for the 5-HT₇

Full text of DOI:10.1021/jm0104264

J . Med. Chem. 2002, 45, 2197-2206
2197
2a -[4-(Tetr a h yd r op yr id oin d ol-2-yl)bu tyl]tetr a h yd r oben zin d ole Der iva tives: New
Selective An ta gon ists of th e 5-Hyd r oxytr yp ta m in e7 Recep tor
Chika Kikuchi,* Takashi Ando, Takashi Watanabe, Hiroshi Nagaso, Masayo Okuno, Toyokazu Hiranuma, and
Masao Koyama
Pharmaceutical Research Center, Meiji Seika Kaisha Ltd., 760 Morooka-cho, Kohoku-ku, Yokohama 222-8567, J apan
Received September 10, 2001
A series of tetrahydrobenzindoles was prepared, and the affinity of these compounds for the
5-hydroxytryptamine7 (5-HT7) receptor and other receptors was evaluated. Most of the
compounds showed high affinity for the 5-HT7 receptor, and 2a-[4-(tetrahydropyridoindol-2-
yl)butyl]tetrahydrobenzindole derivatives (26a -j) exhibited high selectivity for this receptor.
The nature of the substituent at the 9-position of the tetrahydropyridindole ring affected the
affinity for the 5-HT7 receptor, and the 9-carbamoyl moiety afforded increased selectivity.
Compound 26j exhibited high affinity for the 5-HT7 receptor, with at least 280-fold selectivity
over the 5-HT2 receptor. In a functional model of 5-HT7 receptor activation, this compound
was confirmed to have 5-HT7 receptor antagonist activity. It should be a useful tool for clarifying
the biological role of the 5-HT7 receptor.
Ch a r t 1
In tr od u ction
The neurotransmitter serotonin (5-hydroxytryptamine,
5-HT) is involved in a variety of pharmacological effects
in the central and peripheral nervous system. Seven
classes of 5-HT receptor subtypes (5-HT1-5-HT7) have
been characterized by molecular biological techniques.
The 5-HT7 receptor is the most recent addition to the
family of G-protein-coupled 5-HT receptors and has been
cloned from rat,1-3 mouse,4 human,5 and guinea pig.6
The deduced amino acid sequences of 5-HT7 receptors
show a high degree of interspecies homology but only a
limited homology with other types of 5-HT7 receptors.
All four species homologues of the 5-HT7 receptor have
high affinity for 5-HT, 5-carboxyamidotryptamine (5-
CT, 1) (Chart 1), 5-methoxytryptamine (5-MeOT), and
methiothepin and have moderate affinity for 8-hydroxy-
2-dipropylaminotetralin (8-OH-DPAT), clozapine, and
a number of other psychoactive drugs.7 Four 5-HT7
splice variants exist in human and rat. Both the long
(5-HT7a) and short (5-HT7b) forms of the human receptor
exhibit similar distribution patterns and pharma-
cology.8-10
The biological functions of the 5-HT7 receptor are
poorly understood. High levels of 5-HT7 receptor mRNA
have been observed in the brain where it is localized in
the thalamus, hypothalamus, brainstem, and hippocam-
pus.1,3,5,11 The distribution of 5-HT7 receptor binding
sites in rat and guinea pig brain was essentially the
same as the mRNA distribution.11-13 The 5-HT7 receptor
is involved in the control of circadian rhythms of
spontaneous electrical activity in the suprachiasmatic
nucleus (SCN) of the hypothalamus.3,14-16 It may be
involved in the disturbance of circadian rhythms, such
as jet lag, delayed sleep-phase syndrome (DSPS), and
non-24-hour sleep-wake disorder (non-24).17 In addi-
tion, the decrease of 5-HT7 receptors in dorsal raphe
nuclei with aging suggests that these receptors may
have a role of in age-related changes of the circadian
timing system.18 The affinity of a number of antipsy-
chotic agents for the 5-HT7 receptor also led to the
speculation that this receptor may mediate the thera-
peutic actions of these compounds.7 The 5-HT7 receptor
may be of value as a novel therapeutic target.
Only a few selective antagonists for the 5-HT7 recep-
tor, 2-5 (Chart 1), have been reported to date,19-22 and
no selective agonist is yet available. In the previous
paper, we reported the synthesis and the affinities for
the 5-HT7 receptor and other receptors of a novel series
* To whom correspondence should be addressed. Phone: +81-45-
545-3133. Fax: +81-45-545-3120. E-mail: Chika_Kikuchi@meiji.co.jp.
10.1021/jm0104264 CCC: $22.00 © 2002 American Chemical Society
Published on Web 05/01/2002

2198 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11
Kikuchi et al.
Sch em e 1a
a
Reagents: (a) 1,4-dibromobutane, NaH (55%), DMF, -40 to 0 °C; (b) corresponding amine, K2CO3, DMF, 60 °C; (c) bis(trichloro-
methyl)carbonate, AlCl3, 1,2-dichloroethane, MeOH, 0 °C to room temp; (d) LiOH(aq), MeOH, reflux; (e) NH3(aq), DCC, HOBt, DMF; (f)
Br2, 1,2-dichloroethane, -20 °C; (g) mCPBA, TFA; (h) NaOMe, MeOH, 0 °C; (i) MeI, K2CO3, acetone.
of tetrahydrobenzindoles. Compound 5 is a highly potent
antagonist for the 5-HT7 receptor, with 50-fold selectiv-
ity over 5-HT2 receptor.22 In the present paper, we
report the synthesis and the binding affinity for the
5-HT7 and 5-HT2 receptors of 2a-(4-substituted)butyltet-
rahydrobenzindole derivatives 23a -26j. The structure-
activity relationship of these derivatives is also dis-
cussed. On the basis of the relative affinity for the 5-HT7
and 5-HT2 receptors, we selected compound 26j for
further evaluation of the in vitro agonist or antagonist
by reaction with bromine at -20 °C. The reaction
furnished 6-bromobenzindole 13 in high yield, with none
of the alternative 8-bromobenzindole detectable. Bro-
mination of compound 9 at 0 °C mainly provided the
6,8-dibrominated compound. Compound 14 was pre-
pared from compound 11 by treatment with mCPBA
followed by hydrolysis. Compound 15 was prepared from
14 by reaction with iodomethane in the presence of K2-
CO3. Compounds 23a -26j were obtained from 9-15 by
reaction with the corresponding amines in the presence
of K2CO3.
activity. We also evaluated its affinity for the 5-HT1A
,
5-HT1B, 5-HT2C, 5-HT3, 5-HT4, and 5-HT6 receptors.
The tetrahydropyridindoles substituted at the 9-posi-
tion were synthesized starting from 1,2,3,4-tetrahydro-
9H-pyrido[3,4-b]indole (16). Compound 16 is commer-
cially available. Protection of the basic nitrogen of
compound 16 gave compound 17, which was reacted
with the corresponding alkyl halide or acid halide. After
removal of the protective group, compounds 20c-j were
obtained (Scheme 2).24
Compound 7 could not be prepared via N-alkylation
of compound 6, so it was synthesized starting from
benzindole 21 (Scheme 3). Compound 22 was prepared
by reacting compound 21 with sodium hydride and
iodomethane, and the tetrahydrobenzindole 7 was ob-
tained from compound 22 by catalytic hydrogenation
using Raney Ni.
Ch em istr y
The synthetic procedures to the target compounds are
illustrated in Scheme 1. Compound 6 is commercially
available. Compound 9 was prepared by treating tet-
rahydrobenzindole 6 with sodium hydride and 1,4-
dibromobutane.22 This alkylation procedure did not
provide the N-alkylated product. A previous paper
described that the 3-position of a 3-monosubstituted
oxindole was about 30 times as reactive as the 1-posi-
tion.23 In view of the report, our result that compound
6 was not N-alkylated was reasonable. Compound 12
was prepared from compound 9 by Friedel-Crafts
reaction. Compound 13 was obtained from compound 9

Tetrahydrobenzindole Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11 2199
Sch em e 2a
Ta ble 1. 5-HT7 and 5-HT2 Receptor Affinities for Compounds
23a -o
pKia
b
c
compd
R3
5HT7
5HT2
23a
23b
23c
23d
23e
23f
23g
23h
23i
23j
23k
23l
23m
23n
23o
1
phenyl
8.48 ( 0.02
8.29 ( 0.08
8.63 ( 0.02
7.69 ( 0.11
7.91 ( 0.06
8.42 ( 0.67
7.76 ( 0.14
8.10 ( 0.08
7.13 ( 0.11
7.62 ( 0.15
7.98 ( 0.08
6.83 ( 0.10
8.73 ( 0.09
7.34 ( 0.10
7.37 ( 0.05
6.95 ( 0.10
7.19 ( 0.10
6.69 ( 0.05
7.01 ( 0.16
6.98 ( 0.07
6.05 ( 0.06
6.45 ( 0.06
5.86 ( 0.14
7.34 ( 0.07
7.35 ( 0.07
5.85 ( 0.09
7.27 ( 0.06
6.91 ( 0.08
2-methoxyphenyl
3-methoxyphenyl
4-methoxyphenyl
2-chlorophenyl
2-cyanophenyl
2-carbamoylphenyl
2-acetylphenyl
2-trifluoromethylphenyl
2-nitrophenyl
2-methylphenyl
2,6-dimethylphenyl
2-pyridyl
2-pyrimidinyl
cyclohexyl
<6
<6
9.31 ( 0.06 <6
a
b
The pKi values are means ( SEM of 8-12 values. Binding
affinity (human recombinant receptors in mammalian cells; [3H]5-
CT). c Binding affinity (rat cerebral cortex membranes; [3H]ket-
anserin).
a
Reagents: (a) (Boc)2O, K2CO3, 2-propanol/H2O; (b) correspond-
ing halide or acid halide, NaH (55%), DMF; (c) (i) NaOH(aq), THF,
(ii) methylamine(aq), DCC, HOBt, CH3CN; (d) TFA, anisole,
CHCl3.
Tables 1-4. Most of compounds 23a -26j exhibited
moderate to high affinity for the 5-HT7 receptor.
Sch em e 3a
Some of the piperazine derivatives 23a -o showed
high affinity for the 5-HT7 receptor (Table 1). The
phenylpiperazine derivative 23a and the 2-methoxy-
phenylpiperazine 23b showed high affinity for the 5-HT7
receptor with selectivity over the 5-HT2 receptor. The
3-substituted phenylpiperazine 23c also showed high
affinity for the 5-HT7 receptor, but the 4-substituted
phenylpiperazine 23d had lower affinity than 23b,c.
These results suggested that substituent position is
important in determining 5-HT7 receptor affinity. The
other 2-substituted phenylpiperazines 23e-k also had
moderate to high affinity for the 5-HT7 receptor (pKi )
7.13-8.42), with selectivity over the 5-HT2 receptor.
There was no marked difference between the effects on
5-HT7 receptor affinity of an electron-donating substitu-
ent and those of an electron-withdrawing substituent
on the phenyl ring. The 2,6-disubstituted phenylpip-
erazine 23l showed lower affinity for the 5-HT7 receptor
compared with the 2-substituted phenylpiperazines
23b,e-k . This may be due to a conformational differ-
ence generated by rotation around the bond between the
phenyl ring and the piperazine ring. Although pyridyl-
piperazine 23m was a highly potent 5-HT7 ligand,
pyrimidinylpiperazine 23n was not. The cyclohexylpi-
perazine 23o showed affinity for neither the 5-HT7
receptor nor the 5-HT2 receptor. Thus, affinity for the
5-HT7 receptor would appear to depend on the aroma-
ticity of these compounds. The carbamoylphenyl deriva-
tive 23g and the acetylphenyl derivative 23h were the
most selective ligands for the 5-HT7 receptor among the
series of piperazine derivatives 23a -o. 5-CT (1), which
has a carbamoyl moiety, is also a highly selective ligand
for the 5-HT7 receptor over the 5-HT2 receptor. Thus, a
carbamoyl moiety would appear to be important for high
5-HT7 receptor selectivity over the 5-HT2 receptor. The
carbamoyl group and the acetyl group are the hydrogen
a
Reagents: (a) MeI, NaH (55%), DMF, 0 °C to room temp; (b)
Raney Ni, EtOH, H2.
