Model studies on a synthetically facile series of N-substituted phenyl-N'-pyridin-3-yl ureas leading to 1-(3-pyridylcarbamoyl) indolines that are potent and selective 5-HT(2C/2B) receptor antagonists

Article abstract of DOI:10.1016/S0968-0896(99)00228-X

A model series of 5-HT(2C) antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N'-pyridin-3-yl ureas were found to have a range of 5-HT(2C) receptor affinities and selectivities over the closely related 5-HT(2A) receptor. Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridyl-carbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT(2C/2B) antagonists. Copyright (C) 1999 Elsevier Science Ltd.

Full text of DOI:10.1016/S0968-0896(99)00228-X

Bioorganic & Medicinal Chemistry 7 (1999) 2767±2773
Model Studies on a Synthetically Facile Series of N-Substituted
Phenyl-N0-pyridin-3-yl Ureas Leading to 1-(3-Pyridylcarbamoyl)
indolines that are Potent and Selective 5-HT2C/2B
Receptor Antagonists
Steven M. Bromidge,* Steven Dabbs, David T. Davies, Susannah Davies,
D. Malcolm Duckworth, Ian T. Forbes, Angela Gadre, Peter Ham,
Graham E. Jones, Frank D. King, Damian V. Saunders, Kevin M. Thewlis,
Deepa Vyas, 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, UK
Received 19 August 1998; accepted 8 July 1999
AbstractÐA model series of 5-HT2C antagonists have been prepared by rapid parallel synthesis. These N-substituted phenyl-N0-
pyridin-3-yl ureas were found to have a range of 5-HT2C receptor anities and selectivities over the closely related 5-HT2A receptor.
Extrapolation of simple SAR, derived from this set of compounds, to the more active but synthetically more complex 1-(3-pyridyl-
carbamoyl)indoline series allowed us to target optimal substitution patterns and identify potent and selective 5-HT2C/2B antago-
nists. # 1999 Elsevier Science Ltd. All rights reserved.
Introduction
Some years ago we reported the indole urea (1A, SB-
200646) as the ®rst selective 5-HT2C/2B antagonist.8 This
compound had modest 5-HT2C anity (pKi 7) with 50-
fold selectivity over the closely related 5-HT2A receptor
and blocked the hypolocomotion in rats produced by
mCPP, thus demonstrating in vivo activity in a 5-HT2C
centrally mediated functional model. The introduction
of conformational restriction between the indole ring
and the urea linker produced the indolinyl urea (1B, SB-
206553), which had an order of magnitude increased
anity at the 5-HT2C receptor in addition to improved
selectivity over 5-HT2A receptors and 4-fold increased
potency in vivo.9,10 Unfortunately, although (1B)
exhibited signi®cant anxiolytic activity in several di€er-
ent animal models of anxiety, the 1-methylindole moiety
was subject to metabolic demethylation to a non selec-
tive compound and so was not progressed.11 One of the
strategies we pursued to circumvent this metabolic lia-
bility was to investigate the replacement of the tetra-
hydropyrrolo-N-methylindole of (1B) with a variety of
substituted indolines. However, due to the synthetic
complexity of substituted indolines, we decided to initi-
ally undertake this work in the more accessible phenyl
The 5-HT2 receptor family currently consists of 5-HT2A
,
5-HT2B and 5-HT2C subtypes, which have been grouped
together on the basis of primary structure, secondary
messenger system and pharmacological pro®le.1,2 Our
interest in the 5-HT2C receptor stems principally from
the ®nding that the moderately selective 5-HT2C/2B
agonist meta-chlorophenylpiperazine (mCPP) causes
behavioural indications of anxiety both in animal mod-
els and humans, implying that selective 5-HT2C/2B
antagonists might be useful anxiolytic agents without
causing the side e€ects associated with less selective
therapies.3±5 Recent evidence also suggests that 5-HT2C
receptor ligands may have antidepressant properties and
be implicated in the pathophysiology of migraine.6,7
Key words: 5-HT2C/2B antagonists; antidepressants; anxiolytics;
receptors.
* Corresponding author. Tel.: +44-1279-627-684; fax: +44-1279-
627-658; e-mail: steve_bromidge-1@sbphrd.com
0968-0896/99/$ - see front matter # 1999 Elsevier Science Ltd. All rights reserved.
