Indoline derivatives as 5-HT2C receptor agonists

Article abstract of DOI:10.1016/j.bmcl.2003.05.001

A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT_2C receptor agonists for the treatment of obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand

Full text of DOI:10.1016/j.bmcl.2003.05.001

Bioorganic & Medicinal Chemistry Letters 14 (2004) 2367–2370
Indoline derivatives as 5-HT2C receptor agonists
J. M. Bentley,* D. R. Adams, D. Bebbington, K. R. Benwell, M. J. Bickerdike,
J. E. P. Davidson, C. E. Dawson, C. T. Dourish, M. A. J. Duncton, S. Gaur, A. R. George,
P. R. Giles, R. J. Hamlyn, G. A. Kennett, A. R. Knight, C. S. Malcolm, H. L. Mansell,
A. Misra, N. J. T. Monck, R. M. Pratt, K. Quirk, J. R. A. Roffey, S. P. Vickers and
I. A. Cliffe
Vernalis Research Ltd, Oakdene Court, 613 Reading Road, Winnersh, Wokingham, Berkshire RG41 5UA, UK
Received 17 April 2003; revised 28 May 2003; accepted 30 May 2003
Abstract—A series of 1-(1-indolinyl)-2-propylamines was synthesised and evaluated as 5-HT2C receptor agonists for the treatment of
obesity. The general methods of synthesis of the precursor indoles are described. The functional efficacy and radioligand binding
data for all of the compounds at 5-HT2 receptor subtypes are reported. A number of compounds were found to reduce food intake
in rats after oral administration.
Ó 2004 Published by Elsevier Ltd.
F
The rising prevalence of obesity in the developed and
developing world carries an enormous financial burden.1
Obesity is a major risk factor in the development of such
conditions as hypertension, hyperglycemia, dyslipide-
mia, coronary artery disease and cancer. In the US, a
recent survey has suggested that 64% of adults are either
overweight or obese.2
N
Cl
N
Cl
NH
NH2
1
2
The nonselective 5-HT2C receptor agonist meta-chloro-
phenylpiperazine (mCPP; 1) reduces food intake, accel-
erates the appearance of the behavioural satiety
sequence in rats3;4 and decreases food intake in normal
human volunteers5 and obese subjects.6 The anorectic
action of mCPP is absent in mutant mice lacking the
5-HT2C receptor,7 and is attenuated by the selective
5-HT2C receptor antagonist SB-242084 in rats.8
It was reasoned that the incorporation of the two basic
nitrogen atoms from the piperazine ring of mCPP (1)
into the indole structure of RO600175 (2) might produce
new analogues with improved selectivity and oral
potency. Accordingly a discovery research programme
was initiated to investigate 1-(1-indolinyl)-2-propylam-
ines as novel 5-HT2C receptor agonists for the treatment
of obesity.10;11
Several chemical classes of 5-HT2C receptor agonists
have been reported, notably mCPP (1) and the more
potent 1-(1-indolyl)-2-propylamine RO600175 (2).9
Based on these literature leads, 1-(1-indolinyl)-2-
propylamines were proposed as targets for synthesis and
evaluation as 5-HT2C receptor agonists.
In order to obtain a diverse array of 1-(1-indolinyl)-2-
propylamines, a selection of indoles was prepared
using several standard methods (Schemes 1–4). Thus,
KH, THF, 0 oC
tBuLi, -78 oC
(RS)2
(68-81%)
N
H
N
H
Br
RS
4
5 R = Me
6 R = Et
Keywords: Obesity; Serotonin; 5-HT2C; Agonist.
* Corresponding author. Tel.: +44-(0)118-977-3133; fax: +44-(0)118-
989-9300; e-mail: j.bentley@vernalis.com
Scheme 1. Synthesis of 6-alkylthioindoles 5 and 6.
0960-894X/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.bmcl.2003.05.001

