Novel and selective 5-HT(2C/2B) receptor antagonists as potential anxiolytic agents: Synthesis, quantitative structure - Activity relationships, and molecular modeling of substituted 1-(3- pyridylcarbamoyl)indolines

Article abstract of DOI:10.1021/jm970741j

The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously published indole urea 1 (SB- 206553) and illustrate the use of aromatic disubstitution as a replacement for fused five-membered rings in the context of 5-HT(2C/2B) receptor antagonists. By targeting a region of space previously identified as sterically allowed at the 5-HT(2C) receptor but disallowed at the 5-HT(2A) receptor, we have identified a number of compounds which are the most potent and selective 5-HT(2C/2B) receptor antagonists yet reported. 46 (SB-221284) was selected on the basis of its overall biological profile for further evaluation as a novel, potential nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with good predictive value and in addition good qualitative agreement with both our 5-HT(2C) receptor model and our proposed binding mode for this class of ligands within that model.

Full text of DOI:10.1021/jm970741j

1598
J . Med. Chem. 1998, 41, 1598-1612
Novel a n d Selective 5-HT2C/2B Recep tor An ta gon ists a s P oten tia l An xiolytic
Agen ts: Syn th esis, Qu a n tita tive Str u ctu r e-Activity Rela tion sh ip s, a n d
Molecu la r Mod elin g of Su bstitu ted 1-(3-P yr id ylca r ba m oyl)in d olin es
Steven M. Bromidge,*,† Steven Dabbs,† David T. Davies,† D. Malcolm Duckworth,† Ian T. Forbes,† Peter Ham,†
Graham E. J ones,† Frank D. King,† Damian V. Saunders,† Susannah Starr,† Kevin M. Thewlis,†
Paul A. Wyman,† Frank E. Blaney,† Christopher B. Naylor,† Fiona Bailey,‡ Thomas P. Blackburn,‡
Vicky Holland,‡ Guy A. Kennett,‡ Graham J . Riley,‡ and Martyn D. Wood‡
SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue,
Harlow, Essex CM19 5AW, England
Received October 31, 1997
The synthesis, biological activity, and molecular modeling of a novel series of substituted 1-(3-
pyridylcarbamoyl)indolines are reported. These compounds are isosteres of the previously
published indole urea 1 (SB-206553) and illustrate the use of aromatic disubstitution as a
replacement for fused five-membered rings in the context of 5-HT2C/2B receptor antagonists.
By targeting a region of space previously identified as sterically allowed at the 5-HT2C receptor
but disallowed at the 5-HT2A receptor, we have identified a number of compounds which are
the most potent and selective 5-HT2C/2B receptor antagonists yet reported. 46 (SB-221284) was
selected on the basis of its overall biological profile for further evaluation as a novel, potential
nonsedating anxiolytic agent. A CoMFA analysis of these compounds produced a model with
good predictive value and in addition good qualitative agreement with both our 5-HT2C receptor
model and our proposed binding mode for this class of ligands within that model.
The explosive growth of the 5-hydroxytryptamine (5-
HT, serotonin) superfamily of receptors has continued
to provide pharmaceutical research with new opportuni-
ties for drug discovery.1 Advances in molecular biologi-
cal techniques have so far led to the identification of 7
classes of receptor (5-HT1 to 5-HT7) and 14 acknowl-
edged human subclasses.2 The 5-HT2 family of recep-
tors is comprised of 5-HT2A, 5-HT2B, and 5-HT2C sub-
types which have been grouped together on the basis of
primary structure, secondary messenger system, and
operational profile.3 All 3 subtypes are G-protein-
coupled, activate phospholipase C as a principal trans-
duction mechanism, and contain a predicted seven-
transmembrane domain structure. Sequence analysis
indicates approximately 80% amino acid identity in
these regions, and it is therefore not surprising that
many compounds once thought to be selective for the
5-HT2A (classical 5-HT2) receptor also bind with high
affinity to the 5-HT2B and 5-HT2C sites. Consequently
there remains a need to identify more selective ligands
to fully elucidate the functional role of the different
subtypes. There are distinct differences in the distribu-
tion of the three 5-HT2 subtypes. In contrast to the
5-HT2B receptor which is principally located in the
periphery and only sparsely in the central nervous
system (CNS), the 5-HT2C receptor has been found only
in the CNS, being highly expressed in many regions of
the mammalian brain including the choroid plexus and
the limbic and basal ganglia structures. This pattern
of CNS distribution is different and more widespread
than that of the 5-HT2A receptor which is also widely
distributed in peripheral tissues.2
Our interest in the 5-HT2C receptor originally stemmed
from the finding that the moderately selective 5-HT2C/2B
agonist m-chlorophenylpiperazine (mCPP) causes be-
havioral indications of anxiety in both animal models
and humans, implying that selective 5-HT2C/2B antago-
nists might be useful anxiolytic agents.4 Recent evi-
dence suggests that 5-HT2C receptor ligands may also
have antidepressant properties.5 We have recently
reported the synthesis and biological activity of the
pyridylurea 1 (SB-206553) which is a potent 5-HT2C/2B
receptor antagonist (pKi 8.0) with 160-fold selectivity
over the closely related 5-HT2A site.6 This compound
blocked the hypolocomotion in rats produced by mCPP
which is a model of central 5-HT2C receptor function that
can be elicited by direct infusion of mCPP into the
cerebral ventricles7 and is absent in mutant mice
lacking the 5-HT2C receptor.8 Thus, 1 demonstrates oral
activity in a centrally mediated model of 5-HT2C func-
tion. It also exhibited significant anxiolytic activity in
several different animal models of anxiety, providing
strong support for our original hypothesis.9 Unfortu-
nately, the 1-methylindole moiety of 1 was subject to a
metabolic demethylation to a less selective compound
which precluded its development as a potential anxi-
* To whom correspondence should be addressed.
† Department of Medicinal Chemistry.
‡ Department of Neurosciences.
S0022-2623(97)00741-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/17/1998

5-HT2C/ 2B Receptor Antagonists as Anxiolytic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1599
Sch em e 1a
a
Reagents: (a) NaCNBH3, AcOH, rt, 3 h (75-95%); (b) nicotinic
acid azide, toluene, reflux, 0.5 h (50-90%).
Sch em e 2a
F igu r e 1. 5-HT2C-allowed (green) and 5-HT2A-disallowed
(pink) volumes viewed around the structure of compound 1.9
olytic agent.10 Recently the 5-HT2C knockout mouse has
been shown to have a diminished anxiety-like response8
and to be associated with proconvulsant and hyperph-
agic behavior.11
a
Reagents: (a) MeSO2Cl, pyridine, CH2Cl2, 0 °C-rt, 2 h; (b)
We also recently reported12 the synthesis and activity
of a number of other tricyclic analogues of 1 in addition
to a full range of isomeric N-substituted pyrrolo ana-
logues in which the pyrrole ring was fused across each
of the 4-5, 5-6, and 6-7 bonds of the indoline. By use
of the “active analogue approach” developed by Mar-
shall13 to overlap common structural features of com-
pounds of varying activity, we were able to define an
allowed volume for 5-HT2C receptor affinity which
included a volume that was disallowed at the 5-HT2A
receptor (Figure 1). This finding was rationalized by
considering key differences in the sequences of the
5-HT2C and 5-HT2A receptors in a region adjacent to the
indole N-methyl group in the proposed binding mode of
the compound in our model of the 5-HT2C receptor. This
mode invokes hydrogen bonding between the urea
carbonyl oxygen and Ser-312 and Ser-315 as the pri-
mary interaction, placing the indole N-methyl group in
a lipophilic pocket adjacent to valines-212 and -608. In
the 5-HT2A receptor the corresponding receptor residues
which define this pocket are both leucine. These
sequence differences would be expected to give rise to a
smaller binding pocket which can less easily accom-
modate the indole N-methyl group of 1 thus leading to
the observed selectivity. We now report the use of this
information to design a novel series of substituted 1-(3-
pyridylcarbamoyl)indolines, incorporating monocyclic
isosteres of the N-methylindole of 1, which are potent
and selective 5-HT2C/2B receptor antagonists.14 This
approach has culminated in the identification of 46 (SB-
221284) which has improved in vitro and in vivo
properties compared to 1. Significantly, 46 showed no
evidence of either proconvulsant or hyperphagic proper-
ties which are characteristic of mutant mice lacking the
5-HT2C receptor.11 A quantitative structure-activity
relationship (QSAR) analysis of these indolinylureas has
been undertaken as a means of testing the validity of
our 5-HT2C receptor model and also our proposed ligand
docking mode using the comparative molecular field
analysis (CoMFA)15 module within the Sybyl16 molec-
ular modeling environment.
NaH, DMF, 0 °C, (EtO)2CHCH2OTf; (c) TiCl4, toluene, 0 °C, rt,
reflux, 1-2 h; (d) aq NaOH, EtOH, reflux, 0.5 h (overall yields
20-30%).
Ch em istr y
Compounds 2-56 were prepared by reacting the
appropriately substituted indoline with 3-pyridyl iso-
cyanate which was prepared in situ from the acyl azide
(Scheme 1). Compounds 2-4, 6, 7, 9, 10, 12, 13, 20,
24, and 44 were prepared from known or commercially
available indolines or via indolines accessed by sodium
cyanoborohydride/acetic acid reduction of indoles,17
which were themselves either commercially available
or known.
The following compounds were similarly obtained via
reduction of indoles which were themselves prepared
by a variety of routes based on literature methods.
Indoles leading to 5, 8, 15-18, 22, 23, 26-30, 33-37,
and 39-41 were prepared from the corresponding
protected anilines 57 by alkylation with either 2,2-
dimethoxyacetaldehyde or (EtO)2CHCH2OTf followed by
cyclization under either Nordlander18 or, more satisfac-
torily, Sundberg19 conditions (Scheme 2). In the case
of unsymmetrical substituted anilines, mixtures of
indole isomers were obtained which were separated by
fractional crystallization or chromatography following
deprotection of the indole nitrogen. Alternatively, the
mixture of indoles was carried through to give a mixture
of final compounds which were then separated by
preparative HPLC. Indoles leading to 21, 25, 38, and
42 were prepared from the appropriate 2-methylni-
trobenzene by the Leimgru¨ber procedure.20
The 5-alkoxy-6-(trifluoromethyl)indoles 60, which
were the necessary precursors to 51-55, were synthe-
sized from the corresponding 1-alkoxy-2-(fluoroalkyl)-
4-nitrobenzenes 58 by “vicarious” nucleophilic substi-
tution21 with 4-chlorophenoxyacetonitrile using KOtBu
in DMF to give the 5-acetonitrile 1-alkoxy-2-(fluoro-
alkyl)-4-nitrobenzenes 59 which were hydrogenated to
afford the desired indoles 60 (Scheme 3).22

1600 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Bromidge et al.
Sch em e 3a
Sch em e 5a
a
Reagents: (a) NaOR, ROH, reflux, 3 h (99%); (b) 4-chlorophe-
noxyacetonitrile, KOtBu, DMF, -10 °C, 1 h (78%); (c) H2/10% Pd-
C, 50 psi, AcOH, EtOH/H2O, rt, 0.5 h (96%).
a
Reagents: (a) NBS, DMF, -5 °C, 1 h (35%); (b) (1-ethoxyvi-
nyl)tributyl tin/Pd0(Ph3P)3, toluene, reflux, 28 h (58%); (c) (BOC)2O/
NEt3, toluene, reflux, 4 h (58%); (d) (i) MeMgBr, ether, 0 °C, 1.5
h, (ii) TFAA, rt, 1 h (40%); (e) H2/10% Pd-C, EtOH, rt, 2 h (80%).
Sch em e 4a
fluoromethyl)indoline (68) which was hydrogenated to
69 and then coupled in the usual manner to give 50
(Scheme 5).
Resu lts a n d Discu ssion
The affinities of the compounds were measured by
means of radioligand binding studies conducted with
cloned 5-HT2A, 5-HT2B, and 5-HT2C receptors expressed
in HEK 293 cells using [3H]ketanserin, [3H]-5-HT, and
[3H]mesulergine, respectively, as radioligands.9
a
Reagents: (a) KSCN/Br2, MeOH, 0 °C, 0.5 h (72%); (b) aq NH3,
We have previously reported 1 to be a selective
5-HT2C/2B receptor antagonist with 160-fold selectivity
over the closely related 5-HT2A receptor.9 In an attempt
to circumvent the metabolic demethylation of 1 to the
unselective NH-indole,10 we investigated the replace-
ment of the pyrroloindole of 1 with simple substituted
indolines as in 2-30. The rapid synthesis of 1-(3-
pyridylcarbamoyl)indolines containing a wide range of
substituents around the indoline ring was undertaken
to define SAR and optimize activity in this series, and
these results are shown in Table 1. The unsubstituted
indoline 2 had weak activity for 5-HT2C receptors (pKi
5.9). However, introduction of a range of electron-
withdrawing or electron-donating substituents at either
the 5- or 6-position (4-13) led to modest increases in
5-HT2C affinity giving pKi’s in the range 6.5-7.5.
Substitution at the 7-position (19, 20) appeared to have
a detrimental effect on affinity. The 4-chloroindoline 3
was slightly more active than 2, and the 4,5-disubsti-
tuted compounds 14-18 generally showed a modest
increase in potency relative to the corresponding 5-mono-
substituted analogues 4-11. 5,6-Disubstitution (21-
28) was even more beneficial conveying an additive
effect on 5-HT2C activity and resulting in compounds
with pKi’s greater than 8 and moderate selectivity over
5-HT2A receptor affinity. Analysis of the SAR revealed
a correlation between increasing 5-HT2C affinity and
increasing lipophilicity of the 5-substituent and that an
electron-withdrawing group at the 6-position was opti-
mal. Although many of these compounds possess mod-
est selectivity over the 5-HT2A receptor, the 5-thiomethyl
analogue 11 was exceptional demonstrating over 100-
fold selectivity. The 4,5,6-trisubstituted analogues 29
and 30 maintained good affinity over 5-HT2C but had
reduced selectivity.
90 °C, 1 h (100%); (c) Ac2O/NEt3, CH2Cl2, 1 h (94%); (d) PPh3, HCl,
dioxane/H2O, reflux, 1 h (91%); (e) RI, K2CO3, DMF, 80 °C, 1 h
(97%); (f) NaOH, H2O, EtOH, reflux, 1.5 h (99%); (g) (i) KSCN/
Br2, MeOH, 0 °C-rt, 4 h; (ii) aq NaOH, 45 °C, 0.5 h, (iii) MeI, 12
°C-rt, 1.5 h (approximately 60% overall yield).
Compounds 11, 32, 43, 45-49, and 56 were obtained
from indolines prepared by the following routes. The
5-(thioalkyl)indolines 65 leading to 11, 43, and 45-49
were prepared by the route shown in Scheme 4. Treat-
ment of the corresponding 5-unsubstituted indoline 61
with bromine and KSCN gave the thiocyanate23 62
which on treatment with aqueous ammonia gave the
disulfide 63.24 Acylation of the indoline nitrogen fol-
lowed by reduction using PPh3/HCl gave the sulfide 64
which was alkylated and N-deprotected to give the
required indoline 65.25 A convenient one-pot variation
of this procedure was developed for 5-(thiomethyl)-6-
(trifluoromethyl)indoline directly from 6-(trifluorometh-
yl)indoline which avoided the need to protect the indole
nitrogen.26 The 6-cyano-5-(trifluoromethyl) analogue 32
was prepared from the corresponding 6-iodo compound
45 by copper-catalyzed cyanide exchange.27 The 6-(pen-
tafluoroethyl) derivative 56 was also prepared by cop-
per-catalyzed exchange of 1-acetyl-6-bromo-5-(meth-
ylthio)indoline with sodium pentafluoropropionate.28
Compounds 14 and 19 were prepared via lithium
aluminum hydride reduction of the corresponding isat-
ins.29 Compounds 31 and 50 were prepared by the route
shown in Scheme 5. Reaction of 5-bromo-6-(trifluorom-
ethyl)indoline (66) with (1-ethoxyvinyl)tributyl tin30 in
the presence of palladium(0) afforded 5-acetyl-6-(tri-
fluoromethyl)indoline (67) which was converted to 31.
N-Protection of 5-acetyl-6-(trifluoromethyl)indoline fol-
lowed by addition of methyl magnesium bromide and
dehydration/deprotection afforded 5-isopropenyl-6-(tri-

