Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: Identification of 5-methyl-1-[[2-[(2-methyl-3- pyridyl)oxy]5-pyridyl]carbamoyl]-6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent

Article abstract of DOI:10.1021/jm990388c

The evolution, synthesis, and biological activity of a novel series of 5-HT(2C) receptor inverse agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT(2C) affinity and selectivity over 5- HT(2A) receptors. In addition, (pyridyloxypyridyl)carbamoylindolines have been discovered with additional selectivity over the closely related 5-HT(2B) receptor. Compounds from this series are inverse agonists at the human cloned 5-HT(2C) receptor, completely abolishing basal activity in a functional assay. The new series have reduced P450 inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines (Bromidge et al. J. Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40 (SB-243213) have been selected for further evaluation to determine their therapeutic potential for the treatment of CNS disorders such as depression and anxiety.

Full text of DOI:10.1021/jm990388c

J . Med. Chem. 2000, 43, 1123-1134
1123
Bia r ylca r ba m oylin d olin es Ar e Novel a n d Selective 5-HT2C Recep tor In ver se
Agon ists: Id en tifica tion of 5-Meth yl-1-[[2-[(2-m eth yl-3-p yr id yl)oxy]-
5-p yr id yl]ca r ba m oyl]-6-tr iflu or om eth ylin d olin e (SB-243213) a s a P oten tia l
An tid ep r essa n t/An xiolytic Agen t
Steven M. Bromidge,*,# Steven Dabbs,# David T. Davies,# Susannah Davies,# D. Malcolm Duckworth,#
Ian T. Forbes,# Laramie M. Gaster,# Peter Ham,# Graham E. J ones,# Frank D. King,# Keith R. Mulholland,#
Damian V. Saunders,# Paul A. Wyman,# Frank E. Blaney,# Stephen E. Clarke,‡ Thomas P. Blackburn,†
Vicky Holland,† Guy A. Kennett,† Sean Lightowler,† Derek N. Middlemiss,† Brenda Trail,† Graham J . Riley,† and
Martyn D. Wood†
SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue,
Harlow, Essex CM19 5AW, U.K.
Received J uly 30, 1999
The evolution, synthesis, and biological activity of a novel series of 5-HT2C receptor inverse
agonists are reported. Biarylcarbamoylindolines have been identified with excellent 5-HT2C
affinity and selectivity over 5-HT2A receptors. In addition, (pyridyloxypyridyl)carbamoylindolines
have been discovered with additional selectivity over the closely related 5-HT2B receptor.
Compounds from this series are inverse agonists at the human cloned 5-HT2C receptor,
completely abolishing basal activity in a functional assay. The new series have reduced P450
inhibitory liability compared to a previously described series of 1-(3-pyridylcarbamoyl)indolines
(Bromidge et al. J . Med. Chem. 1998, 41, 1598) from which they evolved. Compounds from
this series showed excellent oral activity in a rat mCPP hypolocomotion model and in animal
models of anxiety. On the basis of their favorable biological profile, 32 (SB-228357) and 40
(SB-243213) have been selected for further evaluation to determine their therapeutic potential
for the treatment of CNS disorders such as depression and anxiety.
In tr od u ction
selective 5-HT2C/2B agonist, m-chlorophenylpiperazine
(mCPP), caused behavioral indications of anxiety in both
animal models and humans3 led us to speculate that
selective 5-HT2C/2B antagonists might be useful anxi-
olytic agents. Subsequently, we developed a number of
selective 5-HT2C/B receptor antagonists, such as 1 (SB-
206553) and 2 (SB-221284), which block the centrally
mediated mCPP-induced hypolocomotion in rats. These
compounds also exhibited significant anxiolytic activity
in several different animal models, lending strong
support to our original hypothesis.4-6 More recently, an
accumulating body of published data7-10 has suggested
that 5-HT2C antagonism may also offer significant
therapeutic opportunities for the treatment of other
CNS disorders such as depression,7,8 schizophrenia,8
migraine,9 and Parkinson’s disease.10
The 5-HT2 receptor family is a member of the seven-
transmembrane-spanning G-protein-coupled receptor
superfamily and constitutes one of the 7 classes of 5-HT
receptors (5-HT1 to 5-HT7) which are currently subdi-
vided into 14 recognized human receptors.1 The 5-HT2
receptor family consists of 5-HT2A, 5-HT2B, and 5-HT2C
receptors, which have been grouped together on the
basis of primary structure, secondary-messenger sys-
tem, and pharmacological profile.2 Sequence analysis
indicates approximately 80% amino acid identity in the
predicted seven-transmembrane domains of the 5-HT2
receptors although there are distinct differences in
distribution. The 5-HT2A receptor is widely distributed
in peripheral tissues and also present in the CNS. The
5-HT2B receptor is principally located in the periphery
and only sparsely in the CNS. In contrast, 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.1 There remains a paucity of selective
ligands to more fully elucidate the functional role of the
different 5-HT2 receptors.
Our interest in the 5-HT2C receptor goes back over
several years. The observation that the moderately
Recently we reported the synthesis and biological
activity of a series of substituted 1-(3-pyridylcarbamoyl)-
indolines such as 2-4 which remain the most potent
and selective 5-HT2C/2B receptor antagonists yet re-
ported.5 Compound 2 was selected on the basis of its
overall biological profile for further evaluation of its
* To whom correspondence should be addressed. Tel: (0044)
1279627684. Fax: (0044) 1279627685. E-mail Steve_Bromidge-1@
sbphrd.com.
#
Discovery Chemistry Europe.
† Department of Neurosciences Research.
‡ Department of Drug Metabolism and Pharmacokinetics.
10.1021/jm990388c CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/25/2000

1124 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Bromidge et al.
Sch em e 1a
a
Reagents: (i) CDI, DCM, rt, 2 h; (ii) 5-methylthio-6-trifluo-
romethylindoline or 5-methoxy-6-trifluoromethylindoline, DMF,
100 °C, 1 h.
Sch em e 2a
a
Reagents: (i) PhOCOCl/NEt3, DCM, -20 °C, 1 h; (ii) 5-meth-
oxy-6-trifluoromethylindoline, NEt3/DMF, 100 °C, 1 h.
F igu r e 1. Structure 2 docked into the model of the 5-HT2C
receptor. TM2 and TM3 have been removed for clarity. The
molecular surface (green) has been placed around the residues
on the extracellular side of TM5 and TM6 and shows the deep
aromatic cavity which accommodates the pyridyl ring of 2 at
its mouth.
Sch em e 3a
therapeutic potential. Unfortunately, 2 and related
analogues were found to be potent inhibitors of a
number of human cytochrome P450 enzymes, in par-
ticular the CYP1A2 isoform, which precluded further
development.11 Subsequent structural modification of
the 3-amidopyridyl ring of 2 by the introduction of steric
hindrance around the pyridine nitrogen has revealed
that the unhindered nitrogen is responsible for the P450
inhibitory activity.
a
Reagents: (i) toluene, reflux, 1 h, 5-methoxy-6-trifluorometh-
In conjunction with this work, ligand docking studies
were carried out using a model of the 5-HT2C receptor
which had been constructed as previously described.12
In the proposed binding mode a double hydrogen bond
between the urea carbonyl oxygen of 2 and the hydroxyl
side chains of the two serines in helix 3 (residues 138
and 141) was invoked.5 The 3-pyridyl ring occupies a
lipophilic pocket defined by the side chains of the
aromatic residues Phe-223, Trp-324, Phe-327, and Phe-
328 and is able to form both π-π stacking and edge-to-
face aromatic interactions with several of these resi-
dues. Closer examination of this lipophilic pocket re-
vealed that it was quite deep, extending back to Phe-
220 and Phe-224, and that this might be exploited by
substitution of the pyridyl ring with suitable aryl groups
(Figure 1).
ylindoline, DCM, rt, 18 h; (ii) ArB(OH)2/Na2CO3/Pd(PPh3)4, DME/
H2O, reflux, 10 h.
“allowed” in the 5-HT2C receptor but “disallowed” in the
5-HT2A receptor due to steric differences between the
structures of the two binding sites.5 The work described
in this paper has culminated in the identification of 32
(SB-228357) and 40 (SB-243213) which have been
selected for evaluation as novel nonsedating antidepres-
sant/anxiolytic agents. The bispyridyl ether 40 is cur-
rently in clinical development.
Since the introduction of further steric bulk into the
molecules might also be expected to reduce the cyto-
chrome P450 inhibitory liability, in addition to any
beneficial effects on 5-HT2C activity, a program of work
was undertaken initially investigating substitution of
the pyridyl ring with a variety of aryl groups. As
substituent changes on the indoline ring did not sig-
nificantly affect the level of P450 inhibition, this work
was carried out with our two previously5 optimized
indolines: 5-methylthio-6-trifluoromethylindoline or
5-methoxy-6-trifluoromethylindoline. These particular
substituents were hypothesized to afford the desired
selectivity by occupying a region of space which is
Ch em istr y
The synthetic methods used in the preparation of
compounds 5-41 are shown in Schemes1-6.
Compounds 9 and 13-37 were prepared by coupling
biarylanilines with 5-methylthio-6-trifluoromethylindo-
line or 5-methoxy-6-trifluoromethylindoline using 1,1-
carbonyldiimidazole (Scheme 1). Alternatively, the bi-
arylanilines were converted to the corresponding phenyl
carbamates, by treatment with phenyl chloroformate,
which were then coupled with the indoline (Scheme 2).13

