Discovery and SAR of new benzazepines as potent and selective 5-HT 2C receptor agonists for the treatment of obesity

Article abstract of DOI:10.1016/j.bmcl.2004.12.080

We report on the synthesis, biological evaluation and structure-activity relationships for a series of 3-benzazepine derivatives as 5-HT_2C receptor agonists. The compounds were evaluated in functional assays measuring [³H] phosphoinositol turnover in HEK-293 cells transiently transfected with h5-HT_2C, h5-HT_2A or h5-HT_2B receptors. Several compounds are shown to be potent and selective 5-HT _2C receptor agonists, which decrease food intake in a rat feeding model.

Full text of DOI:10.1016/j.bmcl.2004.12.080

Bioorganic & Medicinal Chemistry Letters 15 (2005) 1467–1470
Discovery and SAR of new benzazepines as potent and selective
5-HT2C receptor agonists for the treatment of obesity
Brian M. Smith,* Jeffrey M. Smith, James H. Tsai, Jeffrey A. Schultz, Charles A. Gilson,
Scott A. Estrada, Rita R. Chen, Douglas M. Park, Emily B. Prieto,
Charlemagne S. Gallardo, Dipanjan Sengupta, William J. Thomsen, Hazel R. Saldana,
Kevin T. Whelan, Frederique Menzaghi, Robert R. Webb and Nigel R. A. Beeley
Arena Pharmaceuticals Inc., 6166 Nancy Ridge Drive, San Diego, CA 92121-3223, USA
Received 3 November 2004; revised 22 December 2004; accepted 29 December 2004
Available online 23 January 2005
Abstract—We report on the synthesis, biological evaluation and structure–activity relationships for a series of 3-benzazepine deriva-
tives as 5-HT2C receptor agonists. The compounds were evaluated in functional assays measuring [3H] phosphoinositol turnover in
HEK-293 cells transiently transfected with h5-HT2C, h5-HT2A or h5-HT2B receptors. Several compounds are shown to be potent
and selective 5-HT2C receptor agonists, which decrease food intake in a rat feeding model.
Ó 2005 Elsevier Ltd. All rights reserved.
The 5-HT2C receptor is one of more than 14 different 5-
HT receptor subtypes, several of which are known to
regulate important behavioural responses.1 Evidence
for the involvement of the 5-HT2C receptor in the regu-
lation of feeding and satiety has been the subject of a
number of reviews.2 The nonselective 5-HT2C receptor
agonist mCPP has been shown to cause weight loss by
reduction of food intake in humans3 and rodents.4
Nor-dexfenfluramine, a circulating metabolite of the
weight loss drug dexfenfluramine, is a nonselective 5-
HT2C receptor agonist, and the anorectic effects of dex-
fenfluramine and nor-dexfenfluramine are blocked by
the selective 5-HT2C receptor antagonist, SB-242084.5
A number of recent papers describe the anorectic effects
in rodents of newer 5-HT2C receptor agonists, such as
RO 60-0175,6 WAY-161503,7 YM3488 and VER-
5384.9 Additionally, 5-HT2C receptor knock-out mice
have been shown to be hyperphagic and nonresponsive
to the anorectic effects of 5-HT2C agonists.10
pathways, particularly of 5-HT2B receptors.12 It has also
been proposed that hallucination caused by serotonergic
drugs may be an effect of 5-HT2A agonism.13 With this
in mind, the discovery of potent 5-HT2C receptor agon-
ists with appropriate selectivity versus 5-HT2A and 5-
HT2B receptors, could lead to a safe and effective treat-
ment for obesity and other diseases or conditions which
could benefit from weight loss.
We reasoned that by taking features from the nonselec-
tive 5-HT2C receptor agonist nor-dexfenfluramine and
constraining them into a fused bicyclic structure, we
might discover new 5-HT2C receptor agonists with im-
proved selectivity versus 5-HT2A and 5-HT2B receptors.
If a different conformation of the nor-dexfenfluramine
ethylamino side chain is required to activate the 5-
HT2C receptor versus other receptors, and if we could
find compounds with this 5-HT2C preferred conforma-
tion by sampling a number of possible constrained ring
systems, then these compounds might also be selective.
What we discovered was that one of these fused bicyclic
core structures, the 3-benzazepines, could in fact yield
Fenfluramine and dexfenfluramine were withdrawn
from the market after reports of valvular heart defects
from use among weight loss patients,11 an effect which
may result from the activation of other serotonergic
Keywords: 5-HT2C; Serotonin; Obesity; Benzazepine.
*
Corresponding author. Tel.: +1 858 453 7200x1301; fax: +1 858 453
7210; e-mail: bsmith@arenapharm.com
0960-894X/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.12.080