P h a r m a cology
Compounds 23a -26j were evaluated for in vitro
affinity for 5-HT7 and 5-HT2 receptors by means of
radioligand binding assays. Compound 26j was also
evaluated for in vitro affinity for 5-HT7, 5-HT2, 5-HT1A
,
5-HT1B, 5-HT2C, 5-HT3, 5-HT4, and 5-HT6 receptors by
means of radioligand binding assays. The specific
ligands and tissue sources used were as follows: (a)
5-HT7 receptors, [3H]5-CT, human recombinant recep-
tors in mammalian cells; (b) 5-HT2 receptors, [3H]-
ketanserin, rat cerebral cortex membranes;25 (c) 5-HT1A
receptors, [3H]8-OH-DPAT, human recombinant recep-
tors in mammalian cells;26 (d) 5-HT1B receptors, [125I]-
(-)-iodocyanopindolol, rat striatal;27 (e) 5-HT2C recep-
tors, [3H]mesulergine, pig choroids plexus;27 (f) 5-HT3
receptors, [3H]GR-65630, N1E-115 cells;28 (g) 5-HT4
receptors, [3H]GR-113808, guinea-pig striatum;29 (h)
5-HT6 receptors, [3H]LSD, human recombinant recep-
tors in mammalian cells.30
The agonist and antagonist activity of compound 26j
at the 5-HT7 receptor was evaluated in terms of the
influence on 5-HT-induced stimulation of cAMP ac-
cumulation in HEK293 cells transfected with an expres-
sion vector containing human 5-HT7 receptor cDNA.
Resu lts a n d Discu ssion
The results of the in vitro binding studies of com-
pounds 23a -26j, expressed as pKi, are summarized in

2200 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11
Kikuchi et al.
Ta ble 2. 5-HT7 and 5-HT2 Receptor Affinities of Compounds
24a -e
Ch a r t 2
pKia
rivatives 25a -h . The 4-phenyltetrahydropyridine de-
rivative 5 (DR4004) has high affinity and selectivity for
the 5-HT7 receptor, so the 4-phenyltetrahydropyridines
25a -h were evaluated for affinity for the 5-HT7 and
5-HT2 receptors. The 4-fluorophenyl derivative 25a and
the 4-methylphenyl derivative 25b were as potent as
compound 5. This information will be applicable to the
improvement of the pharmacokinetic property.
b
c
compd
R4
5HT7
5HT2
24a
24b
24c
24d
24e
H-
HO-
CH3O-
H2NCO-
CH3CO-
8.40 ( 0.11
7.36 ( 0.14
7.66 ( 0.09
6.65 ( 0.24
7.14 ( 0.12
6.84 ( 0.12
6.35 ( 0.08
6.43 ( 0.19
7.80 ( 0.09
7.01 ( 0.10
a
b
The pKi values are means ( SEM of 8-12 values. Binding
affinity (human recombinant receptors in mammalian cells; [3H]5-
CT). c Binding affinity (rat cerebral cortex membranes; [3H]ket-
anserin).
As the next step, the tetrahydrobenzindole moiety was
modified. The N-methyltetrahydrobenzindole 25c showed
a lower affinity for the 5-HT7 receptor compared with
the unsubstituted tetrahydrobenzindole 5. The 6-sub-
stituted tetrahydrobenzindoles 25d -h showed a lower
selectivity than 5 for the 5-HT7 receptor. The acetyl
derivative 25d , the methoxyl derivative 25e, and the
carbamoyl derivative 25g lacked selectivity for the
5-HT7 receptor and also had low affinity for this recep-
tor. There was no appreciable difference between the
effect on 5-HT7 receptor affinity of an electron-donating
substituent and that of an electron-withdrawing sub-
stituent. The bromo derivative 25f had moderate affinity
and selectivity for the 5-HT7 receptor. Although the
hydroxyl derivative 25h showed high affinity for the
5-HT7 receptor, this derivative had lower selectivity
than 5. These results suggested that a large substituent
at the 6-position reduces the affinity for the 5-HT7
receptor. This series 25c-h thus showed lower selectiv-
ity than compound 5 for the 5-HT7 receptor, so it was
not further evaluated.
Ta ble 3. 5-HT7 and 5-HT2 Receptor Affinities of Compounds
25a -h
pKia
b
c
compd
R1
R2
R5
5HT7
5HT2
25a
H-
H-
H-
H-
4-fluoro-
phenyl
8.45 ( 0.05 7.10 ( 0.04
25b
H-
4-methyl- 8.32 ( 0.10 6.94 ( 0.11
phenyl
25c
25d
25e
25f
25g
25h
5
CH3- phenyl
7.60 ( 0.06 6.88 ( 0.06
7.01 ( 0.13 7.12 ( 0.11
6.96 ( 0.12 7.55 ( 0.23
6.38 ( 0.10 6.80 ( 0.09
7.91 ( 0.13 6.54 ( 0.09
8.09 ( 0.06 7.40 ( 0.13
8.67 ( 0.07 7.01 ( 0.05
CH3OC- H-
CH3O- H-
H2NOC- H-
Br-
HO-
H-
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
H-
H-
H-
The 4-phenyltetrahydropyridine 5 has higher affinity
and selectivity than the phenylpiperazine 23a and the
phenylpiperidine 24a for the 5-HT7 receptor. This could
be due to the influence of the conjugated double bond
on the conformation of the 4-phenyltetrahydropyridine.
The 4-phenyltetrahydropyridine can be presumed to
adopt a planar conformation, which may be important
for the 5-HT7 receptor affinity and selectivity.
a
b
The pKi values are means ( SEM of 8-12 values. Binding
affinity (human recombinant receptors in mammalian cells; [3H]5-
CT). c Binding affinity (rat cerebral cortex membranes; [3H]ket-
anserin).
bond acceptors, and this nature may contribute to high
5-HT7 selectivity.
The 4-phenylpiperidine 24a showed high potency for
the 5-HT7 receptor, and 24a had higher selectivity than
the phenylpiperazine derivative 23a . To find the deriva-
tives with high selectivity for the 5-HT7 receptor, the
R4 group was modified and 24b-e were synthesized
(Table 2). However, these 4,4-disubstituted piperidine
derivatives 24b-e were less potent and less selective
than 24a for the 5-HT7 receptor. The hydroxyl derivative
24b and the methoxyl derivative 24c showed moderate
affinity for the 5-HT7 receptor, while the carbamoyl
derivative 24d showed low affinity for the 5-HT7 recep-
tor. The carbamoyl derivative 24d and the acetyl
derivative 24e did not show selectivity for the 5-HT7
receptor. Thus, the 4,4-disubstituted piperidine deriva-
tives 24b-e did not have high affinity for the 5-HT7
receptor. These results suggested that the size of the
R4 group influences the binding to the 5-HT7 receptor.
The small R4 groups may be preferred for the 5-HT7
receptor binding.
F u r th er Mod ifica tion . We mentioned that the low
5-HT7 affinity of 2,6-disubstituted phenylpiperazine 23l
might be due to the conformational difference generated
by rotation around the bond between the phenyl ring
and the piperazine ring. To rationalize the hypothesis,
we carried out the energy minimization of model
compounds and superimposed their lowest energy con-
formations. The 2,6-dimethylphenylpiperazine 27 and
the phenylpiperazine 28 were chosen as the model
compounds (Chart 2). As can be seen in Figure 1, 2,6-
disubstitued phenylpiperazine 27 showed no planar
conformation and the superimposition of 27 and 28 did
not show a good match. This conformational difference
may have a critical influence on the affinity and
selectivity of these derivatives for the 5-HT7 receptor.
To test this idea, the tetrahydropyridoindole deriva-
tives 26a -j were synthesized and evaluated (Table 4).
The tetrahydropyridoindoles have the phenyl ring fixed
to the tetrahydropyridine ring by C-N bonds (Scheme
4). All of the tetrahydropyridoindole derivatives 26a -j
Table 3 summarized the affinities for the 5-HT7 and
5-HT2 receptors of the 4-phenyltetrahydropyridine de-

Tetrahydrobenzindole Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11 2201
Ta ble 5. Receptor Binding Profile of 26ja
receptor
affinity (pKi)b
receptor
affinity (pKi)b
5-HT1A
5-HT1B
5-HT2C
5-HT2
6.89 ( 0.13
5-HT3
5-HT4
5-HT6
5-HT7
<6
<6
<6
<6
6.31 ( 0.06
<6
8.45 ( 0.04
a
b
See Pharmacology section. The pKi values are means ( SEM
of 8-12 values.
F igu r e 1. Superimposition of the lowest energy conformation
of the model compound 27 (pink carbons) and 28 (green
carbons): front view (left) and side view (right).
Ta ble 4. 5-HT7 and 5-HT2 Receptor Affinities for Compounds
26a -j
pKia
b
c
compd
R6
H-
CH3O- H-
R7
5HT7
5HT2
26a
26b
26c
26d
26e
26f
26g
26h
26i
H-
CH3-
8.24 ( 0.08
7.53 ( 0.14
7.72 ( 0.12
7.77 ( 0.13
8.19 ( 0.06
8.22 ( 0.09
8.15 ( 0.09
8.06 ( 0.16
6.62 ( 0.09
6.17 ( 0.06
6.28 ( 0.06
6.24 ( 0.06
6.27 ( 0.06
6.55 ( 0.16
6.12 ( 0.05
6.09 ( 0.10
F igu r e 2. 5-HT-induced stimulation of cAMP accumulation
in HEK293 cells expressing the 5-HT7 receptor and its inhibi-
tion by compound 26j. Data represent the mean ( SEM of at
least three determinations.
H-
H-
H-
H-
H-
H-
H-
H-
CH3OCH2-
CH3CO-
CH2dCHCH2-
(CH3)2NCO-
H2NCOCH2-
As can be seen in Table 4, compounds 26a -j showed
high 5-HT7 receptor selectivity. These results support
the idea that the conformational difference generated
by rotation around the bond between the phenyl ring
and the cyclic amine moiety is important for 5-HT7
receptor affinity and selectivity. The tetrahydropyrido-
indoles have the phenyl ring fixed to the tetrahydro-
pyridine ring by C-N bonds, and this planar structure
may impair the binding ability to the 5-HT2 receptor.
On the basis of its relative affinity for the 5-HT7 and
5-HT2 receptors, compound 26j was selected for further
evaluation. As can be seen in Table 5, compound 26j
had high selectivity over a number of other key recep-
tors. Thus, compound 26j was confirmed to be a high-
affinity ligand for the 5-HT7 receptor with high selec-
tivity.
Compound 26j was next evaluated for influence on
5-HT-induced stimulation of cAMP accumulation in
HEK293 cells expressing the human 5-HT7 receptor.
Intracellular cAMP formation was measured by enzyme
immunoassay. Compound 26j on its own did not stimu-
late basal activity (i.e., it lacked agonist activity), but
it inhibited 5-HT-induced stimulation of cAMP ac-
cumulation (Figure 2). Compound 26j is thus a 5-HT7
receptor antagonist.
(CH3)2NCOCH2- 7.72 ( 0.12 <6
(CH3)HNCOCH2- 8.45 ( 0.04 <6
26j
a
b
The pKi values are means ( SEM of 8-12 values. Binding
affinity (human recombinant receptors in mammalian cells; [3H]5-
CT). c Binding affinity (rat cerebral cortex membranes; [3H]ket-
anserin).