Biarylcarbamoylindolines: 5-HT2C Inverse Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1125
Sch em e 4a
lowed by N-protection and conversion of the resultant
phenol to the triflate 44. Palladium coupling18 of 44 with
tetramethyltin completed the synthesis (Scheme 6). The
bispyridyl ether 38 was prepared similarly from 5-meth-
oxy-6-trifluoromethylindoline5 and 5-amino-2-(3-pyridyl-
oxy)pyridine19 (43b) (Scheme 5).
Resu lts a n d Discu ssion
The affinities of the compounds were measured by
means of radioligand binding studies conducted with
human 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.4
The cytochrome P450 inhibitory potential was deter-
mined using isoform-selective assays and heterologously
expressed human CYP1A2 as has been previously
described20 [caffeine N3-demethylation (500 µM)]. Com-
pounds which satisfied in vitro criteria were evaluated
in vivo in a centrally mediated model of 5-HT2C receptor
function by measuring their ability to block the hypo-
activity in rats produced by a standard dose of the
moderately selective 5-HT2C agonist mCPP.4 This mCPP-
induced hypoactivity is absent in mutant mice lacking
the 5-HT2C receptor.21
a
Reagents: (i) (2,6- or 3,5-diFPh)Bu3Sn/Pd(PPh3)4, xylene,
reflux, 24 h; (ii) NH2NH2‚H2O, MeOH, reflux, 18 h; (iii) NaNO2,
aq HCl, -5 °C, 0.5 h; (iv) toluene, reflux, 1 h, 5-methoxy-6-
trifluoromethylindoline, DCM, rt, 18 h.
Sch em e 5a
P h en ylp yr id ylca r ba m oylin d olin es (Ta ble 1). We
were encouraged to find that in the 5-methoxy-6-
trifluoromethylindoline series incorporating a 5-phenyl
substituent into the 3-pyridyl ring of 3 to give 5 slightly
increased 5-HT2C affinity and selectivity over 5-HT2A
(Table 1). In addition the CYP1A2 inhibitory activity
was reduced by 100-fold (target IC50 > 10 µM). Unfor-
tunately, 5 was found to have low oral activity in the
rat hypolocomotion model. We reasoned that this may
be due to metabolism of the relatively electron-rich
5-phenyl ring so fluoro groups were introduced in an
attempt to block metabolism and improve oral activity.
Unfortunately, these compounds 6-8 showed either
reduced 5-HT2C affinity (7 and 8) or selectivity over
5-HT2A receptors (6 and 7). However, the modest oral
activity of 4-fluorophenyl analogue 6 in the rat hypolo-
comotion model was moderately encouraging. It is
possible that the poor oral bioavailability of these
compounds may be related to their poor aqueous solu-
bility, and in fact the corresponding 6-phenyl-substi-
tuted analogue 9 proved too insoluble to obtain receptor
binding data.
Bisp yr id ylca r ba m oylin d olin es (Ta ble 1). In an
attempt to increase water solubility and metabolic
stability, the 5-phenyl substituent of 5 was replaced by
pyridyl. Both the 5-substituted 4-pyridyl (10) and 3-py-
ridyl (11) analogues demonstrated almost 10-fold im-
proved 5-HT2C affinity relative to 5, suggesting an
additional binding interaction between the terminal
pyridyl and the 5-HT2C receptor. However, both com-
pounds showed a larger increase in affinity at the
5-HT2A receptor resulting in reduced selectivity, al-
though this was still around 100-fold. Compound 12
containing a 4-methyl substituent in the terminal
3-pyridyl, which would have the effect of twisting the
pyridyl rings out of plane, was found to have slightly
increased 5-HT2C affinity, whereas the 5-HT2A affinity
was reduced and consequently selectivity was restored.
Compound 12 also demonstrated moderate oral activity
in the hypolocomotion model. The 5-substituted pyridyl
a
Reagents: (i) NaH, DMF/2-chloro-5-nitropyridine, 0 °C-rt, 18
h; (ii) SnCl2, EtOH/concd HCl, 50 °C, 1 h; (iii) PhOCOCl/NEt3,
DCM, -20 °C, 1 h; (iv) 5-X-6-Y-indoline, NEt3/DMF, 100 °C, 1 h.
Sch em e 6a
a
Reagents: (i) TMSI, CDCl3, reflux, 65 h; (ii) Ac2O, DCM, rt, 1
h; (iii) Tf2O, pyridine, 0 °C-rt, 18 h; (iv) SnMe4/Pd(PPh3)2Cl2/LiCl,
DMF, 110 °C, 3 h; (v) aq NaOH, EtOH, reflux, 18 h.
The biarylanilines were either commercially available,
known, or prepared by Suzuki14 methodology.
Compounds 5, 6, and 10-12 were prepared by reac-
tion of 1-[(5-bromo-3-pyridyl)carbamoyl]-5-methoxy-6-
trifluoromethylindoline (42) with the appropriate aryl-
boronic acid under Suzuki conditions (Scheme 3).14 42
was itself prepared by reacting 5-bromo-3-pyridyl iso-
cyanate, generated in situ from the corresponding
5-bromonicotinic acid azide,15 with 5-methoxy-6-trifluo-
romethylindoline.5 Compounds 7 and 8 were prepared
by an analogous procedure by coupling (3,5-difluorophen-
yl)tributyltin or (2,6-difluorophenyl)tributyltin, respec-
tively, with ethyl 5-bromonicotinate under Stille14,16
conditions (Scheme 4). The resultant biaryl ester was
then converted to the isocyanate, via the azide, and
coupled with 5-methoxy-6-trifluoromethylindoline.
The bispyridyl ethers 39-41 were prepared by cou-
pling the bispyridyl ether amine 43a with 5-methoxy-
6-trifluoromethylindoline,5 6-chloro-5-methylindoline,5
or 5-methyl-6-trifluoromethylindoline, respectively, via
the phenyl carbamate (Scheme 5).13,17 43a was itself
prepared by treating the anion of 3-hydroxy-2-meth-
ylpyridine with 2-chloro-5-nitropyridine followed by
reduction of the resultant nitrobispyridyl ether.11 5-Meth-
yl-6-trifluoromethylindoline was prepared from 5-meth-
oxy-6-trifluoromethylindoline5 by demethylation fol-

1126 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Bromidge et al.
Ta ble 1. 5-HT2A, 5-HT2B, and 5-HT2C Receptor Binding Affinities,a Human CYP1A2 Inhibitory Potential,e and in Vivo Activityf of
1-(Aryl-3-pyridylcarbamoyl)indolines 5-13
pKi
selectivity
b
c
d
compd
R5
R6
5-HT2A
5-HT2B
5-HT2C
5-HT2C/2A
5-HT2C/2B
IC50e (µM) CYP1A2
ID50f (mg/kg po)
35
5
6
7
8
H
Ph
4-FPh
3,5-diFPh
2,6-diFPh
H
4-Py
3-Py
4-Me-3-Py
H
H
H
H
H
H
Ph
H
H
H
6.0
5.8
6.6
5.9
<5
insol
7.2
7.2
7.0
-
8.0
8.3
8.2
7.1
7.6
insol
9.2
9.1
9.4
8.3
120
320
40
-
5
10
6
4
-
16
12
15
2
0.02
2.6
-
-
-
0.8
7.6
7.2
6.3
7.0
insol
8.0
8.0
8.2
8.0
>20
10
-
15
>420
-
-
-
-
5
IA
9
-
-
10
11
12
13
100
80
250
>2000
50%
77%
0.2
7%
3-Py
<5.0
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 The cytochrome P450 inhibitory potential was determined
d
using isoform-selective assays and heterologously expressed human CYP1A2 as has been previously described20 [caffeine N3-demethylation
(500 µM)]. These values are the mean of duplicate determinations which did not vary by more than 10% and are expressed as IC50 (µM)
or percentage reversal at 1 µM. f Dose of compound required to reverse mCPP (7 mg/kg ip administered 30 min pretest) induced
hypolocomotion by 50%.
Ta ble 2. 5-HT2A, 5-HT2B, and 5-HT2C Receptor Binding Affinities,a Human CYP1A2 Inhibitory Potential,e and in Vivo Activityf of
1-(Arylphenylcarbamoyl)indolines 14-24
pKi
selectivity
b
c
d
compd
R3
R4
X
5-HT2A
5-HT2B
5-HT2C
5-HT2C/2A 5-HT2C/2B IC50e (µM) CYP1A2 ID50f (mg/kg po)
14
15
16
17
18
19
20
21
22
23
24
4-Py
3-Py
2-Py
3-Py
4-Me-3-Py
2-Me-3-Py
2,4-diMe-3-Py
4-Me-3-Py
4-Me-3-Py
H
H
H
H
H
H
H
H
Me
Cl
3-Py
4-Py
S
S
6.8
7.1
6.3
6.7
6.6
6.3
6.7
<5.2
<6.0
5.4
7.6
8.1
-
8.1
-
7.8
7.9
8.4
-
8.0
7.9
8.5
8.8
7.7
9.0
9.2
8.3
8.6
9.5
9.2
7.8
8.3
50
50
25
200
400
8
5
-
8
-
3
5
12
-
0.6
-
-
-
-
-
O
O
O
O
O
O
O
O
O
3%
4
8%
2%
-
0.6
5
100
80
>10
-
>20000
>1500
250
>100
1.4
1.4
>10
IA
11%
0%
-
H
<5.0
>2000
3
a
-fSee corresponding footnotes in Table 1.
analogues 10-12 still showed unacceptable CYP1A2
activity although this was considerably reduced relative
to 3. This activity is presumably due to the relatively
unhindered nature of the central 3-amidopyridyl ring,
and therefore compounds of this type were not pursued
further. Moving the 3-pyridyl group from the 5- to
6-position of the 3-amidopyridyl to increase steric
crowding of the central pyridine nitrogen gave 13.
Although this compound showed reduced 5-HT2C affin-
ity, it achieved over 2000-fold selectivity over 5-HT2A
receptors with low CYP1A2 inhibition but was unfor-
tunately orally inactive (10 mg/kg po).
P yr id ylp h en ylca r ba m oylin d olin es (Ta ble 2). As
the exposed nitrogen of the 1-(3-pyridylcarbamoyl)-
indolines such as 1-4 was apparently responsible for
high inhibitory CYP1A2 activity, we investigated the
replacement of this ring with phenyl substituted with
pyridyl to retain solubility and probe for beneficial
interactions with the 5-HT2C receptor. As hoped, these
compounds (14-24) generally retained good 5-HT2C
affinity and selectivity over 5-HT2A receptors combined
with reduced P450 liability. In combination with the
5-thiomethyl-6-trifluoromethylindoline, both the 3-sub-
stituted 4-pyridyl (14) and 3-pyridyl (15) analogues
demonstrated good 5-HT2C affinity but relatively modest
selectivity over 5-HT2A receptors. However, incorporat-
ing the 5-methoxy-6-trifluoromethylindoline led to im-
proved selectivity with the 3-substituted 3-pyridyl ana-
logue 17 exhibiting nanomolar 5-HT2C affinity combined
with good selectivity over 5-HT2A. 17 also demonstrated
potent oral activity in the rat hypolocomotion model
(ID50 ) 0.6 mg/kg), but unfortunately moderate CYP1A2
inhibition was still evident (IC50 ) 4 µM). As previously,
increasing the torsion angle between the two aromatic
rings by introduction of a 4-methyl into the pyridyl ring
ortho to the biaryl bond (18) increased selectivity over
5-HT2A receptors. In contrast, the 2-methyl analogue 19
and the 2,4-dimethyl analogue 20 demonstrated reduced