PII: S0968-0896(99)00228-X

2768
S. M. Bromidge et al. / Bioorg. Med. Chem. 7 (1999) 2767±2773
HT2A and 5-HT2C receptors expressed in HEK 293 cells
using [3H]-ketanserin and [3H]-mesulergine resepectively
as radioligands,10 and results are shown in Tables 1±5.
Considering the biaryl ureas (1A±86A), encouragingly,
some of these compounds demonstrated comparable
and even improved 5-HT2C anity relative to (1A) with
a range of selectivities over 5-HT2A activity (Tables 1±
5). For the mono-substituted compounds (Table 1),
whereas introduction of 2-substituents (3±4A) gave no
increase in 5-HT2C anity relative to the unsubstituted
analogue (2A), substitution at the 3- or 4-positions (5±
26A) was generally bene®cial. Small lipophilic groups
were favoured over polar groups and several analogues
(5, 7, 11, 17, 20A) were identi®ed with anities com-
parable to that of (1A). Whereas electron withdrawing
lipophilic 3-substituents (5, 7A) were marginally
favoured over electron donating lipophilic groups, the
reverse was the case for 4-substitution where the thio-
methylphenyl urea (20A) demonstrated the highest a-
nity. This compound together with the 4-phenyl
analogue (17A) also demonstrated encouraging selectiv-
ity over 5-HT2A activity. As a consequence of the rela-
tively free rotation about the N-aryl bond of the phenyl
urea series (A) the 3- and 5-positions are equivalent.
Thus, the 3-chlorophenyl urea (5A) could be considered
to correspond to both the 6- and 4-chloro-1-(3-pyr-
idylcarbamoyl) indolines (5B and 6B). However, in all
cases where a comparison is available, the 6-substituted
indolines had higher 5-HT2C anity than the corre-
urea series (A) using a rapid parallel synthesis approach.
Our aim was to identify favourable substituents, so that
we could then prepare the equivalently substituted
indolines (B).
Chemistry
The required biaryl ureas (1A±86A) were rapidly pre-
pared (Scheme 1) by parallel reaction of a diverse range
of anilines with 3-pyridylisocyanate, generated in situ
from the corresponding azide.8 Similarly, the 1-(3-pyr-
idylcarbamoyl) indolines (B) were prepared by reacting
the appropriate indolines, which were themselves pre-
pared by a variety of routes based on literature methods,
with 3-pyridylisocyanate.15
Results and Discussion
The anities of the compounds were measured by means
of radioligand binding studies conducted with cloned 5-
Scheme 1. Reagents: (a) toulene, re¯ux, 0.5 h; (b) dichloromethane, room temperature, 16 h (50±90%).

S. M. Bromidge et al. / Bioorg. Med. Chem. 7 (1999) 2767±2773
2769
Table 1. The 5-HT2C receptor binding anities13,14 and selectivities over 5-HT2A of mono-substituted phenyl (A) and indolinyl (B) ureas
R2
R3
R4
R5
Cpd.
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
Cpd.
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
N-Me-pyrrolo-
1A
2A
3A
4A
5A
7.0
<5.3
<5.3
IA
50
Ð
Ð
Ð
50
1B
2B
7.9
5.9
160
H
Cl
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
7.0
5B
6B
7B
7.3
6.3
7.3
13
9
12
H
H
CF3
Me
Ph
OMe
SMe
SO2Me
NO2
H
H
H
H
H
H
H
H
Cl
7A
8A
9A
6.9
5.7
6.4
5.8
6.7
5.7
5.9
6.4
6.1
6.1
7.0
5.6
5.6
7.2
6.5
5.3
6.5
<5
5.2
<6
25
Ð
6
10A
11A
12A
13A
14A
15A
16A
17A
18A
19A
20A
21A
22A
23A
24A
25A
26A
Ð
25
Ð
Ð
Ð
Ð
Ð
60
Ð
Ð
75
20
Ð
40
Ð
Ð
Ð
14B
15B
16B
17B
7.1
6.8
7.1
6.9
30
30
25
45
H
H
Me
iPr
H
Ph
H
H
H
H
H
H
H
H
OMe
OBz
SMe
NMe2
NAcMe
COOEt
COOH
OH
NO2
20B
21B
7.4
6.5
110
20
H
26B
6.5
>20
Table 2. The 5-HT2C receptor binding anities13,14 and selectivities over 5-HT2A of disubstituted phenyl (A) and indolinyl (B) ureas
R2
R3
R4
R5
Cpd.