Sch em e 4
showed high selectivity for the 5-HT7 receptor. The
6-methoxy derivative 26b had lower affinity for the
5-HT7 receptor than the unsubstituted derivative 26a ,
and the 9-methyl derivative 26c and the 9-methoxy-
methyl derivative 26d also had lower affinity compared
with 26a . The 9-acetyl derivative 26e and the 9-allyl
derivative 26f were as potent and selective as compound
26a. The 9-dimethylcarbamoyl derivative 26g had higher
selectivity than 26a for the 5-HT7 receptor. To find
derivatives with higher selectivity for the 5-HT7 recep-
tor, we modified the carbamoyl moiety. The 9-carbam-
oylmethyl derivative 26h was as potent and selective
as compound 26g, and the 9-dimethylcarbamoylmethyl
derivative 26i had lower affinity than compound 26g.
The dimethylcarbamoylmethyl group may be too large
to show high affinity. Finally, the 9-methylcarbamoyl-
methyl derivative 26j showed both high affinity and
high selectivity. Compound 26j had a pKi of 8.45 for the
5-HT7 receptor, with more than 280-fold selectivity over
the 5-HT2 receptor. This result also suggested that a
carbamoyl moiety is important for high selectivity for
the 5-HT7 receptor over the 5-HT2 receptor.
Con clu sion
Tetrahydrobenzindoles were prepared, and the affini-
ties of these compounds for the 5-HT7 and 5-HT2
receptors were evaluated. Most of the tetrahydrobenz-
indole derivatives showed high affinity for the 5-HT7
receptor. The tetrahydropyridindolylbutyltetrahydro-
benzindole derivatives (26a -j) had high selectivity for
the 5-HT7 receptor. The nature of the substituent at the
9-position of the tetrahydropyridindole ring affected the
affinity for the 5-HT7 receptor, and the 9-carbamoyl

2202 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11
Kikuchi et al.
d, J ) 8.1 Hz), 7.94 (1H, d), 8.76 (1H, br s); TSPMS m/z 368,
366 (M + H+).
derivatives showed increased selectivity. Compound 26j
(DR4365) exhibited high affinity for the 5-HT7 receptor,
with high selectivity over the 5-HT2 receptor and other
related receptors. In a functional model of 5-HT7 recep-
tor activation, compound 26j was confirmed to be a
5-HT7 receptor antagonist. This compound should be a
useful tool for clarifying the biological role of the 5-HT7
receptor.
6-Br om o-2a -(4-br om obu tyl)-2a ,3,4,5-tetr a h yd r oben zo-
[cd ]in d ol2(1H)-on e (13). Br2 (0.57 mL, 11 mmol) was added
to 9 (3.1 g, 10 mmol) in 1,2-dichloroethane (120 mL) at -20
°C. The mixture was stirred at -20 °C for 30 min and then
was added to saturated aqueous NaHCO3. The whole was
extracted with CHCl3. The combined organic layers were
washed with saturated aqueous NaHCO3 and brine, dried
(MgSO4), and evaporated. The residue was purified by silica
gel column chromatography (eluent: hexane/AcOEt ) 4/1) to
afford 13 as a colorless solid (3.4 g, 88% yield). 1H NMR
(CDCl3) δ 1.20-1.53 (3H, m), 1.68-1.89 (4H, m), 1.89-2.00
(1H, m), 2.08-2.20 (2H, m), 2.74 (2H, t, J ) 7.0 Hz), 3.32 (2H,
t, J ) 6.8 Hz), 6.59 (1H, d, J ) 7.2 Hz), 7.23 (1H, br s), 7.34
(1H, d); EIMS m/z 389, 387, 385 (M+).
Exp er im en ta l Section
Melting points were determined on a Yanaco melting point
apparatus. Elemental analyses were performed by the Toray
Research Center and were within (0.4% of calculated values.
The 1H NMR spectra were recorded on J EOL J NM-GX400 and
J NM-LA400 spectrometers with chemical shifts reported in
ppm relative to internal tetramethylsilane. Electron-impact
(EI) mass spectra were recorded on a Hitachi M-80B instru-
ment. Fast-atom bombardment (FAB) mass spectra were
recorded on a J EOL J MS-700 instrument. Thermospray (TSP)
mass spectra were recorded on a Hewlett-Packard 5989A
instrument.
1-Me t h yl-2a ,3,4,5-t e t r a h yd r ob e n zo[cd ]in d ol-2(1H )-
on e (7). A mixture of benz[cd]indole-2(1H)-one (5.1 g, 30
mmol) and NaH (55% oil suspension, 1.2 g, 30 mmol) in DMF
(100 mL) was stirred at 0 °C for 20 min. Methyl iodide (2.6
mL, 42 mmol) was added dropwise to the mixture, and the
whole was stirred at room temperature for 1 h and then was
added to H2O. This mixture was extracted with AcOEt. The
organic layer was washed with H2O and brine, dried (MgSO4),
and evaporated to afford 22 as yellow solid (4.7 g, 74% yield).
A mixture of 22 (4.5 g, 25 mmol) and Raney Ni in EtOH (100
mL) was stirred under 1 atm of H2 for 30 h. Raney Ni was
removed by filtration, and the filtrate was evaporated. The
residue was purified by silica gel column chromatography
(eluent: diisopropyl ether) to afford 7 as a colorless solid (3.8
g, 83% yield). 1H NMR (CDCl3) δ 1.22-1.40 (1H, m), 1.80-
2.00 (1H, m), 2.06-2.20 (1H, m), 2.36-2.50 (1H, m), 2.53-
2.70 (1H, m), 2.81-2.99 (1H, m), 3.20-3.32 (4H, m), 6.60 (1H,
d, J ) 7.9 Hz), 6.80 (1H, d, J ) 7.9 Hz), 7.16 (1H, dd); EIMS
m/z 187 (M+).
2a -(4-Br om obu tyl)-2a ,3,4,5-tetr a h yd r oben zo[cd ]in d ol-
2(1H)-on e (9). A mixture of 2a,3,4,5-tetrahydrobenzo[cd]indol-
2(1H)-one (10 g, 58 mmol) and NaH (55% oil suspension, 2.5
g, 58 mmol) in DMF (100 mL) was stirred at 0 °C for 1 h. 1,4-
Dibromobutane (35 mL, 290 mmol) in dry DMF (50 mL) was
added dropwise to the reaction mixture at -40 °C. The mixture
was stirred at 0 °C for 30 min and then was added to H2O.
The whole was extracted with AcOEt. The combined organic
layers were washed with brine, dried (MgSO4), and evaporated.
The residue was purified by silica gel column chromatography
(eluent: hexane/AcOEt ) 4/1) to afford 9 as crystals (9.5 g,
54% yield). Mp 81 °C;1H NMR (CDCl3) δ 1.17-1.28 (1H, m),
1.32-1.51 (2H, m), 1.72-1.90 (5H, m), 2.06-2.19 (2H, m),
2.60-2.70 (1H, m), 2.80-2.89 (1H, m), 3.30 (2H, t, J ) 7.0
Hz), 6.67 (1H, d, J ) 7.4 Hz), 6.81 (1H, d, J ) 7.8 Hz), 7.12
(1H, dd), 7.34 (1H, br s); EIMS m/z 309, 307 (M+). Anal.
(C15H18BrNO) C, H, N.
6-Meth oxycar bon yl-2a-(4-br om obu tyl)-2a,3,4,5-tetr ah y-
d r ob en zo[cd ]in d ol-2(1H )-on e (12). Bis(trichloromethyl)-
carbonate (1.4 g, 4.9 mmol) was added to a suspension of AlCl3
(3.0 g, 15 mmol) in 1,2-dichloroethane (30 mL) at 0 °C. A
solution of 9 (1.5 g, 1.6 mmol) in 1,2-dichloroethane (30 mL)
was added to the mixture, and the whole was stirred for 2 h
at 0 °C. MeOH (50 mL) was added, and stirring was continued
for 1 h at room temperature. The reaction mixture was poured
into 1 N aqueous HCl and extracted with CHCl3. The combined
organic layers were dried (Na2SO4) and evaporated. The
residue was purified by silica gel column chromatography
(eluent: hexane/AcOEt ) 1/1) and then recrystallized from
hexane/AcOEt ) 1/1 to afford 12 as colorless crystals (0.63 g,
35% yield). Mp 127 °C; 1H NMR (CDCl3) δ 1.13-1.30 (1H, m),
1.34-1.51 (2H, m), 1.62-1.96 (5H, m), 2.07-2.22 (2H, m),
3.01-3.12 (1H, m), 3.23-3.37 (3H, m), 3.87 (3H, s), 6.81 (1H,
6-Hydr oxy-2a-(4-br om obu tyl)-2a,3,4,5-tetr ah ydr oben zo-
[cd ]in d ol2(1H)-on e (14). A mixture of 11 (2.9 g, 8.3 mmol),
mCPBA (3.6 g, 21 mmol), and trifluoroacetic acid (0.64 mL,
8.3 mmol) in CH2Cl2 (60 mL) was stirred at 0 °C for 45 min
and then at room temperature for 2 h. It was poured into
CHCl3 and washed with saturated aqueous NaHCO3 and
brine. The organic layer was dried over MgSO4 and evaporated
to afford a residue. Sodium methoxide (1.9 mL, 33 mmol) was
added to a suspension of the residue in MeOH (90 mL) at 0
°C, and the mixture was stirred for 1 h. Aqueous HCl (5 N, 4
mL) was added to the reaction mixture, and the whole was
evaporated. The residue was dissolved in CHCl3, and the
organic layer was washed with 0.1 N aqueous HCl and brine,
dried (MgSO4), and evaporated. The residue was purified by
silica gel column chromatography (eluent: hexane/AcOEt )
2/1) to afford 14 as a colorless solid (1.2 g, 44% yield). 1H NMR
(CDCl3) δ 1.30-1.52 (3H, m), 1.70-1.98 (5H, m), 2.03-2.19
(2H, m), 2.60-2.80 (2H, m), 3.31 (2H, t, J ) 6.8 Hz), 4.66 (1H,
s), 6.56 (1H, d, J ) 8.0 Hz), 6.59 (1H, d), 7.23 (1H, br s); EIMS
m/z 325, 323 (M+).
6-Meth oxy-2a -(4-br om obu tyl)-2a ,3,4,5-tetr a h yd r oben -
zo[cd ]in d ol-2(1H)-on e (15). A solution of 14 (520 mg, 1.6
mmol), methyl iodide (2.0 mL, 3.2 mmol), and K2CO3 (450 mg,
3.3 mmol) in acetone (4 mL) was stirred at room temperature
for 17 h. The reaction mixture was poured into AcOEt and
was washed with H2O. The organic layer was dried (Na2SO4)
and evaporated. The residue was purified by silica gel column
chromatography (eluent: hexane/AcOEt ) 2/1) to afford 15
as colorless solid (310 mg, 56% yield). 1H NMR (CDCl3) δ 1.16-
1.50 (3H, m), 1.67-1.95 (5H, m), 2.12-2.16 (2H, m), 2.54-
2.65 (1H, m), 2.72-2.82 (1H, m), 3.07 (2H, t, J ) 7.2 Hz), 3.79
(3H, s), 6.61 (1H, d, J ) 8.3 Hz), 6.65 (1H, d), 8.22 (1H, br s);
TSPMS m/z 340, 338 (M + H+).
2-ter t-Bu t oxyca r b on yl-2,3,4,9-t et r a h yd r o-1H -p yr id o-
[3,4-b]in d ole (17). A mixture of 1,2,3,4-tetrahydro-9H-pyrido-
[3,4-b]indole (2.5 g, 15 mmol), di-tert-butyl dicarbonate (4.0
mL, 17 mmol), and K2CO3 (2.4 g, 17 mmol) in 2-propanol/
H2O ) 5/6 (55 mL) was stirred at room temperature for 17 h.