5-HT2C/ 2B Receptor Antagonists as Anxiolytic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1601
Ta ble 1. 5-HT2A and 5-HT2C Receptor Binding Affinitiesa of
Substituted 1-(3-Pyridylcarbamoyl)indolines
date. In the 5-methylthio (32, 33, 39, 43, 45, 46, 56)-
and 5-methoxy (44, 51, 55)-disubstituted series, all the
analogues have good affinity and >100-fold selectivity
with the order of affinity for the different 6-substituents
being C2F5 ) CF3 ) I ) Br > Cl > CN ) OCF3. The
selectivities of these analogues are similar, although the
C2F5 substituent (55, 56) imparts enhanced selectivity.
Focusing on the 5-(alkylthio)-6-CF3 (46-49) and the
5-alkoxy-6-CF3 (51-54) series, one can see that the size
and shape of the 5-substituent are clearly crucial to the
selectivity of the compounds with the optimal size of the
thioalkyl group being ethyl (47) or n-propyl (48) and that
of the alkyloxy group being iPr (53). Increasing the size
of the substituents further (49, 54) leads to a fall-off in
affinity and selectivity.
pKi
selectivity
5-HT2C/2A
b
c
compd R4
R5
R6
R7 5-HT2A 5-HT2C
2
3
4
5
6
7
8
9
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
Cl
CF3
NO2
Me
iPr
H
H
H
H
H
H
H
H
H
H
CF3
Cl
H
H
H
H
H
H
5.9
6.3
7.1
7.5
6.5
6.8
7.1
6.9
6.5
7.4
7.3
7.3
7.6
8.1
7.6
7.4
7.2
6.1
6.5
8.1
8.5
8.2
7.3
8.0
8.2
8.4
8.5
8.4
8.6
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
NO2
H
H
H
H
H
H
H
H
H
H
5.4
5.6
5.9
<5.2
5.3
5.7
5.3
<5.2
5.4
6.3
6.1
6.2
6.9
5.6
6.2
5.3
5.3
5.4
6.6
7.0
6.8
5.6
6.4
6.8
7.2
7.2
7.5
7.2
9
32
40
>20
30
27
46
20
110
12
13
24
17
100
20
80
7
12
32
35
27
45
45
26
19
23
7
A small number of compounds were also evaluated
at the cloned 5-HT2B receptor, and although affinities
were reduced at this receptor, the observed selectivities
were modest (<10-fold). Additionally, 46 was evaluated
on a number of other receptor systems and found to
have negligible affinity on a total of 57 different binding
sites. 46 was also found to be a competitive antagonist
with a pKB of 9.8 in the 5-HT-stimulated phosphoinosi-
tol (PI) hydrolysis model of 5-HT2C receptor activation,9
using human cloned receptors in HEK 293 cells.
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
NMe2
SMe
H
H
Cl Cl
Br Me
I
Me
Cl tBu
Cl SMe
H
H
H
H
H
H
H
H
H
H
H
Cl
H
Br
Cl
I
Cl
Br
Cl
Me
Me
Me
In Vivo Eva lu a tion . Compounds which satisfied our
in vitro criteria were evaluated in vivo in a centrally
mediated model of 5-HT2C receptor function by measur-
ing their ability to block the hypoactivity in rats
produced by a standard dose of the moderately selective
5-HT2C agonist mCPP.4 This activity is absent in
mutant mice lacking the 5-HT2C receptor (see introduc-
tory section).8 Several of the compounds (26, 43-47,
51-53) tested have extremely potent oral activity in this
model with ID50’s of around 1 mg/kg po (Table 2), which
compare very favorably with that of 1 (5.5 mg/kg).
Whereas all the 5-alkoxy-6-CF3 analogues 51-53 dem-
onstrate potent oral activity, increasing the size of the
alkyl group of the 5-(alkylthio)-6-CF3 analogues 46-48
led to reduction or loss of in vivo activity. The corre-
sponding 6-halo-disubstituted analogues 39-41 and
43-45 also generally have reduced in vivo activity
compared to the corresponding 6-CF3 compounds 46 and
51-53. The 6-C2F5 analogues 55 and 56, which have
similar in vitro profiles to the 6-CF3 compounds 51 and
46, also show reduced oral activity. The 5-monosubsti-
tuted analogues 9-11 possess no oral activity in this
model. The reason for the observed differences in oral
activity between such close analogues is not obvious but
likely to be the overall result of variation in a number
of complex factors including absorption, metabolism,
and brain penetration.
Cl
Cl
CF3
SMe
Me
Cl
Br
I
Cl Me
Cl SMe
Cl
Cl
26
a
All values represent the mean of at least two determinations,
with each determination lying within 0.2 log unit of the mean.
b Binding affinity (human cloned receptors, HEK 293 cells, [3H]ket-
anserin). c Binding affinity (human cloned receptors, HEK 293
cells, [3H]mesulergine).
Although many of the initial 5,6-disubstituted ana-
logues such as 26 showed good affinity at the 5-HT2C
receptor, demonstrating that they could serve as indole
isosteres in this context, the selectivity of the compounds
over the 5-HT2A receptor was generally modest. In an
attempt to increase the selectivity, a series of further
5,6-disubstituted analogues 31-56 was prepared con-
taining a variety of 5-substituents in combination with
small, lipophilic, electron-withdrawing 6-substituents.
The size and shape of the 5-substituent was varied in
order to probe the crucial 5-HT2C-allowed/5-HT2A-disal-
lowed region previously identified,12 and results are
shown in Table 2. In the 5-alkyl-6-chloro series 26-
37, increasing the size of the 5-alkyl group produced a
modest increase in selectivity although this was ac-
companied by a slight reduction in 5-HT2C affinity. The
5-iPr-6-Cl-indoline 37 (pKi 7.7) was the most selective
compound of this series demonstrating 110-fold selectiv-
ity over 5-HT2A receptor.
The most potent compounds were further evaluated
in two different models of anxiety,4 namely, the Geller-
Seifter Conflict Test and the Social Interaction Test, in
the rat and found to have significant anxiolytic activity
with no evidence of sedative effects at doses (0.2-5 mg/
kg po) similar to those that antagonized mCPP-induced
hypolocomotion. The Geller-Seifter results for com-
pounds 43, 46, 51, and 52 are shown in Table 3. In
trained rats, these compounds markedly increased
footshock punished responding (lever presses for a food
reward) with minimum effective doses of 0.2-1 mg/kg
po but had little effect on unpunished responding. This
The approach was more successful in the case of the
5-alkylthio- and 5-alkyloxy-disubstituted series. Several
of these compounds combine high 5-HT2C affinity (pKi
g 8) with selectivities over 5-HT2A of >100-fold and in
some cases >1000-fold and so represent the most potent
and selective 5-HT2C/2B receptor antagonists reported to

1602 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Bromidge et al.
Ta ble 2. 5-HT2A, 5-HT2B, and 5-HT2C Receptor Binding Affinitiesa and in Vivo Activity of 5,6-Disubstituted
1-(3-Pyridylcarbamoyl)indolines
pKi
e
selectivity
5-HT2C/2A
ID50
b
c
d
compd
R5
R6
5-HT2A
5-HT2B
7.6
5-HT2C
(mg/kg po)
1
31
32
33
26
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
N-methylpyrrolo
5.7
5.5
5.6
5.5
6.8
6.4
5.9
6.2
5.7
5.4
5.6
5.4
<5.2
5.2
6.3
5.8
6.3
6.4
5.5
<5.2
5.3
<5.2
6.0
5.8
5.8
5.4
5.4
5.6
7.9
7.3
7.8
7.6
8.2
8.3
7.7
7.7
7.7
6.9
8.2
7.6
7.8
7.5
8.7
7.9
8.7
8.6
8.5
8.2
7.5
7.6
8.0
8.2
8.5
7.7
7.9
8.4
160
60
140
130
26
76
62
27
110
28
5.5
COMe
CF3
CN
OCF3
Cl
SMe
SMe
Me
37%
14%
0.6
Et
Cl
Cl
Cl
Cl
60%
nPr
tBu
6.8
iPr
33%
Ph
Cl
SMe
OEt
OiPr
CO2Me
SMe
OMe
SMe
SMe
SEt
Cl
Cl
Cl
Cl
Br
Br
I
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
CF3
C2F5
C2F5
420
150
400
190
210
140
250
160
1000
>1000
220
240
120
275
470
200
330
600
10
3.4
4
16
3
1.8
3.2
1.2
4.4
10%
87%
20%
0.8
1
7.9
8.0
7.8
SnPr
SiPr
iPr
OMe
OEt
OiPr
OCH2cPr
OMe
SMe
8.4
7.5
1.4
54%
5
a
b
All values represent the mean of at least two determinations, with each determination lying within 0.2 log unit of the mean. Binding
affinity (human cloned receptors, HEK 293 cells, [3H]ketanserin). c Binding affinity (human cloned receptors, HEK 293 cells, [3H]-5-HT).
Binding affinity (human cloned receptors, HEK 293 cells, [3H]mesulergine). e Dose of compound required to reverse mCPP (7 mg/kg ip
d
adminstration 30 min pretest)-induced hypolocomotion by 50% or percentage reversal at 10 mg/kg (in the case of 49 at 5 mg/kg).
profile is consistent with the compounds having anxi-
olytic-like properties.42 Significantly, acute administra-
tion of 46 showed no evidence of proconvulsant activity
in the rat maximal electroshock threshold test (up to
30 mg/kg po), while chronic administration (up to 30
mg/kg po b.i.d. × 14 days) produced no evidence of
hyperphagic properties. Both these activities are char-
acteristic of mutant mice lacking the 5-HT2C receptor.11
In addition there was no evidence of increased sensitiv-
ity to 5-HT2C agonist-induced effects after chronic dosing
of 46, indicating that there were no effects on receptor
density or sensitivity. Based on its overall biological
profile, 46 was selected for further evaluation as a novel,
nonsedating anxiolytic agent.
Compound 46 was manually docked into a model of
the 5-HT2C receptor which was constructed based on the
structure of bacteriorhodopsin and the ligand-receptor
complex minimized. The proposed binding mode (Fig-
ure 2) is very similar to that previously proposed12 for
1 with the urea carbonyl oxygen double-hydrogen-
bonding to the hydroxyl side chains of Ser-312 and Ser-
315.31 Furthermore, the indole -NH of Trp-613 is also
close enough to interact with the oxygen of the urea
carbonyl, although the hydrogen-bonding geometry is
nonideal. In the minimized receptor-bound conforma-
tion, both the 3-pyridyl ring and the methylthio group
are twisted out of plane and are almost perpendicular
to the indoline ring.
The 3-pyridyl ring occupies a lipophilic pocket defined
by the side chains of the aromatic residues Phe-508,
Trp-613, Phe-616, and Phe-617. Within this pocket the
3-pyridyl ring is able to form both π-π stacking and
edge-to-face aromatic interactions with several of the
aromatic residues lining the pocket. These interactions
probably contribute significantly to the overall binding
of these ligands to the receptor.
Molecu la r Mod elin g Stu d ies on 46. Molecular
modeling reveals that these substituents optimally
interact/occupy the crucial 5-HT2C-allowed/5-HT2A-disal-
lowed volume previously identified12 (Figure 1). The
introduction of a 6-substituent also has the added
beneficial effect of restricting the rotation of the 5-sub-
stituent to favor those conformations in which the alkyl
group occupies the crucial region. This may account for
the finding that the 6-chloro-5-(trifluoromethyl)indoline
39 is more potent and selective than the 5-(trifluorom-
ethyl) analogue 11 which is in turn more selective than
the 4-chloro-5-(trifluoromethyl) analogue 18.
The substituted indoline is placed in another pocket,
the boundary of which is defined by residues Val-212,
Phe-311, Val-608, Phe-609, Met-612, and Tyr-715. This
pocket is also very lipophilic in nature, although less
aromatic than the 3-pyridyl binding pocket. In this

5-HT2C/ 2B Receptor Antagonists as Anxiolytic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1603
Ta ble 3. Effect of Compounds 43, 46, 51, and 52 on Rat
Responses in the Geller-Seifter Conflict Test42
be expected to lead to binding pockets of reduced size,
and it is proposed that these steric differences in the
receptors may also account for the observed 5-HT2C
selectivity.
percentage change in no. of lever
presses from mean score on 2
preceding days after vehicle treatmenta
treatment
QSAR An a lysis: CoMF A Stu d ies. As a possible
means of testing the validity of our 5-HT2C receptor
model, and also our proposed ligand docking mode, the
set of 55 indolinylureas 2-56 shown in Tables 1 and 2
were selected for QSAR analysis using the CoMFA32
module within the Sybyl33 molecular modeling environ-
ment. All compounds were docked into the 5-HT2C
receptor model in a manner analogous to that described
for 46 above. Each receptor-ligand complex was then
subjected to brief energy minimization in order to
remove any bad steric contacts that may have arisen
during the docking procedure. The individual ligands
were then extracted from their respective receptor
complexes (after any necessary realignment of the
backbone atoms of the receptor) and subjected to
CoMFA analysis. For this purpose a subset of 8
compounds was chosen at random to serve as a test set
for predictions from the analysis, leaving a set of 47
compounds on which the analysis was actually per-
formed.
(mg/kg po
unpunished
(VI)
punished
(FR)
compd
43
1 h pretest)
0.5
1
2
5
10
20
0
+2
+5*
+4
+3
+6**
0
+24***
+29***
+28***
+38***
+53***
46
51
0.5
1
2
5
10
20
+3
+10**
+4*
+2
+6
+30***
+36***
+38**
+46***
+76***
-2
0
0.1
0.2
0.5
1
2
5
+8*
+2
+2
-2
+3
+8**
0
-8
+26***
+36***
+28***
+34***
+37***
+63***
+62***
10
20
-1
52
0.2
0.5
1
2
5
-3
+3
+4
+1
0
-5
+31***
+33***
+24***
+31***
The set of 47 aligned ligands were loaded into a Sybyl
database and from there imported into a Sybyl Molec-
ular Spreadsheet. An Autocomfa analysis using all of
the default CoMFA options was then performed. This
yielded a model whose statistical details are listed in
Table 4. The predicted activities for the 47 compounds
versus their actual activities are plotted in Figure 3.
diazepam
5
-19*
70***
a
All data cited as means of groups that contain 6-8 rats.
Significance of the difference from lever presses on each of 2
preceding test days after vehicle treatment indicated by: *,**,***p
< 0.05, 0.01, 0.001, by two-way ANOVA of square-root-transformed
data.
From the residual plot in Figure 3, and from the fitted
r2 value of 0.877 from Table 4, it is clear that the CoMFA
model explains the variance in the biological data for
the 47 compounds used in the derivation of the model
reasonably well. Also, the fact that ∼80% of the
variance in the model is explained by the steric fields
surrounding the molecules and only ∼20% is electro-
static in origin is in good agreement with the proposed
binding pocket the two residues Val-212 and Val-608
are seen to make the closest contacts with the -SMe
and -CF3 substituents around the indoline ring. In the
5-HT2B receptor sequence the corresponding 608 residue
is Leu, and in the 5-HT2A receptor sequence both the
212 and 608 residues are Leu. These differences would
F igu r e 2. Structure 46 docked into the model of the 5-HT2C receptor.

