1-[2-[(Heteroaryloxy)heteroaryl]carbamoyl]indolines: Novel and selective 5-HT(2C) receptor inverse agonists with potential as antidepressant/anxiolytic agents

Article abstract of DOI:10.1016/S0960-894X(00)00364-4

Bisaryl ethers have been identified with excellent 5-HT(2C) affinity and selectivity over both 5-HT(2A) and 5-HT(2B) receptors. Compounds such as 11, 27 and 38 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT(2C) function and their potential as novel non-sedating anxiolytic and antidepressants is under investigation. (C) 2000 Elsevier Science Ltd. All rights reserved.

Full text of DOI:10.1016/S0960-894X(00)00364-4

Bioorganic & Medicinal Chemistry Letters 10 (2000) 1863±1866
1-[2-[(Heteroaryloxy)heteroaryl]carbamoyl]indolines: Novel and
Selective 5-HT2C Receptor Inverse Agonists with Potential as
Antidepressant/Anxiolytic Agents
Steven M. Bromidge,* Steven Dabbs, Susannah Davies, D. Malcolm Duckworth,
Ian T. Forbes, Graham E. Jones, Jerome Jones, Frank D. King, Damian V. Saunders,
Thomas P. Blackburn, Vicky Holland, Guy A. Kennett, Sean Lightowler,
Derek N. Middlemiss, Graham J. Riley, Brenda Trail and Martyn D. Wood
SmithKline Beecham Pharmaceuticals, Discovery Research, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK
Received 7 April 2000; revised 5 June 2000; accepted 21 June 2000
AbstractÐBisaryl ethers have been identi®ed with excellent 5-HT2C anity and selectivity over both 5-HT2A and 5-HT2B receptors.
Compounds such as 11, 27 and 38 have potent oral activity in a centrally mediated pharmacodynamic model of 5-HT2C function
and their potential as novel non-sedating anxiolytic and antidepressants is under investigation. # 2000 Elsevier Science Ltd. All
rights reserved.
The 5-HT2 receptor family consists of 5-HT2A, 5-HT2B
and 5-HT2C subtypes which were grouped together on
the basis of their primary structure, secondary messenger
system and pharmacological pro®le.1 The last few years
have seen extensive interest in the development of selec-
tive 5-HT2C ligands as potential treatments for a range
of CNS disorders, in particular anxiety and depres-
sion.2,3 We have recently disclosed a number of bispyr-
idyl ethers, such as 1 (SB-242084)4 and 2 (SB-243213)
which are potent 5-HT2C receptor inverse agonists with
selectivity over both the 5-HT2A and 5-HT2B receptors
and potent in vivo activity in a number of animal mod-
els of anxiety.3,5 Compound 2 is currently in phase 1
clinical trials for the treatment of depression and anxi-
ety.3 We now describe a detailed SAR around these
compounds which has led to the identi®cation of further
high anity and selective 5-HT2C receptor inverse agonists
with potent oral activity in a number of animal models.
Chemistry
The ®nal compounds were prepared according to
Schemes 1±3. 1±37 were obtained by treating the anion
of the appropriately substituted 3-hydroxypyridines or
4-methyl-5-hydroxypyrimidine6 (in the case of 33) with
appropriately substituted 2-chloro-5-nitropyridines to
a€ord the nitrobisaryl ethers in generally excellent yield
(Scheme 1). Reduction to the corresponding amines and
coupling with the appropriate substituted indolines,7 via
the phenyl carbamate, a€orded the ®nal compounds.4
The 3-hydroxypyridines and 2-chloro-5-nitropyridines
were all commercially available or known in the litera-
ture. The pyrimidine 40 was similarly prepared starting
from 2-chloro-5-nitropyrimidine8 and 3-hydroxy-2-
methylpyridine. The pyridazines 38 and 39 were pre-
pared by an analogous route (Scheme 2) by treating 3-
amino-6-chloropyridazine with 3-hydroxy-2-methylpyr-
idine and aqueous sodium hydroxide at high tempera-
ture to a€ord the amino bisarylether which was then
coupled with the appropriate indoline as above. The
pyrazine 41 was prepared by reacting 5-chloropyr-
azinecarboxylic acid methyl ester9 with 3-hydroxy-2-
methylpyridine under basic conditions to give the
bisaryl ether (Scheme 3). The ester was then converted
to the azide which was heated to generate the isocyanate
and reacted in situ with 5-methyl-6-tri¯uoromethyl-
indoline to a€ord 41.
*Corresponding author. Tel.: +44-1279-627684; fax: +44-1279-
622550; e-mail: steve_bromidge-1@sbphrd.com
0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(00)00364-4