Biarylcarbamoylindolines: 5-HT2C Inverse Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1127
Ta ble 3. 5-HT2A, 5-HT2B, and 5-HT2C Receptor Binding Affinities,a Human CYP1A2 Inhibitory Potential,e and in Vivo Activityf of
1-[3-(3-Pyridyl)phenylcarbamoyl]indolines 25-37
pKi
selectivity
b
c
d
compd
R
5-HT2A
5-HT2B
5-HT2C
5-HT2C/2A
5-HT2C/2B
IC50e (µM) CYP1A2
ID50f (mg/kg po)
25
26
27
28
29
30
31
32
33
34
35
36
37
6-F
2-Me
2-Cl
4-Me
4-t-Bu
4-Cl
4-MeO
5-F
5-Br
5-Et
5-Ph
4-Me-5-F
4,5-OCH2CH2
5.1
6.4
6.6
5.3
6.0
5.9
6.7
6.9
<6.0
6.7
6.2
5.8
6.6
5.7
-
5.7
7.6
8.0
9.0
8.5
8.3
9.3
9.0
8.7
9.2
8.6
9.2
9.3
4
16
25
1
-
0.5
5
13
5
30
10
10
16
6
-
-
-
-
-
-
8.3
8.3
7.4
7.6
7.8
8.0
7.7
8.0
7.8
8.1
8.1
5000
320
250
400
130
>500
320
250
1600
500
7%
-
1.6
IA
5.5
1.2
0.7
5
1.2
>5
>5
2.0
73
3%
28
7%
6%
0%
-
13
16
2%
a-f See corresponding footnotes in Table 1.
5-HT2C activity and selectivity. Combining a 4-methyl-
3-pyridyl at the 3-position of the phenyl with a 4-methyl
to give 21, which modeling showed would result in an
almost orthogonal relationship of the two aryl rings,
gave sub-nanomolar 5-HT2C affinity while effectively
abolishing 5-HT2A activity and thus affording spectacu-
lar selectivity of >20 000. The corresponding 4-chlo-
rophenyl analogue 22 had a similar profile confirming
this trend. Unfortunately, although 18, 19, and 22
showed good oral activity in the rat hypolocomotion
model and low CYP1A2 inhibitory activity, on screening
at other P450 enzymes significant inhibition of the
CYP2D6 isoform (IC50 < 1 µM) was apparent. The
2-pyridyl analogue 16 showed considerably reduced
5-HT2C affinity and selectivity relative to 17. The
4-substituted pyridyl analogues 23 and 24 demonstrated
reduced but still reasonable 5-HT2C affinity with good
selectivity over 5-HT2A receptors and low CYP1A2
inhibitory liability. Unfortunately, both these com-
pounds displayed poor oral activity.
P yr id yl-Su bstitu ted P h en ylca r ba m oylin d olin es
(Ta ble 3). From the work described above, the 3-(3-
pyridyl)phenylcarbamoylindoline 17 emerged with the
best overall in vitro profile, combined with high potency
in the hypolocomotion model. However, time course
studies revealed that the duration of activity in this
model following oral dosing at 3 × ID50 was less than 1
h. We hypothesized that this short duration of action
may be due to metabolism of the relatively electron-rich
phenyl ring. Therefore, a series of analogues was
prepared containing additional substituents in the
phenyl ring to explore binding and P450 SAR and with
the additional aim of blocking putative metabolism.
Introducing substituents into the 2- and 6-positions
(25-27) resulted in a significant drop in 5-HT2C affinity
and selectivity relative to 17. This effect was dramatic
in the case of the 6-fluoro analogue 25 presumably due
to an unfavorable effect on the relative conformation of
the aromatic ring and the carbamoyl moiety. In contrast,
a variety of both electron-withdrawing and electron-
donating substituents were well-tolerated at both the
4- (28-31) and 5-positions (32-35), affording good to
excellent 5-HT2C affinity and selectivity over 5-HT2A
.
The good activity of the triaryl analogue 35 indicates
considerable space in the receptor binding pocket. In
general, the 4-substituted analogues 28-31 demon-
strated increased selectivity over 5-HT2A, relative to 17,
which is consistent with the finding that an out-of-plane
conformation of the aryl rings disfavors 5-HT2A activity.
Incorporating 4,5-disubstitution as in 36 and 37 pro-
duced an additive effect on activity leading to some of
the highest 5-HT2C affinities and selectivities over
5-HT2A so far seen. In addition to excellent binding
profiles, all the compounds tested in this series dem-
onstrated low inhibition of CYP1A2. Several compounds,
in particular 28, 31, 32, 34, and 37, also demonstrated
potent oral activity in the rat hypolocomotion model.
These compounds were further profiled in time course
studies in this model to determine if our aim of increas-
ing metabolic stability relative to 17 had been achieved.
In the case of 32 a 6-h duration of effect was observed
following oral dosing at 3 × ID50, and this compound
was therefore selected for further evaluation.
(3-P yr idyloxy)pyr idylcar bam oylin dolin es (Table
4). Although many of the compounds described above
demonstrated excellent 5-HT2C affinity and selectivity
over 5-HT2A, selectivity over the 5-HT2B receptor was
absent or at best modest. The high affinity of the triaryl
analogue 35, together with further receptor-ligand
modeling work, suggested that the lipophilic pocket
within the 5-HT2C receptor was still not fully exploited.
The model suggested that introducing a linker group
between the aromatic rings would more optimally
occupy these hydrophobic regions (Figure 2). Conse-
quently, the bispyridyl ether 38 was prepared and found
to have excellent 5-HT2C affinity and almost 100-fold
selectivity over 5-HT2A. As previously, increasing the
torsion angle between the two aryl rings by introduction
of a 2-methyl substituent into the terminal pyridyl ring
to give 39 afforded a beneficial effect on 5-HT2C affinity
and a 10-fold increase in selectivity over 5-HT2A. In
addition, we were very excited to discover that 80-fold

1128 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Bromidge et al.
Ta ble 4. 5-HT2A, 5-HT2B, and 5-HT2C Receptor Binding Affinities,a Human CYP1A2 Inhibitory Potential,e and in Vivo Activityf of
[(3-Pyridyl)oxy]-5-pyridylcarbamoylindolines 38-41
pKi
selectivity
b
c
d
compd
R
X
Y
5-HT2A
5-HT2B
5-HT2C
5-HT2C/2A
5-HT2C/2B
IC50e (µM) CYP1A2
ID50f (mg/kg po)
38
39
40
41
H
OMe
OMe
Me
CF3
CF3
CF3
Cl
7.0
6.1
6.8
6.8
7.7
7.3
7.0
7.0
8.9
9.2
9.0
9.0
80
1300
160
16
80
100
100
4%
>100
>100
>100
0.7
2.8
0.7
2.0
Me
Me
Me
Me
160
a
-fSee corresponding footnotes in Table 1.
Ta ble 5. Human Cytochrome P450 Inhibitory Potentiala of
Compounds 2, 32, 40, and 41
IC50 (µM)
compd
1A2
0.013
28
>100
>100
2C9
2C19
2D6
0.11
21
>100
>100
3A4
2
32
40
41
>100
82
23
>100
>100
>100
>100
>100
>100
9
>100
>100
a
The cytochrome P450 inhibitory potential was determined
using isoform-selective assays and heterologously expressed hu-
man CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. IC50's
were determined at the substrate Km as has been previously
described20 [CYP1A2: caffeine N3-demethylation (500 µM),
CYP2C9: tobutamide methylhydroxylation (100 µM), CYP2C19:
S-mephenytoin 4-hydroxylation (100 µM), CYP2D6: bufuralol 1′-
hydroxylation (10 µM), and CYP3A4: total cyclosporin oxidation
(1 µM)]. These values are the mean of duplicate determinations
which did not vary by more than 10%.
F igu r e 2. Structure 40 docked into the model of the 5-HT2C
receptor (TM2 and TM3 removed for clarity) showing the
2-methyl-3-pyridyloxy group extending deep into the cavity.
lated phosphoinositol (PI) hydrolysis model of 5-HT2C
receptor function,6 using human cloned receptors ex-
pressed in HEK 293 cells, 32 and 40 were found to
display negative efficacy and completely abolished the
basal effector activity which is a feature of this cloned
system. Hence, they are inverse agonists with pKB's of
9.3 and 9.5, respectively, which are consistent with their
binding affinities. This phenomenon may be a result of
optimization of the ligand-independent receptor activity
due to overexpression in this cloned system,23 although
there is evidence that constitutively active 5-HT2C
receptors may be biologically significant.24 The P450
inhibitory activity of 32 and 40 across a range of human
isoforms is shown in Table 5 together with that of 2 for
comparison. These compounds, in particular 40, have
generally low inhibitory activity indicating that they are
unlikely to invoke undesirable drug-drug interactions
in a clinical setting.
Compounds 32 and 40 were then further evaluated
in two different rat models of anxiety, namely the Geller
Seifter conflict test and the social interaction test.3,4
Significant anxiolytic activity was observed at doses
(0.2-5 mg/kg po) similar to those that antagonized
mCPP-induced hypolocomotion with no evidence of
sedative effects.25 The observation of marked anxiolytic
activity with both a mixed 5-HT2C/2B antagonist (32) and
a selective 5-HT2C antagonist (40) at similar doses
provides compelling evidence that this effect is 5-HT2C
mediated. Significantly, acute administration of 32 or
40 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
selectivity over the 5-HT2B receptor was now apparent.
Compounds 38 and 39 also demonstrated low CYP1A2
inhibitory liability and good in vivo activity in the rat
hypolocomotion model. Although 39 showed an excellent
overall profile we had concerns that the 5-methoxyin-
doline substituent may be metabolically labile.22 In the
previous 1-(3-pyridylcarbamoyl)indoline series we iden-
tified a number of other indoline substitution patterns,
such as the 6-chloro-5-methylindoline 4, which had good
5-HT2C affinity and reduced but still moderate selectiv-
ity but which promised to be potentially more metaboli-
cally stable.5 Incorporating the 6-chloro-5-methylindo-
line into the bispyridyl ether series afforded 41 (SB-
242084) which maintained both 5-HT2C affinity and 100-
fold selectivity over both 5-HT2A and 5-HT2B, although
selectivity over 5-HT2A was reduced 7-fold relative to
39.11 This compound also demonstrated potent oral
activity (ID50 ) 2.0 mg/kg) in the rat hypolocomotion
model. Replacing the 6-chloro substituent of 41 with
trifluoromethyl gave 40 with an identical 5-HT2 binding
profile but somewhat improved oral activity (ID50 ) 0.7
mg/kg) combined with a good duration of action (6 h).
In addition both 40 and 41 showed negligible CYP1A2
inhibitory activity (Table 5).
From the work described above compounds 32 and
40 were selected for detailed preclinical evaluation
based on their overall biological profile. On further
cross-screening 32 and 40 were found to have >100-
fold selectivity over more than 50 other receptor, ion-
channel, and enzyme binding sites. In a 5-HT-stimu-