1604 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Ta ble 4. Statistical Details of the Derived CoMFA Model
Bromidge et al.
maximum no. of PLS components
no. of cross-validation groups
optimal no. of PLS components
r2
5
5
4
0.877
0.268
75.00
0
standard error of estimate
F values (n1 ) 4, n2 ) 45)
probability of r2 ) 0
q2
0.656
no. of PLS variables
770
relative contribution of steric variables
to final model
relative contribution of electrostatic variables
to final model
79.0%
21.0%
F igu r e 4. Orthogonal views of 46 embedded in color-coded
regions deemed by the CoMFA model to be important for
activity. Green regions are where more steric bulk is predicted
to be beneficial for activity; yellow regions are where less steric
bulk is predicted to be beneficial for activity.
that the obtained CoMFA model not only is robust but
also has good predictivity for similar molecules not used
in its derivation.
Lastly, in relation to the CoMFA model, we used the
graphical capabilities within the Sybyl/CoMFA modeling
environment to display those regions of space around
our ligands that the CoMFA model suggested were
important for explaining the observed biological activi-
ties. The resulting color-coded surfaces are shown in
Figure 4, around 46 for reference. Since the CoMFA
model had limited contributions from the electrostatic
variables, only the steric field terms were contoured and
displayed. The yellow surfaces define regions where the
model suggests that extra steric bulk would be detri-
mental to the observed biological activity. The green
surfaces define regions where extra steric bulk would
be beneficial for increased biological activity. The
predominance of yellow regions in Figure 4 suggests
that the indoline ring and its substituents fit into a very
tight binding pocket with very limited scope for ad-
ditional or larger substituents. This is particularly true
around the 5-position of the indoline. In our proposed
binding model substituents at this position, and to a
lesser extent at the 6- and 7-positions, are seen to make
close steric contacts with the residues Val-212 and Val-
608 of the receptor, as described earlier. These two
residues are thought to play a key role in the observed
5-HT2C selectivity of these ligands over the 5-HT2B and
5-HT2A subtypes where one or both of these residues
respectively are replaced by leucines. Thus the CoMFA
model is in good qualitative agreement both with our
5-HT2C receptor model and with our proposed binding
mode for this class of ligands within that model.
F igu r e 3. Plot of actual vs predicted 5-HT2C pKi values for
the 50 compounds used in the derivation of the CoMFA model.
Ta ble 5. Predictions for the Eight Test Compounds Not Used
in the Derivation of the CoMFA Model
5-HT2C (pKi)
compd
actual
predicted
residual
13
14
25
35
41
43
44
49
7.30
7.60
8.00
7.70
7.80
8.70
7.90
7.50
6.92
7.14
7.94
7.64
7.52
8.13
7.85
8.46
0.38
0.46
0.06
0.06
0.28
0.57
0.05
-0.96
binding mode which hypothesizes that both “ends” of
the structures are bound in lipophilic binding pockets.
Furthermore, the q2 (cross-validated r2) figure of 0.656
suggests that the model should have good predictivity
for similar molecules not present within the original
training set. Accordingly, the eight test compounds that
were originally kept aside were each placed into the
model in turn and their activities predicted. The results
of these predictions are shown in Table 5. This shows
that in six of the eight cases, the CoMFA prediction of
the activity is within 0.5 log unit of the actual value
and in many cases significantly better than this figure.
The remaining two cases have predictions between 0.5
and 1.0 log unit away from the true value, namely, 0.57
for 43 and -0.96 for 49. However, these differences are
accounted for by the statistical variation within the
biological data itself. These results therefore suggest
Con clu sion
In conclusion, we report the synthesis and biological
activity of a series of substituted 1-(3-pyridylcarbamoyl)-
indolines which illustrates the use of 5,6-disubstituted
monocyclic rings as N-methylindole isosteres in the
context of 5-HT2C/2B receptor antagonists. By targeting
a region of space previously identified as allowed at the
5-HT2C receptor but disallowed at the 5-HT2A receptor,
due to steric differences in the receptor, we have
identified a number of metabolically stable compounds
which are the most potent and selective 5-HT2C/2B
receptor antagonists yet reported. Compound 46 was

5-HT2C/ 2B Receptor Antagonists as Anxiolytic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1605
6.99 (1H, m), 7.23 (1H, d, J ) 8 Hz), 7.31-7.38 (1H, m), 7.88
(1H, s), 7.94-8.02 (1H, m), 8.24 (1H, d, J ) 6 Hz), 8.72 (1H,
s), 8.82 (1H, s). Anal. (C14H12N3OCl) C, H, N.
5-Br om o-7-n itr o-1-(3-p yr id ylca r ba m oyl)in d olin e (20).
5-Bromo-7-nitro-1-indoline was treated with 3-pyridyl isocy-
anate as in the preparation of 6 to give the title compound 20
as a yellow solid (19%), mp 185-186 °C (EtOH). NMR
(DMSO-d6) δ: 3.30 (2H, t, J ) 8 Hz), 4.30 (2H, t, J ) 8 Hz),
7.35 (1H, m), 7.79-7.96 (3H, m), 8.26 (1H, m), 8.65 (1H, m),
9.69 (1H, s). Anal. (C14H11N4O3Br) C, H, N.
5-(N,N-Dim et h yla m in o)-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (10). A mixture of 1-acetyl-5-nitroindoline (0.9 g, 4.37
mmol), 37% aqueous formaldehyde (1 mL), and 10% Pd-C
(0.1 g) in ethanol (15 mL) was hydrogenated at 45 psi at room
temperature overnight. The reaction mixture was filtered
through Celite and evaporated to afford 1-acetyl-5-(N,N-
dimethylamino)indoline (0.89 g, 100%). NMR (CDCl3) δ: 2.20
(3H, s), 2.92 (6H, s), 3.18 (3H, m,), 4.02 (2H, J ) 8 Hz), 6.61
(2H, m), 8.08 (1H, m). Without further purification this
material (0.6 g, 2.94 mmol) was heated on a steam bath with
concentrated HCl (10 mL) for 45 min, cooled, and then
partitioned between aqueous K2CO3 (50 mL) and CHCl3 (50
mL). The organic phase was dried (Na2SO4), evaporated to
dryness, and purified by chromatography on silica gel eluting
with 5-10% MeOH in EtOAc to afford 5-(N,N-dimethylamino)-
indoline (0.29 g, 61%) which was immediately treated with
3-pyridyl isocyanate as in the preparation of 6 to afford the
title compound 10 (550 mg, 99%) as an off-white solid, mp
135-137 °C. NMR (DMSO-d6) δ: 2.82 (6H, s), 3.14 (2H, t, J
) 8 Hz), 4.08 (2H, t, J ) 8 Hz), 6.53 (1H, m), 6.68 (1H, d),
7.70 (1H, d), 7.98 (1H, dd), 8.20 (1H, m), 8.58 (1H, s), 8.72
(1H, d). MS: m/ e 282 (M+). Anal. (C16H18N4O‚0.75H2O) C,
H, N.
selected on the basis of its overall biological profile for
further evaluation as a potential, novel, nonsedating
anxiolytic agent. Unfortunately, 46 and related com-
pounds were found to be potent inhibitors of a number
of human cytochrome P450 enzymes which precluded
their further development.41 A CoMFA analysis of these
compounds produced a model with good predictive value
and in addition good qualitative agreement both with
our 5-HT2C receptor model and with our proposed
binding mode for this class of ligands within that model.
Exp er im en ta l Section
Ch em istr y. Melting points are uncorrected. The elemental
analyses were within 0.4% of the theoretical values. HPLC
analysis of test compounds was carried out on a Gilson 712
HPLC system, using a model 231 sample injector and 306
pump with 806 manomeric module detector. A Hypersil BDS
C18 3-µm (100- × 3-mm i.d.) column was used with elution
under the following conditions: eluant A, 0.1% TFA/H2O, v/v;
eluant B, 0.1% TFA/CH3CN, v/v; flow rate, 0.7 mL/min. The
elution gradient was 0% B held for 0.5 min, then linearly
increased to 75% B over 24.5 min, then held for 5 min. The
UV detection wavelength was 218 nm. All final compounds
were greater than 95% pure as judged by area under the curve.
NMR spectra were recorded on a Bruker AC-200, AC-250, or
AM-400 spectrometer using Me4Si as internal standard.
Electron impact mass spectra were determined using a Fisons
VG 302 single quadrupole mass spectrometer. Tetrahydrofu-
ran (THF) was freshly distilled from sodium benzophenone
ketyl under an argon atmosphere before use. N,N-Dimethyl-
formamide (DMF) and dimethyl sulfoxide (DMSO) were of
commercial grade and dried over 4-Å molecular sieves before
use. Other solvents and reagents were of commercial grade
and used without purification. Petroleum ether refers to the
fraction with bp 60-80 °C. All evaporations of solvents were
carried out under reduced pressure, and organic solutions were
dried over Na2SO4. Chromatography was performed on Merck
Art. 7734 silica gel or Fluka silica gel 60 (60739).
The following compounds were prepared from indolines
obtained via reduction of commercially available or known
indoles.
1-(3-P yr idylcar bam oyl)-6-(tr iflu or om eth yl)in dolin e (12).
6-(Trifluoromethyl)indole32 (5.27 g, 28.5 mmol) in glacial acetic
acid (50 mL) was treated with sodium cyanoborohydride (3.60
g, 57.0 mmol) portionwise at room temperature with stirring.
After 3 h at room temperature the reaction mixture was
diluted with water (100 mL) and basified with 40% aqueous
NaOH with cooling. The mixture was then extracted with
dichloromethane (3 × 150 mL), and the combined extracts
were dried (Na2SO4) and evaporated to give 6-(trifluorometh-
yl)indoline (4.83 g, 91%) as a brown solid which was used
without further purification. NMR (CDCl3) δ: 3.07 (2H, t, J
) 8 Hz), 3.62 (2H, t, J ) 8 Hz), 6.80 (1H, s), 6.92 (1H, d, J )
8 Hz), 6.92 (1H, d, J ) 8 Hz), 7.15 (1H, d, J ) 8 Hz). The
6-(trifluoromethyl)indoline was treated with 3-pyridyl isocy-
anate as in the preparation of 6 to give the title compound 12
as a white solid (88%), mp 225-228 °C. NMR (DMSO-d6) δ:
3.30 (2H, t, J ) 8 Hz), 4.22 (2H, t, J ) 8 Hz), 7.25-7.50 (2H,
m), 8.02 (1H, m), 8.19 (1H, s), 8.28 (1H, m), 8.76 (1H, m) 8.89
(1H, s). MS: m/ e 307.0949 (M+), C15H12N3OF3 requires
307.0932.
5-Ch lor o-1-(3-p yr id ylca r ba m oyl)in d olin e (4). 5-Chlor-
oindoline was prepared by reduction of 5-chloroindole as above
and converted to the title compound 4 (82%) as in the
preparation of 6 to afford a white solid, mp 204-205 °C. NMR
(DMSO-d6) δ: 3.18 (2H, t, J ) 8 Hz), 4.15 (2H, t, J ) 8 Hz),
7.15-7.18 (1H, m), 7.25 (1H, s), 7.27-7.35 (1H, m), 7.85 (1H,
d, J ) 8 Hz), 7.93-8.00 (1H, m), 8.19-8.24 (1H, m), 8.70-
8.80 (2H, m). MS: m/ e 273.0668 (M+), C14H12N3OCl requires
273.0669.
The following compounds were prepared from commercially
available or known indolines.
5-Nit r o-1-(3-p yr id ylca r b a m oyl)in d olin e H yd r och lo-
r id e (6). A solution of nicotinic acid azide (0.43 g, 2.9 mmol)
[CAUTION! Heating this material in the absence of solvent
can lead to explosive decomposition. Larger-scale (ca. 20 g or
above) preparations following this procedure are noticeably
exothermic on reaching 70-80 °C, and copious volumes of
nitrogen are rapidly evolved. Appropriate precautions for the
storage and utilization of this reagent are strongly advised.]
in toluene (20 mL) was heated at reflux for 0.5 h to form
3-pyridyl isocyanate and then cooled to room temperature. A
solution of 5-nitroindoline (0.38 g, 2.3 mmol) in dichlo-
romethane (20 mL) was then added, and the mixture was
stirred overnight at room temperature. The resulting precipi-
tate was treated with excess HCl in ether to give the title
compound 6 (0.64 g, 76%) as a light-yellow powder, mp 244-
247 °C dec. NMR (DMSO-d6) δ: 3.32 (2H, t, J ) 8 Hz), 4.35
(2H, t, J ) 8 Hz), 7.8-8.2 (4H, m), 8.5-8.65 (2H, m), 9.14 (1H,
d, J ) 2 Hz), 9.78 (1H, s). MS: m/ e 284.0894 (M+), C14H12N4O3
requires 284.0909.
1-(3-P yr idylcar bam oyl)in dolin e (2). Indoline was treated
with 3-pyridyl isocyanate as in the preparation of 6 to give
the title compound 2 as a white solid (98%), mp 206-208 °C.
NMR (DMSO-d6) δ: 3.29 (2H, t, J ) 8 Hz), 4.24 (2H, t, J ) 8
Hz), 7.03 (1H, dd, J ) 6 Hz), 7.19-7.36 (2H, m), 7.44 (1H, dd,
J ) 5, 7 Hz), 7.98 (1H, d, J ) 7 Hz), 8.09 (1H, m) 8.33 (1H, m),
8.83 (1H, m). MS: m/ e 239 (M+). Anal. (C14H13N3O) C, H,
N.
5-Meth yl-1-(3-p yr id ylca r ba m oyl)in d olin e (7). 5-Meth-
ylindole was treated with sodium cyanoborohydride as for 12
and the resulting indoline reacted with 3-pyridyl isocyanate
as in the preparation of 6 to give the title compound 7 as a
white solid (78%), mp 205-206 °C (MeOH/CH2Cl2). NMR
(DMSO-d6) δ: 2.30 (3H, s), 3.25 (2H, t, J ) 8 Hz), 4.22 (2H, t,
J ) 8 Hz), 7.05 (1H, d, J ) 8 Hz), 7.15 (1H, s), 7.40-7.47 (1H,
m), 7.82 (1H, d, J ) 8 Hz), 8.10 (1H, m), 8.30 (1H, m), 8.78
(1H, s), 8.86 (1H, s). Anal. (C15H15N3O) C, H, N.
6-Ch lor o-1-(3-p yr id ylca r ba m oyl)in d olin e (13). The title
compound was prepared as in the preparation of 6 from
3-pyridyl isocyanate and 6-chloroindoline to give the title
compound 13 (1.54 g, 73%), mp 204-205 °C. NMR (DMSO-
d6-) δ: 3.19 (2H, t, J ) 8 Hz), 4.19 (2H, t, J ) 8 Hz), 6.93-