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
Cpd.
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
CN
Cl
OMe
Me
OMe
OMe
H
Cl
Cl
H
H
H
H
Cl
H
H
CF3
NO2
H
H
H
H
27A
28A
29A
30A
31A
32A
33A
<5
<6.0
6.6
6.5
5.9
Ð
Ð
3
8
Ð
7
28B
6.1
7
H
OMe
Cl
Cl
H
H
6.3
5.7
Ð
sponding 4-substituted isomer and apart from (6B) only
the former have been included in this discussion.
low anity. In contrast, 3,4-disubstitution (Tables 3
and 4) conveyed an additive e€ect on 5-HT2C anity
resulting in compounds with improved anity relative
to (1A). This substitution pattern corresponds to the
position of the fused pyrrolo-functionality of (1A) and
was favoured over mono-substitution. Having estab-
lished early on in this work that a 3-halogen substituent
was optimal, a series of 3-chloro analogues containing a
wide range of 4-substituents was prepared (Table 3) in
order to more fully investigate SAR at this position. As
The results of disubstitution are shown in Tables 2±4. In
the case of 2,3-, 2,4- and 2,5-disubstitution (Table 2) com-
pounds had low to moderate 5-HT2C anity con®rming
the deleterious e€ect of an ortho substituent. This may
be due to a steric e€ect resulting in an unfavourable out
of plane conformation of the urea linker relative to the
aryl ring. The 3,5-dichlorophenyl urea (33A) also had

2770
S. M. Bromidge et al. / Bioorg. Med. Chem. 7 (1999) 2767±2773
Table 3. The 5-HT2C receptor binding anities13,14 and selectivities over 5-HT2A of 3-chloro-4-substituted phenyl (A) and 6-chloro-5-substituted
indoline (B) ureas
R4
p of R4
Cpd.
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
Cpd.
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
H
0
34A
35A
36A
37A
38A
39A
40A
41A
42A
43A
44A
45A
46A
47A
48A
49A
50A
51A
52A
53A
54A
55A
56A
57A
58A
59A
60A
61A
<5.3
5.0
5.0
7
Ð
Ð
Ð
20
12
Ð
12
Ð
25
3
80
200
40
Ð
30
20
40
25
75
30
20
10
50
120
200
7.0
80
50
34B
5.9
SO2Me
SOMe
SO2F
SO2NMe2
CONH2
CHO
CH2OH
COMe
COPh
COOH
COOMe
COOEt
CN
1.63
1.58
0.05
Ð
1.49
0.65
1.03
0.55
Ð
0.32
0.01
0.51
0.57
0.02
0.18
0.56
1.02
1.53
1.55
1.98
Ð
6.5
5.1
6.4
5.5
6.6
6.1
7.1
7.4
7.1
5.9
6.7
6.4
7.8
7.4
7.4
7.4
7.2
6.6
7.3
7.5
7.8
7.3
7.1
7.5
45B
7.5
190
OMe
NMe2
Me
50B
51B
52B
53B
54B
55B
56B
57B
58B
59B
8.2
8.3
7.7
7.7
7.7
6.9
8.2
8.2
8.5
8.0
25
75
110
60
30
30
80
200
370
510
Et
iPr
nPr
tBu
Ph
CHˆCH2
0.82
0.61
1.07
Ð
Ð
0.71
SMe
SEt
SiPr
SCF3
Cl
61B
8.1
30
Table 4. The 5-HT2C receptor binding anities13,14 and selectivities over 5-HT2A of 3-disubstituted phenyl (A) and 5,6-disubstituted indolinyl (B)
ureas
R3
R4
Cpd.
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
Cpd.