The reaction mixture was poured into AcOEt and was washed
with H2O. The organic layer was dried (Na2SO4) and evapo-
rated. The residue was recrystallized from hexane/AcOEt )
1/1 to afford 17 as colorless crystals (3.9 g, 98% yield). Mp 151
1
°C; H NMR (CDCl3) δ 1.50 (9H, s), 2.80 (2H, br s), 3.77 (2H,
br s), 4.64 (2H, br s), 7.09-7.18 (2H, m), 7.32 (1H, d, J ) 8.0
Hz), 7.48 (1H, d, J ) 7.8 Hz).
2-ter t-Bu toxyca r bon yl-9-m eth oxyca r bon ylm eth yl-1,2,-
3,4-tetr a h yd r op yr id o[3,4-b]in d ole (18). A mixture of 17
(0.99 g, 3.6 mmol) and NaH (55% oil suspension, 0.22 g, 5.0
mmol) in DMF (12 mL) was stirred at room temperature for
30 min. Methyl bromoacetate (0.52 mL, 5.5 mmol) was added
dropwise to the reaction mixture. The mixture was stirred at
room temperature for 17 h and then was added to H2O. The
whole was extracted with AcOEt. The combined organic layers
were washed with brine, dried (Na2SO4), and evaporated. The
residue was purified by silica gel column chromatography
(eluent: hexane/AcOEt ) 1/3) to afford 18 as a solid (0.96 g,
77% yield). 1H NMR (CDCl3) δ 1.50 (9H, s), 2.79 (2H, br s),

Tetrahydrobenzindole Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11 2203
3.72 (3H, s), 3.74 (2H, br s), 4.56 (2H, s), 4.68 (2H, s), 7.08-
7.18 (3H, m), 7.48 (1H, d, J ) 7.5 Hz).
m), 1.24-1.50 (4H, m), 1.75-1.92 (3H, m), 2.05-2.20 (2H, m),
2.22-2.35 (2H, m), 2.47-2.55 (4H, m), 2.60-2.69 (1H, m),
2.79-2.89 (1H, m), 3.12-3.18 (4H, m), 3.78 (3H, s), 6.40 (1H,
dd, J ) 8.2, 2.3 Hz), 6.44 (1H, d, J ) 2.3 Hz), 6.52 (1H, dd,
J ) 8.4 Hz), 6.66 (1H, d, J ) 7.6 Hz), 6.81 (1H, d, J ) 7.6 Hz),
7.09-7.17 (2H, m), 7.31 (1H, br s); EIMS m/z 419 (M+).
2-ter t-Bu toxyca r bon yl-9-m eth ylca r ba m oylm eth yl-1,2,-
3,4-tetr a h yd r op yr id o[3,4-b]in d ole (19j). A mixture of 18
(0.62 g, 1.8 mmol) and aqueous NaOH (2.7 N, 5 mL) in THF
(10 mL) was stirred at room temperature for 17 h. Aqueous
HCl (1 N, 10 mL) was added dropwise to the reaction mixture.
The whole was extracted with CHCl3. The organic layer was
washed with brine, dried (Na2SO4), and evaporated. A mixture
of the residue, DCC (560 mg, 2.7 mmol), and HOBT (370 mg,
2.7 mmol) in CH3CN (12 mL) was stirred at room temperature
for 2 h. Then 40% aqueous methylamine (2.0 mL, 23 mmol)
was added to the mixture at 0 °C and the whole was stirred
at room temperature for 30 min. The reaction mixture was
filtrated and evaporated. The residue was purified by silica
gel column chromatography (eluent: CHCl3/MeOH ) 30/1) to
afford 19j as a solid (0.54 g, 88% yield). 1H NMR (CDCl3) δ
1.50 (9H, s), 2.70 (3H, s), 2.80 (2H, br s), 3.76 (2H, br s), 4.54
(2H, s), 4.58 (2H, s), 5.66 (1H, br s), 7.13 (3H, m), 7.50 (1H, d,
J ) 7.5 Hz).
Hydrochloride. Mp 232 °C (dec) (AcOEt/MeOH). Anal. (C26H33
-
N3O2‚2HCl‚2/5H2O) C, H, N.
2a -[4-[4-(4-Meth oxyp h en yl)p ip er a zin yl]bu tyl]-2a ,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23d ). This compound
was prepared from 9 and 1-(4-methoxyphenyl)piperazine
1
hydrochloride (61% yield). H NMR (CDCl3) δ 1.03-1.14 (1H,
m), 1.25-1.52 (4H, m), 1.75-1.91 (3H, m), 2.05-2.20 (2H, m),
2.23-2.35 (2H, m), 2.50-2.57 (4H, m), 2.60-2.70 (1H, m),
2.80-2.90 (1H, m), 3.01-3.09 (4H, m), 3.76 (3H, s), 6.66 (1H,
dd, J ) 7.8 Hz), 6.79-6.89 (5H, m), 7.11 (1H, dd, J ) 7.4 Hz),
7.29 (1H, br s); EIMS m/z 419 (M+). Hydrochloride. Mp 165-
166 °C (MeOH). Anal. (C26H33N3O2‚2HCl‚1/2H2O) C, H, N.
2a -[4-[4-(2-Ch lor op h en yl)p ip er a zin yl]b u t yl]-2a ,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23e). This compound
was prepared from 9 and 1-(2-chlorophenyl)piperazine hydro-
chloride (95% yield). 1H NMR (CDCl3) δ 1.03-1.16 (1H, m),
1.29-1.51 (4H, m), 1.76-1.92 (3H, m), 2.06-2.20 (2H, m),
2.26-2.39 (2H, m), 2.51-2.69 (5H, m), 2.80-2.90 (1H, m),
3.00-3.08 (4H, m), 6.67 (1H, d, J ) 8.0 Hz), 6.81 (1H, d, J )
7.6 Hz), 6.95 (1H, ddd, J ) 8.0, 7.2, 1.5 Hz), 7.03 (1H, dd),
7.12 (1H, dd), 7.20 (1H, ddd), 7.26 (1H, br s), 7.34 (1H, dd);
EIMS m/z 425, 423 (M+). Hydrochloride. Mp 153-154 °C
(AcOEt/MeOH). Anal. (C25H30N3O‚2HCl) C, H, N.
9-Met h ylca r b a m oylm et h yl-1,2,3,4-t et r a h yd r op yr id o-
[3,4-b]in d ole (20j). A mixture of 19j (0.54 g, 1.6 mmol),
anisole (1 mL), and trifluoroacetic acid (1 mL) in CH3Cl (10
mL) was stirred at room temperature for 17 h. The reaction
mixture was evaporated. The residue was washed with acetone
and diisopropyl ether to afford 20j trifluoroacetate as a solid
1
(0.47 g, 89% yield). H NMR (CDCl3) δ 2.75 (3H, s), 3.10 (2H,
t, J ) 6.0 Hz), 3.59 (2H, t), 4.49 (2H, s), 4.78 (2H, s), 7.12 (1H,
dd, J ) 8.0, 7.2 Hz), 7.22 (1H, dd, J ) 7.6 Hz), 7.33 (1H, d),
7.52 (1H, d); EIMS m/z 243 (M+).
2a -[4-[4-(2-Cya n op h en yl)p ip er a zin yl]b u t yl]-2a ,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23f). This compound
was prepared from 9 and 1-(2-cyanophenyl)piperazine (97%
Gen er a l P r oced u r e for th e Syn th esis of Com p ou n d s
23a -o, 24a -e, 25a -e, 25f,g, a n d 26a -i. 2a -[4-(9-Meth yl-
ca r ba m oylm et h yl-1,2,3,4-t et r a h yd r op yr id o[3,4-b]in d ol-
2-yl)b u t yl]-2a ,3,4,5-t et r a h yd r ob en z[cd ]in d ol-2(1H )-on e
(26j). A mixture of the bromide 9 (0.31 g, 1.0 mmol), 9-meth-
ylcarbamoylmethyl-1,2,3,4-tetrahydropyrido[3,4-b]indole tri-
fluoroacetate (0.33 g, 1.0 mmol), and K2CO3 (0.42 g, 3.0 mmol)
in DMF (6 mL) was stirred at room temperature for 4 days
and evaporated. The residue was added to AcOEt, and the
solution was washed with brine, dried (Na2SO4), and evapo-
rated. The residue was purified by silica gel column chroma-
tography (eluent: CHCl3/MeOH ) 30/1) to afford 26j as
crystals (0.40 g, 85% yield). 1H NMR (CDCl3) δ 1.17-1.20 (1H,
m), 1.30-1.42 (2H, m), 1.43-1.59 (2H, m), 1.78-1.95 (3H, m),
2.06-2.21 (2H, m), 2.47-2.60 (2H, m), 2.60-2.74 (4H, m),
2.74-2.90 (5H, m), 3.52 (2H, s), 4.61 (2H, s), 5.42 (1H, br s),
6.67 (1H, d, J ) 7.8 Hz), 6.81 (1H, d, J ) 7.8 Hz), 7.09-7.24
(4H, m), 7.44 (1H, br s), 7.50 (1H, d, J ) 7.6 Hz); TSPMS m/z
471 (M + H+). Fumarate. Mp 184 °C (EtOH). Anal. (C29H34N4O2‚
C4H4O4) C, H, N.
1
yield). H NMR (CDCl3) δ 1.03-1.14 (1H, m), 1.30-1.50 (4H,
m), 1.75-1.92 (3H, m), 2.07-2.19 (2H, m), 2.28-2.38 (2H, m),
2.55-2.70 (5H, m), 2.80-2.90 (1H, m), 3.17-3.22 (4H, m), 6.67
(1H, d, J ) 7.6 Hz), 6.81 (1H, d, J ) 7.8 Hz), 6.96-7.00 (2H,
m), 7.12 (1H, dd), 7.36 (1H, br s), 7.44-7.49 (1H, m), 7.54 (1H,
dd, J ) 7.8, 1.5 Hz); EIMS m/z 414 (M+). Hydrochloride. Mp
184-185 °C. Anal. (C26H30N4O‚HCl‚9/10H2O) C, H, N.
2a-[4-[4-(2-Car bam oylph en yl)piper azin yl]bu tyl]-2a,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23g). This compound
was prepared from 9 and 1-(2-carbamoylphenyl)piperazine
1
(98% yield). H NMR (CDCl3) δ 1.07-1.17 (1H, m), 1.31-1.49
(4H, m), 1.75-1.92 (4H, m), 2.05-2.14 (2H, m), 2.27-2.36 (2H,
m), 2.50-2.70 (5H, m), 2.80-2.90 (1H, m), 2.98-3.03 (4H, m),
5.85 (1H, br s), 6.68 (1H, d, J ) 7.8 Hz), 6.81 (1H, d, J ) 7.8
Hz), 7.12 (1H, dd), 7.19-7.28 (2H, m), 7.45-7.60 (2H, m), 8.15
(1H, dd, J ) 8.2, 1.7 Hz), 9.51 (1H, br s); EIMS m/z 432 (M+).
Hydrochloride. Mp 145-146 °C (AcOEt/MeOH). Anal. (C26H33
-
N4O2‚HCl‚11/4H2O) C, H, N.
2a -[4-(4-P h en ylp ip er a zin yl)bu tyl]-2a ,3,4,5-tetr a h yd r o-
ben zo[cd ]in d ol-2(1H)-on e (23a ). This compound was pre-
pared from 9 and 1-phenylpiperazine hydrochloride (91%
2a -[4-[4-(2-Aceth ylp h en yl)p ip er a zin yl]bu tyl]-2a ,3,4,5-
t et r a h yd r ob en zo[cd ]in d ol-2(1H )-on e (23h ). This com-
pound was prepared from 9 and 1-(2-acetylphenyl)piperazine
1
1
yield). H NMR (CDCl3) δ 1.03-1.15 (1H, m), 1.25-1.51 (4H,
(87% yield). H NMR (CDCl3) δ 1.03-1.14 (1H, m), 1.29-1.48
m), 1.75-1.92 (3H, m), 2.07-2.20 (2H, m), 2.24-2.36 (2H, m),
2.49-2.56 (4H, m), 2.60-2.69 (1H, m), 2.80-2.88 (1H, m),
3.13-3.19 (4H, m), 6.67 (1H, d, J ) 7.6 Hz), 6.79-6.86 (2H,
m), 6.91 (2H, d, J ) 8.4 Hz), 7.11 (1H, dd), 7.22-7.29 (2H, m),
7.50 (1H, br s); EIMS m/z 389 (M+). Hydrochloride. Mp 165-
166 °C (IPE/MeOH). Anal. (C25H31N3O‚HCl‚1/2H2O) C, H, N.