Biarylcarbamoylindolines: 5-HT2C Inverse Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1129
tioned between dilute brine (200 mL) and ethyl acetate (3 ×
150 mL). The combined organic extracts were dried and
evaporated to afford a brown gum (6 g). Chromatography on
silica gel eluting with 50% ethyl acetate/petroleum ether then
100% ethyl acetate afforded 3-(3-pyridyl)aniline as a yellow
crystalline solid (4.8 g, 95%). NMR (CDCl3) δ: 3.8 (2H, br s),
6.70 (1H, m), 6.85 (1H, m), 6.95 (1H, m), 7.25 (1H, m), 7.35
(1H, m) 7.85 (1H, m), 8.60 (1H, m), 8.85 (1H, m). 3-(3-Pyridyl)-
aniline (0.27 g, 1.6 mmol) in dichloromethane (5 mL) was
added dropwise over 5 min to a solution of 1,1-carbonyldiimi-
dazole (0.28 g, 1.7 mmol) in dichloromethane (5 mL). After 2
h at room temperature the mixture was evaporated to dryness
and the residue dissolved in N,N-dimethylformamide (20 mL).
5-Methoxy-6-trifluoromethylindoline5 (0.35 g, 1.6 mmol) was
added and the mixture heated to 100 °C for 1 h. After cooling,
water (30 mL) was added and the mixture was set aside in
the fridge for 1 h. Filtration and drying afforded a brown solid
(0.59 g). Chromatography on silica gel, eluting with a gradient
of 0-3% methanol in dichloromethane, afforded the title
compound as a white solid (0.56 g, 85%), mp 193-194 °C. NMR
(DMSO-d6) δ: 3.25 (2H, t, J ) 8 Hz), 3.85 (3H, s), 4.20 (2H, t,
J ) 8 Hz) 7.20 (1H, s), 7.35-7.55 (3H, m), 7.67 (1H, d, J ) 7
Hz), 7.90 (1H, s), 8.05 (1H, m), 8.15 (1H, s), 8.60 (1H, m), 8.70
(1H, s), 8.86 (1H, s). MS: m/ e 414 (M+). Purity was determined
as 100.0% by HPLC, retention time 21.48 min.
b.i.d. × 14 days) produced no evidence of hyperphagic
properties. Both these activities are characteristic of
mutant mice lacking the 5-HT2C receptor.21 In addition
there was no evidence of increased sensitivity to 5-HT2C
agonist-induced effects after chronic dosing, indicating
no effects on receptor density or sensitivity. On the basis
of their overall biological profile 32 and 40 were selected
for development as novel nonsedating antidepressant/
anxiolytic agents. The bispyridyl ether 40 is currently
in phase 1 clinical development.
Con clu sion
In summary, a series of biarylcarbamoylindolines has
been identified with excellent 5-HT2C affinity and
selectivity over the 5-HT2A receptor. In addition, bispy-
ridyl ether carbamoylindolines have been identified with
additional selectivity over the closely related 5-HT2B
receptor. These compounds are inverse agonists at the
human cloned 5-HT2C receptor completely abolishing
basal activity in a functional PI assay. This series has
reduced P450 inhibitory liability compared to a previ-
ously described series of 1-(3-pyridylcarbamoyl)indo-
lines5 from which they evolved. Some analogues dem-
onstrated excellent oral activity in a rat pharmacody-
namic model and in animal models of anxiety. On the
basis of their favorable biological profile 32 and 40 have
been selected for further development to determine their
therapeutic potential for the treatment of CNS disorders
such as depression and anxiety.
The following examples were prepared in a similar manner:
5-Meth ylth io-1-[[3-(4-p yr id yl)p h en yl]ca r ba m oyl]-6-tr i-
flu or om eth ylin d olin e (14). 3-(4-Pyridyl)aniline, prepared as
described above in 72% yield using 4-bromopyridine instead
of 3-bromopyridine, was coupled with 5-methylthio-6-trifluo-
romethylindoline5 using 1,1-carbonyldiimidazole as above to
give the title compound as a white crystalline solid (47%). NMR
(DMSO-d6) δ: 2.52 (3H, s), 3.30 (2H, t, J ) 8 Hz), 4.25 (2H, t,
J ) 8 Hz), 7.50 (3H, m), 7.70 (3H, m), 8.02 (1H, s), 8.25 (1H,
s), 8.70 (2H, m), 8.80 (1H, s). MS: m/ e 429 (M+). Purity was
determined as 97.0% by HPLC, retention time 23.75 min.
Exp er im en ta l Section
5-Me t h oxy-1-[(6-p h e n yl-3-p yr id yl)ca r b a m oyl]-6-t r i-
flu or om eth ylin d olin e (9). Palladium coupling of 2-bromo-
5-nitropyridine and phenylboronic acid gave 5-nitro-2-phen-
ylpyridine (90%) which was reduced to the corresponding
aniline using catalytic hydrogenation (81%). Treatment with
1,1-carbonyldiimidazole and 5-methoxy-6-trifluoromethylin-
doline5 as above afforded the title compound as a white
crystalline solid (89%), mp 204-207 °C. NMR (DMSO-d6) δ:
3.31 (2H, t, J ) 8 Hz), 3.84 (3H, s), 4.22 (2H, t, J ) 8 Hz) 7.22
(1H, s), 7.36-7.52 (3H, m), 7.92 (1H, d, J ) 8 Hz), 8.01-8.16
(4H, m), 8.82 (1H, m), 8.87 (1H, s). MS: m/ e 414 (M+). Purity
was determined as 93.1% by HPLC, retention time 26.27 min.
5-Meth ylth io-1-[[3-(3-p yr id yl)p h en yl]ca r ba m oyl]-6-tr i-
flu or om eth ylin d olin e (15). 3-(3-Pyridyl)aniline, prepared as
described for 17, was coupled with 5-methylthio-6-trifluoro-
methylindoline5 using 1,1-carbonyldiimidazole as above to
afford the title compound as white solid (42%), mp 208-210
°C. NMR (DMSO-d6) δ: 2.50 (3H, s), 3.30 (2H, t, J ) 8 Hz),
4.20 (2H, t, J ) 8 Hz), 7.40 (3H, m), 7.50 (1H, dd, J ) 5, 7
Hz), 7.65 (1H, dm, J ) 7 Hz), 7.90 (1H, s), 8.10 (1H, dm, J )
7 Hz), 8.20 (1H, s), 8.60 (1H, m), 8.80 (1H, s), 8.90 (1H, m, J
) 5 Hz). MS: m/ e 429 (M+). Purity was determined as 98.6%
by HPLC, retention time 23.38 min.
5-Met h oxy-1-[[3-(2-p yr id yl)p h en yl]ca r b a m oyl]-6-t r i-
flu or om eth ylin d olin e (16). 3-(2-Pyridyl)aniline, prepared by
palladium coupling of 2-bromopyridine and 3-aminophenyl-
boronic acid in 44% yield, was coupled with 1,1-carbonyldi-
imidazole and 5-methylthio-6-trifluoromethylindoline5 as above
to afford the title compound as a white crystalline solid (40%),
mp 220-225 °C. NMR (DMSO-d6) δ: 3.30 (2H, t, J ) 8 Hz),
3.85 (3H, s), 4.20 (2H, t, J ) 8 Hz), 7.20 (1H, s), 7.40 (2H, m),
7.70 (2H, m), 7.90 (2H, m), 8.15 (1H, s), 8.35 (1H, s), 8.65 (1H,
m), 8.70 (1H, s). MS: m/ e 414 (M+). Purity was determined
as 98.1% by HPLC, retention time 23.15 min.
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, 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. Final compounds were greater than
95% pure as judged by area under the curve apart from 9, 10,
23, 30, and 36 which were 90-95% pure. 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 quad-
rupole mass spectrometer. N,N-Dimethylformamide (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 purifica-
tion. Petroleum ether refers to the fraction with bp 60-80 °C.
All reactions were carried out under argon. 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).
Compounds 9, 14-17, 20, and 23-25 were prepared by
coupling biarylamines with 5-methoxy-6-trifluoromethylindo-
line5 using 1,1-carbonyldiimidazole (Scheme 1). The biaryl-
amines were generally prepared by Suzuki palladium coupling
methodology.14 The synthesis of 17 is illustrative:
5-Met h oxy-1-[[3-(3-p yr id yl)p h en yl]ca r b a m oyl]-6-t r i-
flu or om eth ylin d olin e (17). A mixture of 3-bromopyridine
(2.9 mL, 30 mmol), 3-aminophenylboronic acid (4.6 g, 30
mmol), sodium carbonate (10 g, 90 mmol) and tetrakis(tri-
phenylphosphine)palladium(0) (0.9 g) in 1,2-dimethoxyethane
(150 mL) and water (50 mL) was heated under reflux for 12
h. The cooled reaction mixture was concentrated, then parti-
5-Met h oxy-1-[[4-(3-p yr id yl)p h en yl]ca r b a m oyl]-6-t r i-
flu r om eth ylin d olin e (23). 4-(3-Pyridyl)aniline, prepared by
palladium coupling of 3-bromopyridine and 4-aminophenyl-
boronic acid in 27% yield, was coupled with 1,1-carbonyldi-