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
F
Br
Br
Br
Me
Me
SMe
SEt
Me
OEt
Cl
CH2OEt
NO2
Me
COOMe
CH2OMe
SO2NMe2
Me
CO2Ph
COMe
COOH
COOMe
CH2OMe
62A
63A
64A
65A
66A
67A
68A
69A
70A
71A
72A
73A
74A
75A
76A
77A
78A
79A
80A
6.7
7.8
7.9
8.0
8.4
7.6
7.8
6.8
6.8
6.8
5.7
5.7
5.4
5.8
5.6
7.1
5.5
7.2
<5.2
Ð
70
210
160
25
250
25
40
Ð
40
3
8
5
7
3
70
Ð
90
Ð
62B
63B
64B
65B
66B
67B
68B
7.3
8.4
8.7
8.7
8.5
8.2
8.2
25
20
215
1000
25
I
CF3
CF3
CF3
CF3
Me
OMe
COOEt
COMe
CH2OMe
OH
275
25
OH
OH
OH
CONHEt

S. M. Bromidge et al. / Bioorg. Med. Chem. 7 (1999) 2767±2773
2771
for the 4-mono-substituted ureas small lipophilic sub-
stituents (e.g. 50, 57, 58, 61A) were favoured with
polar groups poorly tolerated (e.g. 35, 36, 39A). Con-
sidering that the simple aryl ureas have relatively free
rotation about the N-aryl bond, and hence the mea-
sured pKi is probably a composite of at least two pos-
anities and selectivities greater than (1B). Especially
outstanding was the 6-bromo-5-thioethyl indoline (65B)
which had a 5-HT2C binding anity of 2 nM and a
selectivity against the 5-HT2A receptor of 1000-fold. We
have proposed15 that the thioalkyl substituent is con-
ferring the desired selectivity by occupying a region of
space which is ``allowed'' for the 5-HT2C receptor but
``disallowed'' for the 5-HT2A receptor due to steric dif-
ferences between the structures of the two binding sites.
In addition, several compounds (58B, 64B and 65B)
were tested against a range of other monoamine recep-
tors, including serotinergic and dopaminergic subtypes,
and found to be greater than 100-fold selective. The
synthesis, biological pro®le, QSAR relationships and
molecular modelling of these inolinyl ureas are the sub-
jects of a separate publication.15
sible binding modes, a good correlation was observed
13,14
between the lipophilicity ꢀꢀ†
of small 4-substituents
and 5-HT2C binding anity (Fig. 1). Most of these
compounds had improved 5-HT2C anity relative to
(1A) and several such as the 3-chloro-4-thioalkylphenyl
ureas (57A and 58A) were identi®ed with good 5-HT2C
anities and >100-fold selectivity over 5-HT2A recep-
tor anity.
Table 4 shows the activity of other 3,4-disubstituted
phenyl ureas. As for 3-monosubstitution small lipo-
philic electron withdrawing groups are favoured with
bromo (63±65A), iodo (66A) and tri¯uoromethyl (67±
68A) giving compounds with good 5-HT2C anity when
in combination with small lipophillic 4-substituents. The
3-bromo-4-thioalkyl (64A and 65A) and the 3-tri-
¯uoromethyl-5-ethoxy (67A) phenyl ureas demonstrated
good 5-HT2C anity and selectivity. The trisubstituted
analogues (Table 5) demonstrated moderate 5-HT2C
anity and low selectivity.
Having rapidly delineated SAR in our model series (A),
favourable substitution patterns were then incorporated
into the indolinyl series (B) together with a small num-
ber of less favourable combinations in order to con®rm
a correlation between the two series. As hoped, the
indolines generally demonstrated improved 5-HT2C
anity with comparable or improved selectivities over
5-HT2A receptors relative to the model phenyl urea ser-
ies (A) (Tables 1±4). The validity of extrapolating from
the less active phenyl urea series was con®rmed by a
plot of the 5-HT2C anities of corresponding com-
pounds from the two series (Fig. 2), which revealed an
excellent correlation (r=0.927). In all cases, apart from
(17) (R4=Ph), the indolines were more potent than the
corresponding phenyl ureas with an average increase in
the 5-HT2C pKi of 0.5. Several 5,6-disubstituted indo-
lines (57±59B, 64±65B and 67B) were identi®ed with
Figure 1. Plot of the 5-HT2C receptor binding anities of 3-chloro-4-
substituted phenyl ureas against the lipophilicity (p) of the 4-sub-
stituent (Table 3).