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J. M. Bentley et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2367–2370
HNO3
Cl3CCH(OH)2
NH2OH.HCl
Na2SO4
Me
F
Me
F
OH
N
H2SO4
-10 oC
+ O
H2N
H2N
N
O
(94%)
HCl, H2O
N
H
O
NH2
O
100 oC
(38%)
O
7
8
NaNO2, 0 oC CuCl
or KI
21
0 oC
20
HCl, H2O
MeSO3H
(80%)
DMF-DMA
Me
F
X
N
F
X
DMF
O
130 oC
+ O
+ O
NaBH4
N
O
N
O
BF3.OEt2
-20 oC
(43%)
O
10 X = Cl
13 X = I
9 X = Cl (75%, 2 steps)
12 X = I
N
H
N
O
O
H
23
Raney Ni
N2H4.H2O
MeOH
THF
22
or Fe, AcOH
EtOH, 90 oC
Scheme 4. Synthesis of 7,8-dihydro-1H-furo[2,3-g]indole (23).
F
X
The use of potassium iodide in the place of copper(I)
chloride gave 5-fluoro-4-iodo-2-nitrotoluene (12), and
this afforded a synthesis of 5-fluoro-6-iodoindole (14).
The iodoenamine 13 was reductively cyclised using iron
in acetic acid.
N
H
11 X = Cl (50%, 2 steps)
14 X = I (35%, 4 steps)
Scheme 2. Synthesis of 5-fluoro-6-haloindoles 11 and 14.
Reaction of 5,6-difluoroisatin (15)14 with sodium thio-
methoxide gave 5-fluoro-6-methylthioisatin (16), which
was reduced with lithium aluminium hydride to give
5-fluoro-6-methylthioindole (17) (Scheme 3). In the
same way, 6-ethylthio-5-fluoroindole (19) was prepared
via 6-ethylthio-5-fluoroisatin (18) using sodium ethane–
thiolate.
O
O
F
F
F
NaSR
DMF
O
O
N
N
RS
H
H
15
16 R = Me (35%)
18 R = Et
7,8-Dihydro-1H-furo[2,3-g]indole (23) and 1,7,8,9-tetra-
hydropyrano[2,3-g]indole (24) were both obtained from
arenecarboxaldehyde precursors and methyl azido-
acetate using the Hemetsberger indole synthesis.15;16 In
addition, a regiospecific synthesis of the furoindole 23
from 4-amino-2,3-dihydrobenzofuran (20) using chloral
hydrate and hydroxylamine and via the a-isonitroso-
acetanilide and isatin intermediates 21 and 22, respec-
tively, was also developed (Scheme 4).17;18
LiAlH4
THF
F
N
H
RS
17 R = Me (37%)
19 R = Et
Scheme 3. Synthesis of 6-alkylthio-5-fluoroindoles 17 and 19.
MeSO2O
O
HN
6-methylthioindole (5) was prepared by metallation of
6-bromoindole (4) with potassium hydride and tert-
butyllithium, followed by treatment with methyl disul-
fide (Scheme 1).12 6-Ethylthioindole (6) was also
prepared using this approach. 6-Chloroindole (3) and
6-bromoindole (4) are commercially available.
N
H
O
O
24
25
The target indolines 48–58 were then obtained from the
indoles 3–6, 11, 14, 17, 19, 23 and 24 as outlined in
Scheme 5. Alkylation of the appropriate indole with (S)-
tert-butyl [2-(1-methanesulfonyloxy)propyl]carbamate
(25) produced the indole carbamates 26–31 and 33–36.19
A sequence involving the Leimgruber–Batcho reaction
was employed to prepare 6-chloro-5-fluoroindole (11)
from 2-fluoro-4-methylaniline (7) (Scheme 2).13 Thus
nitration of the aniline 7 gave the nitrotoluene 8, which
was treated with sodium nitrite and copper(I) chloride
to give the chlorofluoronitrotoluene 9. The nitrotoluene
9 reacted with N,N-dimethylformamide dimethyl acetal
to give the nitroenamine 10, which underwent reductive
cyclisation with Raney nickel and hydrazine to yield 11.
Reduction of 26–36 with sodium cyanoborohydride in
acetic acid gave the indoline carbamates 37–47, which
were deprotected under acidic conditions to form the
indolines 48–58.