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B. M. Smith et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1467–1470
potent and selective 5-HT2C receptor agonists when
properly substituted. Herein we describe some of the
more interesting SAR for this series.
prepared similarly, starting with mono- or disubstituted
halophenethylamines. In this case, the deactivated aro-
matics were iodinated with bispyridine iodoniumtetra-
fluoroborate. Alternatively, benzazepines 15–19 were
also prepared using a Friedel–Crafts cyclization as the
key step as shown in Scheme 2 for 8-chlorobenzazepine
15. Phenethylamine 12 was acylated to form chloroace-
tamide 13, which underwent Friedel–Crafts alkylation
to benzazepinone 14. Reduction with BH3 or LAH,
led to the final benzazepine 15. In this manner, the reg-
ioisomeric 7- and 9-chlorobenzazepines 16b and c were
made from 3-chlorophenethylamine, separating the
regioisomers at the benzazepinone stage. Variations on
the Friedel–Crafts acylation were explored, and in some
cases, found to have advantages. Racemic compounds
of interest were separated by chiral HPLC and the abso-
lute stereochemistry determined by crystallography or
comparison of synthetic derivatives. In the case of (R)-
and (S)-18c, these compounds were prepared via NCS
chlorination of the N-trifluoroacetyl protected (R)- or
(S)-15, separation of the regioisomers and then
deprotection.
Entry into the benzazepine series was first accomplished
with the synthesis of 8-bromo-7-methoxy-1-meth-
ylbenzazepine, 8 (Scheme 1). Important features of this
route include the use of a methoxy substituent to acti-
vate and direct halogenation on two occasions, and
the intramolecular Heck reaction to close the 7-mem-
bered ring.14 A further advantage of this synthesis was
the ease at which substitution could be introduced into
this series by appropriate manipulation of the late-stage
intermediates 6 and 7. Compounds 9a–d were prepared
by eliminating the bromination step (9a), substituting
NCS (9b) or NIS (9c) for NBS, or by treating the pro-
tected bromide with sodium trifluoroacetate and copper
(I) iodide (9d). Compounds 10a–d were prepared by re-
moval of the methyl group from intermediate 7 with
BBr3, followed by alkylation of the resulting phenol
with the appropriate alkyl halide, and then deprotection.
Substitution was also introduced at the 1-position by
choosing appropriate allyl bromides for the preparation
of intermediates similar to 4, leading to compounds 11b
and c. Oxidation of the olefin 5 to the ketone, followed
by reduction with Pd–H2, resulted in the 1-unsubstituted
11a. To further explore the SAR of this series, it was
desired to make compounds without the 7-methoxy
substituent. Benzazepines 15–18 were in some cases
The functional activity of the compounds for the h5-
HT2C (INI isoform), h5-HT2A and h5-HT2B receptors
was determined by measurement of [3H]phosphoinositol
turnover in transiently transfected HEK-293 cells, and
the results are summarized in Tables 1–4. Compound
8, our first designed compound in this series, demon-
strated excellent 5-HT2C receptor potency and moderate
selectivities versus the 5-HT2A and 5-HT2B receptors
(Table 1). With this result in hand, a small set of com-
pounds based on 8 was designed to explore the effects
of substitution at the 8-, 7- and 1-positions. At the 8-po-
sition, substitution of chlorine (9b), iodine (9c) or triflu-
oromethyl (9d) resulted in compounds of similar 5-HT2C
receptor potencies and selectivities towards 5-HT2A and
5-HT2B receptors. The 8-unsubstituted compound (9a)
was of much lower potency at all receptors. At the 7-po-
sition, replacing the methyl with hydrogen (10a), ethyl
(10b) or isopropyl (10c) showed a trend towards decreas-
ing potency at the 5-HT2C receptor with increasing size
of the substituent, but little change in potencies at the 5-
HT2A and 5-HT2B receptors was observed. The anomaly
was the 7-benzyl ether (10d), which was of similar po-
tency to the isopropyl ether (10c) at the 5-HT2C recep-
OMe
OMe
O
a
NH2
HN
CF3
1
2
b
OMe
O
OMe
O
f
c
N
CF3
HN
CF3
I
I
3
4
d
O
O
CF3
e
N
N
O
CF3
MeO
MeO
Cl
Cl
a
NH2
HN
6
5
Cl
f
12
13
b
Br
Br
g
O
NH
N
O
CF3
MeO
MeO
Cl
Cl
c
NH
8
NH
7
Scheme 1. Reagents and conditions: (a) (CF3CO)2O, pyridine, CH2Cl2;
(b) ICl, MeOH; (c) allylbromide, NaOH, K2CO3, n-Bu4NBr, toluene;
(d) Pd(OAc)2, various conditions; (e) 10% Pd–C, H2, MeOH; (f) NBS,
CH3CN; (g) NaOH, MeOH–H2O.
15
14
Scheme 2. Reagents and conditions: (a) CH3CHClCOCl, pyridine,
CH2Cl2; (b) AlCl3, 150–200 °C; (c) BH3, ether.