1606 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Bromidge et al.
4-Ch lor o-1-(3-p yr id ylca r ba m oyl)in d olin e (3). 4-Chlor-
oindole was treated with sodium cyanoborohydride as for 12.
The resulting indoline was reacted with 3-pyridyl isocyanate
as in the preparation of 6 to give the title compound 3 as a
white solid (76%), mp 203-205 °C (MeOH/CH2Cl2). NMR
(DMSO-d6) δ: 3.21 (2H, t, J ) 8 Hz), 4.21 (2H, t, J ) 8 Hz),
6.99 (1H, d, J ) 8 Hz), 7.18 (1H, dd, J ) 8 Hz), 7.35 (1H, m),
7.81 (1H, d, J ) 8 Hz), 8.00 (1H, m), 8.24 (1H, m), 8.75 (1H,
s), 8.80 (1H, s). MS: m/ e 273.0670 (M+), C14H12N3OCl
requires 273.0669. Anal. (C14H12N3ClO) C, H, N.
dium cyanoborohydride as for 12 to give 6-chloro-5-tert-
butylindoline as a yellow oil. NMR (CDCl3) δ: 1.38 (9H, s),
2.89 (2H, t, J ) 8 Hz), 3.46 (2H, t, J ) 8 Hz), 3.60 (1H, bs),
6.53 (1H, s), 7.09 (1H, s). The indoline was treated with
3-pyridyl isocyanate as in the preparation of 6 to give the title
compound 36 (35%) as a white crystalline solid, mp 200 °C
(ethanol/diethyl ether). NMR (DMSO-d6) δ: 1.40 (9H, s), 3.15
(2H, t, J ) 8 Hz), 4.15 (2H, t, J ) 8 Hz), 7.30 (1H, s), 7.33 (1H,
m), 7.85 (1H, s), 7.98 (1H, d, J ) 9 Hz), 8.22 (1H, d, J ) 5 Hz),
8.73 (1H, m), 8.78 (1H, s). Anal. (C18H20N3OCl) C, H, N.
4-Ch lor o-5-t er t -b u t yl-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (17). 4-Chloro-5-tert-butylindole was treated with sodium
cyanoborohydride as for 12 to give 4-chloro-5-tert-butylindoline
as a yellow oil. NMR (CDCl3) δ: 1.44 (9H, s), 3.09 (2H, t, J )
8 Hz), 3.58 (2H, b, J ) 8 Hz), 3.76 (1H, b), 6.47 (1H, d), 7.07
(1H, d). The indoline was treated with 3-pyridyl isocyanate
as in the preparation of 6 to give the title compound 17 (58%)
as a white crystalline solid, mp 174-176 °C (ethanol/diethyl
ether). NMR (DMSO-d6) δ: 1.42 (9H, s), 3.21 (2H, t, J ) 8
Hz), 4.19 (2H, t, J ) 8 Hz), 7.25 (1H, d, J )7 Hz), 7.33 (1H,
m), 7.70 (1H, d, J ) 7 Hz), 7.99 (1H, d, J ) 9 Hz), 8.22 (1H, d,
5 Hz), 8.77 (2H, m). Anal. (C18H20N3OCl) C, H, N.
5-P h en yl-1-(3-p yr id ylca r ba m oyl)in d olin e (9). 5-Phe-
nylindole33 was reduced to 5-phenylindoline as described for
12 and treated with 3-pyridyl isocyanate as in the preparation
of 6 to give the title compound 9 as a white solid (52%), mp
241-242 °C. NMR (DMSO-d6) δ: 3.25 (2H, t, J ) 8 Hz), 4.19
(2H, t, J ) 8 Hz), 7.23-7.69 (8H, m), 7.89-8.03 (2H, m), 8.11
(1H, m), 8.75-8.80 (2H, m). MS: m/ e 315.1371 (M+),
C
20H17N3O requires 315.1372.
The following compounds were prepared by the Nordlander18
synthesis or, more satisfactorily, by the Sundberg modifica-
tion19 of the Nordlander synthesis.
5-(2-P r op yl)in d ole. A mixture of 4-(2-propyl)aniline (20.4
g, 151 mmol) and 2,2-dimethoxyethanal (49.8 g, 196 mmol) in
ethanol (400 mL) was stirred with 5% palladium on charcoal
(5 g) under hydrogen (1 atm) for 18 h. The mixture was then
filtered through Kieselgu¨hr and evaporated. The residue was
dissolved in ethyl acetate and washed with brine. The organic
solution was dried and evaporated to give N-[(2,2-dimethoxy-
ethyl)amino]-4-(2-propyl)aniline (33.69 g, 100%) as a red oil.
NMR (CDCl3) δ: 1.20 (6H, d, J ) 6 Hz), 2.81 (1H, m, J ) 6
Hz), 3.22 (2H, d, J ) 5 Hz), 3.40 (6H, s), 3.75 (1H, broad), 4.58
(1H, t, J ) 5 Hz), 6.59 (2H, d, J ) 8 Hz), 7.05 (2H, d, J ) 8
Hz). The acetal (1.02 g, 4.55 mmol) was heated in trifluoro-
acetic acid/trifluoroacetic anhydride according to the method
of Nordlander.18 The crude product was chromatographed on
silica gel eluting with 1:1 dichloromethane/petroleum ether to
give 5-(2-propyl)-1-(trifluoroacetyl)indole (0.25 g, 22%). NMR
(CDCl3) δ: 1.29 (6H, d, J ) 7 Hz), 3.00 (1H, m, J ) 7 Hz),
6.68 (1H, d, J ) 5 Hz), 7.27 (1H, d, J ) 7 Hz), 7.42 (2H, s),
8.32 (1H, d, J ) 7 Hz). The (trifluoroacetyl)indole (0.25 g, 0.99
mmol) was stirred with potassium carbonate (0.20 g, 1.5 mmol)
in methanol (7.5 mL) at 55 °C for 1.5 h. Solvent was
evaporated, and the residue was partitioned between water
and dichloromethane. The organic extract was dried and
evaporated to give the title compound (0.14 g, 86%). NMR
(CDCl3) δ: 1.30 (6H, d, J ) 7 Hz), 3.00 (1H, m, J ) 7 Hz),
6.48 (1H, m), 7.01 (1H, m), 7.09 (1H, d, J ) 8 Hz), 7.20 (1H, d,
J ) 8 Hz), 7.49 (1H, s), 7.71 (1H, broad).
The following compounds were prepared according to the
general procedures described above employing the appropriate
3-chloro-4-alkylanilines (themselves prepared by the general
procedure described by Lampooy34).
6-Ch lor o-5-isop r op yl-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (37): recrystallized from ethanol/diethyl ether as a white
crystalline solid (57%), mp 183-185 °C. NMR (DMSO-d6) δ:
1.19 (6H, d, J ) 8 Hz), 2.18 (2H, t, J ) 8 Hz), 3.23 (1H, m, J
) 8 Hz), 4.15 (2H, t, J ) 8 Hz), 7.24 (1H, s), 7.33 (1H, m), 7.86
(1H, s), 7.98 (1H, d, J ) 9 Hz), 8.22 (1H, d, J ) 5 Hz), 8.73
(1H, m), 8.78 (1H, s). Anal. (C17H18N3OCl) C, H, N.
6-Ch lor o-5-m eth yl-l-(3-pyr idylcar bam oyl)in dolin e (26):
obtained as a white powder (62%), mp 221-223 °C. NMR
(DMSO-d6) δ: 2.25 (3H, s), 3.15 (2H, t, J ) 8 Hz), 4.16 (2H, t,
J ) 8 Hz), 7.17 (1H, s), 7.33 (1H, dd, J ) 8, 4 Hz), 7.88 (1H,
s), 7.98 (1H, m), 8.23 (1H, dd, J ) 5, 2 Hz), 8.75 (2H, m). MS:
m/ e 287.289 (M+), requires 287.289. Anal. (C15H14ClN3O) C,
H, N.
6-Ch lor o-5-eth yl-1-(3-p yr id ylca r ba m oyl)in d olin e (34):
recrystallized from ethanol/diethyl ether as a white crystalline
solid (59%), mp 227 °C. NMR (DMSO-d6) δ: 1.13 (3H, t, J )
8 Hz), 2.62 (2H, q, J ) 8 Hz), 3.17 (2H, t, J ) 8 Hz), 4.16 (2H,
t, J ) 8 Hz), 7.18 (1H, s), 7.33 (1H, m), 7.87 (1H, s), 7.99 (1H,
d, J ) 9 Hz), 8.23 (1H, d, J ) 5 Hz), 8.73 (1H, m), 8.79 (1H, s).
Anal. (C16H16N3ClO) C, H, N.
6-Ch lor o-5-pr opyl-1-(3-pyr idylcar bam oyl)in dolin e (35):
recrystallized from ethanol/diethyl ether as a white crystalline
solid (58%), mp 218-220 °C. NMR (DMSO-d6) δ: 1.00 (3H, t,
J ) 8 Hz), 1.66 (2H, q, J ) 8 Hz), 2.70 (2H, t, J ) 8 Hz), 3.27
(2H, t, J ) 8 Hz), 4.26 (2H, t, J ) 8 Hz), 7.25 (1H, s), 7.42 (1H,
m), 7.98 (1H, s), 8.08 (1H, d, J ) 8 Hz), 8.32 (1H, d, J ) 5 Hz),
8.83 (1H, m), 8.89 (1H, s). MS: m/ e 315.1143 (M+), C17H18N3-
OCl requires 315.1138.
4,6-Dich lor o-5-m e t h yl-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (29). Starting with 3,5-dichloro-4-methylaniline and
following the general procedures described above, the title
compound was prepared as a white solid (27%), mp 234-235
°C (dichloromethane/ethanol). NMR (DMSO-d6) δ: 8.82 (1H,
s), 8.7 (1H, m), 8.25 (1H, d, J ) 5 Hz), 7.95 (1H, m), 7.32 (1H,
m), 4.20 (2H, t, J ) 8 Hz), 3.17 (2H, t, J ) 8 Hz), 2.32 (3H, s).
Anal. (C15H13N3Cl2O) C, H, N.
5-(2-P r op yl)-1-(3-p yr id ylca r ba m oyl)in d olin e (8). 5-(2-
Propyl)indole was treated with sodium cyanoborohydride as
for 12 to give 5-(2-propyl)indoline (84%). NMR (CDCl3) δ: 1.23
(6H, d, J ) 7 Hz), 2.81 (1H, m, J ) 7 Hz), 2.91 (2H, t, J ) 8
Hz), 3.38 (2H, t, J ) 8 Hz), 3.59 (1H, s), 6.47 (1H, d, J ) 8
Hz), 6.85 (1H, d, J ) 8 Hz), 6.98 (1H, s). Treatment of the
indoline with 3-pyridyl isocyanate as in the preparation of 6
gave the title compound 8 as a white solid (45%), mp 163-
165 °C. NMR (DMSO-d6) δ: 1.18 (6H, d, J ) 7 Hz), 2.83 (1H,
m, J ) 7 Hz), 3.18 (2H, t, J ) 8 Hz), 4.13 (2H, t, J ) 8 Hz),
7.00 (1H, d, J ) 7 Hz), 7.10 (1H, s), 7.32 (1H, dd, J ) 7, 5 Hz),
7.77 (1H, d, J ) 7 Hz), 7.99 (1H, dm, J ) 7 Hz), 8.22 (1H, d,
J
) 5 Hz), 8.69 (1H, s), 8.74 (1H, d, J ) 2 Hz). Anal.
(C17H19N3O) C, H, N.
6-Ch lor o-5-ter t-bu tylin d ole a n d 4-Ch lor o-5-ter t-bu tyl-
in d ole. 3-Chloro-4-tert-butylaniline34 was converted to a 5:4
mixture of the title compounds by the method developed by
Sundberg19 in an overall yield of 37%. The isomers were
separated by column chromatography on silica gel using 5%
ethyl acetate in petroleum ether (60-80 °C) to give in order
of elution 6-chloro-5-tert-butylindole [NMR (CDCl3) δ: 1.54
(9H, s), 6.50 (1H, m), 7.17 (1H, m), 7.41 (1H, s), 7.69 (1H, s),
8.02 (1H, bs)] and 4-chloro-5-tert-butylindole [NMR (CDCl3)
δ: 1.55 (9H, s), 6.70 (1H, m), 7.15-7.28 (3H, m)].
The following compounds were prepared according to the
general procedures described above starting from the ap-
propriate 3-halo-4-methylaniline.
6-Iod o-5-m eth yl-1-(3-p yr id ylca r ba m oyl)in d olin e (28)
an d 4-Iodo-5-m eth yl-1-(3-pyr idylcar bam oyl)in dolin e (16).
6-Iodo-5-methylindoline and 4-iodo-5-methylindoline were pre-
pared as a 4:1 mixture starting from 3-iodo-4-methylaniline.
Treatment of this mixture with 3-pyridyl isocyanate as in the
preparation of 6 gave the title compounds as a mixture (4:1,
38% combined yield), a portion of which was separated by
preparative HPLC.
6-Ch lor o-5-t er t -b u t yl-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (36). 6-Chloro-5-tert-butylindole was reduced with so-