1864
S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1863±1866
Scheme 1. Reagents and conditions: (i) NaH, DMF, 0 ꢁC±rt, 18 h (25±95%); (ii) SnCl2, EtOH/concd HCl, 50 ꢁC, 1 h (80±100%); (iii) PhOCOCl/
NEt3,CH2Cl2, 20 ꢁC, 1 h; (iv) NEt3/DMF, 100 ꢁC, 1 h (35±85%).
Scheme 2. Reagents and conditions: (i) 3-hydroxy-2-methylpyridine, NaOH, H2O, 175 ꢁC, bomb, 24 h (14%); (ii) PhOCOCl/NEt3, CH2Cl2, 20 ꢁC,
1 h; (iii) 5-methyl-6-R6-indoline, NEt3/DMF, 100 ꢁC, 1 h (65%).
ꢁ
.
Scheme 3. Reagents and conditions: (i) 3-hydroxy-2-methylpyridine/NaH, DMF, 0 C±rt, 1 h (94%); (ii) NH2NH2 H2O, MeOH, re¯ux, 4 h (76%);
(iii) NaNO2, aqueous HCl, 0 ꢁC, 0.5 h (74%); (iv) 5-methyl-6-tri¯uoromethylindoline, toluene, re¯ux, 1 h (63%).
tunately were inactive in vivo. In contrast some of the
5,6-disubstituted compounds such as 1, 2 and 23
Optimization of indoline substitution (Table 1)
In marked contrast to a previous series of 1-(3-pyr-
idylcarbamoyl)indolines,4 where 5,6-disubstitution of
the indoline was crucial for selectivity and 4-substitution
detrimental, the bispyridyl ethers 1±26 retained selectiv-
ity over both 5-HT2A and 5-HT2B with a variety of
indoline substitution. Surprisingly, even the unsub-
stituted indoline 3, despite having a pKi of only 7.0 at
the 5-HT2C receptor retained ꢀ100-fold selectivity over
5-HT2A anity. The 4-CF3 analogue 6 demonstrated a
similar pro®le to 3, whereas the 4-halo analogues 4 and
5 showed increased anity and selectivity. The 5-
monosubstituted indolines 7±11 demonstrated even
greater 5-HT2C anity and the most impressive selec-
tivities. The 6-monosubstituted indolines 12 and 13 had
similar 5-HT2C anity but somewhat reduced selectivity
over 5-HT2A. Despite excellent in vitro pro®les, from
the monosubstituted analogues only 11 showed sig-
ni®cant in vivo activity in the rat hypolocomotion
model (ID50 of 2.1 mg/kg po). In this centrally mediated
pharmacodynamic model of 5-HT2C function, the abil-
ity of compounds to block the hypolocomotion in rats
produced by a standard dose of the moderately selective
5-HT2C agonist m-chlorophenylpiperazine (mCPP) was
measured.5 Disubstitution was found to have a bene-
®cial additive e€ect on 5-HT2C anity with both 4,5-
and 5,6-disubstitution a€ording excellent anity and
selectivity (1, 2 and 14±24). The 4,5-disubstituted
analogues 14 and 15 had greatest selectivity but unfor-
showed potent oral activity in the hypolocomotion
model. The trisubstituted analogues 25 and 26 also
demonstrated nanomolar 5-HT2C anity and modest
oral activity but reduced selectivity. From this study 1 and
2 emerged as the compounds with best overall pro®les
combined with favourable metabolic stability. Therefore,
either 5-chloro- or 5-tri¯uoro-6-methylindoline was
incorporated into subsequent compounds prepared to
further investigate modi®cations to other parts of the
molecule.
Optimization of terminal aryl ring (Table 2)
We have previously reported that the 2-methyl group of
the terminal pyridyl ring is important for selectivity.4
Therefore, further modi®cations series were restricted to
the 2- and 4-positions. Increasing the size of the 2-subs-
tituent from methyl to ethyl gave 27 with a similar
pro®le to 1 but reduced selectivity over 5-HT2B. The
nPr analogue 28 showed a similar binding pro®le but
i
poor in vivo activity. The Pr analogue 29 su€ered a
dramatic fall in 5-HT2C anity. The 2-Cl analogue 30
exhibited twofold reduced 5-HT2A/B selectivity and oral
activity relative to 1. The 4-methyl 31 and 4-chloro 32
analogues maintained excellent 5-HT2C anity but
lacked selectivity as did the pyrimidine 33. These ®nd-
ings con®rm the 2-methyl-3-pyridyl ring as optimal in
this series.