1130 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Bromidge et al.
The following examples were prepared similarly:
imidazole and 5-methylthio-6-trifluoromethylindoline5 as above
to afford the title compound as a white crystalline solid (85%),
mp >230 °C. NMR (DMSO-d6) δ: 3.30 (2H, t, J ) 8 Hz), 3.85
(3H, s), 4.20 (2H, t, J ) 8 Hz), 7.20 (1H, s), 7.45 (1H, m), 7.70
(4H, m), 8.05 (1H, m), 8.15 (1H, s), 8.55 (1H, m), 8.70 (1H, s),
8.90 (1H, m). MS: m/ e 414 (MH+). Purity was determined as
91.9% by HPLC, retention time 22.39 min.
5-Met h oxy-1-[[4-(4-p yr id yl)p h en yl]ca r b a m oyl]-6-t r i-
flu or om eth ylin d olin e (24). 4-(4-Pyridyl)aniline, prepared by
palladium coupling of 4-bromoaniline and 4-pyridylboronic acid
in 31% yield, was coupled with 1,1-carbonyldiimidazole and
5-methylthio-6-trifluoromethylindoline5 as above to afford the
title compound as a white crystalline solid (5%), mp >210 °C.
NMR (DMSO-d6) δ: 3.30 (2H, t, J ) 8 Hz), 3.85 (3H, s), 4.20
(2H, t, J ) 8 Hz), 7.20 (1H, s), 7.70 (2H, d), 7.75 (4H, m),
8.15 (1H, s), 8.60 (2H, d), 8.85 (1H, s). MS: m/ e 413 (M+).
Purity was determined as 100.0% by HPLC, retention time
22.10 min.
5-Met h oxy-1-[[3-(2,4-d im et h yl-3-p yr id yl)p h en yl]ca r -
ba m oyl]-6-tr iflu or om eth ylin d olin e (20). 3-(2,4-Dimethyl-
3-pyridyl)aniline, prepared by palladium coupling of 2,4-
dimethyl-3-trifluoromethylsulfonyloxypyridine and 3-amino-
phenylboronic acid in 31% yield,26 was coupled with 1,1-car-
bonyldiimidazole and 5-methylthio-6-trifluoromethylindoline5
as above to afford the title compound as a white crystalline
solid (17%), mp 202-204 °C. NMR (DMSO-d6) δ: 2.03 (3H,
s), 2.20 (3H, s), 3.28 (2H, t, J ) 8 Hz), 3.85 (3H, s), 4.20 (2H,
t, J ) 8 Hz), 6.87 (1H, d, J ) 7 Hz), 7.18 (1H, d, J ) 5 Hz),
7.20 (1H, s), 7.41 (2H, m), 7.51 (1H, d, J ) 8 Hz), 8.10 (1H, s),
8.32 (1H, d, J ) 5 Hz), 8.64 (1H, s). MS: m/ e 442 (MH+).
Purity was determined as 99.9% by HPLC, retention time
16.60 min.
1-[[2-Flu or o-5-(3-pyr idyl)ph en yl]car bam oyl]-5-m eth oxy-
6-t r iflu or om et h ylin d olin e (25). 2-Fluoro-5-(3-pyridyl)-
aniline, prepared in 74% overall yield by palladium coupling
of 2-fluoro-5-bromonitrobenzene and 3-pyridylboronic acid
followed by reduction using stannous chloride in aqueous HCl,
was coupled with 1,1-carbonyldiimidazole and 5-methylthio-
6-trifluoromethylindoline5 as above to afford the title com-
pound as a white crystalline solid (10%), mp 233 °C dec. NMR
(DMSO-d6) δ: 3.20 (2H, t, J ) 8 Hz), 3.82 (3H, s), 3.94 (2H, t,
J ) 8 Hz), 7.13-7.28 (2H, m), 7.38-7.58 (3H, m), 7.87 (1H,
m), 7.98 (1H, s), 8.35 (1H, s), 8.55 (1H, dd), 8.64 (1H, d). MS:
m/ e 432 (MH+).
5-Meth oxy-1-[[6-(3-p yr id yl)-3-p yr id yl]ca r ba m oyl]-6-tr i-
flu or om eth ylin d olin e (13). 3-Amino-6-(3-pyridyl)pyridine,
prepared in 69% overall yield by palladium coupling of
2-bromo-5-nitropyridine and 3-pyridylboronic acid followed by
reduction using catalytic hydrogenation, was converted to the
phenyl carbamate (100%) and reacted with 5-methoxy-6-
trifluoromethylindoline5 as above to afford the title compound
(78%), mp >270 °C. NMR (DMSO-d6) δ: 3.32 (2H, t, J ) 8
Hz), 3.88 (3H, s), 4.23 (2H, t, J ) 8 Hz), 7.20 (1H, s), 7.45-
7.55 (1H, m), 7.98-8.18 (3H, m), 8.35-8.43 (1H, m), 8.55-
8.60 (1H, m), 8.85 (1H, d, J ) 4 Hz), 8.91 (1H, s), 9.23 (1H, s).
MS: m/ e 415 (MH+). Purity was determined as 96.5% by
HPLC, retention time 21.82 min.
5-Meth oxy-1-[[3-(4-m eth yl-3-pyr idyl)ph en yl]car bam oyl]-
6-t r iflu or om et h ylin d olin e (18). 3-(4-Methyl-3-pyridyl)-
aniline, prepared in 91% overall yield by palladium coupling
of 3-bromo-4-methylpyridine and 3-nitrophenylboronic acid
followed by reduction using stannous chloride in aqueous HCl,
was converted to the phenyl carbamate (100%) and re-
acted with 5-methoxy-6-trifluoromethylindoline5 as above to
afford the title compound (34%), mp 178-180 °C. NMR
(DMSO-d6) δ: 2.29 (3H, s), 3.29 (2H, t, J ) 8 Hz), 3.84 (3H, s),
4.19 (2H, t, J ) 8 Hz), 7.01 (1H, d, J ) 6 Hz), 7.20 (1H, s),
7.31-7.43 (2H, m), 7.55-7.62 (2H, m), 8.10 (1H, s), 8.32 (1H,
s), 8.40 (1H, d, J ) 6 Hz), 8.62 (1H, s). MS: m/ e 428 (MH+).
Purity was determined as 95.2% by HPLC, retention time
16.82 min.
5-Meth oxy-1-[[3-(2-m eth yl-3-pyr idyl)ph en yl]car bam oyl]-
6-t r iflu or om et h ylin d olin e (19). 3-(2-Methyl-3-pyridyl)-
aniline, prepared in 63% overall yield by palladium coupling
of 3-bromo-2-methylpyridine and 3-nitrophenylboronic acid
followed by reduction using stannous chloride in aqueous HCl,
was converted to the phenyl carbamate (90%) and reacted with
5-methoxy-6-trifluoromethylindoline5 as above to afford the
title compound as an off-white solid (53%), mp 179-180 °C.
NMR (CDCl3) δ: 2.50 (3H, s), 3.28 (2H, t, J ) 8 Hz), 3.85 (3H,
s), 4.12 (2H, t, J ) 8 Hz), 6.56 (1H, s), 6.86 (1H, s), 7.03 (1H,
m), 7.18 (1H, dd, J ) 6, 8 Hz), 7.32-7.47 (3H, m), 7.51 (1H,
dd, J ) 2, 8 Hz) 8.22 (1H, s), 8.50 (1H, m). MS: m/ e 428 (MH+).
Purity was determined as 99.4% by HPLC, retention time
16.10 min.
1-[[5-Br om o-3-(3-pyr idyl)ph en yl]car bam oyl]-5-m eth oxy-
6-t r iflu or om et h ylin d olin e (33). 5-Bromo-3-(3-pyridyl)-
aniline, prepared in 53% overall yield by palladium coupling
of 3-pyridylboronic acid and 3,5-dibromonitrobenzene followed
by reduction using stannous chloride in aqueous HCl, was
converted to the phenyl carbamate and reacted with 5-meth-
oxy-6-trifluoromethylindoline5 as above to afford the title
compound (24%). NMR (CDCl3) δ: 3.25 (2H, t, J ) 8 Hz), 3.85
(3H, s), 4.15 (2H, t, J ) 8 Hz), 6.82 (1H, s), 7.32-7.44 (3H,
m), 7.60 (1H, m), 7.74 (1H, m), 7.88 (1H, d, J ) 7 Hz), 8.19
(1H, s), 8.54 (1H, m, J ) 5 Hz), 8.74 (1H, m). Purity was
determined as 100.0% by HPLC, retention time 18.73 min.
The following examples 13, 18, 19, 21, 22, and 26-37 were
prepared from biarylamines via the phenyl carbamate (Scheme
2). The synthesis of 32 is illustrative:
1-[[3-Flu or o-5-(3-pyr idyl)ph en yl]car bam oyl]-5-m eth oxy-
6-t r iflu or om et h ylin d olin e (32). 3-Fluoro-5-(3-pyridyl)-
aniline was prepared in 55% overall yield by palladium
coupling of 3-fluoro-5-iodonitrobenzene and 3-pyridylboronic
acid followed by reduction using stannous chloride in aqueous
HCl. The aniline (1.0 g, 0.50 mmol) in dry dichloromethane
(20 mL) was treated with triethylamine (1.1 mL, 0.80 mmol)
followed dropwise by phenyl chloroformate (0.97 mL, 0.77
mmol) and stirred at ambient temperature for 18 h. The
reaction mixture was washed with water (2 × 20 mL), dried
and evaporated in vacuo to afford phenyl N-[3-fluoro-5-(3-
pyridyl)phenyl]carbamate (1.1 g, 71%) as an off-white solid.
NMR (DMSO-d6) δ: 7.20-7.49 (3H, m), 7.49-7.59 (5H, m),
7.63 (1H, d), 8.07 (1H, m), 8.63 (1H, d), 8.87 (1H, s), 10.61 (1H,
s). Phenyl N-[3-fluoro-5-(3-pyridyl)phenyl]carbamate in dry
dimethylformamide was treated with 5-methoxy-6-trifluorom-
ethylindoline5 and triethylamine as in the preparation of 40,
followed by chromatography on silica gel, eluting with a
gradient of 0-3% methanol in dichloromethane to afford the
title compound as a white solid in 26% yield, mp 220-223 °C.
NMR (DMSO-d6) δ: 3.29 (2H, t, J ) 8 Hz), 3.85 (3H, s), 4.21
(2H, t, J ) 8 Hz), 7.23 (1H, s), 7.30 (1H, d, J ) 8 Hz), 7.54
(1H, dd, J ) 5, 7 Hz), 7.65 (1H, dm, J ) 10 Hz), 7.76 (1H, s),
8.09 (1H, dm, J ) 7 Hz), 8.15 (1H, s), 8.62 (1H, m), 8.78-9.00
(2H, m). MS: m/ e 432 (MH+). Anal. (C22H17N3O2F4) C, H, N.
Purity was determined as 100.0% by HPLC, retention time
17.68 min.
1-[[5-Eth yl-3-(3-pyr idyl)ph en yl]ca r ba m oyl]-5-m eth oxy-
6-t r iflu or om et h ylin d olin e (34). 5-Bromo-3-(3-pyridyl)ni-
trobenzene, prepared as described above for 33, was coupled
with tributylethenylstannane and reduced using catalytic
hydrogenation to give 5-ethyl-3-(3-pyridyl)aniline in 77%
overall yield. Conversion to the phenyl carbamate (100%)
and reaction with 5-methoxy-6-trifluoromethylindoline5 as
above afforded the title compound (40%) as a tan powder, mp
205-207 °C. NMR (CDCl3) δ: 1.3 (3H, t, J ) 7 Hz), 2.60
(2H, q, J ) 7 Hz), 3.28 (2H, t, J ) 8 Hz), 3.88 (3H, s), 4.12
(2H, t, J ) 8 Hz), 6.52 (1H, s), 6.85 (1H, s), 7.12 (1H, s), 7.32
(2H, m), 7.48 (1H, s), 7.88 (1H, m, J ) 7 Hz), 8.22 (1H, s),
8.58 (1H, m, J ) 5 Hz), 8.81 (1H, m). MS: m/ e 442 (MH+).
Purity was determined as 98.7% by HPLC, retention time
18.45 min.
5-Meth oxy-1-[[5-ph en yl-3-(3-pyr idyl)ph en yl]car bam oyl]-
6-t r iflu or om et h ylin d olin e (35). 5-Bromo-3-(3-pyridyl)ni-
trobenzene, prepared as above for 33, was coupled with
phenylboronic acid and reduced using stannous chloride in
aqueous HCl to give 5-phenyl-3-(3-pyridyl)aniline in 43% yield.