5-HT2C/ 2B Receptor Antagonists as Anxiolytic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1607
6-Iod o-5-m eth yl-1-(3-p yr id ylca r ba m oyl)in d olin e (28):
obtained as a white solid, mp 252-254 °C. NMR (DMSO-d6)
δ: 2.32 (3H, s), 3.13 (2H, t, J ) 9 Hz), 4.15 (2H, t, J ) 9 Hz),
7.19 (1H, s), 7.33 (1H, m), 7.98 (1H, m), 8.23 (1H, m), 8.34
(1H, s), 8.73 (1H, m). MS: m/ e 379.0188 (M+), C15H14N3OI
requires 379.0182.
4-Iod o-5-m eth yl-1-(3-p yr id ylca r ba m oyl)in d olin e (16):
obtained as a white solid, mp 222-224 °C. NMR (DMSO-d6)
δ: 2.33 (3H, s), 3.11 (2H, t, J ) 9 Hz), 4.17 (2H, t, J ) 9 Hz),
7.09 (1H, d, J ) 8 Hz), 7.34 (1H, m), 7.76 (1H, d, J ) 8 Hz),
7.97 (1H, m), 8.23 (1H, m), 8.71 (1H, s), 8.74 (1H, m). MS:
m/ e 379.0183 (M+), C15H14N3OI requires 379.0182.
6-Br om o-5-m eth yl-1-(3-p yr id ylca r ba m oyl)in d olin e (27)
a n d 4-Br om o-5-m et h yl-1-(3-p yr id ylca r ba m oyl)in d olin e
(15). 6-Bromo-5-methylindoline and 4-bromo-5-methylindoline
were prepared as a 3:1 mixture starting from 3-bromo-4-
methylaniline. Treatment with 3-pyridyl isocyanate as in the
preparation of 6 gave the title compounds as a mixture (3:1,
52%), a portion of which was separated by preparative HPLC.
115.7, 120.8, 123.1, 127.2, 131.2, 136.2, 137.7, 141.9, 142.5,
148.0, 152.2. MS: m/ e 331.1096 (M+), C17H18ClN3O2 requires
331.1102.
5-Ch lor o-6-(tr iflu or om eth yl)-1-(3-p yr id ylca r ba m oyl)-
in d olin e (23): obtained as a white solid (86%), mp >220 °C.
NMR (DMSO-d6) δ: 3.30 (2H, t, J ) 8 Hz), 4.20 (2H, t, J ) 8
Hz), 7.35 (1H, m), 7.55 (1H, s), 8.00 (1H, m), 8.25 (1H, m),
8.30 (1H, s), 8.75 (1H, m) 8.90 (1H, s). MS: m/ e 341.0530
(M+), C15H11N3OClF3 requires 341.0543.
4,6-Dich lor o-5-(m et h ylt h io)-1-(3-p yr id ylca r b a m oyl)-
in d olin e (30). The title compound was prepared from 3,5-
dichloro-4-(methylthio)aniline26 as a white crystalline solid
(67%), mp 199-200 °C (EtOAc/CH2Cl2). NMR (DMSO-d6) δ:
2.32 (3H, s), 3.20 (2H, t, J ) 8 Hz), 4.21 (2H, t, J ) 7 Hz), 7.34
(1H, m), 8.98 (2H, m), 8.27 (1H, m), 8.71 (1H, d), 8.91 (1H, s).
MS: m/ e 321.0430 (M+), C15H13N3OCl2 requires 321.0436.
Starting with the appropriate o-nitrotoluene, the following
compounds (21, 25, 38, 42) were prepared by the Leimgruber20
procedure.
6-Br om o-5-m eth yl-1-(3-pyr idylcar bam oyl)in dolin e (27):
obtained as a white solid, mp 246-247 °C. NMR (CDCl3) δ:
2.34 (3H, s), 3.20 (2H, t, J ) 9 Hz), 4.12 (2H, t, J ) 9 Hz), 6.42
(1H, bs), 7.04 (1H, s), 7.27 (1H, m), 8.11 (1H, m), 8.16 (1H, s),
8.35 (1H, m), 8.50 (1H, s). MS: m/ e 331.0331 (M+), C15H14N3-
OBr requires 331.0320.
4-Br om o-5-m eth yl-1-(3-pyr idylcar bam oyl)in dolin e (15):
obtained as a white solid, mp 211-213 °C. NMR (CDCl3) δ:
2.36 (3H, s), 3.27 (2H, t, J ) 9 Hz), 4.15 (2H, t, J ) 9 Hz), 6.45
(1H, b s), 7.09 (1H, d, J ) 8 Hz), 7.28 (1H, m), 7.75 (1H, d, J
) 8 Hz), 8.09 (1H, m), 8.32 (1H, m), 8.50 (1H, s). MS: m/ e
331.0323 (M+), C15H14N3OBr requires 331.0320.
5,6-Dich lor o-1-(3-pyr idylcar bam oyl)in dolin e (21). 2-Ni-
tro-4,5-dichlorotoluene35 was treated with N,N-dimethylfor-
mamide dimethyl acetal followed by TiCl3 according to the
general method described by Leimgruber20 to give 5,6-dichlor-
oindole (1.3 g, 72%). NMR (CDCl3) δ: 6.48-6.52 (1H, m),
7.22-7.25 (1H, m), 7.50 (1H, s), 7.73 (1H, s), 8.01-8.31 (1H,
br s). 5,6-Dichloroindole was then reduced as for 12 with
sodium cyanoborohydride in acetic acid to give 5,6-dichloroin-
doline NMR (CDCl3) δ: 3.01 (2H, t, J ) 8 Hz), 3.63 (1H, t, J
) 8 Hz), 3.75-3.91 (1H, br s), 6.70 (1H, s), 7.15 (1H, s).
Treatment with 3-pyridyl isocyanate as in the preparation of
6 gave the title compound 21 as a white solid (1.27 g, 65%),
mp 236-238 °C. NMR (DMSO-d6) δ: 3.18 (2H, t, J ) 8 Hz),
4.21 (2H, t, J ) 8 Hz), 7.28-7.35 (1H, m), 7.47 (1H, s), 7.92-
7.99 (1H, m), 8.00 (1H, s), 8.23 (1H, d, J ) 6 Hz), 8.70 (1H, s),
8.83 (1H, s). Anal. (C14H11N3OCl2) C, H, N.
5-Ch lor o-6-m eth yl-1-(3-pyr idylcar bam oyl)in dolin e (25).
Starting with 2-chloro-5-nitro-p-xylene, the title compound was
obtained as a white solid (73%), mp 217-218 °C (ethanol/
dichloromethane). NMR (DMSO-d6) δ: 2.27 (3H, s), 3.13 (2H,
t, J ) 8 Hz), 4.13 (2H, t, J ) 8 Hz), 7.21 (1H, s), 7.29-7.37
(1H, m), 7.82 (1H, s), 7.93-7.99 (1H, m), 8.22 (1H, d, J ) 6
Hz), 8.73 (1H, s). Anal. (C15H14N3OCl) C, H, N.
6-Ch lor o-5-ph en yl-1-(3-pyr idylcar bam oyl)in dolin e (38).
To a stirred solution of 2-chloro-5-methyl-4-nitrophenol36 (5
g, 26.6 mmol) and pyridine (2.4 mL, 30 mmol) in dichlo-
romethane (100 mL) at -5 °C (ice/salt) was added a solution
of trifluoroacetic anhydride (5 mL, 30 mmol) in dichlo-
romethane (5 mL) dropwise. The mixture was warmed to room
temperature and washed with 2 N aqueous HCl (50 mL) and
water (50 mL). The organic phase was dried and evaporated
to give trifluoromethanesulfonic acid 2-chloro-5-methyl-4-
nitrophenyl ester (8.2 g, 96%) as an oil. NMR (CDCl3) δ: 2.68
(3H, s), 7.40 (1H, s), 8.20 (1H, s). The crude triflate (8.2 g,
25.6 mmol) was taken up in dioxane (100 mL) together with
phenyltrimethyltin (4.9 mL, 26.9 mmol), tetrakis(triphenylphos-
phine)palladium (0.6 g, 0.5 mmol), and lithium chloride (3.2
g, 76.1 mmol) and heated at reflux for 2 h.37 After cooling the
reaction mixture was treated with a solution of KF (1.78 g,
30.7 mmol) in water (10 mL), and the resulting solution was
filtered and partitioned between ether (3 × 100 mL) and water
(100 mL). The combined organics were washed with water
(100 mL), dried, and evaporated to give an oily residue which
was purified by chromatography on silica gel eluting with 2%
EtOAc/petroleum ether to give 4-chloro-2-nitro-5-phenyltolu-
ene (3.3 g, 52%) as a pale-yellow oil. NMR (CDCl3) δ: 2.61
(3H, s), 7.33 (1H, s), 7.35-7.50 (5H, m), 8.16 (1H, s). Without
further purification this toluene was converted to 6-chloro-5-
phenylindole by the method of Liemgruber20 as described for
21 to give a brown oil (93%). NMR (CDCl3) δ: 6.60 (1H, m),
7.25 (1H, m), 7.34-7.60 (7H, m), 8.20 (1H, br s). The indole
was reduced as for 12 to give 6-chloro-5-phenylindoline. NMR
(CDCl3) δ: 3.02 (2H, t, J ) 8 Hz), 3.61 (1H, t, J ) 8 Hz), 3.87
(1H, br s), 6.70 (1H, s), 7.09 (1H, s), 7.25-7.50 (5H, m).
Treatment with 3-pyridyl isocyanate as in the preparation of
The following compounds were prepared in analogous ways
starting from the appropriate anilines.
5-(Tr iflu or om eth yl)-1-(3-pyr idylcar bam oyl)in dolin e (5):
recrystallized from ethanol/diethyl ether as a white crystalline
solid (38%), mp 188-189 °C. NMR (DMSO-d6) δ: 3.28 (2H, t,
J ) 8 Hz), 4.22 (2H, t, J ) 8 Hz), 7.31-7.37 (1H, m), 7.47-
7.57 (2H, m), 7.95-8.03 (2H, m), 8.24 (1H, d, J ) 6 Hz), 8.75
(1H, s), 8.90 (1H, s). MS: m/ e 307.0923 (M+), C15H12N3OF3
requires 307.0932.
6-Ch lor o-5-(m eth ylth io)-1-(3-p yr id ylca r ba m oyl)in d o-
lin e (39): recrystallized from ethanol/diethyl ether as a white
crystalline solid (81%), mp 241-242 °C. NMR (DMSO-d6) δ:
2.48 (3H, s), 3.22 (2H, t, J ) 8 Hz), 4.18 (2H, t, J ) 8 Hz), 7.22
(1H, s), 7.33 (1H, dd, J ) 9, 5 Hz), 7.91 (1H, s), 7.98 (1H, d, J
) 9 Hz), 8.23 (1H, d, J ) 5 Hz), 8.74 (1H, m), 8.80 (1H, s).
Anal. (C15H14N3OSCl) C, H, N.
4-Ch lor o-5-(m eth ylth io)-1-(3-p yr id ylca r ba m oyl)in d o-
lin e (18): recrystallized from ethanol as a white crystalline
solid (84%), mp 237-241 °C. NMR (DMSO-d6) δ: 2.43 (3H,
s), 3.20 (2H, t, J ) 8 Hz), 4.20 (2H, t, J ) 8 Hz), 7.14 (1H, d,
J ) 7 Hz), 7.34 (1H, dd, J ) 9, 5 Hz), 7.83 (1H, d, J ) 7 Hz),
7.98 (1H, d, J ) 7 Hz), 8.24 (1H, d, J ) 5 Hz), 8.73 (1H, m),
8.78 (1H, s). Anal. (C15H14N3OSCl) C, H, N.
6-Ch lor o-5-iod o-1-(3-p yr id ylca r ba m oyl)in d olin e (22):
obtained as a white crystalline solid, mp >200 °C. NMR
(DMSO-d6) δ: 3.15 (2H, t, J ) 8 Hz), 4.20 (2H, t, J ) 8 Hz),
7.35 (1H, m), 7.75 (1H, s), 7.95 (1H, m), 8.00 (1H, s), 8.25 (1H,
m), 8.70 (1H, m), 8.85 (1H, s). MS: m/ e 399 (M+).
6-Ch lor o-5-eth oxy-1-(3-pyr idylcar bam oyl)in dolin e (40):
isolated as a white crystalline solid (72%), mp 219 °C. NMR
(DMSO-d6) δ: 1.33 (3H, t, J ) 7 Hz), 3.20 (2H, t, J ) 8 Hz),
4.07 (2H, t, J ) 7 Hz), 4.18 (2H, t, J ) 8 Hz), 7.08 (1H, s), 7.33
(1H, dd, J ) 7, 5 Hz), 7.90 (1H, s), 7.99 (1H, dd, J ) 7, 2 Hz),
8.22 (1H, dd, J ) 7, 2 Hz), 8.72 (2H, m). MS: m/ e 317.0948
(M+), C16H16N3O2Cl requires 317.0931.
6-Ch lor o-5-isop r op oxy-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (41): prepared as a white crystalline solid (80%), mp 169-
171 °C. 1H NMR (DMSO-d6) δ: 1.28 (6H, d, J ) 7 Hz), 3.19
(2H, t, J ) 8 Hz), 4.17 (2H, t, J ) 7 Hz), 4.42-4.60 (1H, m),
7.10 (1H, s), 7.32 (2H, m, J ) 5, 7 Hz), 7.88 (1H, s), 7.98 (1H,
dd, J ) 2, 7 Hz), 8.22 (1H, dd, J ) 2, 5 Hz), 8.72 (1H, d, J )
2 Hz). 13C NMR (D6-DMSO) δ: 21.8, 27.3, 47.6, 72.0, 113.9,