S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1863±1866
1865
Table 1. The 5-HT2A/B/C receptor binding anities,a selectivities over 5-HT2A and 5-HT2B and in vivo activitye of substituted 1-[2-[[(2-methyl-3-
pyridyl)oxy]-5-pyridyl]carbamoyl]indolines 1±26
e
Compound
R4
R5
R6
pKi
pKi (selectivity)
ID50
(mg/kg po)
b
c
d
5-HT2C
5-HT2A
5-HT2B
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
1
H
Cl
Br
CF3
H
H
H
H
H
H
H
Br
Cl
H
H
H
H
H
H
H
H
H
F
Cl
Br
I
CF3
H
H
Me
Cl
H
H
H
H
H
H
H
H
H
Cl
CF3
H
H
Cl
Cl
CF3
F
7.0
7.8
7.8
6.7
7.4
8.2
8.5
8.5
8.4
8.4
8.3
8.8
8.5
8.2
8.7
8.9
8.8
9.0
9.1
9.0
8.6
8.9
9.2
9.4
9.0
8.9
<5.0 (>100)
<5.0 (>630)
<5.2 (>400)
<5.0 (>50)
<5.0 (>250)
<5.0 (>1600)
<5.4 (>1300)
5.8 (500)
5.6 (630)
6.5 (80)
6.8 (30)
<6.0 (>630)
5.5 (1000)
6.3 (80)
6.6 (130)
6.9 (100)
6.1 (500)
6.8 (160)
6.8 (200)
6.8 (160)
6.3 (200)
6.8 (130)
5.7 (20)
5.6 (160)
5.7 (>130)
<5.0 (>50)
5.3 (130)
5.7 (320)
6.2 (200)
6.5 (100)
6.2 (160)
6.1 (200)
6.4 (80)
6.6 (160)
6.3 (160)
6.2 (100)
6.5 (160)
7.0 (80)
6.8 (100)
7.0 (100)
7.2 (80)
7.0 (100)
6.9 (50)
6.9 (100)
7.3 (80)
7.4 (100)
7.4 (40)
7.2 (50)
Ð
6%
3%
Ð
4%
40%
10%
14%
2.1
3%
Ð
0%
4%
16%
32%
2%
46%
2.0
49%
1.0
12%
7.3
F
Cl
Br
Me
Me
Me
Me
Et
Cl
20
2
H
H
H
H
H
H
Cl
Br
CF3
CF3
Me
CF3
CF3
Cl
21
22
23
24
25
26
Cl
OMe
SMe
Me
6.1 (1300)
6.6 (630)
7.2 (60)
2.8
31%
85%
9.0
CH2CH2O±
CF3
6.3 (400)
aAll values represent the mean of at least two determinations, with each determination lying within 0.2 log unit of the mean.
bBinding anity (human cloned receptors; HEK 293 cells; [3H]-mesulergine).4
cBinding anity (human cloned receptors; HEK 293 cells; [3H]-ketanserin).4
dBinding anity (human cloned receptors; HEK 293 cells; [3H]-5-HT).4
eDose of compound required to reverse mCPP (7 mg/kg i.p. admin 30 min pretest) induced hypolocomotion by 50% or percentage reversal at 5 mg/kg.4
Table 2. The 5-HT2A/B/C receptor binding anities,a selectivities over 5-HT2A and 5-HT2B and in vivo activitye of 1-[2-[2-(aryloxy)-5-pyr-
idyl]carbamoyl]indolines 1, 27±33
e
Compound
Y
R1
R2
R6
pKi
pKi (selectivity)
ID50
(mg/kg po)
b
c
d
5-HT2C
5-HT2A
5-HT2B
1
CH
CH
CH
CH
CH
CH
CH
N
Me
Et
H
H
H
H
H
Me
Cl
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
CF3
9.0
8.7
8.8
6.9
8.9
9.0
9.3
8.7
6.8 (160)
6.7 (100)
6.8 (100)
6.1 (6)
7.0 (80)
8.1 (8)
7.0 (100)
7.3 (25)
7.0 (60)
6.7 (2)
7.3 (40)
7.5 (30)
7.9 (25)
7.9 (6)
2.0
1.8
18%
Ð
4.5
Ð
27
28
29
30
31
32
33
nPr
iPr
Cl
H
H
Me
7.8 (30)
7.1 (40)
Ð
Ð
a
eSee corresponding footnotes in Table 1.
Optimization of central aryl ring (Table 3)
observed in the simple biaryl series. Although the 3-
methylpyridyl 35 had high 5-HT2C anity combined
with good oral activity, the compound failed to achieve
100-fold selectivity over 5-HT2A receptors. The 3-chloro
Introduction of a methyl group into the 4-position (34)
was clearly not tolerated as had previously been