Biarylcarbamoylindolines: 5-HT2C Inverse Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1131
Conversion to the phenyl carbamate (99%) and reaction with
5-methoxy-6-trifluoromethylindoline5 as above afforded the
title compound (47%) as an off-white solid, mp 150-151 °C.
NMR (CDCl3) δ: 3.28 (2H, t, J ) 8 Hz), 3.85 (3H, s), 4.12 (2H,
t, J ) 8 Hz), 6.65 (1H, br s), 6.85 (1H, s), 7.30-7.50 (5H, m),
7.55-7.70 (4H, m), 7.90 (1H, m, J ) 7 Hz), 8.24 (1H, s), 8.60
(1H, m, J ) 5 Hz), 8.87 (1H, m). Purity was determined as
95.5% by HPLC, retention time 20.09 min.
5-Meth oxy-1-[[5-flu or o-4-m eth yl-3-(3-p yr id yl)p h en yl]-
ca r ba m oyl]-6-tr iflu or om eth ylin d olin e (36). 5-Fluoro-4-
methyl-3-(3-pyridyl)aniline, prepared in 77% overall yield by
palladium coupling of 3-pyridylboronic acid and 3-fluoro-5-iodo-
4-methylnitrobenzene followed by reduction using stannous
chloride in aqueous HCl, was converted to the phenyl carbam-
ate (96%) and reacted with 5-methoxy-6-trifluoromethylindo-
line5 as above to afford the title compound as an off-white solid
(93%), mp 244-247 °C. NMR (DMSO-d6) δ: 2.08 (3H, d, J )
2 Hz), 3.27 (2H, t, J ) 8 Hz), 3.85 (3H, s), 4.16 (2H, t, J ) 8
Hz), 7.20 (1H, s), 7.33 (1H, br s), 7.52 (1H, dd, J ) 6, 8 Hz),
7.59 (1H, dd, J ) 2, 12 Hz), 7.82 (1H, m), 8.10 (1H, s), 8.59
(1H, m), 8.62 (1H, dd, J ) 2, 6 Hz), 8.72 (1H, s). MS: m/ e 446
(MH+). Purity was determined as 91.0% by HPLC, retention
time 17.45 min.
1-[[2,3-Dih yd r o-7-(3-p yr id yl)ben zofu r a n -5-yl]ca r ba m -
oyl]-5-m eth oxy-6-tr iflu or om eth ylin d olin e (37). 2,3-Dihy-
dro-7-iodo-5-nitrobenzofuran, prepared in 26% yield from 2,3-
dihydro-7-iodobenzofuran by treatment with copper nitrate in
acetic anhydride, was coupled with 3-pyridylboronic acid, as
described generally above, in 30% yield. Reduction using
stannous chloride in aqueous HCl followed by conversion to
the phenyl carbamate (80% overall) and reaction with 5-meth-
oxy-6-trifluoromethylindoline5 as above afforded the title
compound (26%) as a beige solid. NMR (DMSO-d6) δ: 3.12-
3.49 (4H, m), 3.85 (3H, s), 4.15 (2H, t, J ) 8 Hz), 4.61 (2H, t,
J ) 8 Hz), 7.21 (1H, s), 7.40-7.58 (3H, m), 8.07 (1H, dd, J )
1, 7 Hz), 8.13 (1H, s), 8.43-8.60 (2H, m), 8.88 (1H, d, J ) 1
Hz). MS: m/ e 456 (MH+). Purity was determined as 98.7%
by HPLC, retention time 16.29 min.
5-Meth oxy-1-[[4-m eth yl-3-(3-pyr idyl)ph en yl]car bam oyl]-
6-t r iflu or om et h ylin d olin e (28). 4-Methyl-3-(3-pyridyl)-
aniline, prepared in 87% overall yield by palladium coupling
of 3-pyridylboronic acid and 3-bromo-4-methylnitrobenzene
followed by reduction using stannous chloride in aqueous HCl,
was converted to the phenyl carbamate (93%) and reacted with
5-methoxy-6-trifluoromethylindoline5 as above to afford the
title compound (26%) as a white solid, mp 211-212 °C. NMR
(DMSO-d6) δ: 2.20 (3H, s), 3.28 (2H, t, J ) 8 Hz), 3.85 (3H, s),
4.11 (2H, t, J ) 8 Hz), 6.44 (1H, s), 6.85 (1H, s), 7.18-7.45
(4H, m), 7.59-7.72 (1H, m), 8.22 (1H, s), 8.49-8.69 (2H, m).
MS: m/ e 427 (M+). Purity was determined as 100.0% by
HPLC, retention time 16.33 min.
1-[[4-ter t-Bu tyl-3-(3-pyr idyl)ph en yl]car bam oyl]-5-m eth -
oxy-6-tr iflu or om eth ylin d olin e (29). 4-tert-Butyl-3-(3-py-
ridyl)aniline, prepared in 39% overall yield by palladium
coupling of 3-pyridylboronic acid and 3-bromo-4-tert-butylni-
trobenzene followed by reduction using stannous chloride in
aqueous HCl, was converted to the phenyl carbamate (68%)
and reacted with 5-methoxy-6-trifluoromethylindoline5 as
above to afford the title compound (23%). NMR (CDCl3) δ: 1.25
(9H, s), 3.27 (2H, t, J ) 9 Hz), 3.85 (3H, s), 4.09 (2H, t, J ) 9
Hz), 6.43 (1H, s), 6.85 (1H, s), 7.00 (1H, d, J ) 1 Hz), 7.18-
7.35 (1H, m), 7.39-7.69 (3H, m), 8.20 (1H, s), 8.42-8.69 (2H,
m). MS: m/ e 470 (MH+). Purity was determined as 98.7% by
HPLC, retention time 26.47 min.
1-[[4-Ch lor o-3-(3-pyr idyl)ph en yl]car bam oyl]-5-m eth oxy-
6-t r iflu or om et h ylin d olin e (30). 4-Chloro-3-(3-pyridyl)-
aniline, prepared in 14% overall yield by palladium coupling
of 3-pyridylboronic acid and 4-chloro-3-iodonitrobenzene fol-
lowed by reduction using stannous chloride in aqueous HCl,
was converted to the phenyl carbamate (95%) and reacted with
5-methoxy-6-trifluoromethylindoline5 as above to afford the
title compound (36%) as an off-white solid, mp 210-213 °C.
NMR (CDCl3) δ: 3.30 (2H, t, J ) 9 Hz), 3.87 (3H, s), 4.12 (2H,
t, J ) 9 Hz), 6.56 (1H, s), 6.87 (1H, s), 7.29-7.58 (4H, m), 7.81
(1H, d, J ) 8 Hz), 8.21 (1H, s), 8.60 (1H, d, J ) 5 Hz), 8.69
(1H, d, J ) 3 Hz). MS: m/ e 447 (M+). Purity was determined
as 93.5% by HPLC, retention time 23.72 min.
1-[[4-Meth oxy-3-(3-p yr id yl)p h en yl]ca r ba m oyl]-5-m eth -
oxy-6-t r iflu or om et h ylin d olin e (31). 4-Methoxy-3-(3-pyri-
dyl)aniline, prepared in 47% overall yield by palladium
coupling of 3-pyridylboronic acid and 3-bromo-4-methoxyni-
trobenzene followed by reduction using stannous chloride in
aqueous HCl, was converted to the phenyl carbamate (75%)
and reacted with 5-methoxy-6-trifluoromethylindoline5 as
above to afford the title compound (32%). NMR (DMSO-d6) δ:
3.26 (2H, t, J ) 9 Hz), 3.76 (3H, s), 3.83 (3H, s), 4.14 (2H, t, J
) 9 Hz), 7.10 (1H, d, J ) 7 Hz), 7.19 (1H, s), 7.45 (1H, dd, J
) 1, 5 Hz), 7.54 (1H, s), 7.59 (1H, d, J ) 3 Hz), 7.87 (1H, dd,
J ) 1, 5 Hz), 8.10 (1H, s), 8.47-8.55 (2H, m), 8.67 (1H, d, J )
3 Hz). MS: m/ e 444 (MH+). Purity was determined as 99.0%
by HPLC, retention time 22.37 min.
5-Meth oxy-1-[[2-m eth yl-3-(3-pyr idyl)ph en yl]car bam oyl]-
6-t r iflu or om et h ylin d olin e (26). 2-Methyl-3-(3-pyridyl)-
aniline, prepared in 53% overall yield by palladium coupling
of 3-pyridylboronic acid and 3-bromo-2-methylnitrobenzene
followed by reduction using stannous chloride in aqueous HCl,
was converted to the phenyl carbamate (87%) and reacted with
5-methoxy-6-trifluoromethylindoline5 as above to afford the
title compound as an off-white solid (56%), mp 192-193 °C.
NMR (DMSO-d6) δ: 2.11 (3H, s), 3.28 (2H, t, J ) 8 Hz), 3.84
(3H, s), 4.20 (2H, t, J ) 8 Hz), 7.13 (1H, d, J ) 8 Hz), 7.22
(1H, s), 7.27-7.42 (2H, m), 7.51 (1H, dd, J ) 6, 8 Hz), 7.78
(1H, m), 8.10 (1H, s), 8.37 (1H, s), 8.55 (1H, m), 8.61 (1H, m).
MS: m/ e 428 (MH+). Purity was determined as 99.5% by
HPLC, retention time 21.52 min.
1-[[2-Ch lor o-3-(3-pyr idyl)ph en yl]car bam oyl]-5-m eth oxy-
6-tr iflu or om eth ylin d olin e (27). 3-Bromo-2-chloronitroben-
zene was coupled with 3-pyridylboronic acid under the usual
conditions and the resulting nitroarylpyridine reduced using
stannous chloride in aqueous HCl to give 2-chloro-3-(3-pyridyl)-
aniline (57% overall). Conversion to the phenyl carbamate
(100%) and reaction with 5-methoxy-6-trifluoromethylindoline5
as above afforded the title compound as an off-white solid
(45%), mp 214-216 °C. NMR (CDCl3) δ: 3.33 (2H, t, J ) 8
Hz), 3.88 (3H, s), 4.21 (2H, t, J ) 8 Hz), 6.89 (1H, s), 7.05 (1H,
dd, J ) 2, 7 Hz), 7.22 (1H, s), 7.34-7.43 (2H, m), 7.76 (1H,
m), 8.28 (1H, s), 8.40 (1H, dd, J ) 2, 8 Hz), 8.62-8.69 (2H,
m). MS: m/ e 448 (MH+). Purity was determined as 99.6% by
HPLC, retention time 22.63 min.
5-Meth oxy-1-[[4-m eth yl-3-(4-m eth yl-3-p yr id yl)p h en yl]-
ca r ba m oyl]-6-tr iflu or om eth ylin d olin e (21). 4-Methyl-3-(4-
methyl-3-pyridyl)aniline, prepared in 74% overall yield by
palladium coupling of 4-methyl-3-pyridylboronic acid and
3-bromo-4-methylnitrobenzene followed by reduction using
stannous chloride in aqueous HCl, was converted to the phenyl
carbamate (97%) and reacted with 5-methoxy-6-trifluoro-
methylindoline5 as above to afford the title compound as an
off-white solid (47%), mp 153-155 °C. NMR (CDCl3) δ: 2.00
(3H, s), 2.10 (3H, s), 3.27 (2H, t, J ) 8 Hz), 3.84 (3H, s), 4.12
(2H, t, J ) 8 Hz), 6.64 (1H, s), 6.85 (1H, s), 7.12-7.28 (3H,
m), 7.43 (1H, dd, J ) 7, 2 Hz), 8.22 (1H, s), 8.30 (1H, s), 8.44
(1H, d, J ) 6 Hz). MS: m/ e 442 (MH+). Purity was determined
as 96.2% by HPLC, retention time 17.29 min.
1-[[4-Ch lor o-3-(4-m eth yl-3-p yr id yl)p h en yl]ca r ba m oyl]-
5-m eth oxy-6-tr iflu or om eth ylin d olin e (22). Palladium cou-
pling of 3-bromo-4-chloronitrobenzene and 4-methyl-3-pyridyl-
boronic acid gave 4-chloro-3-(4-methyl-3-pyridyl)nitrobenzene
in 33% yield which was reduced in 95% yield by stannous
chloride in aqueous HCl to 4-chloro-3-(4-methyl-3-pyridyl)-
aniline. Conversion to the phenyl carbamate (98%) in the usual
manner and then treatment with 5-methoxy-6-trifluorometh-
ylindoline5 gave the title compound (49%), mp 140-141 °C.
NMR (CDCl3) δ: 2.19 (3H, s), 3.28 (2H, t, J ) 8 Hz), 3.82 (3H,
s), 4.15 (2H, t, J ) 8 Hz), 6.81 (1H, s), 7.09 (1H, s), 7.20 (1H,
d, J ) 6 Hz), 7.25 (1H, s), 7.40 (1H, d, J ) 8 Hz), 7.52-7.59
(1H, m), 8.20 (1H, s), 8.30 (1H, s), 8.45 (1H, d, J ) 6 Hz). MS:
m/ e 462 (MH+). Purity was determined as 97.0% by HPLC,
retention time 17.15 min.