1608 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Bromidge et al.
6 gave the title compound 38 as a white solid (57%), mp 214-
215 °C (ethanol/dichloromethane). NMR (DMSO-d6) δ: 3.23
(2H, t, J ) 8 Hz), 4.22 (2H, t, J ) 8 Hz), 7.25 (1H, s), 7.12-
7.50 (6H, m), 7.96-8.04 (2H, m), 8.26 (1H, m), 8.76 (1H, d, J
) 2 Hz), 8.87 (1H, s). Anal. (C20H16N3OCl) C, H, N.
over 0.75 h to a stirred solution of KOtBu (103.9 g, 0.927 mol)
in dry DMF (400 mL) at -10 °C.21 After complete addition
the resulting purple solution was maintained at -10 °C for 1
h and then poured into a mixture of ice/water (1.5 L) and 5 M
aqueous HCl (1.5 L). The resulting mixture was extracted
with dichloromethane (3 × 1 L). The combined extracts were
washed with water (3 L), dried (Na2SO4), and evaporated
under reduced pressure. The residue was chromatographed
on silica gel using 10-40% ethyl acetate/petroleum ether as
eluant to give the crude product which was recrystallized from
ethyl acetate/petroleum ether to afford the title compound (85.1
g, 78%) as a white solid, mp 103-104 °C. NMR (CDCl3) δ:
4.10 (3H, s), 4.37 (2H, s), 7.34 (1H, s), 8.53 (1H, s).
5-Meth oxy-6-(tr iflu or om eth yl)in d ole. [5-Methoxy-2-ni-
tro-4-(trifluoromethyl)phenyl]aceonitrile (85.0 g, 0.327 mol) in
ethanol/water (9:1, 1.6 L) and glacial acetic acid (16 mL) were
hydrogenated over 10% palladium on carbon (50 g) at 50 psi
for 0.5 h at room temperature.22 The reaction mixture was
filtered and evaporated in vacuo. The residue was partitioned
between aqueous K2CO3 (1 L) and dichloromethane (2 × 1 L),
and the combined organic extract was dried (Na2SO4) and
evaporated to afford the title indole (67.6 g, 96%) as a gray
solid, mp 104 °C. NMR (CDCl3) δ: 3.94 (3H, s), 6.53 (1H, m),
7.21 (1H, s), 7.32 (1H, m), 7.64 (1H, s), 8.25 (1H, br s).
5-Meth oxy-1-(3-pyr idylcar bam oyl)-6-(tr iflu or om eth yl)-
in d olin e (51). The indole (67.6 g, 0.637 mol) was treated with
sodium cyanoborohydride (40 g, 0.637 mol) in glacial acetic
acid (500 mL) as in the method described for 12 to afford
5-methoxy-6-(trifluoromethyl)indoline (67.7 g, 99%) as an off-
white solid, mp 83 °C. NMR (CDCl3) δ: 3.07 (2H, t, J ) 8
Hz), 3.58 (2H, t, J ) 8 Hz), 3.67 (1H, br s), 3.83 (3H, s), 6.83
(1H, s), 6.88 (1H, s). This indoline (67.7 g, 0.312 mol) was
treated with 3-pyridyl isocyanate according to the general
method described for 6 and the crude product was recrystal-
lized from ethanol/dichloromethane to give the title compound
51 (67.2 g, 64%) as a white crystalline solid, mp 265-267 °C.
On partial evaporation of the mother liquors, a second crop
(12 g, 11%) was obtained, mp 263-265 °C. NMR (DMSO-d6)
δ: 3.29 (2H, t, J ) 8 Hz), 3.87 (3H, s), 4.20 (2H, t, J ) 8 Hz),
7.23 (1H, s), 7.34 (1H, dd, J ) 4, 7 Hz), 8.00 (1H, d, J ) 7 Hz),
8.13 (1H, s), 8.24 (1H, d, J ) 4 Hz), 8.73 (1H, m), 8.78 (1H, s).
Anal. (C16H14F3N3O2) C, H, N.
Met h yl 6-Ch lor o-1-(3-p yr id ylca r b a m oyl)in d olin e-5-
ca r boxyla te (42). A solution of trifluoromethanesulfonic acid
2-chloro-5-methyl-4-nitrophenyl ester (4.6 g, 14.4 mmol) and
vinyltributyltin (6 g, 19.2 mmol) in dioxane (50 mL) was
treated with lithium chloride (1.8 g, 42.6 mmol), tetrakis-
(triphenylphosphine)palladium (0.33 g, 0.3 mmol), and 2,6-di-
tert-butyl-4-methylphenol (10 mg).37 The mixture was heated
at reflux overnight (∼17 h). After cooling the mixture was
added to a mixture of ether (100 mL) and aqueous KF (100
mL) with vigorous swirling. The mixture was filtered and the
organic phase separated, dried, and evaporated to give a brown
solid which was chromatographed on silica gel eluting with
0-5% EtOAc in petroleum ether to give 4-chloro-2-nitro-5-
vinyltoluene (2.2 g, 79%) as a yellow crystalline solid. NMR
(CDCl3) δ: 2.63 (3H, s), 5.58 (1H, d, J ) 13 Hz), 5.90 (1H, d,
J ) 20 Hz), 7.08 (1H, dd, J ) 20, 13 Hz), 7.51 (1H, s), 8.06
(1H, s). A solution of the crude olefin (2.2 g, 11.1 mmol) in
dichloromethane (100 mL) was ozonolyzed for 1 h at -78 °C.
Oxygen was then bubbled through the solution for 0.5 h
followed by argon for 0.5 h. Triphenylphosphine (3.05 g, 11.6
mmol) was then added, and the mixture was allowed to warm
to room temperature. After 2 h silica gel was added, and the
solvents were evaporated. Chromatography on silica gel,
eluting with 0-10% EtOAc in petroleum ether, afforded
2-chloro-5-methyl-4-nitrobenzaldehyde (1.72 g, 77%) as a yel-
low crystalline solid. NMR (CDCl3) δ: 2.63 (3H, s), 7.91 (1H,
s), 8.06 (1H, s), 10.48 (1H, s). The crude aldehyde (1.72 g, 8.6
mmol) in acetic acid (20 mL) was treated with sodium
perborate (3.96 g, 25.8 mmol) at 80 °C for 0.75 h. After cooling
the reaction mixture was partitioned between EtOAc (150 mL)
and brine (100 mL). The organic phase was separated, washed
with brine (2 × 100 mL), dried, and evaporated to afford
2-chloro-5-methyl-4-nitrobenzoic acid (1.43 g, 77%) as a white
solid. NMR (CDCl3) δ: 2.50 (3H, s), 2.70-4.00 (1H, br s), 7.89
(1H, s), 8.17 (1H, s). Without further purification this acid
was subjected to the procedures described above for 21 to give
methyl 6-chloroindole-5-carboxylate as a white solid (40%).
NMR (CDCl3) δ: 3.96 (3H, s) 6.60 (1H, m), 7.27 (1H, m), 7.49
(1H, s), 8.23 (1H, s), 8.42 (1H, br s). The indole was reduced
with sodium cyanoborohydride in acetic acid as described for
12 to give methyl 6-chloroindoline-5-carboxylate. NMR (CDCl3)
δ: 3.03 (2H, t, J ) 8 Hz), 3.67 (1H, t, J ) 8 Hz), 3.88 (3H, s),
6.58 (1H, s), 7.68 (1H, s). Treatment with 3-pyridyl isocyanate
as in the preparation of 6 gave the title compound 42 as a
white solid (57%), mp 210 °C (methanol). NMR (DMSO-d6) δ:
3.23 (2H, t, J ) 8 Hz), 3.81 (3H, s), 4.24 (2H, t, J ) 8 Hz), 7.35
(1H, dd, J ) 8, 6 Hz), 7.72 (1H, s), 7.95-8.05 (2H, m), 8.27
(1H, m, J ) 6 Hz), 8.76 (1H, m), 8.95 (1H, s). Anal. (C15H14N3-
OCl) C, H, N.
Reacting 1-chloro-4-nitro-2-(trifluoromethyl)benzene with
the appropriate alkoxide salt and following the same proce-
dures as detailed for 51, the following compounds were
prepared.
5-Eth oxy-1-(3-p yr id ylca r ba m oyl)-6-(tr iflu or om eth yl)-
in d olin e (52): recrystallized from ethanol as a white crystal-
line solid (81%), mp 258-259 °C. NMR (DMSO-d6) δ: 1.32
(3H, t, J ) 7 Hz), 3.26 (2H, t, J ) 8 Hz), 4.11 (2H, q, J ) 7
Hz), 4.18 (2H, t, J ) 8 Hz), 7.21 (1H, s), 7.34 (1H, dd, J ) 4,
7 Hz), 7.99 (1H, d, J ) 7 Hz), 8.12 (1H, s), 8.24 (1H, d, J ) 4
Hz), 8.72 (1H, m), 8.76 (1H, s). Anal. (C17H16N3O2F3) C, H,
N.
The following compounds (51-55) were prepared via vicari-
ous nucleophilic substitution using 4-chlorophenoxyacetoni-
trile.21
5-Isop r op oxy-1-(3-p yr id ylca r b a m oyl)-6-(t r iflu or o-
m eth yl)in d olin e (53): recrystallized from ethanol/diethyl
ether as a white crystalline solid (58%), mp 237 °C. NMR
(DMSO-d6) δ: 1.27 (6H, d, J ) 7 Hz), 3.26 (2H, t, J ) 8 Hz),
4.18 (2H, t, J ) 8 Hz), 4.69 (1H, sept, J ) 7 Hz), 7.23 (1H, s),
7.32 (1H, dd, J ) 4, 7 Hz), 7.98 (1H, d, J ) 7 Hz), 8.08 (1H, s),
8.22 (1H, d, J ) 4 Hz), 8.72 (1H, m), 8.77 (1H, s). Anal.
(C18H18F3N3O2) C, H, N.
5-(Cyclop r op ylm eth oxy)-1-(3-p yr id ylca r ba m oyl)-6-(tr i-
flu or om eth yl)in d olin e (54): recrystallized from methanol/
diethyl ether as a white solid (33%), mp 224-225 °C. NMR
(CDCl3) δ: 0.32-0.48 (2H, m), 0.55-0.64 (2H, m), 1.20-1.33
(1H, m), 3.28 (2H, t, J ) 7 Hz), 3.85 (2H, d, J ) 7 Hz), 4.12
(2H, t, J ) 7 Hz), 6.51 (1H, s), 6.82 (1H, s), 7.21-7.30 (1H,
m), 8.02-8.11 (1H, m), 8.20 (1H, s), 8.28-8.32 (1H, m), 8.43-
8.48 (1H, m). MS: m/ e 377.1362 (M+), C19H18N3O2F3 requires
377.1351.
P r ep a r a t ion of 5-Met h oxy-1-(3-p yr id ylca r b a m oyl)-6-
(tr iflu or om eth yl)in d olin e (51). 1-Meth oxy-4-n itr o-2-(tr i-
flu or om eth yl)ben zen e. Sodium (11.8 g, 0.512 mol) was
dissolved in dry methanol (1 L), and to the resulting solution
was added a solution of 1-chloro-4-nitro-2-(trifluoromethyl)-
benzene (96.2 g, 0.427 mol) in methanol (100 mL). The
reaction mixture was refluxed for 3 h, then cooled, and
evaporated in vacuo. The residue was partitioned between
water (500 mL) and dichloromethane (3 × 400 mL). The
combined organic extracts were dried (Na2SO4) and evaporated
to give the title compound (93.8 g, 99%) as a white solid. NMR
(CDCl3) δ: 4.05 (3H, s), 7.12 (1H, d, J ) 9 Hz), 8.45 (1H, dd,
J ) 3, 9 Hz), 8.52 (1H, d, J ) 3 Hz).
[5-Meth oxy-2-n itr o-4-(tr iflu or om eth yl)p h en yl]a ceton i-
tr ile. A mixture of 1-methoxy-4-nitro-2-(trifluoromethyl)-
benzene (93.0 g, 0.421 mol) and 4-chlorophenoxyacetonitrile
(77.6 g, 0.463 mol) in dry DMF (500 mL) was added dropwise
5-Meth oxy-6-(pen taflu or oeth yl)-1-(3-pyr idylcar bam oyl)-
in d olin e (55). 2-Bromo-4-nitroanisole (3.5 g, 0.015 mol) was
treated with sodium pentafluoropropionate28 (5.2 g, 0.028 mol)