1866
S. M. Bromidge et al. / Bioorg. Med. Chem. Lett. 10 (2000) 1863±1866
Table 3. The 5-HT2A/B/C receptor binding anities,a selectivities over 5-HT2A and 5-HT2B and in vivo activitye of 1-[[2-[(2-methyl-3-pyridyl)
oxy]aryl]carbamoyl]indolines 1 and 34±41
R5
R6
pKi
pKi (selectivity)
ID50
(mg/kg po)
e
Compound
B
b
c
d
5-HT2C
5-HT2A
5-HT2B
1
Me
OMe
Me
Cl
CF3
Cl
9.0
6.7
8.8
6.8 (160)
6.2 (3)
7.0 (100)
6.6 (1.3)
7.5 (20)
2.0
Ð
34
35
6.9 (80)
0.8
36
37
38
39
40
Me
Me
Me
Me
Me
CF3
Cl
8.8
9.2
8.7
8.5
8.5
6.6 (160)
6.9 (200)
7.4 (25)
7.7 (30)
6.8 (80)
6.9 (40)
7.2 (20)
>5
>5
1.6
1.2
3.7
Cl
5.8 (800)
CF3
Cl
6.4 (130)
<6.2 (>200)
41
Me
CF3
8.7
6.2 (320)
7.1 (40)
3.6
a
eSee corresponding footnotes in Table 1.
P. P. A. Pharmacological Reviews 1994, 46, 157. (b) Baxter, G.;
Kennett, G. A.; Blaney, F.; Blackburn, T. P. Trends Pharma-
col. Sci. 1995, 16, 105.
2. (a) Kennett, G. A.; Lightowler, S.; De Biasi, V.; Stevens, N.
C.; Wood, M. D.; Tulloch, I. F.; Blackburn, T. P. Neuro-
pharmacology 1994, 33, 1581. (b) Palvimaki, E. P.; Roth, B. L.;
Majasuo, H.; Laakso, A.; Kuoppamaki, M.; Syvalahti, E.;
Hietala, J. Psychopharmacology 1996, 126, 234.
3. Bromidge, S. M.; Duckworth, M.; Forbes, I. T.; Ham, P.;
King, F. D.; Thewlis, K. M.; Blaney, F. E.; Naylor, C. B.;
Blackburn, T. P.; Kennett, G. A.; Wood, M. D.; Clarke, S. E.
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Duckworth, D. M.; Forbes, I. T.; Gaster, L. M.; Ham, P.;
Jones, G. E.; King, F. D.; Mulholland, K. R.; Saunders, D.
V.; Wyman, P. A.; Blaney, F. E.; Clarke, S. E.; Blackburn, T.
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G.; Holland, V.; Avenell, K. Y.; Stean, T.; Upton, N.; Bro-
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P. Khim. Geterotsikl. Soedin. 1989, 5, 636.
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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,
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analogues 36 and 37 had improved selectivity over 5-
HT2A but reduced oral activity. Incorporation of dia-
zines was moderately successful giving compounds 38±41
with good 5-HT2C anity and selectivity over 5-HT2A
,
although unfortunately, none of these achieved 100-fold
selectivity over the 5-HT2B receptor. These compounds
also had good oral activity in the hypolocomotion
model, in particular the pyridazines 38 and 39.
Summary
A number of bisaryl ethers have been identi®ed with
excellent 5-HT2C anity and selectivity over both the 5-
HT2A and 5-HT2B receptors in addition to a range of
other monoamine receptors, including serotinergic and
dopaminergic subtypes. In a human 5-HT2C receptor
functional assay they were found to be inverse agonists
completely abolishing basal activity.4 A number of
compounds from this series such as 11, 27 and 38
demonstrated potent oral activity in the rat hypoloco-
motion assay and are being further investigated for their
potential as novel non-sedating anxiolytics and anti-
depressants.
References and Notes
1. (a) Hoyer, D.; Clarke, D. E.; Fozard, J. R.; Hartig, P. R.;
Martin, G. R.; Mylecharane, E. J.; Saxena, P. R.; Humphrey,
8. Hurst, D. T. Heterocycles 1984, 22, 79.
9. Sato, N.; Arai, S. J. Heterocycl. Chem. 1982, 19, 407.