Table 5. The 5-HT2C receptor binding anities13,14 and 5-HT2A
selectivities of trisubstituted phenyl ureas (A)
Cpd.
R2
R3
R4
R5
5-HT2C
(pKi)
Selectivity
5-HT2C/2A
81A
82A
83A
84A
85A
86A
Cl
Me
Me
Me
H
Cl
H
H
H
Cl
Cl
Cl
H
Cl
Me
Cl
Cl
Cl
5.5
7.7
6.6
7.7
5.5
5.6
SMe
NO2
SEt
Me
15
10
15
Figure 2. Plot of the corresponding 5-HT2C binding anities of sub-
stituted phenyl (A) and indolinyl (B) ureas.
H
OH

2772
S. M. Bromidge et al. / Bioorg. Med. Chem. 7 (1999) 2767±2773
Summary
determined using a Fisons VG 302 single quadrupole mass
spectrometer. Solvents and reagents were of commercial
grade and used without puri®cation. Chromatography
where required was performed on Merck Art. 7734 silica
gel or Fluka silica gel 60 (60739).
In conclusion we have used a synthetically accessible
model series of phenyl ureas (A) to generate a large data
set of 5-HT2C binding anities and selectivities and
rapidly elucidate SAR. Extrapolation of these results to
the more active but synthetically complex 1-(3-pyr-
idylcarbamoyl) indoline series (B) allowed us to target
optimal substitution patterns and identify potent and
selective 5-HT2C/2B antagonists such as (57±59B, 64±
65B and 67B).
The compounds were prepared from commercially
available or known anilines and indolines12 according to
the following general procedure. The preparations of
(50A) and (26B) are detailed as representative examples.
NMR spectral data and melting points of representative
phenyl ureas are illustrated in Table 6.
N-(3-Chloro-4-methylphenyl)-N0-(3-pyridyl) urea (50A).
Nicotinoyl azide (0.40 g, 2.7 mmol) [CAUTION! Heat-
ing 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±80ꢁC, and
copious volumes of nitrogen are rapidly evolved.
Appropriate precautions for the storage and utilisation
of this reagent are strongly advised] was stirred at
re¯ux under nitrogen atmosphere in dry toluene
(10 mL) for 1 h, with gas evolution. The solution was
cooled to ambient temperature, and 3-chloro-4-methyl-
aniline (0.30 mL, 2.4 mmol) was added. The resultant
suspension was stirred for 1 h, when the solid was ®l-
tered o€, washed with 1:1 toluene/dichloromethane, and
dried in vacuo at 70ꢁC. This gave the title compound
(0.64 g, 85%) as a white solid. The hydrochloride salt
Experimental
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 mM (100Â3 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; ¯ow rate 0.7 mL/
min. The elution gradient was 0% B held for 0.5 min, then
linearly increased to 75% B over 24.5min, then held for
5 min. The UV detection wavelength was 218 nm. All ®nal
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
Table 6. 1H NMR spectral data and melting points of some representative phenyl ureas (A)
Cmpd.