(4H, m), 1.75-1.91 (3H, m), 2.06-2.19 (2H, m), 2.23-2.36 (2H,
m), 2.48-2.55 (4H, m), 2.60-2.70 (4H, m), 2.78-2.89 (1H, m),
2.95-3.00 (4H, m), 6.67 (1H, d, J ) 7.6 Hz), 6.80 (1H, d, J )
7.8 Hz), 7.12-7.14 (3H, m), 7.36-7.42 (3H, m); EIMS m/z 431
(M+). Hydrochloride. Mp 130 °C (AcOEt/MeOH). Anal. (C27
-
H
33N3O2‚2HCl‚3/2H2O) C, H, N.
2a -[4-[4-(2-Tr iflu or op h en yl)p ip er a zin yl]bu tyl]-2a ,3,4,5-
2a -[4-[4-(2-Meth oxyp h en yl)p ip er a zin yl]bu tyl]-2a ,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23b). This compound
was prepared from 9 and 1-(2-methoxyphenyl)piperazine (94%
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23i). This compound
was prepared from 9 and 1-(2-trifluorophenyl)piperazine (62%
1
1
yield). H NMR (CDCl3) δ 1.04-1.15 (1H, m), 1.26-1.51 (4H,
yield). H NMR (CDCl3) δ 1.01-1.15 (1H, m), 1.22-1.50 (4H,
m), 1.76-1.92 (3H, m), 2.07-2.20 (2H, m), 2.25-2.38 (2H, m),
2.54-2.68 (5H, m), 2.80-2.90 (1H, m), 3.05 (4H, br s), 3.85
(3H, s), 6.84 (1H, d, J ) 8.2 Hz), 6.66 (1H, d, 7.6 Hz), 6.80
(1H, d, 7.6 Hz), 6.88-7.00 (3H, m), 7.12 (1H, dd), 7.42 (1H, br
s); TSPMS m/z 420 (M + H+). Hydrochloride. Mp 170-171 °C
(AcOEt/MeOH). Anal. (C26H33N3O2×e1‚2HCl‚1/4H2O) C, H, N.
m), 1.71-1.91 (3H, m), 2.03-2.20 (2H, m), 2.25-2.39 (2H, m),
2.42-2.70 (5H, m), 2.80-3.00 (5H, m), 6.67 (1H, d, J ) 7.6
Hz), 6.81 (1H, d, J ) 7.8 Hz), 7.11 (1H, dd), 7.16-7.23 (2H,
m), 7.35 (1H, d, J ) 8.3 Hz), 7.49 (1H, t), 7.60 (1H, d); EIMS
m/z 457 (M+). Hydrochloride. Mp 233-234 °C (AcOEt/MeOH).
Anal. (C26H30N3OF3‚HCl‚2/5H2O) C, H, N.
2a -[4-[4-(3-Meth oxyp h en yl)p ip er a zin yl]bu tyl]-2a ,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23c). This compound
was prepared from 9 and 1-(3-methoxyphenyl)piperazine
2a -[4-[4-(2-Nitr op h en yl)p ip er a zin yl]bu tyl]-2a ,3,4,5-tet-
r a h yd r oben zo[cd ]in d ol-2(1H)-on e (23j). This compound
was prepared from 9 and 1-(2-nitrophenyl)piperazine (47%
1
1
hydrochloride (85% yield). H NMR (CDCl3) δ 1.03-1.15 (1H,
yield). H NMR (CDCl3) δ 1.02-1.14 (1H, m), 1.26-1.46 (4H,

2204 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11
Kikuchi et al.
m), 1.76-1.92 (3H, m), 2.04-2.20 (2H, m), 2.22-2.38 (2H, m),
2.44-2.58 (5H, m), 2.60-2.70 (1H, m), 2.80-2.90 (1H, m),
3.00-3.10 (4H, m), 6.67 (1H, d, J ) 7.8 Hz), 6.81 (1H, d, J )
7.6 Hz), 7.02 (1H, d, J ) 7.7, 1.2 Hz), 7.09-7.14 (2H, m), 7.33
(1H, br s), 7.46 (1H, td, J ) 1.7 Hz), 7.74 (1H, dd); EIMS m/z
434 (M+). Hydrochloride. Mp 228-229 °C. Anal. (C25H30N4O3‚
HCl‚1/2H2O) C, H, N.
2a -[4-[4-(2-Met h ylp h en yl)p ip er a zin yl]b u t yl]-2a ,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23k ). This compound
was prepared from 9 and 1-(2-methylphenyl)piperazine hy-
drochloride (91% yield). 1H NMR (CDCl3) δ 1.04-1.14 (1H, m),
1.28-1.51 (4H, m), 1.76-1.93 (3H, m), 2.06-2.19 (2H, m),
2.25-2.38 (5H, m), 2.44-2.70 (5H, m), 2.80-2.93 (5H, m), 6.67
(1H, d, J ) 7.8 Hz), 6.81 (1H, d, J ) 7.4 Hz), 6.95-7.01 (3H,
m), 7.10-7.17 (2H, m), 7.28 (1H, br s); EIMS m/z 403 (M+).
Hydrochloride. Mp 244 °C (MeOH). Anal. (C26H33N3O‚2HCl‚
1/2H2O) C, H, N.
2.71-2.90 (3H, m), 6.67 (1H, d, J ) 7.6 Hz), 6.81 (1H, d, J )
7.6 Hz), 7.12 (1H, dd), 7.23-7.51 (6H, m); EIMS m/z 404 (M+).
Hydrochloride. Mp 258 °C (AcOEt/MeOH). Anal. (C26H32N2O2‚
HCl) C, H, N.
2a -[4-(4-Meth oxy-4-p h en ylp ip er id in yl)bu tyl]-2a ,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (24c). This compound
was prepared from 9 and 4-methoxy-4-phenylpiperidine (96%
1
yield). H NMR (CDCl3) δ 1.04-1.16 (1H, m), 1.25-1.31 (2H,
m), 1.36-1.50 (1H, m), 1.76-1.92 (4H, m), 1.99-2.20 (6H, m),
2.38-2.53 (4H, m), 2.60-2.69 (1H, m), 2.77-2.89 (3H, m), 2.95
(3H, s), 6.67 (1H, d, J ) 7.4 Hz), 6.80 (1H, d, J ) 7.8 Hz), 7.11
(1H, dd), 7.24-7.40 (5H, m), 7.43 (1H, br s); EIMS m/z 418
(M+). Hydrochloride. Mp 243 °C (AcOEt/MeOH). Anal. (C27
H
-
34N2O2‚HCl‚1/4H2O) C, H, N.
2a-[4-(4-Car bam oyl-4-ph en ylpiper idin yl)bu tyl]-2a,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (24d ). This compound
was prepared from 9 and 4-carbamoyl-4-phenylpiperidine (75%
yield). Mp 224 °C ; 1H NMR (CDCl3) δ 0.99-1.10 (1H, m),
1.21-1.44 (4H, m), 1.70-1.88 (3H, m), 2.01-2.26 (6H, m),
2.30-2.42 (4H, m), 2.48-2.68 (3H, m), 2.78-2.88 (1H, m), 5.22
(2H, br s), 6.65 (1H, d, J ) 7.8 Hz), 6.80 (1H, d, J ) 7.8 Hz),
7.10 (1H, dd), 7.22-7.41 (6H, m); EIMS m/z 431 (M+). Anal.
(C27H33N3O2‚3/10H2O) C, H, N.
2a -[4-(4-Acetyl-4-p h en ylp ip er id in yl)bu tyl]-2a ,3,4,5-tet-
r a h yd r oben zo[cd ]in d ol-2(1H)-on e (24e). This compound
was prepared from 9 and 4-acethyl-4-phenylpiperidine (24%
yield). Mp 224 °C ; 1H NMR (CDCl3) δ 0.98-1.11 (1H, m),
1.22-1.45 (5H, m), 1.72-1.93 (7H, m), 1.98-2.27 (6H, m),
2.37-2.49 (2H, m), 2.58-2.71 (3H, m), 2.77-2.87 (1H, m), 6.66
(1H, d, J ) 7.6 Hz), 6.79 (1H, d, J ) 7.8 Hz), 7.10 (1H, dd),
7.22-7.36 (5H, m), 7.48 (1H, br s); EIMS m/z 430 (M+). Anal.
(C28H34N3O2‚1/5H2O) C, H, N.
2a -[4-[4-(4-F lu or op h en yl)-1,2,3,6-t et r a h yd r op yr id yl]-
bu tyl]-2a,3,4,5-tetr ah ydr oben zo[cd]in dol-2(1H)-on e (25a).
This compound was prepared from 9 and 4-(4-fluorophenyl)-
1,2,3,6-tetrahydropyridine (32% yield). Mp 165-166 °C ; 1H
NMR (CDCl3) δ 1.04-1.19 (1H, m), 1.29-1.56 (4H, m), 1.74-
1.93 (3H, m), 2.06-2.18 (2H, m), 2.29-2.41 (2H, m), 2.45-
2.53 (2H, m), 2.58-2.69 (3H, m), 2.80-2.89 (1H, m), 3.04-
3.09 (2H, m), 5.69 (1H, s), 6.67 (1H, d, J ) 7.6 Hz), 6.80 (1H,
d, J ) 7.8 Hz), 6.94-7.01 (2H, m), 7.11 (1H, dd), 7.28-7.34
(2H, m), 7.69 (1H, br s); EIMS m/z 404 (M+). Anal. (C26H29N2-
OF‚1/5H2O) C, H, N.
2a -[4-[4-(4-Met h ylp h en yl)-1,2,3,6-t et r a h yd r op yr id yl]-
bu tyl]-2a,3,4,5-tetr ah ydr oben zo[cd]in dol-2(1H)-on e (25b).
This compound was prepared from 9 and 4-(4-methylphenyl)-
1,2,3,6-tetrahydropyridine (26% yield). 1H NMR (CDCl3) δ
1.04-1.16 (1H, m), 1.29-1.39 (2H, m), 1.51-1.64 (2H, m),
1.77-1.92 (3H, m), 2.04-2.18 (2H, m), 2.33 (3H, s), 2.51-2.69
(5H, m), 2.80-2.90 (3H, m), 3.27-3.34 (2H, br s), 5.95 (1H, s),
6.67 (1H, d, J ) 7.6 Hz), 6.80 (1H, d, J ) 7.9 Hz), 7.09-7.14
(3H, m), 7.23-7.28 (2H, m), 7.63 (1H, br s); EIMS m/z 400
(M+). Hydrochloride. Mp 170-171 °C (AcOEt/MeOH). Anal.
(C27H32N2O‚HCl‚1/10H2O) C, H, N.
1-Meth yl-2a -[4-(4-p h en yl-1,2,3,6-tetr a h yd r op yr id yl)bu -
t yl]-2a ,3,4,5-t et r a h yd r ob en zo[cd ]in d ol-2(1H )-on e (25c).