J. M. Bentley et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2367–2370
2369
receptors expressed in CHO cells using a fluorometric
imaging plate reader (FLIPR) (Table 1).21 The maxi-
mum fluorescent signal was measured and compared
with the response produced by 10 lM 5-HT(defined as
100%).21
KOH
25
31 (5-F 6-I)
DMSO
32 (5-F 6-CF3)
N
H
N
40 oC
R
R
26-36
3-6, 11, 14, 17, 19, 23-24
HN
O
The most efficacious compounds from the functional
assay were then compared in radioligand binding at
recombinant human 5-HT2A, 5-HT2B and 5-HT2C
receptors expressed in mammalian cell lines.22
O
NaBH3CN
AcOH
CH2Cl2
0 oC
HCl
Dioxan
MeOH
In general indolines 48–58 were potent partial agonists
at 5-HT2C receptors. In binding studies, compounds 48,
50, 51 and 55–58 had greater selectivity for 5-HT2C
receptors over 5-HT2A (6.0-fold) and 5-HT2B (3.6-fold)
receptors than mCPP (1). Compounds 50–58 showed a
broadly similar relative efficacy profile to RO600175 (2).
However, compounds 50–58 did show less functional
selectivity than 2 for 5-HT2B over 5-HT2C receptors
(0.55–4.2-fold vs 4.2-fold). Compound 52, containing
the 6-chloro-5-fluoro substitution pattern of RO600175,
showed similar binding selectivities to the dehydro var-
iant 2 for the 5-HT2 subtypes (5-HT2C=2A: 12-fold;
5-HT2C=2B: 2.2-fold) but significantly lower binding
affinities. However the 6-alkylthio analogues 50, 51, 55
and 56, and the furo and pyrano g fused derivatives 57
and 58 had greater binding selectivity for 5-HT2C
receptors over 5-HT2B receptors than both the 6-chloro-
5-fluoro analogues 2 and 52.
N
N
R
R
48-58
37-47
NH2
HN
O
O
Scheme 5. Synthesis of 1-(1-indolinyl)-2-propylamines 48–58.
The 5-fluoro-6-trifluoromethylindole 32 was obtained
from 31 via reaction with methyl 2-chloro-2,2-difluoro-
acetate, copper(I) iodide and potassium fluoride
(Scheme 6).20
The indolines 48–58 were screened for functional activ-
ity at recombinant human 5-HT2A, 5-HT2B and 5-HT2C
ClF2CCO2Me
KF, CuI
DMF, 120 oC
(84%)
Selected compounds were tested for their ability to
decrease food intake.23 23-Hour, food-deprived rats
were administered compounds 1, 49, 55 and 57 either
subcutaneously (sc) or orally (po). Compounds 1, 49, 55
and 57 significantly reduced feeding in a dose-dependent
manner with the minimal efficacious doses (MEDs)
shown in Table 2. Compounds 49, 55 and 57 showed
>100-fold binding selectivity for 5-HT2C receptors over
non-5-HT2 receptor subtypes.
F
F
I
N
N
F3C
31
32
O
HN
O
O
HN
O
Scheme 6. Synthesis of 5-fluoro-6-trifluoromethylindole 32.
Table 1. 5-HT2 receptor subtype functional efficacy, potency and binding for 5-HT, 1, 2 and 1-(1-indolinyl)-2-propylamines 48–58
Compound
Substituent(s)
Percentage relative efficacy (EC50, nM)21
Binding affinity (nM)22
ah5-HT2A
ah5-HT2B
ah5-HT2C
bKi h5-HT2A cKi h5-HT2B cKi h5-HT2C
5-HT
1 (mCPP)
[5-OH]
[meta-Cl]
98% (11)
41% (75)
101% (1.5)
99% (1.7)
14
54
12
32
6.9
9
33% (>1 lM) 83% (26)
2 (RO600175) [6-Cl-5-F]
48 6-Cl
49 (VER-3323) 6-Br
72% (131)
55% (602)
54% (719)
72% (164)
71% (378)
66% (367)
54% (432)
45% (1063)
87% (76)
71% (4.3)
76% (6.5)
78% (11)
78% (10)
67% (72)
77% (7.3)
71% (22)
86% (49)
72% (4.1)
66% (31)
74% (3.0)
67% (36)
93% (18)
91% (44)
88% (44)
95% (26)
90% (40)
89% (31)
79% (64)
86% (130)
97% (6.7)
92% (21)
98% (4.5)
94% (28)
38
5.1
2.3
364
351
171
184
167
139
432
53
54
46
13
24
5.7
50
51
52
53
54
6-MeS
6-EtS
89
189
31
16
14
17
26
6-Cl-5-F
5-F-6-I
5-F-6-F3C
38
88
55 (VER-5593) 5-F-6-MeS
56 6-EtS-5-F
57 (VER-5384) 2,3,7,8-Tetrahydro-1H-furo[2,3-g]
58
21
62
3.2
80% (181)
81% (62)
58
6.4
8.7
112
395
49
355
1,2,3,7,8,9-Hexahydropyrano[2,3-g] 71% (125)
38
Relative efficacy, EC50 and Ki values are the mean of two determinations run at 11 different concentrations. Each experiment was carried out in
triplicate. Standard errors were within Æ20% of the mean.
a Efficacy relative to 10 lM 5-HT(100%).
b Displacement of [125I]-DOI.
c Displacement of [3H]-5-HT.

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J. M. Bentley et al. / Bioorg. Med. Chem. Lett. 14 (2004) 2367–2370
Table 2. 23-Hour food-deprived rat feeding test results for compounds 1, 49, 55 and 57
Compound
Substituent(s)
MED (mg/kg)
Orally (po)
Subcutaneously (sc)
1 (mCPP)
[meta-Cl]
6-Br
1
10
30
3
49 (VER-3323)
55 (VER-5593)
57 (VER-5384)
3
5-F-6-MeS
2,3,7,8-Tetrahydro-1H-furo[2,3-g}
0.3
0.1
1
€
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A variety of indoles have been synthesised and trans-
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deprotection. Several analogues including 49 (VER-
3323), 55 (VER-5593) and 57 (VER-5384) were shown
to be potent 5-HT2C receptor agonists and reduced
feeding in rats following oral administration. Thus, the
1-(1-indolinyl)-2-propylamines 48–58 have potential for
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