1H NMR (d6-DMSO d: ppm J=Hz)
mp (ꢁC)
180±184
7A
7.3 (2H, m), 7.55 (2H, m), 7.95 (1H, d, J=8), 8.0 (1H, s), 8.2 (1H, d, J=4), 8.6 (1H, d, J=2),
9.0 (1H, s), 9.2 (1H, s)
8A (HCl)
14A
2.3 (3H, s), 6.85 (1H, d, J=7), 7.2 (1H, t, J=8), 7.3 (2H, m), 7.9 (1H, dd, J=8.5), 8.3 (1H, m),
8.5 (1H, d, J=5), 9.1 (1H, d, J=2), 9.5 (1H, s), 10.35 (1H, s)
7.3 (3H, m), 7.5 (2H, d, J=9), 7.95 (1H, m), 8.2 (1H, m), 8.6 (1H, d, J=2),
8.9 (1H, s), 9.0 (1H, s)
182±183
207±209
185±187
206±210
5A
7.0 (1H, m), 7.3 (3H, m), 7.7 (1H, s), 7.95 (1H, m), 8.2 (1H, m), 8.6 (1H, d, J=2),
8.95 (1H, s), 9.05 (1H, s)
7.25±7.42 (2H, m), 7.50 (1H, d, J=7), 7.83±7.90 (2H, m), 8.23 (1H, d, J=3),
8.62 (1H, d, J=1), 8.98 (1H, s), 9.23 (1H, s)
61A
62A
23A
7.02±7.48 (4H, m), 7.94 (1H, m), 8.19 (1H, m), 8.59 (1H, m), 8.87 (1H, s), 8.92 (1H, s)
1.32 (3H, t, J=8), 4.30 (2H, q, J=8), 7.34 (1H, dd, J=7.4), 7.60 (2H, m), 7.86±8.02 (3H, m),
8.21 (1H, m), 8.63 (1H, m), 8.96 (1H, s), 9.24 (1H, s)
190±191
156±160
45A
63A
47A
70A
68A
43A
29A
51A
53A
54A
3.82 (3H, s), 7.30 (2H, m), 7.78±8.00 (3H, m), 8.25 (1H, m), 8.64 (1H, m), 9.08 (1H, s),
9.39 (1H, s)
170±171
168±171
262±264
214±216
196±199
170±175
210
2.28 (3H, s), 7.21±7.39 (3H, m), 7.83±8.00 (2H, m), 8.20 (1H, m), 8.61 (1H, m),
8.89 (2H, m)
7.28±7.56 (2H, m), 7.80±8.06 (3H, m), 8.26 (1H, m), 8.64 (1H, s), 9.17 (1H, s),
9.54 (1H, s)
7.37 (1H, dd, J=7.4), 7.87 (1H, m, J=7), 7.97 (1H, m, J=7), 8.14±8.29 (3H, m),
8.67 (1H, m), 9.22 (1H, s), 9.81 (1H, s)
7.33 (1H, dd, J=7.4), 7.59±7.71 (2H, m), 7.95 (1H, m), 8.10 (1H, m), 8.22 (1H, m),
8.63 (1H, m), 9.04 (1H, s), 9.32 (1H, s)
7.41 (2H, m), 7.76±7.88 (2H, m), 7.99 (1H, d, J=7), 8.25 (1H, br.s), 8.68 (1H, br.s),
9.13 (1H, s), 9.37 (1H, s)
4.00 (3H, s), 7.16±7.45 (3H, m), 7.98 (1H, m, J=7 Hz), 8.23 (1H, m), 8.48±874 (3H, m),
9.60 (1H, s)
1.16 (3H, t, J=5), 2.64 (2H, q, J=5), 7.20±7.40 (3H, m), 7.67 (1H, s), 7.94 (1H, m),
8.20 (1H, d, J=2), 8.60 (1H, d, J=1), 8.90 (2H, m)
0.91 (3H, t, J=5), 1.56 (2H, q, J=5), 2.60 (2H, t, J=5), 7.20±7.35 (3H, m),
7.68 (1H, s), 7.94 (1H, m), 8.19 (1H, d, J=2), 8.59 (1H, d, J=1), 8.92 (2H, m)
1.42 (9H, s), 7.20±7.40 (3H, m), 7.66 (1H, d, J=2), 7.93 (1H, m), 8.19 (1H, d, J=5),
8.60 (1H, d, J=2), 8.90 (2H, m)
193±196
184±186
190±193

S. M. Bromidge et al. / Bioorg. Med. Chem. 7 (1999) 2767±2773
2773
was prepared as a white solid, mp 214.5±216ꢁC. NMR
(d6-DMSO) d: 2.25 (3H, s), 7.25 (2H, m), 7.68 (1H, s),
7.92 (1H, dd, J=8, 5 Hz), 8.33 (1H, d, J=8 Hz), 8.49
(1H, d), 9.07 (1H, s), 9.79 (1H, s), 10.37 (1H, s). C,H,N
anal. Found: C, 51.4%; H, 4.5%; N, 14.5%.
2. Baxter, G.; Kennett, G. A.; Blaney, F.; Blackburn, T. P.
Trends Pharmacol. Sci. 1995, 16, 105.
3. Kahn, R. S.; Wetzler, S. Biol. Psychiat. 1991, 30, 1139.
4. Kennett, G. A. Curr. Opin. Invest. Drugs 1993, 2, 317 and
references therein.