This compound was prepared from 10 and 4-phenyl-1,2,3,6-
tetrahydropyridine hydrocloride (14% yield). Mp 110-111 °C;
1H NMR (CDCl3) δ 0.94-1.10 (1H, m), 1.10-1.35 (3H, m),
1.40-1.96 (7H, m), 2.02-2.20 (2H, m), 2.28-2.42 (1H, m),
2.50-2.58 (1H, m), 2.60-2.71 (2H, m), 2.81-2.91 (1H, m),
3.05-3.24 (5H, m), 6.02 (1H, br s), 6.64 (1H, d, J ) 7.8 Hz),
6.82 (1H, d, J ) 7.6 Hz), 7.15-7.40 (6H, m); EIMS m/z 400
(M+). Anal. (C27H32N2O‚3/5H2O) C, H, N.
6-Acetyl-2a -[4-(4-p h en yl-1,2,3,6-tetr a h yd r op yr id yl)bu -
tyl]-2a ,3,4,5-tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (25d ).
This compound was prepared from 11 and 4-phenyl-1,2,3,6-
tetrahydropyridine hydrocloride (24% yield). 1H NMR (CDCl3)
δ 1.01-1.14 (1H, m), 1.29-1.52 (4H, m), 1.76-1.95 (3H, m),
2.05-2.20 (2H, m), 2.28-2.42 (2H, m), 2.49-2.72 (7H, m),
3.04-3.16 (3H, m), 3.18-3.28 (1H, m), 6.01 (1H, m), 6.75 (1H,
d, J ) 8.0 Hz), 7.19-7.36 (5H, m), 7.72 (1H, d), 8.73 (1H, s);
TSPMS m/z 429 (M + H+). Hydrochloride. Mp 246-247 °C
(IPE/MeOH). Anal. (C28H32N2O2‚HCl‚2/3H2O) C, H, N.
2a-[4-[4-(2,6-Dim eth ylph en yl)piper azin yl]bu tyl]-2a,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (23l). This compound
was prepared from 9 and 1-(2,6-dimethylphenyl)piperazine
1
(86% yield). H NMR (CDCl3) δ 1.03-1.17 (1H, m), 1.26-1.53
(4H, m), 1.77-1.92 (3H, m), 2.08-2.20 (2H, m), 2.21-2.38 (8H,
m), 2.42-2.50 (4H, m), 2.60-2.70 (1H, m), 2.80-2.90 (1H, m),
3.03-3.11 (4H, m), 6.67 (1H, d, J ) 7.8 Hz), 6.81 (1H, d, J )
7.8 Hz), 6.90-7.00 (3H, m), 7.12 (1H, dd), 7.40 (1H, br s);
TSPMS m/z 418 (M + H+). Hydrochloride. Mp 235-236 °C
(IPE/MeOH). Anal. (C27H35N3O‚HCl‚H2O) C, H, N.
2a -[4-[4-(2-P yr id yl)p ip er a zin yl]bu tyl]-2a ,3,4,5-tetr a h y-
d r oben zo[cd ]in d ol-2(1H)-on e (23m ). This compound was
prepared from 9 and 2-pyridylpiperazine hydrochloride (100%
1
yield). H NMR (CDCl3) δ 1.03-1.52 (5H, m), 1.75-1.92 (5H,
m), 2.06-2.19 (2H, m), 2.32-2.34 (2H, m), 2.45-2.51 (4H, m),
2.60-2.69 (1H, m), 2.79-2.89 (1H, m), 3.47-3.52 (4H, m),
6.59-6.63 (2H, s), 6.67 (1H, d, J ) 7.4 Hz), 6.80 (1H, d, J )
7.8 Hz), 7.17 (1H, dd), 7.46 (1H, ddd, J ) 8.0, 7.6, 2.0 Hz),
7.62 (1H, br s), 8.17 (1H, m); TSPMS m/z 391 (M + H+).
Hydrochloride. Mp 170 °C (IPE/MeOH). Anal. (C24H30N4O‚
2HCl‚5/4H2O) C, H, N.
2a -[4-[4-(2-P yr im id in yl)p ip er a zin yl]bu tyl]-2a ,3,4,5-tet-
r a h yd r oben zo[cd ]in d ol-2(1H)-on e (23n ). This compound
was prepared from 9 and 2-pyrimidylpiperazine hydrochloride
1
(79% yield). H NMR (CDCl3) δ 1.02-1.14 (1H, m), 1.26-1.51
(4H, m), 1.75-1.92 (3H, m), 2.06-2.18 (2H, m), 2.22-2.34 (2H,
m), 2.39-2.48 (4H, m), 2.60-2.70 (1H, m), 2.80-2.90 (1H, m),
3.77-3.79 (4H, m), 6.47 (1H, t, J ) 4.7 Hz), 6.66 (1H, d, J )
7.8 Hz), 6.80 (1H, d, J ) 7.8 Hz), 7.11 (1H, dd), 7.28 (1H, br
s), 8.29 (2H, dd, J ) 1.6 Hz); FABMS m/z 392 (M + H+).
Hydrochloride. Mp 219-220 °C (AcOEt/MeOH). Anal. (C23H29
-
N5O‚HCl‚1/2H2O) C, H, N.
2a -[4-(4-Cycloh exylp ip er a zin yl)bu tyl]-2a ,3,4,5-tetr a h y-
d r oben zo[cd ]in d ol-2(1H)-on e (23o). This compound was
1
prepared from 9 and 1-cyclohexylpiperazine (100% yield). H
NMR (CDCl3) δ 0.97-1.49 (11H, m), 1.57-1.65 (1H, m), 1.71-
1.93 (7H, m), 2.03-2.29 (5H, m), 2.33-2.69 (8H, m), 2.79-
2.89 (1H, m), 6.66 (1H, d, J ) 7.4 Hz), 6.80 (1H, d, J ) 7.8
Hz), 7.11 (1H, dd), 7.86 (1H, br s); FABMS m/z 395 (M + H+).
Hydrochloride. Mp 246 °C (dec) (AcOEt/MeOH). Anal. (C25H37
-
N3O‚2HCl‚1/2H2O) C, H, N.
2a -[4-(4-P h en ylp ip er id in yl)bu tyl]-2a ,3,4,5-tetr a h yd r o-
ben zo[cd ]in d ol-2(1H)-on e (24a ). This compound was pre-
pared from 9 and 4-phenylpiperidine hydrochloride (91% yield).
1H NMR (CDCl3) δ 1.02-1.14 (1H, m), 1.22-1.54 (4H, m),
1.75-1.93 (7H, m), 1.94-2.07 (2H, m), 2.07-2.20 (2H, m),
2.23-2.36 (2H, m), 2.41-2.51 (1H, m), 2.60-2.70 (1H, m),
2.80-2.90 (1H, m), 2.95-3.04 (2H, m), 6.67 (1H, d, J ) 7.8
Hz), 6.81 (1H, d, J ) 7.8 Hz), 7.12 (1H, dd), 7.16-7.24 (3H,
m), 7.25-7.33 (3H, m); TSPMS m/z 389 (M + H+). Hydrochlo-
ride. Mp 148-149 °C (IPE/AcOEt). Anal. (C26H32N2O‚HCl‚H2O)
C, H, N.
2a -[4-(4-Hyd r oxy-4-p h en ylp ip er id in yl)bu tyl]-2a ,3,4,5-
tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (24b). This compound
was prepared from 9 and 4-hydroxy-4-phenylpiperidine (99%
1
yield). H NMR (CDCl3) δ 1.02-1.15 (1H, m), 1.28-1.91 (9H,
m), 2.05-2.20 (4H, m), 2.25-2.43 (4H, m), 2.54-2.69 (1H, m),

Tetrahydrobenzindole Derivatives
J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11 2205
6-Meth oxy-2a -[4-(4-p h en yl-1,2,3,6-tetr a h yd r op yr id yl)-
bu tyl]-2a,3,4,5-tetr ah ydr oben zo[cd]in dol-2(1H)-on e (25e).
This compound was prepared from 15 and 4-phenyl-1,2,3,6-
tetrahydropyridine hydrocloride (50% yield). Mp 134 °C; 1H
NMR (CDCl3) δ 1.06-1.19 (1H, m), 1.27-1.55 (4H, m), 1.75-
1.90 (3H, m), 2.03-2.17 (2H, m), 2.29-2.41 (2H, m), 2.52-
2.64 (5H, m), 2.72-2.82 (1H, m), 3.03-3.13 (2H, m), 3.79 (3H,
s), 6.01 (1H, m), 6.56-6.65 (2H, m), 7.19-7.37 (5H, m), 8.07
(1H, br s); TSPMS m/z 417 (M + H+). Anal. (C27H32N2O2‚H2O)
C, H, N.
m), 1.45-1.60 (2H, m), 1.77-1.96 (3H, m), 2.00-2.10 (1H, m),
2.11-2.24 (1H, m), 2.43-2.54 (2H, m), 2.59-2.69 (1H, m),
2.72-2.90 (5H, m), 3.60 (2H, s), 3.80 (3H, s), 6.69 (2H, m), 6.79
(1H, d, J ) 7.8 Hz), 6.88 (1H, d, J ) 2.2 Hz), 7.12 (2H, m),
7.85 (1H, br s), 7.85 (1H, br s); TSPMS m/z 430 (M + H+).
Anal. (C27H31N3O2‚H2O) C, H, N.
2a -[4-(9-Meth yl-1,2,3,4-tetr a h yd r op yr id o[3,4-b]in d ol-2-
yl)bu tyl]-2a,3,4,5-tetr ah ydr oben z[cd]in dol-2(1H)-on e (26c).
This compound was prepared from 9 and 20c trifluoroacetate
(57% yield). Mp 180-181 °C; 1H NMR (CDCl3) δ 1.03-1.16
(1H, m), 1.27-1.40 (2H, m), 1.44-1.60 (2H, m), 1.74-1.93 (3H,
m), 2.02-2.18 (2H, m), 2.45-2.67 (3H, m), 2.70-2.90 (5H, m),
3.53 (3H, s), 3.60 (2H, s), 6.65 (1H, d, J ) 7.5 Hz), 6.77 (1H, d,
J ) 7.8 Hz), 7.02-7.15 (3H, m), 7.22 (1H, d, J ) 7.3 Hz), 7.43
(1H, d, J ) 7.5 Hz), 8.76 (1H, br s); TSPMS m/z 414 (M + H+).
Anal. (C27H31N3O‚1/2H2O) C, H, N.
2a -[4-(9-Meth oxym eth yl-1,2,3,4-tetr a h yd r op yr id o[3,4-
b]in dol-2yl)bu tyl]-2a,3,4,5-tetr ah ydr oben z[cd]in dol-2(1H)-
on e (26d ). This compound was prepared from 9 and 20d
trifluoroacetate (39% yield). Mp 100-101 °C; 1H NMR (CDCl3)
δ 1.06-1.16 (1H, m), 1.28-1.40 (2H, m), 1.45-1.60 (2H, m),
1.74-1.93 (3H, m), 2.01-2.18 (2H, m), 2.47-2.64 (3H, m),
2.71-2.88 (5H, m), 3.19 (3H, s), 3.67 (2H, br s), 5.30 (2H, s),
6.66 (1H, d, J ) 7.8 Hz), 6.77 (1H, d, J ) 7.8 Hz), 7.05-7.11
(2H, m), 7.16 (1H, dd), 7.37 (1H, d, J ) 8.1 Hz), 7.43 (1H, d,
J ) 7.5 Hz), 8.56 (1H, br s); TSPMS m/z 444 (M + H+). Anal.
(C28H33N3O2‚3/2H2O) C, H, N.
2a -[4-(9-Acetyl-1,2,3,4-tetr a h yd r op yr id o[3,4-b]in d ol-2-
yl)bu tyl]-2a,3,4,5-tetr ah ydr oben z[cd]in dol-2(1H)-on e (26e).