B. M. Smith et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1467–1470
1469
Table 1. 5-HT2C, 5-HT2A and 5-HT2B functional activity for com-
pounds 8–11
Table 3. 5-HT2C, 5-HT2A and 5-HT2B functional activity for com-
pounds 18
Me
Me
Me
R
Cl
Br
NH
NH
NH
MeO
MeO
X
18
8
9
Compd
X
EC50 (nM)
5-HT2A
R
Me
Br
Br
5-HT2C
5-HT2B
NH
NH
18a
18b
18c
18d
18e
6,8-DiCl
7,8-DiCl
8,9-DiCl
8-Cl, 7-F
8-Cl, 9-F
20
4
170
16
840
78
MeO
RO
11
10
6
220
72
1800
360
7
22
Compd
R
EC50 (nM)
5-HT2A
840
>10,000
5-HT2C
5-HT2B
8
9a
5
2000
11
2
80
>10,000
100
Not active
140
H
Cl
I
Table 4. 5-HT2C, 5-HT2A and 5-HT2B functional activity and percent
responses relative to serotonin control for compounds 19, (R)-15, (S)-
15, (R)-18c and (S)-18c
9b
9c
80
61
64
130
9d
CF3
4
42
63
Me
Me
Cl
10a
10b
10c
10d
11a
11b
11c
11d
11e
H
Et
3
190
180
Cl
Cl
Cl
28
68
56
8
110
97
NH
NH
NH
i-Pr
Bn
230
22
100
>10,000
400
40
H
Et
19
15
18c
11
160
3
100
Compd
EC50 in nM (% maximal response relative to
serotonin)
i-Pr
(R)-Me
(S)-Me
Not active
80
30
1000
220
5
30
5-HT2C
5-HT2A
5-HT2B
19
12 (85)
11 (100)
16 (100)
230 (85)
3 (90)
90 (100)
190 (70)
265 (70)
2400 (100)
135 (35)
1000 (100)
1000 (100)
1400 (100)
>10,000
(R)-15
(S)-15
(R)-18c
(S)-18c
Table 2. 5-HT2C, 5-HT2A and 5-HT2B functional activity for com-
pounds 15–17
Me
Me
Me
(25 @ 10 uM)
X
Cl
NH
Cl
NH
NH
HT2B receptors. Data for some mono substituted ana-
logues is shown in Table 2. The first compound from
this group to be prepared, the 8-chloro derivative 15,
showed improved receptor selectivity over the previous
set of compounds, 8–11. Moving the chloro substituent
around the ring shows the 6-chloro (16a) and 9-chloro
(16c) to be nearly 100-fold less potent at the 5-HT2C
receptor, with reduced potencies also observed at the
5-HT2A and 5-HT2B receptors. Moving the chlorine to
the 7-position (16b), results in a 3-fold drop in potency
at the 5-HT2C receptor, but slightly increased potency
at the 5-HT2A and 5-HT2B receptors.
15
16
17
Compd
X
EC50 (nM)
5-HT2A
5-HT2C
5-HT2B
15
8-Cl
6-Cl
7-Cl
9-Cl
8-F
11
860
35
260
>5000
150
1100
>5000
530
16a
16b
16c
17a
17b
17c
17d
17e
930
410
12
>5000
1600
510
>5000
>10,000
1500
8-Br
8-CF3
8-OMe
8-H
7
100
940
380
780
420
340
1600
>5000
Replacement of the 8-chloro substituent with fluorine
(17a), methoxy (17d) or hydrogen (17e) results in a 30-
fold reduction in potency at the 5-HT2C receptor and
a 5-fold reduction in potency at the 5-HT2A receptor.
Interestingly, a similar 5-fold reduction in potency is ob-
served at the 5-HT2B receptor for the 8-fluoro (17a) and
8-unsubstituted (17c) compounds, but no shift in 5-
HT2B potency is observed for the 8-methoxy compound
(17d). For replacement of 8-chloro (15) with 8-bromo
(17b) or 8-trifluoromethyl (17c), similar 5-HT2C poten-
cies are observed, with 5-HT2A and 5-HT2B selectivities
being somewhat increased for the bromo analogue and
decreased for the trifluoromethyl analogue. Functional
activity data for some dihalo analogs, 18a–e, is dis-
played in Table 3. The 6,8-dichlorobenzazepine (18a)
tor, but with increased potency at the 5-HT2A receptor
and greatly reduced potency at the 5-HT2B receptor.
At the 1-position, the difference in 5-HT2C receptor po-
tency observed between hydrogen (11a), ethyl (11b), R-
methyl (11d) or S-methyl (11e) is small, when compared
to the greater than 10-fold reduction in potency
observed for the isopropyl substitution (11c). There
appears to be a trend towards increasing potency at
the 5-HT2B receptor for S-methyl > ethyl > R-
methyl > hydrogen. Comparison of the enantiomers
11d and e shows the R-methyl enantiomer 11d to be
somewhat more potent at the 5-HT2C receptor and sig-
nificantly more selective versus the 5-HT2A and 5-