1132 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Bromidge et al.
Compounds 5, 6, and 10-12 were prepared by reaction of
1-[(5-bromo-3-pyridyl)carbamoyl]-5-methoxy-6-trifluorometh-
ylindoline (42) with the appropriate arylboronic acid under
Suzuki conditions (Scheme 3).14 The synthesis of 5 is illustra-
tive:
Compounds 7 and 8 were prepared by an analogous proce-
dure to that described above by coupling ethyl 5-bromonico-
tinate with the appropriate arylstannane under Stille condi-
tions (Scheme 4).16 The synthesis of 8 is illustrative:
1-[[5-(2,6-Diflu or oph en yl)-3-pyr idyl]car bam oyl]-5-m eth -
oxy-6-t r iflu or om et h ylin d olin e (8). A mixture of (2,6-di-
fluorophenyl)tributyltin27 (1.18 g, 2.9 mmol), ethyl 5-bromoni-
cotinate (0.69 g, 3.0 mmol) and tetrakis(triphenylphosphine)-
palladium(0) (0.10 g) in xylene (10 mL) was heated under
reflux for 24 h, then cooled, filtered and evaporated. The
residue was chromatographed on silica gel eluting with 20%
ethyl acetate/petroleum ether to give ethyl 5-(2,6-difluoro-
phenyl)nicotinate (0.64 g, 84%) as a white solid. NMR (CDCl3)
δ: 1.43 (3H, t, J ) 7 Hz), 4.44 (2H, q, J ) 7 Hz), 7.06 (2H, t,
J ) 7 Hz), 7.39 (1H, m), 8.42 (1H, s), 8.88 (1H, s), 9.23 (1H, s).
MS: m/ e 264 (MH+). A mixture of this ester (0.64 g, 2.4 mmol)
and 98% hydrazine hydrate (1 mL) in methanol (10 mL) was
heated under reflux overnight and then cooled in ice and the
resultant precipitate collected. The filtrate was evaporated and
the residue was triturated with water before combining with
the initial precipitate. The crude product was washed with
ether and dried in vacuo to give 5-(2,6-difluorophenyl)nicoti-
noyl hydrazide (0.50 g, 84%) as a solid which was used without
further purification. NMR (DMSO-d6) δ: 4.60 (2H, s), 7.29 (2H,
t, J ) 7 Hz), 7.57 (1H, m), 8.28 (1H, s), 8.80 (1H, s), 9.03 (1H,
s), 10.05 (1H, s). MS: m/ e 250 (MH+). To a suspension of the
hydrazide (0.50 g, 2.0 mmol) in concentrated hydrochloric acid
(3 mL) and water (2 mL) at -5 °C was added dropwise a
solution of sodium nitrite (0.14 g, 2.0 mmol) in water (2 mL).
The mixture was stirred at -5 °C for 0.5 h, then a solution of
potassium carbonate (2.3 g) in water (25 mL) was added
cautiously. The precipitate was collected, washed with water
and dried in vacuo at room temperature to give 5-(2,6-
difluorophenyl)nicotinoyl azide (0.48 g, 93%) as a solid. NMR
(CDCl3) δ: 7.05 (2H, t, J ) 7 Hz), 7.40 (1H, m, J ) 7 Hz), 8.41
(1H, s), 8.93 (1H, s), 9.22 (1H, s). MS: m/ e 261 (MH+), 233
(MH+ - N2). A solution of 5-(2,6-difluorophenyl)nicotinoyl azide
(0.46 g, 1.8 mmol) in toluene (10 mL) was heated under reflux
for 2 h. After cooling, a solution of 5-methoxy-6-trifluoro-
methylindoline5 (0.40 g, 1.8 mmol) in dichloromethane (10 mL)
was added and the mixture was stirred overnight at room
temperature. The precipitate was collected and washed with
petrol. The crude product was recrystallized from dichlo-
romethane/petroleum ether to give the title compound (0.66
g, 82%), mp 217-219 °C. NMR (DMSO-d6) δ: 3.29 (2H, t, J )
8 Hz), 3.84 (3H, s), 4.21 (2H, t, J ) 8 Hz), 7.22 (1H, s), 7.29
(2H, t, J ) 7 Hz), 7.56 (1H, m, J ) 7 Hz), 8.11 (1H, s), 8.15
(1H, s), 8.32 (1H, s), 8.80 (1H, s), 8.93 (1H, s). MS: m/ e 450
(MH+). Anal. (C22H16N3O2F5) C, H, N. Purity was determined
as 100.0% by HPLC, retention time 18.71 min.
1-[(5-Br om o-3-p yr id yl)ca r b a m oyl]-5-m e t h oxy-6-t r i-
flu or om eth ylin d olin e (42). A solution of (5-bromo-3-pyridyl)-
carbonyl azide15 (3.16 g, 13.9 mmol) in toluene (500 mL) was
heated to reflux for 1 h [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 may be 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.] The solution was allowed to cool
to room temperature then added to a solution of 5-methoxy-
6-trifluoromethylindoline5 (2.7 g, 13 mmol) in dichloromethane
(200 mL). The mixture was set aside in the refrigerator for 1
h and then the precipitate was collected and dried to afford
the title compound 42 as a white solid (4.62 g, 89%), mp 220-
222 °C. NMR (DMSO-d6) δ: 3.30 (2H, t, J ) 8 Hz), 3.84 (3H,
s), 4.19 (2H, t, J ) 8 Hz), 7.20 (1H, s), 8.10 (1H, s), 8.30-8.35
(2H, m), 8.73 (1H, s), 8.94 (1H, s).
5-Me t h oxy-1-[(5-p h e n yl-3-p yr id yl)ca r b a m oyl]-6-t r i-
flu or om eth ylin d olin e (5). A mixture of 1-[(5-bromo-3-py-
ridyl)carbamoyl]-5-methoxy-6-trifluoromethylindoline (42) (0.21
g, 0.50 mmol), phenylboronic acid (0.30 g, 2.4 mmol), sodium
carbonate (0.32 g, 3.0 mmol) and tetrakis(triphenylphosphine)-
palladium(0) (0.03 g) in a mixture of dimethoxyethane (5 mL)
and water (1 mL) was heated to reflux for 10 h. The cooled
reaction mixture was partitioned between brine (20 mL) and
ethyl acetate (3 × 30 mL). The combined organic extract was
dried and evaporated to give a brown solid (0.14 g). Column
chromatography on silica gel, eluting with a gradient of 0-5%
methanol in ethyl acetate, afforded the title compound as a
white crystalline solid (0.10 g, 48%), mp 162-164 °C. NMR
(DMSO-d6) δ: 3.30 (2H, t, J ) 8 Hz), 3.85 (3H, s), 4.20 (2H, t,
J ) 8 Hz), 7.20 (1H, s), 7.50 (3H, m), 7.70 (2H, m), 8.10 (1H,
s), 8.30 (1H, m), 8.55 (1H, m), 8.75 (1H, m), 8.85 (1H, s). MS:
m/ e 414 (MH+). Purity was determined as 98.1% by HPLC,
retention time 25.51 min.
The following examples were prepared in a similar manner
from 42 and known arylboronic acids:
5-Meth oxy-1-[[5-(4-flu or oph en yl)-3-pyr idyl]car bam oyl]-
6-tr iflu or om eth ylin d olin e (6). Isolated as a white crystal-
line solid (30%), mp >200 °C. NMR (DMSO-d6) δ: 3.31 (2H, t,
J ) 8 Hz), 3.85 (3H, s), 4.22 (2H, t, J ) 8 Hz), 7.22 (1H, s),
7.37 (2H, m), 7.76 (2H, dd, J ) 6, 8 Hz), 8.13 (1H, s), 8.28 (1H,
m), 8.54 (1H, s), 8.75 (1H, d), 8.87 (1H, s). MS: m/ e 431 (M+).
Purity was determined as 99.9% by HPLC, retention time
25.21 min.
5-Meth oxy-1-[[5-(4-p yr id yl)-3-p yr id yl]ca r ba m oyl]-6-tr i-
flu or om eth ylin d olin e (10). Isolated as a white crystalline
solid (71%), mp 230-234 °C. NMR (DMSO-d6) δ: 3.30 (2H, t,
J ) 8 Hz), 3.85 (3H, s), 4.20 (2H, t, J ) 8 Hz), 7.20 (1H, s),
7.75 (2H, m) 8.15 (1H, s), 8.40 (1H, t, J ) 2 Hz), 8.65 (1H, d,
J ) 2 Hz), 8.70 (2H, m), 8.85 (1H, m), 8.98 (1H, br s). MS:
m/ e 414 (M+). Purity was determined as 93.9% by HPLC,
retention time 18.43 min.
1-[[5-(3,5-Diflu or oph en yl)-3-pyr idyl]car bam oyl]-5-m eth -
oxy-6-tr iflu or om eth ylin d olin e (7). The title compound was
similarly prepared, via coupling of ethyl 5-bromonicotinate and
the corresponding arylstannane in 70% yield, as a white
crystalline solid (52%), mp 226-229 °C. NMR (DMSO-d6) δ:
3.30 (2H, t, J ) 8 Hz), 3.87 (3H, s), 4.25 (2H, t, J ) 8 Hz),
7.20-7.34 (2H, m), 7.48 (2H, m), 8.18 (1H, s), 8.33 (1H, s), 8.61
(1H, m), 8.87 (1H, m), 8.90 (1H, br s). MS: m/ e 450 (MH+).
Purity was determined as 99.6% by HPLC, retention time
19.34 min.
5-Meth oxy-1-[[5-(3-p yr id yl)-3-p yr id yl]ca r ba m oyl]-6-tr i-
flu or om eth ylin d olin e (11). Isolated as a white crystalline
solid (29%), mp 113-114 °C. NMR (DMSO-d6) δ: 3.30 (2H, t,
J ) 8 Hz), 3.85 (3H, s), 4.20 (2H, t, J ) 8 Hz), 7.20 (1H, s),
7.55 (1H, m), 8.10 (1H, m), 8.15 (1H, s), 8.30 (1H, m), 8.60-
8.65 (2H, m), 8.80 (1H, m), 8.95 (2H, m). Purity was deter-
mined as 99.5% by HPLC, retention time 18.90 min.
5-Meth oxy-1-[[5-(4-m eth yl-3-pyr idyl)-3-pyr idyl]car bam -
oyl]-6-tr iflu or om eth ylin d olin e (12). Isolated as a white
crystalline solid (65%), mp 125-128 °C. NMR (CDCl3) δ: 2.32
(3H, s), 3.32 (2H, t, J ) 8 Hz), 3.85 (3H, s), 4.18 (2H, t, J ) 8
Hz), 6.90 (2H, s), 7.21 (1H, d, J ) 4 Hz), 8.10 (1H, s), 8.18
(1H, s), 8.27 (1H, s), 8.40 (1H, s), 8.45-8.53 (2H, m). MS: m/ e
429 (M+). Purity was determined as 100.0% by HPLC, reten-
tion time 19.15 min.
The bispyridyl ethers 39-41 were prepared by coupling the
aniline 43a with 5-methoxy-6-trifluoromethylindoline, 6-chloro-
5-methylindoline, and 5-methyl-6-trifluoromethylindoline, re-
spectively, via the phenyl carbamate (Scheme 5).13,17 38 was
prepared similarly from 5-amino-2-(3-pyridyloxy)pyridine
(43b).19 5-Methyl-6-trifluoromethylindoline was prepared ac-
cording to Scheme 6.
5-Meth yl-6-tr iflu or om eth ylin dolin e. A mixture of 5-meth-
oxy-6-trifluoromethylindoline5 (7.50 g, 34.3 mmol) and iodo-
trimethylsilane (12.5 mL, 89.3 mmol) in dry chloroform (70
mL) was heated under reflux for 65 h. The mixture was cooled
and methanol (5 mL) was cautiously added with stirring. The
solvent was removed in vacuo and the residue treated with
aqueous sodium bicarbonate solution until basic and then