5-HT2C/ 2B Receptor Antagonists as Anxiolytic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1609
and copper(I) iodide (5.7 g, 0.030 mol) in dry DMF (70 mL)
and toluene (25 mL) at 120 °C with removal of the toluene by
means of a Dean-Stark trap.24 The reaction mixture was then
heated to 155 °C for 6 h. After cooling to ambient temperature,
the mixture was poured into H2O (100 mL) and diethyl ether
(100 mL) and filtered through Kieselguhr. The filtrate was
separated and the organic layer washed with H2O, dried (Na2-
SO4), and evaporated in vacuo to leave a brown oil which was
purified by flash column chromatography on silica gel to afford
1-methoxy-4-nitro-2-(pentafluoroethyl)benzene (1.9 g, 47%) as
a yellow oil. NMR (CDCl3) δ: 4.02 (3H, s), 7.14 (1H, d, J ) 9
Hz), 8.44 (1H, d, J ) 8 Hz), 8.47 (1H, s). This anisole was
subjected to the same procedures as detailed for the prepara-
tion of 51 to give the title compound 55 which was recrystal-
lized from ethanol/dichloromethane as a white crystalline solid
(47%), mp 255 °C dec. NMR (DMSO-d6) δ: 3.28 (2H, t, J ) 9
Hz), 3.83 (3H, s), 4.20 (2H, t, J ) 9 Hz), 7.26 (1H, s), 7.35 (1H,
q, J ) 4, 8 Hz), 7.98 (1H, m), 8.10 (1H, s), 8.25 (1H, dd, J ) 3,
5 Hz), 8.73 (1H, d, J ) 3 Hz), 8.79 (1H, s). MS: m/ e 387.0988
(M+), C17H14N3O2F5 requires 387.1006.
solid. NMR (CDCl3) δ: 2.24 (3H, s), 3.20 (2H, t, J ) 8 Hz),
3.68 (1H, m), 4.11 (2H, t, J ) 8 Hz), 7.22 (1H, s), 8.51 (1H, s).
1-Acetyl-5-(m eth ylth io)-6-(tr iflu or om eth yl)in d olin e. A
mixture of the thiol (26 g, 99 mmol), anhydrous K2CO3 (15.1
g,109 mmol), and iodomethane (18.6 mL, 300 mmol) in dry
DMF (500 mL) was heated at 80 °C for 1 h. The reaction
mixture was cooled, evaporated in vacuo, and partitioned
between water (200 mL) and dichloromethane (3 × 200 mL).
The combined organics were washed with water (400 mL),
dried (Na2SO4), and evaporated to yield the title compound
(26.3 g, 97%) as a yellow oil. NMR (CDCl3) δ: 2.22 (3H, s),
2.49 (3H, s), 3.24 (2H, t, J ) 8 Hz), 4.12 (2H, t, J ) 8 Hz), 7.23
(1H, s), 8.51 (1H, s).
5-(Meth ylth io)-6-(tr iflu or om eth yl)in d olin e. The acetyl-
indoline (26.3 g, 95 mmol) was treated with NaOH (30 g, 750
mL) in water (150 mL) and ethanol (200 mL) at reflux for 1.5
h. The reaction mixture was cooled and diluted with water
(200 mL) and most of the ethanol evaporated in vacuo. The
remaining aqueous mixture was extracted with dichlo-
romethane (3 × 200 mL), and the combined extracts were dried
(Na2SO4) and evaporated to afford the title compound (21.9 g,
99%) as a yellow oil. NMR (CDCl3) δ: 2.41 (3H, s), 3.07 (2H,
t, J ) 8 Hz), 3.63 (2H, t, J ) 8 Hz), 3.90 (1H, br s), 6.88 (1H,
s), 7.30 (1H, s).
P r ep a r a t ion of 5-(Met h ylt h io)-6-(t r iflu or om et h yl)-
in d olin e. Meth od b. A stirred solution of potassium thio-
cyanate (38.6 g, 0.39 mol) in methanol (470 mL) at -2 °C under
argon was treated dropwise over 10 min with bromine (10.3
mL, 0.195 mol) giving a yellow precipitate. The reaction
mixture was stirred at 0 °C for a further 15 min, then treated
with a solution of 6-(trifluoromethyl)indoline (33.2 g, 0.177
mol) in methanol (320 mL), and allowed to warm to room
temperature and stir for 4 h. A solution of potassium
hydroxide (49.5 g, 0.88 mol) in water (300 mL) was added in
one portion, causing the temperature to rise to 43 °C and a
brown solution to be produced. The mixture was stirred at
43-45 °C for 25 min, then cooled to 12 °C, and treated with
iodomethane (10.9 mL, 0.177 mol). The resulting mixture was
allowed to warm to room temperature, stirred for 1.5 h, and
then concentrated in vacuo to ca. 350 mL volume. The residual
aqueous mixture was extracted with dichloromethane (2 × 400
mL) and the combined extract dried (Na2SO4) and concentrated
in vacuo to give a brown oil (43 g), which was chromatographed
on silica gel eluting with dichloromethane to afford the title
compound as a light-brown low-melting solid (25.3 g, 61%) with
spectral properties identical to those described above.
5-(Me t h ylt h io)-1-(3-p yr id ylca r b a m oyl)-6-(t r iflu or o-
m eth yl)in d olin e (46). A solution of nicotinic acid azide (15.3
g, 103 mmol) [CAUTION! Heating this material in the
absence of solvent can lead to explosive decomposition. Larger-
scale (ca. 20 g or above) preparations following this procedure
are noticeably exothermic on reaching 70-80 °C, and copious
volumes of nitrogen are rapidly evolved. Appropriate precau-
tions for the storage and utilization of this reagent are strongly
advised.] in toluene (300 mL) was heated at reflux for 0.5 h to
form 3-pyridyl isocyanate, then cooled to room temperature,
and treated with the indoline (21.9 g, 0.4 mmol) as in the
preparation of 6. The resulting precipitate was filtered off and
recrystallized from methanol/dichloromethane to afford the
title compound 46 (27.2 g, 82%) as a white solid, mp 262-264
°C. NMR (DMSO-d6) δ: 2.50 (3H, s), 3.28 (2H, t, J ) 8 Hz),
4.21 (2H, t, J ) 8 Hz), 7.33 (1H, dd, J ) 4, 7 Hz), 7.47 (1H, s),
7.98 (1H, d, J ) 7 Hz), 8.21 (1H, s), 8.24 (1H, d, J ) 4 Hz),
8.73 (1H, m), 8.84 (1H, s). MS: m/ e 353 (M+). Anal.
(C16H14F3N3OS) C, H, N.
The following 5-thioalkyl compounds were prepared via
thiocyanation of the appropriately substituted indoline.
P r ep a r a t ion of 5-(Met h ylt h io)-6-(t r iflu or om et h yl)-
in d olin e. Meth od a . 5-(Th iocya n a to)-6-(tr iflu or om eth -
yl)in d olin e. A mixture of 6-(trifluoromethyl)indoline32 (9.7
g, 52 mmol) and potassium thiocyanate (10.09 g, 104 mmol)
in methanol (200 mL) was treated with a solution of bromine
(2.82 mL, 55 mmol) in methanol (35 mL) dropwise over 0.5 h
at -5-0 °C.23 The reaction mixture was allowed to warm to
room temperature, stirred overnight, and then evaporated to
dryness. The residue was partitioned between aqueous K2-
CO3 (100 mL) and dichloromethane (3 × 100 mL). The
combined extracts were dried (Na2SO4) and evaporated and
the residue chromatographed on silica gel using 2-30% ethyl
acetate/petroleum ether as eluant to afford the title compound
(9.1 g, 72%) as a yellow solid. NMR (CDCl3) δ: 3.12 (2H, t, J
) 8 Hz), 3.72 (3H, t, J ) 8 Hz), 4.23 (1H, br s), 6.89 (1H, s),
7.50 (1H, s).
Bis[5-[6-(tr iflu or om eth yl)in d olin yl]] Disu lfid e. The
thiocyanate (28.5 g, 0.116 mol) in dioxane (200 mL) and water
(100 mL) was treated with aqueous ammonia (880, 200 mL)
at 90 °C for 1 h.24 The mixture was cooled and evaporated to
give a residue which was partitioned between water (300 mL)
and dichloromethane (4 × 300 mL). The combined extracts
were dried (Na2SO4) and evaporated to give the title compound
(25.5 g, 100%) as a yellow solid. NMR (CDCl3) δ: 3.03 (2H, t,
J ) 8 Hz), 3.67 (2H, t, J ) 8 Hz), 4.00 (1H, br s), 6.80 (1H, s),
7.49 (1H, s).
Bis[5-[1-Acet yl-6-(t r iflu or om et h yl)in d olin yl]] Disu l-
fid e. The disulfide (26 g, 0.119 mol) in dichloromethane (300
mL) and triethylamine (47.3 mL, 0.339 mol) was treated
dropwise with a solution of acetic anhydride (22.5 mL, 0.238
mol) in dichloromethane (50 mL) at 0 °C. The mixture was
allowed to warm to room temperature, stirred for 1 h, and then
poured into 2.5 M aqueous HCl (400 mL). The organic layer
was separated, and the aqueous was further extracted with
dichloromethane (200 mL). The combined organic extracts
were dried (Na2SO4) and evaporated to give the title compound
(29.1 g, 94%) as a yellow solid. NMR (CDCl3) δ: 2.22 (3H, s),
3.21 (2H, t, J ) 8 Hz), 4.10 (2H, t, J ) 8 Hz), 7.68 (1H, s), 8.47
(1H, s).
1-Acetyl-5-m er capto-6-(tr iflu or om eth yl)in dolin e. A mix-
ture of the diacetyl disulfide (28.5 g, 54.8 mmol), triph-
enylphosphine (20.9 g, 79.5 mmol), and concentrated aqueous
HCl (1 mL) in dioxane (300 mL) and water (75 mL) was heated
at reflux for 1.5 h.25 The reaction mixture was cooled and
evaporated to a residue which was partitioned between dichlo-
romethane (300 mL) and 1% aqueous NaOH (300 mL). The
organic phase was further extracted with 1% aqueous NaOH
(200 mL), and the combined aqueous fractions were carefully
acidified and extracted with dichloromethane (3 × 300 mL).
The combined organic extracts were dried (Na2SO4) and
evaporated to afford the title compound (26 g, 91%) as a yellow
By reacting 1-acetyl-5-mercapto-6-(trifluoromethyl)indoline
with the appropriate alkyl halide according to the same
procedures as detailed for 46, the following final compounds
were prepared.
5-(Eth ylth io)-1-(3-p yr id ylca r ba m oyl)-6-(tr iflu or om eth -
yl)in d olin e (47): recrystallized from ethanol/diethyl ether as
a white crystalline solid (68%), mp 246-247 °C. NMR (DMSO-
d6) δ: 1.20 (3H, t, J ) 7 Hz), 2.99 (2H, q, J ) 7 Hz), 3.28 (2H,
t, J ) 8 Hz), 4.22 (2H, t, J ) 8 Hz), 7.34 (1H, dd, J ) 4, 7 Hz),

1610 J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10
Bromidge et al.
7.55 (1H, s), 7.99 (1H, d, J ) 7 Hz), 8.23 (1H, s), 8.24 (1H, d,
J ) 4 Hz), 8.73 (1H, m), 8.87 (1H, s). Anal. (C17H16F3N3SO)
C, H, N.
8.75-8.99 (1H, br s). MS: m/ e 403.0790 (M+), C17H14F5N3-
OS requires 403.0778.
5-(Me t h ylt h io)-1-(3-p yr id ylca r b a m oyl)-6-(t r iflu or o-
m eth oxy)in d olin e (33). 3-(Trifluoromethoxy)aniline was
converted to 6-(trifluoromethoxy)indoline by the Norlander
procedure18 as described for 8 followed by sodium cyanoboro-
hydride reduction as described for 12. Treatment of this
indoline with potassium thiocyanate and bromine followed
with aqueous potassium hydroxide and methyl iodide as in
the procedure described for the preparation of 46 (method b)
afforded 5-(methylthio)-6-(trifluoromethoxy)indoline which was
converted to the title compound 33 as in the preparation of 6
to give a white solid (39%), mp 264-267 °C (Et2O/CH2Cl2).
NMR (DMSO-d6) δ: 2.46 (3H, s), 3.22 (2H, t, J ) 8 Hz), 4.21
(2H, t, J ) 8 Hz), 7.25-7.39 (2H, m), 7.89 (1H, d, J ) 2 Hz),
8.00 (1H, dd, J ) 2, 7 Hz), 8.26 (1H, dd, J ) 2, 5 Hz), 8.73
(1H, d, J ) 2 Hz), 8.83 (1H, s). Anal. (C16H14F3N3O2S) C, H,
N.
5-(Met h ylt h io)-1-(3-p yr id ylca r b a m oyl)in d olin e (11).
Starting with indoline and following the same procedures as
described for 46, the title compound 11 was prepared (77%)
as a white solid, mp 160-162 °C (50% aqueous ethanol). NMR
(DMSO-d6) δ 2.44 (3H, s), 3.18 (2H, t, J ) 8 Hz), 4.15 (2H, t,
J ) 8 Hz), 7.08 (1H, d, J ) 7 Hz), 7.19 (1H, s), 7.33 (1H, dd,
J ) 7, 5 Hz), 7.82 (1H, d, J ) 7 Hz), 7.98 (1H, d, J ) 7 Hz),
8.22 (1H, d, J ) 5 Hz), 8.74 (1H, s). Anal. (C15H15N3OS) C,
H, N.
5-(P r op ylt h io)-1-(3-p yr id ylca r b a m oyl)-6-(t r iflu or o-
m eth yl)in d olin e (48): recrystallized from ethanol/diethyl
ether as a white crystalline solid (56%), mp 240-243 °C. NMR
(DMSO-d6) δ: 0.96 (3H, t, J ) 7 Hz), 1.57 (2H, m, J ) 7 Hz),
2.96 (2H, t, J ) 7 Hz), 3.29 (2H, t, J ) 8 Hz), 4.22 (2H, t, J )
8 Hz), 7.33 (1H, dd, J ) 4, 7 Hz), 7.55 (1H, s), 7.99 (1H, d, J
) 7 Hz), 8.22 (1H, s), 8.25 (1H, d, J ) 4 Hz), 8.73 (1H, m),
8.86 (1H, s). Anal. (C18H18N3F3SO) C, H, N.
5-(I s o p r o p y lt h i o )-1-(3-p y r i d y lc a r b a m o y l)-6-(t r i -
flu or om eth yl)in d olin e (49): recrystallized from ethanol/
diethyl ether to yield a white crystalline solid (60%), mp 234-
237 °C. NMR (DMSO-d6) δ: 1.22 (6H, d, J ) 7 Hz), 3.28 (2H,
t, J ) 8 Hz), 3.47 (1H, m, J ) 7 Hz), 4.23 (2H, t, J ) 8 Hz),
7.33 (1H, dd, J ) 4, 7 Hz), 7.60 (1H, s), 7.99 (1H, d, J ) 7 Hz),
8.23 (1H, s), 8.24 (1H, d, J ) 4 Hz), 8.73 (1H, m), 8.86 (1H, s).
Anal. (C18H18N3F3SO) C, H, N.
Starting from 6-bromoindoline or 6-iodoindoline and follow-
ing the same procedures as described for 46, the following final
compounds were prepared.
6-Br om o-5-(m et h ylt h io)-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (43): recrystallized from ethanol to afford a white crystal-
line solid (71%), mp 242-244 °C. NMR (DMSO-d6) δ: 2.47
(3H, s), 3.19 (2H, t, J ) 8 Hz), 4.18 (2H, t, J ) 8 Hz), 7.19 (1H,
s), 7.34 (1H, dd, J ) 4, 7 Hz), 7.97 (1H, d, J ) 7 Hz), 8.09 (1H,
s), 8.24 (1H, d, J ) 4 Hz), 8.73 (1H, m), 8.81 (1H, s). MS: m/ e
363.0020 (M+), C15H14N3OBrS requires 363.0041.
The following compounds were prepared by alkylation of the
corresponding thiol or alcohol.
5-Br om o-6-(m et h ylt h io)-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (24). 1-Acetyl-6-mercaptoindoline38 was alkylated with
methyl iodide as in the preparation of 46. The resulting
1-acetyl-6-(methylthio)indoline (2.4 mmol) was taken up in
CHCl3 (50 mL) and treated with bromine (2.6 mmol) in CHCl3
(1 mL) at 0 °C. After complete addition the reaction mixture
was heated to reflux for 4 h, then cooled, and poured into
aqueous Na2SO3. The organics were separated to give, after
drying and removal of solvent, 1-acetyl-5-bromo-6-(methylth-
io)indoline (98%). Heating with aqueous sodium hydroxide
hydrolyzed the acetyl group to afford the indoline which was
treated with 3-pyridyl isocyanate as in the preparation of 6 to
give the title compound 24 as a white solid (72%), mp >220
°C. NMR (DMSO-d6) δ: 2.4 (3H, s), 3.2 (2H, t, J ) 8 Hz), 4.2
(2H, t, J ) 8 Hz), 7.3 (1H, m), 7.4 (1H, s), 7.9 (1H, s), 8.0 (1H,
m), 8.2 (1H, m), 8.7 (1H, m) 8.8 (1H, s). MS: m/ e 363.0033
(M+), C15H14N3OBrS requires 363.0041.
6-Br om o-5-m et h oxy-1-(3-p yr id ylca r b a m oyl)in d olin e
(44). 1-Acetyl-6-bromo-5-hydroxyindoline39 was alkylated with
sodium hydride and methyl iodide as in the preparation of 46.
Hydrolysis of the acetyl group and treatment of the resultant
indoline with 3-pyridyl isocyanate as in the preparation of 6
gave the title compound 44 as a white solid (43%), mp 238-
240 °C. 1H NMR (DMSO-d6) δ: 3.18 (2H, t, J ) 8 Hz), 3.80
(3H, s), 4.15 (2H, t, J ) 8 Hz), 7.07 (1H, s), 7.32 (1H, dd, J )
2, 7 Hz), 7.96 (1H, dd, J ) 2, 7 Hz), 8.06 (1H, s), 8.22 (1H, d,
J ) 5 Hz), 8.72 (2H, m). 13C NMR (DMSO-d6) δ: 27.5, 47.6,
56.3, 107.9, 109.7, 118.5, 123.1, 127.2, 132.0, 136.2, 137.7,
141.9, 143.4, 150.6, 152.2. MS: m/ e 348/350 (MH+). MS: m/ e
347.0274 (M+), C15H14N3O2Br requires 347.0269.
6-Iod o-5-(m e t h ylt h io)-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (45): recrystallized from ethanol to afford a white crystal-
line solid (53%), mp 235-237 °C. NMR (DMSO-d6) δ: 2.42
(3H, s), 3.18 (2H, t, J ) 8 Hz), 4.13 (2H, t, J ) 8 Hz), 7.15 (1H,
s), 7.32 (1H, dd, J ) 4, 7 Hz), 7.97 (1H, d, J ) 7 Hz), 8.24 (1H,
d, J ) 4 Hz), 8.42 (1H, s), 8.70 (1H, m), 8.78 (1H, s). MS: m/ e
410.9912 (M+), C15H14N3OIS requires 410.9902.
6-Cya n o-5-(m et h ylt h io)-1-(3-p yr id ylca r b a m oyl)in d o-
lin e (32). 6-Iodo-5-(methylthio)-1-(3-pyridylcarbamoyl)indo-
line (45) (0.19 g, 0.46 mmol) and copper(I) cyanide (0.086 g,
0.96 mmol) were heated together in DMF (10 mL) at 150 °C
for 1 h.27 The mixture was cooled, poured into 2 N aqueous
ammonium hydroxide (100 mL), and extracted with EtOAc (3
× 100 mL). The combined extracts were dried (Na2SO4) and
evaporated to give a residue which was purified by chroma-
tography to affford a white crystalline solid (14%), mp 228-
229 °C. NMR (DMSO-d6) δ: 2.49 (3H, s), 3.31 (2H, t, J ) 8
Hz), 4.21 (2H, t, J ) 8 Hz), 7.35 (1H, m), 7.45 (1H, s), 8.00
(1H, m), 8.08 (1H, s), 8.26 (1H, d), 8.74 (1H, m), 8.90 (1H, s).
MS: m/ e 311 (MH+).
5-(Met h ylt h io)-6-(p en t a flu or oet h yl)-1-(3-p yr id ylca r -
ba m oyl)in d olin e (56). 1-Acetyl-6-bromo-5-(methylthio)in-
doline (2.5 g, 0.0087 mol) was dissolved in dry DMF (40 mL)
and toluene (15 mL) under argon. Sodium pentafluoropropi-
onate (3.0 g, 0.016 mol) and copper(I) iodide (3.3 g, 0.017 mol)
were added, and the mixture was heated to 120 °C with
removal of the toluene by means of a Dean-Stark trap.24 The
reaction mixture was then heated to 155 °C for 6 h. After
cooling to ambient temperature, the mixture was poured into
H2O (100 mL) and diethyl ether (100 mL) and filtered through
Kieselgu¨hr. The filtrate was separated and the organic layer
washed with H2O, dried (Na2SO4), and evaporated in vacuo
to leave an orange solid. This was purified by flash column
chromatography on silica gel eluting with 2% methanol in
dichloromethane to give 1-acetyl-5-(methylthio)-6-(pentafluo-
roethyl)indoline (0.62 g, 22%) as a pale-yellow solid. NMR
(CDCl3) δ: 2.22 (3H, s), 2.46 (3H, s), 3.26 (2H, t, J ) 8 Hz),
4.11 (2H, t, J ) 8 Hz), 7.22 (1H, s), 8.44 (1H, s). The indoline
was converted to the title compound according to the proce-
dures detailed for 46 to give the title compound 56 as a white
solid (74%), mp 227 °C dec. NMR (DMSO-d6) δ: 2.50 (3H, s),
3.30 (2H, t, J ) 8 Hz), 4.21 (2H, t, J ) 8 Hz), 4.21 (2H, t, J )
8 Hz), 7.32 (1H, dd, J ) 4, 7 Hz), 7.56 (1H, s), 8.00 (1H, d, J
) 7 Hz), 8.13 (1H, s), 8.23 (1H, d, J ) 4 Hz), 8.71 (1H, m),
The following compounds (14, 19) were prepared via reduc-
tion of the corresponding isatins.29
4,5-Dich lor o-1-(3-p yr id ylca r ba m oyl)in d olin e (14). 4,5-
Dichloroisatin (8.4 g, 0.039 mol)40 was treated with lithium
aluminum hydride (15.0 g, 0.390 mol) in THF (500 mL) under
reflux. Aqueous workup and treatment of the intermediate
hydroxyindoline compound with p-toluenesulfonic acid in
toluene gave 4,5-dichloroindole (1.34 g, 19%). NMR (CDCl3)
δ: 6.60-6.70 (1H, m), 7.19-7.35 (3H, m), 8.10-8.45 (1H, br
s). This was reduced to the indoline using sodium cyanoboro-
hydride as for 12. NMR (CDCl3) δ: 3.10 (2H, t, J ) 8 Hz),
3.61 (2H, t, J ) 8 Hz), 3.76-3.91 (1H, br s), 6.41 (1H, d, J )
10 Hz), 7.10 (1H, d, J ) 10 Hz). This indoline was converted
directly to the title compound 14 as in the preparation of 6 to
give a white solid (25%), mp >240 °C. NMR (DMSO-d6) δ:

5-HT2C/ 2B Receptor Antagonists as Anxiolytic Agents
J ournal of Medicinal Chemistry, 1998, Vol. 41, No. 10 1611
3.28 (2H, t, J ) 8 Hz), 4.21 (2H, t, J ) 8 Hz), 7.30-7.42 (2H,
m), 7.80 (1H, d, J ) 8 Hz), 7.92-7.98 (1H, m), 8.20-8.24 (1H,
m), 8.72 (1H, s), 8.82 (1H, s). MS: m/ e 307.0275 (M+),
dried and concentrated to leave an orange solid which was
chromatographed on silica gel eluting with 25% ether/60-80
petroleum ether to afford the title compound (0.1 g, 40%) as
the first component to elute. NMR (CDCl3) δ: 2.03 (3H, s),
3.04 (2H, t, J ) 8 Hz), 3.30-3.75 (1H, br), 3.61 (2H, t, J ) 8
Hz), 4.84 (1H, s), 5.14 (1H, s), 6.84 (1H, s), 6.97 (1H, s).
5-Isop r op yl-6-(tr iflu or om eth yl)in d olin e. A solution of
5-isopropenyl-6-(trifluoromethyl)indoline (0.1 g, 0.46 mmol) in
ethanol (30 mL) was hydrogenated over 10% Pd-C (50 mg)
at atmospheric temperature and pressure for 2 h. The catalyst
was removed by filtration through Kieselgu¨hr and the filtrate
concentrated under vacuum to give a residue which was
chromatographed on silica gel eluting with 25% ether/
petroleum ether to yield the title compound (0.08 g, 80%) as a
colorless oil. NMR (CDCl3) δ: 1.21 (6H, d, J ) 6 Hz), 3.05
(2H, t, J ) 8 Hz), 3.24 (1H, septet, J ) 6 Hz), 3.58 (2H, t, J )
8 Hz), 3.80 (1H, br s), 6.82 (1H, s), 7.20 (1H, s).
5-Isop r op yl-1-(3-p yr id ylca r ba m oyl)-6-(tr iflu or om eth -
yl)in d olin e (50). 5-Isopropyl-6-(trifluoromethyl)indoline was
treated with 3-pyridyl isocyanate as in the preparation of 6 to
give the title compound 50 as a white solid (33%), mp 210-
211 °C (ethyl acetate/petroleum ether). NMR (CDCl3) δ: 1.23
(6H, d, J ) 7 Hz), 3.30 (2H, t, J ) 8 Hz), 3.32 (1H, m), 4.15
(2H, t, J ) 8 Hz), 6.69 (1H, s), 7.27 (2H, m), 8.09 (1H, m), 8.21
(1H, s), 8.32 (1H, m), 8.48 (1H, m). MS: m/ e 349 (M+). Anal.
(C18H18N3OF3) C, H, N.
5-Acet yl-1-(3-p yr id ylca r b a m oyl)-6-(t r iflu or om et h yl)-
in dolin e (31). 5-Acetyl-6-(trifluoromethyl)indoline was treated
with 3-pyridyl isocyanate as in the preparation of 6 to give
the title compound 31 as a white solid (37%), mp 238-240 °C
(chloroform). NMR (CDCl3) δ: 2.57 (3H, s), 3.38 (2H, t, J ) 8
Hz), 4.28 (2H, t, J ) 8 Hz), 7.42 (1H, dd, J ) 5, 7 Hz), 7.57
(1H, s), 8.08 (1H, m, J ) 7 Hz), 8.27 (1H, m, J ) 5 Hz), 8.34
(1H, s), 8.72 (1H, m). MS: m/ e 349.1025 (M+), C17H14N3O2F3
requires 349.1038.
m CP P -In d u ced Hyp olocom otion . Rats were placed in
a room adjacent to the experimental room on the day of the
procedure. They were dosed orally 1 h before the locomotion
test with test compound or vehicle and injected ip 20 min
before the test with mCPP or saline, in groups of 4. Rats were
returned to their home cages after dosing. At 0 h, they were
each placed in automated locomotor activity cages, made in
black perspex with a clear perspex lid and sawdust-covered
floor, under red light for 10 min. During this time, locomotion
was recorded by means of consecutively breaking two photocell
beams traversing opposite ends of the box (for full details, see
ref 4).
Geller -Seifter Test. A colony of rats (male, Sprague-
Dawley) were housed in pairs under a 12-h light/dark cycle
and fed restricted diet to maintain their body weight to 80%
of a free-feeding animal. The rats were trained initially in a
typical operant box to associate pressing of a lever with a food
pellet reward. As training progressed, the rats were intro-
duced to a multiple schedule of reinforcement, i.e., five 3-min
variable interval components (one reinforcement every 10-
50 s (mean 30), VI30) alternating with five 3-min fixed ratio
(one reinforcement every five lever presses, FR5) components.
The FR component was signalled to the rat by a light above
the lever, and in this component reinforcement was contingent
with a footshock pulse width of 15 ms, at intervals of 200 ms
for 1 s. The magnitude of the footshock was individually
titrated for each rat up to a maximum of 0.75 mA, to give a
lever-pressing rate of between two and seven reinforcements
during each of the five, 3-min punished responding periods.
Fully trained rats also had a high level of responding in the
VI phases (typically 180 presses in 3 min) to detect nonspecific
effects such as sedation or stimulant properties. Before use,
all rats had met specific performance criteria and had shown
a significant positive response to a reference anxiolytic drug
(e.g., chlordiazepoxide). For full details, see ref 4d.
C
14H11N3OCl2 requires 307.0279.
6,7-Dich lor o-1-(3-p yr id ylca r ba m oyl)in d olin e (19): pre-
pared from 6,7-dichloroisatin40 following the procedures de-
scribed above for 14 as a white solid (46% from indoline, 19%
overall), mp 178-180 °C. NMR (DMSO-d6) δ: 3.11 (2H, t, J
) 8 Hz), 4.19 (2H, t, J ) 8 Hz), 7.21-7.35 (3H, m), 7.89-7.94
(1H, m), 8.09-8.12 (1H, m), 8.70 (1H, s), 9.68 (1H, s). MS:
m/ e 307.0274 (M+), C14H11N3OCl2 requires 307.0279.
The following compounds (31, 50) were prepared via bro-
mination and Stille coupling of 6-(trifluoromethyl)indoline with
(1-ethoxyvinyl)tributyl tin.
5-Br om o-6-(tr iflu or om eth yl)in d olin e. A stirred solution
of 6-(trifluoromethyl)indoline (3.0 g, 0.016 mol) in dry DMF
(30 mL) at -5 °C under argon was treated dropwise over 30
min with a solution of freshly recrystallized N-bromosuccin-
imide (3.03 g, 0.017 mol) in dry DMF (15 mL). After complete
addition the reaction mixture was stirred at 0 °C for a further
20 min, then poured into cold 10% aqueous Na2CO3 solution
(100 mL), and extracted with ethyl acetate (100 mL). The
extract was washed with water (3 × 100 mL) to remove any
DMF, then dried, and concentrated under vacuum to leave a
brown oil which was chromatographed on silica gel eluting
with 40% ether/60-80 petroleum ether. The first product to
elute was 7-bromo-6-(trifluoromethyl)indoline (1.0 g), followed
by the title compound (1.5 g, 35%) as a brown oil. NMR
(CDCl3) δ: 3.07 (2H, t, J ) 8 Hz), 3.63 (2H, t, J ) 8 Hz), 6.88
(s, 1H), 7.35 (s, 1H).
5-Acetyl-6-(tr iflu or om eth yl)in d olin e. A stirred solution
of 5-bromo-6-(trifluoromethyl)indoline (1.5 g, 5.6 mmol) in
toluene (70 mL) under argon was treated with (1-ethoxyvinyl)-
tributyl tin (2.0 g, 5.6 mmol) followed by tetrakis(triph-
enylphosphine)palladium(0) (120 mg).30 The mixture was then
heated under reflux for 28 h, then cooled, diluted with ether
(70 mL), washed with 1% Na2CO3 solution, then dried, and
concentrated under vacuum. The residue was treated with a
mixture of 2 M HCl acid (10 mL) and THF (30 mL) and stirred
vigorously at room temperature for 1 h. The reaction mixture
was concentrated to remove the THF and the residual acid
solution diluted with water (30 mL), then basified with K2-
CO3, and extracted with ethyl acetate (3 × 100 mL). The
combined extracts were dried and concentrated and the residue
chromatographed on silica gel eluting with 1:1 ether/60-80
petroleum ether to afford the required product (0.75 g, 58%)
as a light-brown solid. NMR (CDCl3) δ: 2.52 (3H, s), 3.10 (2H,
t, J ) 8 Hz), 3.70 (2H, t, J ) 8 Hz), 4.20 (1H, br s), 6.84 (1H,
s), 7.33 (1H, s).
5-Isop r op en yl-6-(tr iflu or om eth yl)in d olin e. A mixture
of 5-acetyl-6-(trifluoromethyl)indoline (0.36 g, 1.6 mmol), tri-
ethylamine (0.25 mL, 1.8 mmol), and di-tert-butyl dicarbonate
(0.37 g, 1.7 mmol) in toluene (10 mL) was heated under reflux
for 4 h. The cooled solution was treated with 10% aqueous
Na2CO3 solution (25 mL) and extracted with ethyl acetate (50
mL). The extract was dried and concentrated and the residue
chromatographed on silica gel eluting with 1:1 ether/60-80
petroleum ether to give the N-Boc-5-acetyl-6-(trifluoromethyl)-
indoline (0.3 g, 58%) as a beige solid. NMR (CDCl3) δ: 1.60
(9H, s), 2.55 (3H, s), 3.17 (2H, t, J ) 8 Hz), 4.07 (2H, t, J ) 8
Hz), 7.28 (1H, s), 8.20 (1H, br s). A stirred solution of the
N-Boc-5-acetylindoline (0.36 g, 1.1 mmol) in dry ether (15 mL)
at 0 °C under argon was treated with a 3 M solution of
methylmagnesium bromide in ether (0.55 mL, 1.6 mmol). A
yellow precipitate was immediately formed. The reaction
mixture was allowed to warm to room temperature over 1.5 h
and then added to excess 2 M HCl acid with efficient stirring.
The aqueous mixture was basified with aqueous K2CO3 and
extracted with ethyl acetate. The extract was dried and
concentrated to leave a yellow oil, which was dissolved in
dichloromethane (10 mL) and treated with trifluoroacetic acid
(3 mL) for 1 h at room temperature. The reaction mixture
was treated with excess 10% aqueous Na2CO3 solution and
extracted with dichloromethane (100 mL). The extract was
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