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B. M. Smith et al. / Bioorg. Med. Chem. Lett. 15 (2005) 1467–1470
has a slightly lower 5-HT2C potency compared to 15 and
lower selectivity.
of 3-benzazepines was designed. This series has provided
a number of potent and selective 5-HT2C receptor agon-
ists which are orally active in an acute feeding model in
Sprague–Dawley rats. Further studies have resulted in
the identification and advancement of one compound
from this series into human clinical trials.
Adding a 7-position substituent to 15 increases 5-HT2C
potency as seen with compounds 18b and 18d (compare
also compound 8), but an even greater increase in 5-
HT2A and 5-HT2B receptor potencies results in reduced
selectivities. In contrast, the 8,9-disubstituted benzaze-
pines 18c and e, show significant improvement in recep-
tor selectivity compared to 15, with 5-HT2C potency
slightly increased for 18c, and decreased for 18e. Upon
comparison of the enantiomers of 15 with the enantio-
mers of 18c, unexpected results were obtained. It can
be seen that (R)-15, (S)-15 and 1915 are all of similar po-
tency and selectivity. A slight advantage in 5-HT2C po-
tency for (R)-15 and 19 over (S)-15 is observed and a
slight advantage in 5-HT2A selectivity is observed for
(R)-15 and (S)-15 over 19. In comparison,(S)-18c is
about 70-fold more potent at the 5-HT2C receptor than
(R)-18c, which represents not only a change in magni-
tude, but also a switch in preferred stereochemistry.
Also of interest is the drop in 5-HT2A maximal response,
relative to the serotonin control, observed for (S)-18c. In
all previous cases, compounds have been full, or nearly
full agonists at the three receptors. The 5-HT2C and 5-
HT2B responses have all been in the 90–100% range.
The 5-HT2A responses have occasionally dipped to
70%. For (S)-18c, the 5-HT2A maximal response is only
35%, and for the 5-HT2B receptor only 25% response is
observed at the highest test concentration of 10 uM. In
this case, we believe that a steric interaction between
the (S)-1-methyl and 9-chloro substituents further locks
the seven-membered ring into a conformation favorable
to 5-HT2C receptor activation and less favourable to
either 5-HT2A or 5-HT2B activation. In contrast, the
interaction between the (R)-1-methyl and 9-chloro sub-
stituents of (R)-18c locks the seven-membered ring into
a conformation less favourable to activation of all three
receptors.
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Using structural features from known 5-HT2C agonists
and incorporating these into a rigid framework, a series