This compound was prepared from 9 and 20e trifluoroacetate
(56% yield). Mp 141-142 °C; 1H NMR (CDCl3) δ 1.02-1.15
(1H, m), 1.28-1.42 (2H, m), 1.42-1.60 (2H, m), 1.75-1.94 (3H,
m), 2.03-2.28 (2H, m), 2.44-2.55 (2H, m), 2.58-2.88 (9H, m),
3.88 (2H, s), 6.67 (1H, d, J ) 7.5 Hz), 6.77 (1H, d, J ) 7.8 Hz),
7.08 (1H, dd), 7.20-7.29 (2H, m), 7.37 (1H, d, J ) 6.8 Hz),
7.78 (1H, d, J ) 6.8 Hz), 8.55 (1H, s); TSPMS m/z 442 (M +
H+). Anal. (C28H31N3O2‚2/5H2O) C, H, N.
2a-[4-(9-Allyl-1,2,3,4-tetr ah ydr opyr ido[3,4-b]in dol-2-yl)-
bu tyl]-2a ,3,4,5-tetr a h yd r oben z[cd ]in d ol-2(1H)-on e (26f).
This compound was prepared from 9 and 20f trifluoroacetate
(46% yield). Mp 140 °C; 1H NMR (CDCl3) δ 1.06-1.18 (1H,
m), 1.30-1.42 (2H, m), 1.46-1.59 (2H, m), 1.76-1.94 (3H, m),
2.06-2.19 (2H, m), 2.46-2.57 (2H, m), 2.60-2.69 (1H, m),
2.74-2.90 (5H, m), 3.88 (2H, s), 4.54-4.60 (2H, m), 4.88 (1H,
dd, J ) 17.1, 1.3 Hz), 5.09 (1H, dd, J ) 10.3 Hz), 5.89 (1H, m),
6.67 (1H, d, J ) 7.8 Hz), 6.77 (1H, d, J ) 7.7 Hz), 7.04-7.16
(3H, m), 7.22 (1H, d, J ) 8.0 Hz), 7.36 (1H, br s), 7.46 (1H, d,
J ) 7.5 Hz); EIMS m/z 439 (M+). Anal. (C29H33N3O‚1/2H2O) C,
H, N.
2a -[4-(9-Dim eth ylca r ba m oyl-1,2,3,4-tetr a h yd r op yr id o-
[3,4-b]in d ol-2-yl)bu tyl]-2a ,3,4,5-tetr a h yd r oben z[cd ]in d ol-
2(1H)-on e (26g). This compound was prepared from 9 and
20g trifluoroacetate (90% yield). Mp 141 °C; 1H NMR (CDCl3)
δ 1.00-1.13 (1H, m), 1.25-1.38 (2H, m), 1.44-1.58 (2H, m),
1.74-1.92 (3H, m), 2.02-2.18 (2H, m), 2.44-2.65 (3H, m),
2.70-2.86 (5H, m), 3.01 (6H, s), 3.70 (2H, br s), 6.65 (1H, d,
J ) 7.6 Hz), 6.75 (1H, d, J ) 7.8 Hz), 7.06 (1H, dd), 7.10-7.21
(3H, m), 7.41 (1H, d, J ) 7.6 Hz), 8.98 (1H, br s); TSPMS m/z
471 (M + H+). Anal. (C29H34N4O2‚9/5H2O) C, H, N.
6-Car bam oyl-2a-[4-(4-ph en yl-1,2,3,6-tetr ah ydr opyr idyl)-
bu tyl]-2a ,3,4,5-tetr a h yd r oben zo[cd ]in d ol-2(1H)-on e (25f).
A solution of 12 (270 mg, 0.74 mmol), 1,2,3,6-tetrahydro-4-
phenylpyridine hydrochloride (290 mg, 1.5 mmol), and diiso-
propylethylamine (0.51 mL, 2.9 mmol) in DMF was stirred at
room temperature for 17 h. The reaction mixture was poured
into AcOEt, and the whole was washed with H2O. The organic
layer was dried (Na2SO4) and evaporated. The residue was
purified by silica gel column chromatography (eluent: CHCl3/
MeOH ) 30/1) to afford colorless crystals. Aqueous LiOH (4
N, 6 mL, 24 mmol) was added to the crystals in THF (6 mL),
and the mixture was refluxed for 30 h. Aqueous HCl (5 N)
was added, and the mixture was extracted with CHCl3. The
organic layer was dried (Na2SO4) and evaporated to afford the
carboxylic acid derivative as colorless crystals. A solution of
the crystals, DCC (270 mg, 1.3 mmol), and HOBT (170 mg,
1.3 mmol) in DMF (12 mL) was stirred at room temperature
for 3 h and then was cooled to 0 °C. Aqueous NH3 (28%, 6 mL)
was added, and the mixture was stirred at room temperature
for 2 h and then was evaporated. The residue was purified on
an HP-20 (Mitsubishi Chemical) (eluent: H2O/MeOH ) 10/1
and then MeOH) to afford 25f as colorless crystals (150 mg,
48% yield). Mp 119 °C; 1H NMR (CD3OD) δ 0.96-1.08 (1H,
m), 1.08-1.54 (4H, m), 1.54-1.64 (1H, m), 1.65-2.00 (3H, m),
2.00-2.12 (1H, m), 2.12-2.28 (1H, m), 2.30-2.45 (2H, m),
2.51-2.61 (2H, m), 2.63-2.74 (2H, m), 2.95-3.11 (4H, m),
3.40-3.50 (1H, m), 6.07 (1H, m), 6.76 (1H, d, J ) 8.0 Hz),
7.19-7.50 (6H, m), 7.86 (1H, br s); TSPMS m/z 430 (M + H+).
Anal. (C27H31N3O2‚13/5H2O) C, H, N.
6-Br om o-2a -[4-(4-p h en yl-1,2,3,6-tetr a h yd r op yr id yl)bu -
t yl]-2a ,3,4,5-t et r a h yd r oben zo[cd ]in d ol-2(1H)-on e (25g).
This compound was prepared from 13 and 4-phenyl-1,2,3,6-
tetrahydropyridine hydrocloride (73% yield). Mp 140-141 °C;
1H NMR (CDCl3) δ 1.03-1.17 (1H, m), 1.24-1.55 (4H, m),
1.72-1.93 (3H, m), 2.03-2.20 (2H, m), 2.28-2.42 (2H, m),
2.48-2.79 (6H, m), 3.03-3.14 (2H, m), 6.01 (1H, s), 6.59 (1H,
d, J ) 8.3 Hz), 7.19-7.31 (6H, m), 9.16 (1H, br s); TSPMS m/z
465, 467 (M + H+). Anal. (C26H29N2OBr‚1/2H2O) C, H, N.
6-Hyd r oxy-2a -[4-(4-p h en yl-1,2,3,6-tetr a h yd r op yr id yl)-
bu tyl]-2a,3,4,5-tetr ah ydr oben zo[cd]in dol-2(1H)-on e (25h ).
This compound was prepared from 14 and 4-phenyl-1,2,3,6-
tetrahydropyridine hydrocloride (89% yield). 1H NMR (CDCl3)
δ 1.01-1.14 (1H, m), 1.22-1.37 (2H, m), 1.39-1.54 (2H, m),
1.73-1.93 (3H, m), 2.00-2.22 (3H, m), 2.31-2.42 (2H, m),
2.50-2.82 (6H, m), 3.08-3.14 (2H, m), 6.04 (1H, m), 6.53 (1H,
d, J ) 8.0 Hz), 6.59 (1H, d), 7.19-7.38 (5H, m), 7.98 (1H, br
s); TSPMS m/z 403 (M + H+). Hydrochloride. Mp 120-122 °C
(AcOEt/MeOH). Anal. (C26H30N2O3‚HCl‚3/5H2O) C, H, N.
2a -[4-(2,3,4,9-Tet r a h yd r o-1H -p yr id o[3,4-b]in d ol-2-yl)-
bu tyl]-2a,3,4,5-tetr ah ydr oben zo[cd]in dol-2(1H)-on e (26a).
This compound was prepared from 9 and 1,2,3,4-tetrahydro-
9H-pyrido[3,4-b]indole (38% yield). Mp 151-152 °C; 1H NMR
(CD3OD) δ 1.06-1.10 (1H, m), 1.22-1.36 (2H, m), 1.46-1.60
(2H, m), 1.76-1.95 (3H, m), 2.01-2.08 (1H, m), 2.11-2.24 (2H,
m), 2.44-2.57 (2H, m), 2.60-2.70 (1H, m), 2.75-2.90 (5H, m),
3.60 (2H, s), 6.69 (1H, d, J ) 7.5 Hz), 6.79 (1H, d, J ) 7.8 Hz),
6.96 (1H, dd, J ) 7.4, 7.0 Hz), 7.04 (1H, dd, J ) 6.8 Hz), 7.12
(1H, dd), 7.25 (1H, d), 7.36 (1H, d), 7.85 (1H, br s); TSPMS
m/z 400 (M + H+). Anal. (C26H29N2O‚9/5H2O) C, H, N.
2a -[4-(6-Meth oxy-2,3,4,9-tetr a h yd r o-1H-p yr id o[3,4-b]-
in d ol-2-yl)bu tyl]-2a ,3,4,5-tetr a h yd r oben z[cd ]in d ol-2(1H)-
on e (26b). This compound was prepared from 9 and 6-methoxy-
1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole (88% yield). Mp 132-
133 °C; 1H NMR (CD3OD) δ 1.00-1.10 (1H, m), 1.22-1.35 (2H,
2a -[4-(9-Ca r b a m oylm et h yl-1,2,3,4-t et r a h yd r op yr id o-
[3,4-b]in d ol-2-yl)bu tyl]-2a ,3,4,5-tetr a h yd r oben z[cd ]in d ol-
2(1H)-on e (26h ). This compound was prepared from 9 and
20h trifluoroacetate (91% yield). Mp 139-140 °C; 1H NMR
(CDCl3) δ 1.01-1.14 (1H, m), 1.20-1.36 (2H, m), 1.40-1.55
(2H, m), 1.75-1.90 (3H, m), 1.99-2.18 (2H, m), 2.42-2.53 (2H,
m), 2.55-2.67 (1H, m), 2.70-2.87 (5H, m), 3.52 (2H, s), 4.58
(2H, s), 5.58 (1H, br s), 6.52 (1H, br s), 6.65 (1H, d, J ) 7.5
Hz), 6.76 (1H, d, J ) 7.8 Hz), 7.05-7.20 (4H, m), 7.44 (1H, d,
J
) 7.8 Hz), 9.04 (1H, s); TSP m/z 457 (M + H+). Anal.
(C28H32N4O2‚H2O) C, H, N.
2a -[4-(9-Dim eth ylca r ba m oylm eth yl-1,2,3,4-tetr a h yd r o-
p yr id o[3,4-b]in d ol-2-yl)b u t yl]-2a ,3,4,5-t et r a h yd r ob en z-
[cd ]in d ol-2(1H)-on e (26i). This compound was prepared from
9 and 20i trifluoroacetate (72% yield). Mp 220 °C (dec); 1H

2206 J ournal of Medicinal Chemistry, 2002, Vol. 45, No. 11
Kikuchi et al.
(10) Stam, N. J .; Roesink, C.; Dijcks, F.; Garritsen, A.; van Herpen,
A.; Olijve, W. Human Serotonin 5-HT7 Receptor: Cloning and
Pharmacological Characterisation of Two Receptor Variants.
FEBS Lett. 1997, 413, 489-494.
NMR (CDCl3) δ 1.00-1.13 (1H, m), 1.25-1.40 (2H, m), 1.42-
1.60 (2H, m), 1.76-1.90 (3H, m), 2.01-2.20 (2H, m), 2.47-
2.89 (8H, m), 2.98 (3H, s), 3.09 (3H, s), 3.53 (2H, s), 4.75 (2H,
s), 6.66 (1H, d, J ) 7.6 Hz), 6.76 (1H, d, J ) 8.0 Hz), 7.02-
7.15 (4H, m), 7.43 (1H, d, J ) 7.6 Hz), 9.11 (1H, br s); EIMS
m/z 484 (M+). Anal. (C30H36N4O2‚1/2H2O) C, H, N.