5. Kennett, G. A.; Pittaway, K.; Blackburn, T. P. Psycho-
pharmacology 1994, 114, 90.
.
.
C13H12ClN3O HCl 0.25H2O requires C, 51.6%; H,
4.5%; N, 13.9%
6. Moreau, J. L.; Bos, M.; Jenck, F.; Martin, J. R.; Mortas, P.;
Wichmann, J. Eur. Neuropsychopharmacology 1996, 6, 169.
7. Bonhaus, D. W.; Weinhardt, K. K.; Taylor, M.; DeSouza,
A.; McNeeley, P. M.; Szczepanski, K.; Fontana, D. J.; Trinh,
J.; Rocha, C. L.; Dawson, M. W.; Cao, Z.; Wong, L.; Eglen,
R. M. CNS Drug Reviews 1997, 3, 278.
8. Forbes, I. T.; Kennett, G. A.; Gadre, A.; Ham, P.; Hay-
ward, C. J.; Martin, R. T.; Thompson, M.; Wood, M. D.;
Baxter, G. S.; Glen, A.; Murphy, O. E.; Stewart, B. A.;
Blackburn, T. P. J. Med. Chem. 1993, 36, 1104.
9. Forbes, I. T.; Dabbs, S.; Duckworth, D. M.; Ham, P.;
Jones, G. E.; King, F. D.; Saunders, D. V.; Blaney, F. E.;
Naylor, C. B.; Baxter, G. S.; Blackburn, T. P.; Kennett, G. A.;
Wood, M. D. J. Med. Chem. 1996, 39, 4966.
10. Kennett, G. A.; Wood, M. D.; Bright, F.; Cilia, J.; Piper,
D. C.; Gager, T.; Thomas, D.; Baxter, G. S.; Forbes, I. T.;
Ham, P.; Blackburn, T. P. Br. J. Pharmacol. 1996, 117, 427.
11. Unpublished results; Department of Drug Metabolism and
Pharmacokinetics, SmithKline Beecham.
5-Nitro-1-(3-pyridylcarbamoyl)indoline hydrochloride (26B).
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±
80ꢁC, and copious volumes of nitrogen are rapidly
evolved. Appropriate precautions for the storage and
utilisation of this reagent are strongly advised] in tolu-
ene (20 mL) was heated at re¯ux for 0.5 h to form 3-
pyridylisocyanate, then cooled to room temperature. A
solution of 5-nitroindoline (0.38 g, 2.3 mmol) in
dichloromethane (20 mL) was then added and the mix-
ture was stirred overnight at room temperature. The
resulting precipitate was treated with excess HCl in
ether to give the title compound (26B) (0.64 g, 76%) as a
light yellow powder, mp 244±247ꢁC (dec.). NMR (d6-
DMSO) d: 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.
12. All values represent the mean of at least two determina-
tions, with each determination lying within 0.2 log unit of the
mean. 5-HT2C binding anity: human cloned receptors; HEK
293 cells; [3H]-ketanserin. 5-HT2A binding anity: human
cloned receptors; HEK 293 cells; [3H]-mesulergine.
13. Hansch, C.; Leo, A.J. In Substituent Constants for Corre-
lation Analysis; Wiley: New York, 1979.
14. Abraham, M.H. Chem. Soc. Rev. 1993, 73.
15. Bromidge, S. M.; Dabbs, S.; Davies, D. T.; Duckworth, D.
M.; Forbes, I. T.; Ham, P.; Jones, G. E.; King, F. D.; Saun-
ders, D. V.; Starr, S.; Thewlis, K. M.; Wyman, P. A.; Blaney,
F. E.; Naylor, C. B.; Bailey, F.; Blackburn, T. P.; Holland, V.;
Kennett, G. A.; Riley, G. J.; Wood, M. D. J. Med. Chem.
1998, 41, 1598.
References and Notes
1. Hoyer, D.; Clarke, D. E.; Fozard, J. R.; Hartig, P. R.;
Martin, G. R.; Mylecharane, E. J.; Saxena, P. R.; Humphrey,
P. P. A. Pharmacological Reviews 1994, 46, 157.