Biarylcarbamoylindolines: 5-HT2C Inverse Agonists
J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6 1133
extracted with a 3:1 mixture of dichloromethane and methanol
(4 × 100 mL). The combined organic extracts were washed
with brine (250 mL), dried and evaporated. The residue was
extracted with ether in a Soxhlet apparatus, and concentration
of the resultant solution gave 5-hydroxy-6-trifluoromethylin-
doline in three crops (total 2.9 g, 41%), mp > 180 °C dec. NMR
(CDCl3/CD3OD) δ: 3.02 (2H, t, J ) 8 Hz), 3.52 (2H, t, J ) 8
Hz), 4.00 (2H, s), 6.77 (1H, s), 6.83 (1H, s). A mixture of this
indoline (2.8 g, 14 mmol) and acetic anhydride (1.3 mL, 14
mmol) in dry dichloromethane (50 mL) was stirred at room
temperature for 3 h, then evaporated. The residue was treated
cautiously with saturated aqueous sodium bicarbonate solu-
tion, then the solid product was filtered off, washed with water
and dried to give 1-acetyl-5-hydroxy-6-trifluoromethylindoline
(3.3 g, 96%), mp 244-247 °C. NMR (DMSO-d6) δ: 2.10 (3H,
s), 3.11 (2H, t, J ) 8 Hz), 4.06 (2H, t, J ) 8 Hz), 6.88 (1H, s),
8.18 (1H, s). To a solution of the acetylindoline (1.2 g, 4.9 mmol)
in dry pyridine (10 mL) at 0 °C was added trifluoromethane-
sulfonic anhydride (1.5 g, 5.4 mmol). The mixture was then
stirred overnight, while slowly warming to room temperature.
The mixture was partially evaporated, the residual liquor was
diluted with water and the precipitate was collected. The crude
material was dissolved in dichloromethane (150 mL) and the
solution was washed with 1 N hydrochloric acid (50 mL) and
brine (50 mL), dried and evaporated to give 1-acetyl-6-
trifluoromethyl-5-trifluoromethylsulfonyloxyindoline (44) (1.8
g, 96%). NMR (CDCl3) δ: 2.28 (3H, s), 3.32 (2H, t, J ) 8 Hz),
4.19 (2H, t, J ) 8 Hz), 7.29 (1H, s), 8.60 (1H, s). MS: m/ e 378
(MH+). To a mixture of 44 (1.8 g, 4.7 mmol), lithium chloride
(0.60 g, 14 mmol) and bis(triphenylphosphine)palladium(II)
chloride (0.10 g, 0.14 mmol) in dry dimethylformamide (15 mL)
was added tetramethyltin (0.72 mL, 5.2 mmol). The mixture
was heated at 110 °C for 3.5 h, then cooled and evaporated.
The residue was partitioned between dichloromethane (3 ×
100 mL) and water (75 mL), and the combined organic phases
washed with brine (100 mL), dried and evaporated. A mixture
of this crude product, ethanol (30 mL), 10% aqueous sodium
hydroxide solution (7.5 mL) and solid sodium hydroxide (1 g)
was heated under reflux overnight. Ethanol was removed in
vacuo, and the residue was diluted with water (20 mL) and
extracted with dichloromethane (3 × 50 mL). The organic
extracts were washed with brine (50 mL), dried and evaporated
and the residue was chromatographed on silica gel, eluting
with 2:1 ether/petroleum ether to give the title compound (0.70
g, 74%), mp 43-44 °C. NMR (CDCl3) δ: 2.34 (3H, s), 3.02 (2H,
t, J ) 8), 3.57 (2H, t, J ) 8), 3.78 (1H, broad), 6.85 (1H, s),
7.00 (1H, s).
chloroformate (41 mL, 0.33 mol) was added dropwise to a
stirred solution of 43a (60 g, 0.30 mol) and triethylamine (46
mL, 0.33 mol) in dry dichloromethane (2.5 L) at -20 °C. The
mixture was stirred at -20 °C for 1 h then warmed to ambient
temperature and washed with dilute aqueous NaHCO3 (2 ×
500 mL), dried and evaporated in vacuo. The residue was
recrystallized from ethyl acetate/petroleum ether to afford
phenyl N-[[2-(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamate (54
g, 56%) as a pink solid. NMR (CDCl3) δ: 2.44 (3H, s), 6.94
(1H, d, J ) 7 Hz), 7.08-7.29 (4H, m), 7.33-7.45 (3H, m), 7.90
(1H, br s), 7.98-8.13 (2H, m), 8.39 (1H, d, J ) 5 Hz). A mixture
of phenyl N-[[2-(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamate
(32 g, 100 mmol) and triethylamine (14 mL, 100 mmol) was
treated with 5-methyl-6-trifluoromethylindoline (20 g, 100
mmol) in dry dimethylformamide (1 L) at 95-105 °C for 1 h.
After cooling the reaction mixture was evaporated in vacuo
and the residue diluted with dichloromethane (500 mL) and
washed with 10% aqueous sodium hydroxide (200 mL), with
addition of methanol (100 mL) to keep the product in organic
solution. The organic phase was then washed with water (200
mL) and brine (200 mL), dried and evaporated. The crude
product was recrystallized from dichloromethane to give the
title compound (33 g, 76%), mp 112-114 °C. NMR (DMSO-d6)
δ: 2.32 (3H, s), 2.38 (3H, s), 3.22 (2H, t, J ) 8 Hz), 4.16 (2H,
t, J ) 8 Hz), 7.09 (1H, d, J ) 8 Hz), 7.25 (1H, s), 7.30 (1H, dd,
J ) 5, 8 Hz), 7.49 (1H, d, J ) 8 Hz), 8.06 (1H, dd, J ) 2, 8 Hz),
8.16 (1H, s), 8.20 (1H, d, J ) 2 Hz), 8.31 (1H, d, J ) 5
Hz), 8.78 (1H, s). The hydrochloride salt was isolated from
methanol/ether as a white solid, mp 241-246 °C. NMR
(DMSO-d6) δ: 2.35 (3H, s), 2.58 (3H, s), 3.23 (2H, t, J ) 8
Hz), 4.20 (2H, t, J ) 8 Hz), 7.24 (1H, d, J ) 8 Hz), 7.26
(1H, s), 7.83 (1H, dd, J ) 5, 8 Hz), 8.15 (1H, s), 8.18 (1H,
m), 8.21 (1H, d, J ) 8 Hz), 8.32 (1H, d, J ) 2 Hz), 8.51 (1H, d,
J ) 8 Hz), 9.00 (1H, s). Anal. (C22H19N4O2F3‚HCl) C, H, N.
Purity was determined as 99.0% by HPLC, retention time
17.72 min.
Compounds 38, 39, and 41 were similarly prepared:
6-Ch lor o-5-m et h yl-1-[[2-[(2-m et h yl-3-p yr id yl)oxy]-5-
p yr id yl]ca r ba m oyl]in d olin e (41). Phenyl N-[2-[(2-methyl-
3-pyridyl)oxy]-5-pyridyl]carbamate was reacted with 6-chloro-
5-methylindoline,5 as described above for 40, to afford the title
compound as a white crystalline solid (71%), mp 181-183 °C.
NMR (DMSO-d6) δ: 2.25 (3H, s), 2.31 (3H, s), 3.13 (2H, t, J )
8 Hz), 4.13 (2H, t, J ) 8 Hz), 7.10 (1H, d, J ) 8 Hz), 7.17 (1H,
s), 7.30 (1H, dd, J ) 5, 8 Hz), 7.48 (1H, d, J ) 6 Hz), 7.87 (1H,
s), 8.03 (1H, dd, J ) 2, 8 Hz), 8.21 (1H, d, J ) 2 Hz), 8.32 (1H,
d, J ) 5 Hz), 8.74 (1H, s). MS: m/ e 395 (MH+). Anal.
(C21H19N4O2Cl‚1.1HCl) C, H, N.
5-Met h oxy-1-[[2-[(2-m et h yl-3-p yr id yl)oxy]-5-p yr id yl]-
ca r ba m oyl]-6-tr iflu or om eth ylin d olin e (39). Phenyl N-[2-
[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamate was reacted with
5-methoxy-6-trifluoromethylindoline,5 as described above for
40, to afford the title compound as a white crystalline solid
(71%), mp 227-230 °C. NMR (DMSO-d6) δ: 2.32 (3H, s), 3.28
(2H, t, J ) 8 Hz), 3.85 (3H, s), 4.15 (2H, t, J ) 8 Hz), 7.09 (1H,
d, J ) 8 Hz), 7.21 (1H, s), 7.30 (1H, dd, J ) 8, 5 Hz), 7.49 (1H,
d, J ) 8 Hz), 8.04 (1H, dd, J ) 8, 2 Hz), 8.10 (1H, s) 8.20 (1H,
d, J ) 2 Hz), 8.32 (1H, d, J ) 5 Hz), 8.72 (1H, s). MS: m/ e
445 (MH+). Purity was determined as 100.0% by HPLC,
retention time 15.33 min.
5-Meth yl-1-[[2-[(2-m eth yl-3-p yr id yl)oxy]-5-p yr id yl]ca r -
ba m oyl]-6-tr iflu or om eth ylin d olin e (40). Sodium hydride
(11 g of an 80% dispersion in oil, 0.37 mol) was added
portionwise to a solution of 3-hydroxy-2-methylpyridine (40
g, 0.37 mol) in dry DMF (1.3 L) at 0 °C. The resultant mixture
was stirred at 0 °C for 15 min and then room temperature for
3 h before 2-chloro-5-nitropyridine (59 g, 0.37 mol) was added
portionwise. The reaction mixture was stirred for 18 h at room
temperature then water (50 mL) was added dropwise and the
solvent was removed in vacuo. The residue was dissolved in
dichloromethane (400 mL), washed with 10% aqueous sodium
hydroxide (200 mL), and water (200 mL), dried and evaporated
in vacuo to afford 2-[(2-methyl-3-pyridyl)oxy]-5-nitropyridine
(81 g, 95%) as a yellow solid. NMR (CDCl3) δ: 2.22 (3H, s),
6.93 (1H, d, J ) 8 Hz), 7.00-7.13 (1H, m), 7.23 (1H, dd, J )
1, 8 Hz), 8.25 (1H, dd, J ) 1, 5 Hz), 8.32 (1H, dd, J ) 3, 8 Hz),
8.79 (1H, d, J ) 3 Hz). 2-[(2-Methyl-3-pyridyl)oxy]-5-nitropy-
ridine (81 g, 0.35 mol) in ethanol (2 L) was treated with tin-
(II) chloride (232 g, 1.23 mol) in concentrated hydrochloric acid
(500 mL) and heated to 50 °C for 1 h. After cooling to ambient
temperature, the mixture was basified with 40% aqueous
sodium hydroxide solution, extracted into ethyl acetate (300
mL), dried and evaporated in vacuo to afford 5-amino-2-[(2-
methyl-3-pyridyl)oxy]pyridine (43a ) (60 g, 86%) as a brown
solid. NMR (CDCl3) δ: 2.26 (3H, s), 3.40 (2H, br s), 6.56 (1H,
d, J ) 9 Hz), 6.81-6.97 (2H, m), 7.08 (1H, dd, J ) 1, 5 Hz),
7.43 (1H, d, J ) 3 Hz), 8.09 (1H, dd, J ) 1, 4 Hz). Phenyl
5-Meth oxy-1-[[2-[(3-pyr id yl)oxy]-5-pyr idyl]ca r ba m oyl]-
6-tr iflu or om eth ylin d olin e (38). Phenyl N-[2-[(3-pyridyl)-
oxy]-5-pyridyl]carbamate, prepared as described above for
40 but using 5-amino-2-(3-pyridyl)oxypyridine (43b),19 was
treated with 5-methoxy-6-trifluoromethylindoline5 as above to
give the title compound as a white crystalline solid (74%), mp
202-204 °C. NMR (DMSO-d6) δ: 3.28 (2H, t, J ) 8 Hz), 3.86
(3H, s), 4.18 (2H, t, J ) 8 Hz), 7.12 (1H, d, J ) 9 Hz), 7.22
(1H, s), 7.47 (1H, dd, J ) 7, 5 Hz), 7.51 (1H, m, J ) 7
Hz), 8.08 (1H, dd, J ) 8, 2 Hz), 8.10 (1H, s), 8.27 (1H, d, J )
2 Hz), 8.40-8.47 (2H, m), 8.78 (1H, s). MS: m/ e 431 (MH+).
Purity was determined as 100.0% by HPLC, retention time
21.38 min.

1134 J ournal of Medicinal Chemistry, 2000, Vol. 43, No. 6
Bromidge et al.
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