Com p u ta tion a l Meth od s. All molecular modeling studies
were performed on a Silicon Graphics O2 graphic workstation
using the molecular modeling software package SYBYL,
version 6.7, from Tripos Associates (St. Louis, MO). Geometry
optimization was carried out using MMFF94s31 force field with
MMFF94 charge. For the superimposition, the piperazine
moiety was used as fitting points.
(11) To, Z. P.; Bonhaus, D. W.; Eglen, R. M.; J akeman, L. B.
Characterization and Distribution of Putative 5-HT7 Receptors
in Guinea Pig Brain. Br. J . Pharmacol. 1995, 115, 107-116.
(12) Gustafson, E. L.; Durkin, M. M.; Bard, J . A.; Zgombick, J .;
Branchek, T. A. A Receptor Autoradiographic and in Situ
Hybridization Analysis of the Distribution of the 5-HT7 Receptor
in Rat Brain. Br. J . Pharmacol. 1996, 117, 657-666.
(13) Branchek, T. A.; Gustafson, E. L.; Durkin, M. M.; Bard, J . A.;
Weinshank, R. L. Autoradiographic Localization of 5-HT7 and
Its mRNA in Rat CNS by Radioligand Binding and in Situ
Hybridization Histochemistry. Br. J . Pharmacol. 1994, 112,
100P.
(14) Sleight, A. J .; Carolo, C.; Petit, N.; Zwingelstein, C.; Bourson,
A. Identification of 5-Hydroxytryptamine7 Receptor Binding
Sites in Rat Hypothalamus: Sensitivity to Chronic Antidepres-
sant Treatment. Mol. Pharmacol. 1995, 47, 99-103.
(15) Sumova, A.; Maywood, E. S.; Selvage, D.; Ebling, F. J . P.;
Hastings, M. H. Serotonergic Antagonists Impair Arousal-
Induced Phase Shifts of the Circadian System of the Syrian
Hamster. Brain Res. 1996, 709, 88-96.
5-HT7 Recep tor Bin d in g Assa y. Radioligand binding
assay at human 5-HT7 receptors were carried out using
membranes from COS-7 cells expressed h5-HT7 receptors.
Membranes (10 µg of protein) were incubated with 0.3 nM
[3H]5-CT in 50 mM Tris-HCl buffer (pH 7.4), which contained
10 mM MgCl2 and 0.5 mM EDTA, for 30 min at 37 °C in the
presence or absence of competing compounds (1 µM to 1 nM).
Nonspecific binding was determined with 10 µM metergoline.
Membranes were collected by rapid filtration through GF/B
filters and washed with 5 mL of ice-cold 50 mM Tris-HCl buffer
(pH 7.4). The radioactivity on the filters was counted by liquid
scintillation counter (Packard TRI-CARB2000). The concentra-
tion displacing 50% of specific [3H]-5-CT binding (IC50) was
determined by a computer curve-fitting technique. The inhibi-
tion dissociation constant (Ki) of each compound was then
determined according to the method of Cheng and Prusoff.32
(16) Ying, S.-W.; Rusak, B. 5-HT7 Receptors Mediate Serotonergic
Effects on Light-Sensitive Suprachiasmatic Nucleus Neurons.
Brain Res. 1997, 755, 246-254.
(17) Schwartz, W. J . A Clinician’s Primer on the Circadian Clock:
Its Localization, Function and Resetting. Adv. Int. Med. 1993,
38, 81-106.
(18) Duncan, M. J .; Short, J .; Wheeler, D. L. Comparison of the
Effects of Aging on 5-HT7 and 5-HT1A Receptors in Discrete
Regions of the Circadian Timing System in Hamsters. Brain Res.
1999, 829, 39-45.
(19) Forbes, I. T.; Dabbs, S.; Duckworth, D. M.; J ennings, A. J .; King,
F. D.; Lovell, P. J .; Brown, A. M.; Collin, L.; Hagan, J . J .;
Middlemiss, D, N.; Riley, G. J .; Thomas, D. R.; Upton, N. (R)-
3,N-Dimethyl-N-[1-methyl-3-(4-methylpiperidin-1-yl)propyl]ben-
zenesulfonamide: The First Selective 5-HT7 Receptor Antago-
nist. J . Med. Chem. 1998, 41, 655-657.
(20) Lovell, P. J .; Bromidge, S. M.; Dabbs, S.; Duckworth, D. M.;
Forbes, I. T.; J ennings, A. J .; King, F. D.; Middlemiss, D. N.;
Rahman, S. K.; Saunders, D. V.; Collin, L. L.; Hagan, J . J .; Riley,
G. J .; Thomas, D. R. A Novel, Potent, and Selective 5-HT7
Antagonist: (R)-3-(2-(2-(4-Methylpiperidin-1-yl)ethyl)pyrrolidine-
1-sulfonyl)-phenol (SB-269970). J . Med. Chem. 2000, 43, 342-
345.
cAMP Assa y. HEK293 cells transiently transfected with
an expression vector containing human 5-HT7 receptor cDNA
were incubated for 10 min at 37 °C with appropriate drugs in
Dulbecco’s modified Eagle’s medium containing 10 mM HEPES,
100 µM 3-isobutyl-1-methylxanthine, and 100 µM pargyline.
Intracellular cAMP formation was measured by enzyme im-
munoassay.
Refer en ces
(21) Linnanen, T.; Brisander, M.; Unelius, L.; Rosqvist, S.; Nordvall,
G.; Hacksell, U.; J ohansson, A. M. Atropisomeric Derivatives of
2′,6′-Disubstituted (R)-11-Phenylaporphine: Selective Serotonin
5-HT7 Receptor Antagonist. J . Med. Chem. 2001, 41, 1337-1340.
(22) Kikuchi, C.; Nagaso, H.; Hiranuma, T.; Koyama, M. Tetrahy-
drobenzindoles: Selective Antagonists of the 5-HT7 Receptor.
J . Med. Chem. 1999, 42, 533-535.
(23) Gruda, I. Formation of N- and C-Substituted Derivatives during
Alkylation of Indol-2(3H)-one. Can. J . Chem. 1972, 50, 18-23.
(24) Meiji Seika Kaisha Ltd. Patent WO 9933804, J uly 8, 1999.
(25) Leysen, J . E.; Niemegeers, C. J . E.; Van Nueten, J . M.; Laduron,
P. M. [3H]Ketanserin (R 41 468), a Selective 3H-Ligand for
Serotonin2 Receptor Binding Sites. Binding Properties, Brain
Distribution, and Functional Role. Mol. Pharmacol. 1982, 21,
301-314.
(26) Martin, G. R.; Humphrey, P. P. A. Receptors for 5-Hydroxy-
tryptamine: Current Perspectives on Classification and Nomen-
clature. Neuropharmacology 1994, 33, 261-273.
(27) Hoyer, D.; Engel, G.; Kalkman, H. O. Molecular Pharmacology
of 5-HT1 and 5-HT2 Recognition Sites in Rat and Pig Brain
Membranes: Radioligand Binding Studies with [3H]5-HT, [3H]8-
OH-DPAT, [125I]Iodocyanopindolol, [3H]Mesulergene and [3H]-
Ketanserin. Eur. J . Pharmacol. 1985, 118, 13-23.
(28) Lummis, S. C. R.; Sepulveda, M. I.; Kilpatrick, G. J .; Baker, J .
Characterization of [3H]m-Chlorophenylbiguanide Binding to
5-HT3 Receptors in N1E-115 Neuroblastoma Cells. Eur. J .
Pharmacol. 1993, 243, 7-11.
(29) Grossman, C. J .; Kilpatrick, G. J .; Bunce, K. T. Development of
a Radioligand Binding Assay for 5-HT4 Receptors in Guinea Pig
and Rat Brain. Br. J . Pharmacol. 1993, 109, 618-624.
(30) Monsma, F. J ., J r.; Shen, Y.; Ward, R. P.; Hamblin, M. W.; Sibley,
D. R. Cloning and Expression of a Novel Serotonin Receptor with
High Affinity for Tricyclic Psychotropic Drugs. Mol. Pharmacol.
1993, 43, 320-327.
(1) Shen, Y.; Monsma, F. J .; Metcalf, M. A.; J ose, P. A.; Hamblin,
M. W.; Sibley, D. R. Molecular Cloning and Expression of a 5-HT7
Serotonin Receptor Subtype. J . Biol. Chem. 1993, 268, 18200-
18204.
(2) Lovenberg, T. W.; Baron, B. M.; de Lecea, L.; Miller, J . O.;
Prosser, R. A.; Rea, M. A.; Foye, P. E.; Rucke, M.; Slone, A. L.;
Siegel, B. W.; Danielson, P. E.; Sutcliffe, J . G.; Erlander, M. G.
A Novel Adenyl Cyclase-Activating Serotonin Receptor (5-HT7)
Implicated in the Regulation of Mammalian Circadian Rhythms.
Neuron 1993, 11, 449-458.
(3) Ruat, M.; Traiffort, E.; Leurs, R.; Tardivel-Lacombe, J .; Diaz,
J .; Arrang, L. M.; Schwartz, J . C. Molecular Cloning, Charac-
terization and Localization of a High-Affinity Serotonin Receptor
(5-HT7) Activating cAMP Formation. Proc. Natl. Acad. Sci.
U.S.A. 1993, 90, 8547-8551
(4) Plassat, J .-L.; Amlaiky, N.; Hen, R. Molecular Cloning of a
Mammalian Serotonin Receptor That Activates Adenylate Cy-
clase. Mol. Pharmacol. 1993, 44, 229-236.
(5) Bard, J . A.; Zgombick, J .; Adham, N.; Vaysse, P.; Branchek, T.
A.; Weinshank, R. L. Cloning of Novel Human Serotonin
Receptor (5-HT7) Positively Linked to Adenylate Cyclase. J . Biol.
Chem. 1993, 268, 23422-23426.
(6) Tsou, A.-p.; Kosaka, A.; Bach, C.; Zuppan, P.; Yee, C.; Tom, L.;
Alvarez, R.; Ramsey, S.; Bonhaus, D. W.; Stefanich, E.; J akeman,
L.; Eglen, R. M.; Chan, H. W. Cloning and Expression of a
5-Hydroxytryptamine7 Receptor Positively Coupled to Adenylyl
Cyclase. J . Neurochem. 1994, 63, 456-464.
(7) Roth, B. L.; Craigo, S. C.; Choudhary, M. S.; Uluer, A.; Monsma,
F. J .; Shen, Y.; Meltzer, H. Y.; Sibley, D. R. Binding of Typical
and Atypical Antipsychotic Agents to 5-Hydroxytryptamine6 and
5-Hydroxytryptamine7 Receptors. J . Pharmacol. Exp. Ther.
1994, 268, 1403-1410.
(8) Heidmann, D. E. A.; Metcalf, M. A.; Kohen, R.; Hamblin, M. W.
Four 5-Hydroxytryptamine7 (5-HT7) Receptor Isoforms in Hu-
man and Rat Produced by Alternative Splicing: Species Differ-
ences Due to Altered Intron-Exon Organization. J . Neurochem.
1997, 68, 1372-1381.
(31) Halgren, T. A. MMFF VI. MMFF94s Option for Energy Mini-
mization Studies. J . Comput. Chem. 1999, 20, 720-729.
(32) Cheng, Y. C.; Prusoff, W. H. Relationship between Inhibition
Constant (Ki) and the Concentration of Inhibitor Which Causes
50 Percent Inhibition (IC50) of an Enzymatic Reacion. Biochem.
Pharmacol. 1973, 92, 881-894.
(9) J asper, J . R.; Kosaka, A.; To, Z. P.; Chang, D. J .; Eglen, R. M.
Cloning, Expression and Pharmacology of a Truncated Splice
Variant of the Human 5-HT7 Receptor (h5-HT7(b)). Br. J . Phar-
macol. 1997, 122, 126-132.
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